Immunotherapy Safety for the Primary Care ... - U.S. Coast Guard

Immunotherapy Safety for 

the Primary Care Provider 

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Capt. J. Montgomery MC, USN 

February 04, 2008

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Welcome to 

“Immunotherapy Safety for the Primary Care Provider” or “Optimizing the Safety of 

Immunotherapy Administration Outside of the Allergist’s Office” 

I am deeply indebted to the American Academy of Allergy, Asthma, and Immunology’s 

Immunotherapy & Allergy Diagnostics Committee and to the Immunization and Allergy 

Specialty Course of the Walter Reed Army Medical Center for much of the material 

contained within this training CD. 

The purpose of this CD is to provide a comprehensive overview of allergen 

immunotherapy for primary care physicians and their ancillary staff with a primary focus 

on risk factors that affect immunotherapy safety and measures that may enhance 

immunotherapy safety. 

Learning Objectives: 

1. Understand immunotherapy indications, potential risks, contraindications, 

protocols, potential mechanisms and risk factors for systemic reactions after 

allergen and vaccination injections. 

2. Be familiar with the current recommended guidelines in terms of proper personnel 

and emergency equipment required for administration of allergen immunotherapy 

and adult and pediatric vaccines. 

3. Recognize the signs and symptoms of adverse immunotherapy reactions and the 

appropriate treatment for them. 

4. Apply the greater understanding of potential risks associated with immunotherapy 

and immunizations into a clinical practice with office protocols designed to screen 

high risk individuals prior to receiving injections and to make appropriate clinical 

decisions based on this screen. 

5. Apply the competencies and learning assessments contained herein to assure 

the safe administration of immunotherapy and vaccines. 

CD format: The didactic program begins with the lecture slide show. Handouts include 

a lecture summary and a position statement addressing administration of allergen 

immunotherapy by non-physician staff, as well as suggested formats for a clinic SOP, 

nurse/technician competency assessment, patient informed consent, AIT administration 

form, and a dosage adjustment guide. Upon completion of this program, participants 

are encouraged to take the included self-assessment test. 

I hope that you find the material helpful and the format convenient. 

Capt. Jay Montgomery MC, USN 

Head, Division of Allergy & Immunology 

National Naval Medical Center 

Production Team: Ms. Sally Bentsi-Enchill, HM3 Harrison Wright USN, Ms. Anna 

Harrison, Ms. Denise Chambers, and HN Joy Lewis USN





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Immunotherapy for the 

Primary Care Provider 

-or- 

Optimizing The Safety Of Immunotherapy Administration 

Outside Of The Prescribing Allergist’s Office 

Jay Montgomery MD, FAAFP, FAAAAI 

Captain, Medical Corps, United States Navy 

Head, Division of Allergy & Immunology 

National Naval Medical Center

Immunotherapy at Remote Sites 

Standard of Care 

• In the case of professionals, the standard 

of care refers to the level of care that a 

reasonable professional in the same or 

similar circumstances would take to 

prevent harm or injury to another person. 

• “The standard of care concerning the 

administration of immunotherapy should be 

the same regardless of where the 

immunotherapy is given and the specialty 

of the supervising physician.” 

Position Statement on administration of immunotherapy outside of the prescribing allergist facility. Drug 

and Anaphylaxis Committee of ACAAI. Ann Allergy Asthma and Immunol 1998;81:101-102

What is Immunotherapy? 

• Gradually increasing quantities of specific 

allergens to an optimal dose 

• Raises the patient’s tolerance to the 

allergens 

• Thereby minimizing the symptomatic 

expression of the allergic disease 

• Allergen extract vs Allergen vaccine 

– Proteins ‘extracted’ from various materials 

– ‘Immune modifier’

What Immunotherapy Is Not 

• Not prescribed by a remote laboratory: 

– Immunotherapy should be prescribed by physicians 

specifically trained to diagnosis and treat allergic 

diseases. 

• Not based on skin test or in vitro tests alone: 

– Treatment MUST be based on the combination of a 

thorough history and physical exam and allergy tests. 

• Not administered at home 

– Must be administered in a properly equipped facility 

staffed with personal able to recognize/ treat IT systemic 

reactions.

What Immunotherapy Is Not 

• Not administered through non-injectable 

routes 

– Subcutaneous route is the only approved method in the 

U.S.; sublingual route currently is not approved by FDA. 

– Sublingual immunotherapy used outside of US, but with 

higher doses (10- 500 x subcutaneous IT) may make 

treatment cost prohibitive. Further studies required 

before approved in US.

How Does Immunotherapy Work? 

• Decrease in cellular responsiveness 

• Production of blocking antibody 

• Induction of tolerance (B-cell, 

T-cell, or both) 

• Presence of anti-idiotypic 

antibodies 

• Activation of T-cell suppressor 

mechanism

History of Immunotherapy 

1911 

• Leonard Noon at the St. Mary’s Hospital, 

London injected extract of grass pollen 

into a patient whose symptoms coincided 

with the pollinating season of grasses 

1965-present 

• Norman, Lichtenstein, et. al. defined AIT 

effectiveness in allergic rhinitis, allergic 

conjunctivitis, allergic asthma, and 

hymenoptera hypersensitivity

Who Benefits? 

•Those with… 

– Allergic disease identified through an 

adequate history & in vivo testing (in vitro 

testing is not adequately specific) 

– Well-defined clinically relevant allergic triggers 

– Significant effect on quality of life or daily 

function 

– Inadequate relief through avoidance 

measures and pharmacotherapy

What Benefits? 

• Marked reduction in allergy symptom scores 

• Marked reduction in medication use 

• Reduced sensitivity to other allergens 

• May prevent progression or development of 

multiple allergies 

• May reduce risk of later development of 

asthma

Immunotherapy Efficacy 

• Effective treatment for allergic rhinitis 

– A meta-analysis of 18 studies involving 789 patients concluded that 

AIT is effective in the treatment of allergic rhinitis. 1 

• Effective treatment for asthma 

– Two meta-analyses of 43 prospective studies showed that AIT is 

effective in the treatment of allergic asthma. 2,3,4 

• Highly effective treatment for insect venom allergy 

– A meta-analysis of 9 studies indicated that a course of venom 

immunotherapy (VIT) is highly effective in the management of 

insect sting hypersensitivity. 5,6

Indications for Immunotherapy 

• Hymenoptera venom hypersensitivity, 

allergic rhinitis, allergic conjunctivitis, and 

allergic asthma 

• Desire to avoid long-term use or potential 

adverse effects of medications 

• Symptoms not adequately controlled by 

avoidance and pharmacotherapy 

• Cost of immunotherapy is less than cost of 

long-term medications

Not Efficacious For… 

• Atopic dermatitis 

• Urticaria 

• Headaches 

• Food allergies

Allergen Immunotherapy 

Safety

The Extracts/Vaccines 

• Bioequivalent Allergy Unit (BAU) 

– Determined through quantitative skin testing on 

a reference population of allergic patients 

highly skin-test reactive to that allergen 

• Standardized Allergens 

– Cat, Bermuda & Northern Pasture Grasses (3), 

Dust Mite (2), and Ragweed 

• Non-standardized Allergens 

– Wt/V or PNU

The Extracts 

• Storage 

– Refrigerated at 4°C (39°F) 

• Loss of potency within weeks at room temp 

• More concentrated = more stable 

• Identification 

– Name & identifying number (SSN, DOB, etc.) 

– Contents of vial 

• Tree: T, Mold: M, Grass: G, Cat: C, Weed: W, 

Dog: D, Ragweed: R, Cockroach: Cr, Dust Mite: Dm 

– Expiration date 

– Dilution v/v (from maintenance vial) 

– Number identifier (#1=maintenance=red cap) 

– Standard colored caps 

• Red= 1:1, yellow= 1:10, blue= 1:100, green= 1:1,000

Lots of Numbers! 

Vial v/v W/V 

(example) 

AU/ML 

(example) 

BAU/ML 

(example) 

1 

Red 

2 

Gold 

3 

Blue 

4 

Green 

5 

Silver 

1:1 

(maintenance) 

1:10 

1:100 

1:1000 

1:10,000 

1:100 2000 7750 

1:1,000 200 775 

1:10,000 20 77.5 

1:100,000 2 7.75 

1:1,000,000 0.2 .775

Dilution Labeling, Color- 

Coding and Vial Nomenclature 

Patient’s name on all vials 

Contents 

Vial concentration 

Expiration date

Immunotherapy Phases 

• Maintenance concentration = therapeutically effective dose 

as determined by the Allergist 

• Build up phase (vials up to & including maintenance vial) 

– Involves receiving injections of increasing amounts of allergen(s) 

– Frequency of injections ranges from 1 - 2 times a week, although 

more rapid build-up schedules are possible. 

– The duration of this phase generally ranges from 3 to 6 months, 

depending upon the frequency of the 18-27 injections. 

• Maintenance phase (maintenance vial) 

– Begins when the effective therapeutic dose is reached. 

– Differs for each person, depending on their level of allergen 

sensitivity (how 'allergic’ they are to the allergens in their vaccine) 

and their response to the build-up phase. 

– The intervals between maintenance immunotherapy injections 

generally ranges from 2 to 4 weeks (3-4 weeks). 

– Administered for 3-5 years. 

• AIT schedules ≠ VIT schedules

Immunotherapy Reactions 

Local reactions: 

• Are fairly common 

• Present as redness and 

swelling at the injection 

site. 

• Can happen immediately, 

or several hours after 

injections. 

Systemic reactions: 

• Less common 

• Include allergy symptoms such as sneezing, 

itching palms, nasal congestion, or hives. 

• Can include swelling in the throat, wheezing 

or a sensation of tightness in the chest, 

nausea, dizziness, fainting, and/or other 

severe systemic symptoms. 

• Systemic reactions require immediate 

treatment.

Reaction Prevention - Avoidance 

• Circumstances warranting dose change 

– Follow prescribing Allergist’s written instructions 

– Missed doses 

– Buildup phase 

– Maintenance phase 

– Reactions, local or systemic 

• Local >1” (quarter size) or lasts >12 hr 

• Systemic 

– Renewed maintenance vial - reduce dose 50% 

– Communication with Allergist ALWAYS!

Reaction Therapy – BLS+ Level 

• Treatment of local 

reactions 

– Local reaction 

• Cold pack, oral 

antihistamine, topical 

steroid 

– Large local reaction 

(Arthus reaction) 

• Oral steroids, NSAIDs, oral 

antihistamines

Reaction Therapy – BLS+ Level 

• Treatment of systemic reactions 

– Anaphylaxis 3%, Death 1:1,000,000 

• Training and Equipment for Basic Life Support 

• Physician at bedside w/in 2-3 minutes 

• ABC assessment TO BE PERFORMED 

AT THE SAME TIME AS THE 

ADMINISTRATION OF 

EPINEPHRINE

Treatment Guidelines 

• Treatment (airway/breathing) 

– Maintain an open airway 

– High flow oxygen (4-10 l/m) with pulse oximetry 

– Intubation when PaCO 2 >65 mm Hg / SaO 2 90 mm Hg 

– Place patient in Trendelenburg position 

– Insertion of large-bore IV 

• 0.9% saline 

– Severe Hypotension 

• Dextran, Hetastarch

Treatment Guidelines 

• Treatment (drugs) 

– EPINEPHRINE 

• 0.3 - 0.5 cc 1:1,000 IM adult 

• 0.01cc/kg 1:1,000 IM child 

• Repeat q 10 min prn 

• Glucagon 1-5 mg over 2-5 min IV push 

– Antihistamines 

• Diphenhydramine (Benadryl): 50-75 mg IM/IV adult 

1-2mg/kg IM/IV child 

• Cimetidine (Zantac): 300 mg q6-8 hr PO/IV 

– For Bronchospasm - Albuterol MDI/Nebulized 

– Methylprednisolone 60 - 80 mg IV

Immunotherapy Contraindications 

•Who? 

– Conditions posing reaction survivability risk 

• Lung disease with FEV 1

Frequency of Systemic Reactions 

• 0.8% to 46.7% (mean 12.92%) systemic reaction 

rate for conventional AIT schedule. 

Stewart GE and Lockey RF J Allergy Clin Immunol 1992; 90: 567-78 

• 45% of reactions occur in patients who have had 

previous systemic reactions. 

Matloff SM et al Allergy Proceed 1993; 14: 347-350

Worse Case Scenario: Fatalities 

• 46 fatalities between 1945 and 1984 

• 10 fatalities during seasonal exacerbation 

• 4 fatalities in patients symptomatic prior to injection 

• 22/30 onset of reaction within 30 minutes 

Lockey RF, et. al., J Allergy Clin Immunol 1987; 79: 660-77 


• 76% had asthma, 36% reported prior systemic reactions 

• 5 – new vial, 5 – dosing error, 4 – prior symptoms 

• 11/17 onset anaphylaxis within 20 minutes 

Reid MJ, et. Al., J Allergy Clin Immunol 1993; 92: 6-15 


• Death rate of 1 per 2,540,000 injections, 3.4 deaths per year 

• 15 were asthmatic not optimally controlled 

• 3 deaths in patients receiving AIT outside of a medical facility 

• Most occurred with maintenance concentrates 

Bernstein DI, et al., J Allergy Clin Immunol 2004; 113: 1129-36

Immunotherapy Safety 

• To lessen risk of reaction 

– Identify patient (100%) 

– Check health status 

• Acutely ill, asthma/allergy exacerbation, new medications? 

• Previous delayed reactions? 

– Use standard immunotherapy administration form 

• Right Patient (check ID) 

• Right Extract (extract contents / Rx number must be on vial) 

• Right Strength (extract cap color, written concentration) 

• Right Time (date of injection is within prescribed schedule) 

• Right Dose (have patient verify vial # and amount drawn) 

– Document everything!



– Allergen immunotherapy should be given in settings where 

emergency resuscitative equipment and trained personnel are 

immediately available to treat systemic reactions under the 

supervision of a physician or licensed physician extender.” 

– Patients at high risk for systemic reactions (those who are highly 

sensitive or have severe symptoms, co-morbid conditions, or a 

history of recurrent reactions) should receive immunotherapy in 

the office of the Allergist. The Allergist who prepared the 

patient’s vaccine and the support staff should have experience 

and procedures in place for administering immunotherapy to 

high-risk patients. 

- Position Statement On: Administration Of Immunotherapy Outside Of The Prescribing Allergist 

Facility. Ann Allergy Asthma and Immunol 1998;81:101-102 

- Allergen Immunotherapy: a practice parameter. Ann Allergy Asthma and Immunol 2003;90:1-40



– Trained personnel should be familiar with the 

following procedures: 

• Adjustment of dose of allergen immunotherapy 

extract to minimize reactions. 

• Recognition and treatment of local and systemic 

reactions to immunotherapy injections. 

• Basic cardiopulmonary resuscitation. 

• Ongoing patient education in recognition and 

treatment of local and systemic reactions that 

occur outside the Allergist's office.”


• Injection 

– Once patient and extract verified … 

• Wipe injection site (the dorsal aspect of upper arm, halfway 

between elbow and shoulder). 

• Wipe extract tops with alcohol, draw up extracts per protocol. 

• With gloved hands, administer injections subcutaneously at a 

90° angle with 1/2 - 5/8 inch needle or 45° angle with 1 inch 

needle after first drawing back plunger & checking for blood. 

• Hold 2x2 on site firmly for a few seconds. Do not rub. 

• Dispose of syringe and needle in the sharps container. 

• NEVER RE-CAP NEEDLES. 

• Apply band aid/ice/ topical steroid cream, if needed.


• After Injection 

– After 30 minutes, examine the injection sites for 

induration and/or erythema. 

– Document all findings on the AIT shot record. 

– Document any protocol-directed dose reductions of 

future injections on the AIT shot record and SF-600. 

– If needed, further modify dose reduction instructions 

as per delayed reaction dose-reduction protocol.


• Patient instructions: 

– Must remain in clinic 30 minutes after injection. 

– Have staff inspect site(s) for swelling before leaving. 

– Report any abnormal signs or symptoms to staff 

immediately. 

– Don’t exercise for 2 hrs after receiving AIT. 

– Notify staff prior to next shot of any delayed reaction. 

– Keep to their AIT/VIT schedule.


• Equipment: 

• Aeroallergen & venom extract 

storage (4º C refrigerator with 

alarm) 

• 1 ml (for AIT) & 3ml (for VIT) 

disposable (safety) syringes 

with 27gauge 5/8 inch needles 

• Epi-pen Auto-injectors 0.3mg 

for adults & 0.15mg for children 

• Alcohol pads 

• 2x2 gauze pads 

• Gloves 

• Sharps container 

• Crash cart – BLS+ level 

– Vital signs monitor, SO 2 

– Equipment to establish an 

oral airway 

– AMBU bag & oxygen 

equipment 

– Intravenous access/fluids 

– Injectable epinephrine 

– Injectable antihistamine 

– Injectable steroids 

• Phone (911)

So You Still Want to Give Shots? 

• What is needed? 

– Good communication between you and your Allergist 

• Precise instructions/protocols IAW ACAAI Practice Parameters 

• AIT/VIT Vials labeled IAW ACAAI Practice Parameters 

• Precise descriptions of reactions and their treatment 

– Facility 

• Refrigeration, supplies 

• Standard forms 

• Equipment to manage anaphylaxis (ABCD’s) 

– Personnel 

• Trained to give shots, recognize and treat anaphylaxis 

• Staff BLS capable 

• Physician available within 2-3 minutes

What To Expect (Demand) from 

the Allergist 

• A record of previous responses to and compliance 

with the allergy shot program 

• Full, clear, and detailed documentation of the 

patient’s immunotherapy schedule 

• General instructions for administration of 

immunotherapy 

• Recommendations for dose adjustment for 

reactions & unexpected intervals between shots 

• Instructions on how to treat reactions to 

immunotherapy injections 

Li JT, et. al., Allergen immunotherapy: A Practice Parameter. Ann Allergy Asthma Immunol 2003; 90(suppl).

Summary 

• Immunotherapy is an effective and potentially 

disease-modifying treatment for asthma, allergic 

rhinitis and stinging insect anaphylaxis. 

• Effectiveness of immunotherapy depends on 

appropriate dose and duration of treatment. 

• Serious reactions to immunotherapy are uncommon. 

• Appropriate safety measures based on known risk 

factors may prevent or reduce incidence of serious 

reactions.

Summary 

• Risk factors for adverse events during immunotherapy 

administration include: 

– “A Momentary Lapse in Concentration” 

• Check and double-check 

– Right Patient (check ID) 

– Right Extract (extract contents / Rx number must be on vial) 

– Right Strength (extract cap color, written concentration) 

– Right Time (date of injection is within prescribed schedule) 

– Right Dose (have patient verify vial # and amount drawn) 

– Presence of symptomatic asthma 

• Do not administer allergy shot(s) until asthma is stable and PF > 

70% of personal best.

Summary 

• Risk factors for adverse events during immunotherapy 

administration include: 

– Use of beta-blockers: ask about ALL new medications 

each visit 

– Injections from new vials: dosage adjustment per 

prescribing allergist – review previous schedules 

– High degree of shot sensitivity 

• Consider premedication 

• Consult prescribing allergist if recurrent and/or persistent large 

local reactions 

• Always consult allergist before further administration if patient 

experienced a systemic reaction with the previous injection





reference article

• Alcohol pads 

• 2x2 gauze pads 

• 1ml for (AIT) & 3ml for VIT 

disposable (safety) syringe 

with 27gauge 5/8’ needle 

• Aeroallergen or venom 

extract 

• Epinephrine autoinjector 

0.3mg for adults and 

0.15mg for children 

• Glucagon 

• Vital Signs monitor 

• Oxygen administration equipment 

• Crash cart 

• Gloves 

• Tourniquet 

• Sharps container 

Safety needles

• Allergen immunotherapy (allergy shot) is a form of treatment 

aimed at decreasing sensitivity to substances called allergens. 

• Allergens are the substances that trigger your allergy 

symptoms when you are exposed to them and are identified by 

allergy testing. 

• Allergen immunotherapy involves injecting increasing amounts 

of an allergen until a maintenance dose is reached and 

continued over 3 to 5 years. 

• Immunotherapy has been shown to decrease current 

symptoms, prevent the development of new allergies and, in 

some children, prevent the progression of the allergic rhinitis to 

asthma. 

• Allergen immunotherapy can result in long-lasting relief of 

allergy symptoms after treatment is stopped.

The 2 Phases of Immunotherapy 

Prior to immunotherapy; provide patient with immunotherapy education 

packet and review material with patient to his/her/guardian’s full 

understanding and satisfaction. 

Build-up phase: 

Involves receiving injections with increasing amounts of allergens. 

Frequency of injections during this phase generally ranges from 1 to 

2 times a week, though more rapid build-up schedules are sometimes 

used. 

The duration of this phase depends on the frequency of the 

injections but generally ranges from 3 to 6 months. 

Maintenance phase: 

This phase begins when the effective therapeutic dose is reached. 

The effective maintenance dose is different for each person, 

depending on their level of allergen sensitivity (how 'allergic they are' 

to the allergens in their vaccine) and their response to the 

immunotherapy build-up phase. 

Once maintenance dose is reached, there will be longer periods of 

time between immunotherapy shots. The intervals between 

maintenance immunotherapy injections generally ranges from every 2 

to every 4 weeks.

BEFORE EACH SHOT!!! 

• Screen patient’s current health and medication status. 

• Perform these safety checks: 

– Right Patient (positively confirm – photo ID, etc.) 

– Right Extract (extract contents, prescription #, & name must be 

on vial) 

– Right Strength / Color/ Concentration 

– Right Time (make sure date of injection is within prescribed 

schedule) 

– Right Dose (have patient verify vial # and amount drawn correct) 

* Patient verification of all the above. 

• All asthmatic patients receiving immunotherapy 

must perform peak flow measurements (three 

measurement attempts) with best reading meeting or 

exceeding set parameters, prior to injections!

Wipe injection site (the dorsal aspect of upper arm, halfway between elbow and 

shoulder). 

Wipe tops of extracts with alcohol, draw up extracts per protocol. 

With gloved hands, administer injections subcutaneously at a 90 0 angle with ½ 

- 5/8 inch needles or 45 0 angle with 1 inch needle. 

Hold 2x2 on site firmly for a few seconds. Do not rub. 

Dispose of syringe and needle in the sharps container 

NEVER RE-CAP NEEDLES. 

Apply band aid/ice/ topical steroid cream, if needed. 

Instruct patient to remain in the waiting area for 30 minutes after the allergy 

injection and return to the treatment (injection) room to have area checked and 

documented prior to leaving the clinic.

instruct patient to report any abnormal signs and or symptoms they 

may experience to staff immediately for appropriate medical 

intervention. 

After 30 minutes, feel the injection sites for any swelling (induration); 

also note any redness (erythema). 

Document any initial findings on AIT record per reactions 

instructions noted below. 

Document further dose reduction instructions for future injections per 

physician’s orders on the SF-600 and on the treatment record, 

based on reactions. 

Instruct patient to notify staff of any delayed reactions after they 

leave the clinic, prior to injections. Follow “Grading” delayed 

reactions dose reduction protocol below for injections.

Local reactions: 

• Are fairly common 

• Present as redness and 

swelling at the injection 

site. 

• Can happen immediately, 

or several hours after 

injections. 

Systemic reactions: 

• Less common. 

• Include increased allergy symptoms such 

as sneezing, nasal congestion or hives. 

• Can include swelling in the throat, 

wheezing or a sensation of tightness in the 

chest, nausea, dizziness, fainting, and/or 

other severe systemic symptoms. 

• Systemic reactions require immediate 

treatment. See treatment for anaphylaxis.

• Negative (swelling up to 15mm; i.e., dime size) – progress 

according to schedule. 

• “A” (swelling 15-20 mm; i.e., dime to nickel size) – Follow 

Allergist’s written instructions (e.g., continue to advance). 

• “B” (swelling 20 – 25 mm; i.e., nickel to quarter size) – Follow 

Allergist’s written instructions (e.g., repeat last dose given) 

• “C” (swelling persisting more than 12 hours or over 25mm; i.e., 

quarter size or larger) – Follow Allergist’s written instructions (e.g., 

decrease dosage by 1 dose). 

• Systemic reactions (hives, sneezing, itching, asthma, difficulty breathing, or 

shock) – Immediate care/action, then follow Allergist’s written instructions. 

• Generally, the subsequent allergen extract dose is reduced to 1/3 of the last 

dose that did not cause a reaction and repeated 3 times before advancing 

per schedule. 

• If the injections cause repeated reactions or are suspected of causing 

repeated delayed symptoms, or if reactions prevent progression of treatment, 

contact the Allergist for further instructions.

• Apply hydrocortisone (topical steroid) 

• Apply ice to site 

• Non-steroidal anti-inflammatory drugs (NSAIDS) to 

reduce swelling 

• Take oral antihistamine (Benadryl, Allegra, etc.) 

• Non-prescription pain-relievers (acetaminophen) to 

relieve pain

Epi-Pen Adult 

Epi-Pen JR 

TwinJect 

• Notify the physician! 

• May be controlled by immediately placing a tourniquet above 

the injection site 

• Giving up to 0.01 ml/kg of 1: 1000 epinephrine up to 0.50 ml 

every 10-20 minutes subcutaneously. 

• For the average adult, give 0.10ml of 1:1000 epinephrine 

subcutaneously in the injection site and 0.2ml of 1:1000 

epinephrine in the other arm or inject 0.3mg EpiPen / TwinJect 

auto injector intramuscularly into the anterolateral aspect of the 

thigh. 

• For children, administer 0.15mg EpiPen/TwinJect IM into the 

thigh.

• Expiration Dates: 

– Vials 1-3 (Silver, Green, Blue) = 6 MONTHS FROM DATE OF 

RECONSTITUTION 

– Vials 4-5 (Gold, Red) = 1 YEAR FROM DATE OF RECONSTITUTION 

*Expiration dates on vials 1-4 (Silver-Gold) must not exceed 

expiration date on vial 5 (Red). 

• Vial is good for 6 months if concentration is < 1:1000 w/v 

• Vial is good for 1 year if concentration is ≥ 1:1000 w/v

How to dilute from available vials: 

• Example: To make vial #4 from vial #5: 

– Equipments needed – 

• 1cc syringe/needle 

• 9cc Sterile Albumin Saline vial (from WRAMC extract lab) 

– Draw up 1cc of extract from vial #5 and inject into a 

9cc Sterile Albumin Saline vial (extract diluent) 

– Mix well to make a 1:10 v/v dilution 

– Label the newly made vial #4 with the following: 

• Patient’s name & SSN 

• Prescription number 

• Extract contents (abbreviations) 

• New concentration & vial color (as will not have proper cap) 

• Expiration date

~Making 10-fold Dilutions~ 

9cc 

• To 9 cc Sterile Albumin 

Saline vial- draw up 1.0cc 

of extract and inject into 

new vial. 

• To 4.5 cc Sterile Albumin 

Saline vial- draw up 0.5 

cc of extract and inject 

into new vial. 

• To 1.8 cc Sterile Albumin 

Saline vial- draw up 0.2 

cc of extract and inject 

into new vial. 

1.0cc 

0.5cc 

0.2cc 

4.5cc 

1.8cc

Vial v/v W/V AU/ML BAU/ML 

5 

Red 

4 

Gold 

3 

Blue 

2 

Green 

1 

Silver 

1:1 

1:10 

1:100 

1:1000 

1:10,000 

1:100 2000 7750 

1:1,000 200 775 

1:10,000 20 77.5 

1:100,000 2 7.75 

1:1,000,000 0.2 .775

Venom Extract Dilutions: 

(follow manufacturer’s dilution instruction for maintenance vial) 

**For further VIT dilutions, follow same protocol for AIT dilutions above** 

Strength 

100mcg/ml or 300mcg/ml 



0.1mcg/ml or 0.3mcg/ml 

0.01mcg/ml or 0.03mcg/ml 

Expiration from date of dilution 

6 months (not to exceed 

manufacturer’s expiration date) 

30 days 

30 days 

14 days 

1 day (24 hours) 

0.001 mcg or 0.003mcg/ml 1 day (24 hours)

Summary 

• Pull the patient's allergy record. 

• Pull the patient's extract. Ensure that the right extract is pulled for the right 

patient, that the vial content agrees with what is ordered. 

• Question the patient about any delayed local reaction or systemic symptoms. 

Make the appropriate adjustment in the dosage IAW protocol guidelines. If the 

patient states he or she had a delayed systemic symptoms, record this on the 

injection administration record and make a follow up appointment with the 

Allergist for the patient to be seen before proceeding with immunotherapy. 

• Check dosage progression schedule for the amount of extract to be given. 

Document the dosage in the appropriate column on the injection record. The 

technician who is administering immunotherapy will initial the appropriate 

areas on the treatment record. Annotate the date and time of administration, 

and the injection site. 

• Gently shake the vial before using. Draw up the dosage required using 1cc or 

3cc syringe with a 26 - 27 gauge (5/8 – ½ inch) safety needle. Change the 

needle prior to injection. Ensure that the pertinent information is checked: 

confirm this information with the patient. 

(1) Right patient 

(2) Right extract 

(3) Right dosage 

(4) Right interval 

(5) Right method or technique

Summary (cont.) 

• Administer the allergy injection. Give the injection subcutaneously into the 

posterolateral surface of the middle third of the upper arm. Always pull back 

on the plunger before the allergy extract is administered; if blood returns, 

withdraw the needle and use the other arm. Avoid massaging the injection 

site to lessen unduly rapid absorption of the allergen. 

• Instruct the patient to wait 30 minutes in the patient waiting area and to 

report any problems immediately. 

• Check the injection site(s) prior to the patient leaving the clinic. 

• Document all reactions in the patient's allergy record. Notify the Physician 

In Charge and the Allergist if there are recurrent local reactions limiting 

advancement of the allergy shot or any systemic reactions or other 

problems. 

• Unless reactions dictate a change in dosage and/or the Allergist annotates 

otherwise, the technician will always follow the prescribed schedule on the 

Allergen Extract Prescription Form. Any questions will be directed to the 

Allergist before administering a shot. 

• No patient will be permitted to administer their own injections. Only the 

Allergist may determine if patient may receive their injections at another 

location. summation





reference article

Optimizing the Safety of Immunotherapy Administration Outside of the 

Prescribing Allergist’s Office 

I. Immunotherapy overview: 

Definition: Allergen Immunotherapy is a treatment aimed at modifying the allergic 

disease through a series of injections of a mixture of aeroallergen 

extracts composed or clinically relevant allergens identified during the allergy evaluation 

1. Immunotherapy has been shown to be effective in multiple controlled studies for 

the treatment of allergic rhinitis, asthma and stinging insect venom hypersensitivity 

2. Potential prophylactic treatment: may prevent the development of new allergies or 

progression from allergic rhinitis to asthma 

II. Immunotherapy potential mechanisms: Immunologic changes during 

immunotherapy are complex. Successful immunotherapy is often associated with a shift 

from TH2 to TH1 CD4 lymphocyte immune response to allergen. Immunotherapy 

induces a number of immunologic changes. Studies over several seasons of 

immunotherapy show that the usual seasonal rise of IgE is blunted by immunotherapy. 

On the other hand, it is believed that IgG protective “blocking antibody” production is 

stimulated by immunotherapy. However, these changes in IgE and IgG may not 

correlate with clinical efficacy. Immunotherapy inhibits the early and late phase 

responses, which results in decreased inflammation. Partial desensitization may play a 

role in immunotherapy. Immunotherapy may also induce production of “regulatory” T 

cells (CD4+CD25+) which may produce factors (IL-10and/or TGF-β) to down-regulate 

allergic immune responses. Clinically effective immunotherapy may be the result of 

some or all of these mechanisms. 

III. Indications and Contraindication for Allergen Immunotherapy 

1. Candidates: Patients with allergic rhinitis and/or asthma* with symptoms after 

natural exposure to aeroallergens and demonstrable evidence of clinically relevant 

specific IgE poor response to pharmacotherapy and/or allergen avoidance and 1 of 

the following 1 

a. Unacceptable adverse effects of medications 

b. Desire to reduce or avoid long-term pharmacotherapy and the cost of 

medication. 

c. Coexisting allergic rhinitis and asthma 

d. Immunotherapy may prevent the development of asthma in patients with 

allergic rhinitis 

e. Immunotherapy may prevent the development of new allergen sensitivities 

2. Patients who are not allergen immunotherapy candidates: Medical conditions 

that reduce the patient’s ability to survive a systemic reaction are relative 

contraindications for allergen immunotherapy. 1

a. Medical conditions that reduce the patient’s ability to survive a systemic 

reaction are relative contraindications for allergen immunotherapy such as 

severe coronary artery diseases 

b. Patients who are mentally or physically unable to communicate clearly with 

the allergist 

c. Patients who have a history of noncompliance 

d. Cautious attitude in prescribing immunotherapy to patients on beta-blocker 

medications. 

e. Pregnancy (do not initiate therapy in newly pregnant women but can 

continue in those already on immunotherapy) 

IV: Immunotherapy protocol 2 

• Build-up phase: involves receiving injections with increasing amounts of 

the allergens. The frequency of injections during this phase generally ranges 

from 1 to 2 times a week, though more rapid build-up schedules are 

sometimes used. The duration of this phase depends on the frequency of the 

injections but generally ranges from 3 to 6 months (at a frequency of 2 times 

and 1 time a week, respectively). 

• Maintenance phase: This phase begins when the effective therapeutic 

dose is reached. The effective therapeutic dose is based on 

recommendations from a national collaborative committee called the Joint 

Task Force for Practice Parameters: Allergen Immunotherapy: A Practice 

Parameter 2003 and was determined after review of a number of published 

studies on immunotherapy. The effective maintenance dose may be 

individualized for a particular person based on their degree of allergen 

sensitivity (how ‘allergic they are’ to the allergens in their vaccine) and their 

response to the immunotherapy build-up phase. Once the maintenance dose 

is reached, the intervals between the allergy injections can be increased. The 

intervals between maintenance immunotherapy injections generally ranges 

from every 2 to every 4 weeks but should be individualized to provide the best 

combination of effectiveness and safety for each person. Allergists may 

consider several factors in determining maintenance injection frequency 

including degree of symptomatic control at a particular maintenance interval 

and reactions from allergy injections. Shorter intervals between allergy 

injections may lead to less reactions and greater efficacy in some people. 

V. Allergen Immunotherapy Safety: 

1. Risk factors for allergen immunotherapy 3 

a. Error in dosage 

b. Presence of symptomatic asthma 

c. High degree of allergen hypersensitivity 

d. Use of beta-blockers 

e. Injections from new vials 

f. Injections given during periods when symptoms are exacerbated

2. Allergen immunotherapy local and systemic reactions 

a. Local reactions common 

b. Incidence of systemic reactions (SR) with conventional immunotherapy 

schedules in the published literature for combined build-up and maintenance 

phase ranged from: 3 0.05% - 3.2 % per injection or 0.84% to 46.7% of 

patients (mean 12.92%, SD 10.8 % of pts) 4 

3. Treatment of Immunotherapy Adverse Reactions 

a. Local reactions common occurrence: redness, swelling and heat at 

injection site 

i. If persistent large local reaction consider: 

1. Pre-medication with H1 blockers 

2. Decreasing dose or rate of build-up 

b. Systemic reactions: the recommendations for epinephrine administration 

are derived from the most recent practice parameters for treatment of 

anaphylaxis 9 

i. Epinephrine 1:1000 w/v 

1. Adults: 0.2 to 0.5ml intramuscularly (IM), preferably the thigh or 

subcutaneously (SQ) into the arm (deltoid) every 5 minutes, as needed 

to control symptoms and raise blood pressure 

2. Children: 0.01ml/kg (max 0.3 mg dosage) every 5 minutes as 

needed to, as needed to control symptoms and raise blood pressure 

3. Alternately, an epinephrine autoinjector (e.g., EpiPen or EpiPen 

Jr or TwinJect ) can be administered through clothing into the 

lateral thigh. 

4. Do not use crash cart injectables in pre-filled syringe, which are 

1:10,000 wt/v and indicated for intravenous (IV) use 

5. Location of injection: arm permits easy access for administration of 

epinephrine, although intramuscular injection into the anterolateral 

thigh produces higher and more rapid peak plasma levels compared 

with IM or SQ injections in the arm. 9 

ii. Other interventions: 

1. H1 antihistamines: diphenhydramine IM or IV 

a. Adults: 25 to 50 mg 

b. Children: 1-2 mg/kg 

2. H2 blockers p.o. or IV (cimetidine, ranitidine, famotidine) – for 

epinephrine – resistant hypotension 

3. Intravenous fluids or vasopressors as needed for vascular collapse 

4. Consider glucagon if patient on beta-blocker 

5. Maintain the airway 

iii. Call prescribing allergists for further instructions before administering 

another allergy injection after a patient has had a systemic reactions 

4. Allergen Immunotherapy Administration Supervision: appropriate 

setting, personnel and equipment.

Allergen immunotherapy should be given in settings where emergency 

resuscitative equipment and trained personnel are immediately available to treat 

systemic reactions under the supervision of a physician or licensed physician 

extender 6 

The trained personnel should be familiar with the following procedures: 

a. Adjustment of dose of allergen immunotherapy extract to minimize 

reactions. 

b. Recognition and treatment of local and systemic reactions to 

immunotherapy injections. 

c. Basic cardiopulmonary resuscitation. 

d. Ongoing patient education in recognition and treatment of local and 

systemic reactions that occur outside the physician’s office. 

Equipment 

a. Stethoscope and sphygmomanometer. 

b. Tourniquet, syringes, hypodermic needles (14-gauge) and large bore 

needles. 

c. Aqueous epinephrine HCL 1:1000. 

d. Equipment to administer oxygen by mask. 

e. Intravenous fluid set-up. 

f. Antihistamine. 

g. Corticosteroids for intravenous injection. 

h. Vasopressor 

i. Oral airway. 

j. Equipment to maintain an airway appropriate for the supervising physician 

expertise and skill. 

5. Immunotherapy Administrations documentation: what you should receive 

and record 

A full, clear, and detailed documentation of the patient’s immunotherapy schedule 

must accompany the patient when he or she transfers from one physician to 

another. Also, a record of previous responses to and compliance with the program 

should be communicated to the new physician. Finally, a detailed record of the 

results of the patient’s specific- IgE antibody tests (immediate-type skin tests or in 

vitro tests) should be provided. 1 

6. Allergy Extract Nomenclature: Recommended Dilution Labeling, Color- 

Coding and Vial Nomenclature 1 

Unfortunately, there is considerable diversity in the allergy extract nomenclature in 

US and this may lead to confusion and administration errors in outside offices 

particularly if they supervise immunotherapy from several offices with different 

nomenclature systems. The Joint Task Force On Practice Parameters developed

a proposed uniform nomenclature system with the goal to have this system 

eventually adopted by all practicing US allergists. Number 1 vial is color coded red 

and called the 1:1 v/v dilution or maintenance concentrate. The subsequent dilutions 

are colored and named as below. However not all practices have adopted this 

standard nomenclature and therefore it is very important for you to review the, 

labeling nomenclature from each office that you receive allergy immunotherapy 

vaccines. 

Dilution from 

maintenance 

Dilution designation 

in volume per volume 

(V/V) 

Number 

Color 

Maintenance 1:1 1 Red 

10-fold 1:10 2 Yellow 

100-fold 1:100 3 Blue 

1000-fold 1:1000 4 Green 

10,000-fold 1:10,000 5 Silver 

7. Administration Form Information: 

• Patient name, date of birth and telephone number 

• Prescribing physician with practice demographics 

• Vaccine name and dilution from maintenance in volume per volume, bottle 

letter, color and number (if used) 

• Expiration date of all dilutions 

• Date of injection 

• Arm injection administered 

• Delivered volume reported in milliliters 

• Immunotherapy schedules 

• Injection reactions: to be used to document local or systemic reactions 

• Health screen - Verbal or written interview of patient to evaluate patient’s health 

status prior to administering the allergy vaccine 

• Peak expiratory flow rate (PEFR); In patients with asthma (unstable asthma in 

particular), peak expiratory flow rate measurements should be obtained before 

each injection. If done repeatedly over time, this permits better determination of 

baseline peak expiratory flow rate and variability. PEFR variability, the difference 

in peak expiratory readings taken at different times, has a diurnal pattern with the 

lowest reading usually in the morning. Normal PEFR variability is

patient’s peak expiratory flow rate is 20% below baseline, the clinical condition of 

the patient should be evaluated before administration of the injection. 

• Obtain peak flow measurement in asthmatic patients before 

administering 

• If 20 % below best baseline withhold allergy injection until further 

evaluation 

• Antihistamine use: Ask whether the patient has taken an antihistamine that 

day to improve consistency in interpretation of reactions: 

• May reduce adverse reactions: a concern with the use of 

premedication is that it may mask milder systemic reactions allowing the 

build-up to proceed to a subsequent more serious systemic reaction. To 

the contrary, the published literature on studies utilized accelerated 

schedules for inhalant and venom allergen immunotherapy have 

demonstrated less incidence of local and systemic reactions with 

antihistamine premedication 6,7 

VI. Allergen Immunotherapy Administration Supervision: practical tips to enhance 

safety 

1. Review all documents carefully 

2. Inspect the allergy vaccine vials and familiarize yourself with the nomenclature 

and dosing schedule 

3. Vials in transit should be not be exposed to temperature extremes (freezing or 

extreme heat) because this could decrease extract potency 

4. Storage of allergy vaccine vials: keep refrigerated at 4° .Prolonged exposure of 

allergy vaccine vials to room temperature over time may diminish extract 

potency: one study found loss of potency pollen extracts exposed to room 

temperature for 13 hours a week for longer than 3 months 8 

5. Do not administer injection unless you have written verification of the last 

injection dose and date 

6. Interview the patient about current health status including medication changes 

7. Have the patient wait in the office for 30 minutes after the injection and instruct 

them to immediately report to the staff any symptoms suggestive of an allergic 

reaction. 

Do not hesitate to contact prescribing allergist if you have ANY questions or concerns! 

VII. Allergen immunotherapy adverse reactions: measures that can minimize the 

risk: 

Serious reactions to immunotherapy are uncommon. Appropriate safety measures 

based on the known risk factors may prevent or reduce incidence of serious reactions.

Risk factors for immunotherapy and some measures that may help prevent 

include: 

1. Error in dosage: check and double-check: vials, patient name and dosing record, 

have patient confirm vials 

2. Presence of symptomatic asthma: do not administer injection until asthma 

stabilize 

3. High degree of hypersensitivity: consider premedication, consult prescribing 

allergists if recurrent and persistent large local reactions 

4. Use of beta-blockers: ask about new medications each visit 

5 Injections from new vials: dosage adjustment per prescribing allergist 

6. Injections made during periods of exacerbation of symptoms: consider consulting 

prescribing allergist before administering 

Remember: Take your time and review the records to ensure that: 

You are giving the right dose of the right allergy immunotherapy vial to the right 

patient because…. 

No patient ever died from an allergy shot waiting to receive the injection … 

The extra time and wait will not harm you or the patient but dosing errors and allergy 

injections to actively symptomatic patients may seriously harm 

References For Optimizing The Safety Of Immunotherapy Administration Outside 

Of The Prescribing Allergist’s Office 

1. Li JT et al Joint Task Force On Practice Parameter: Allergen immunotherapy: A 

practice parameter. Ann Allergy Asthma Immunol 2003; 90(suppl). 

2. What are “Allergy Shots?” Tips to Remember are created by the Public Education 

Committee of the American Academy of Allergy, Asthma and Immunology. This 

brochure was updated in 2003 available at AAAAI website (www.aaaai.org) 

http://www.aaaai.org/patients/publicedmat/tips/whatareallergyshots.stm 

3. Bousquet J., Lockey R., Malling H.J. WHO Position Paper Allergen immunotherapy: 

therapeutic vaccines for allergic diseases Allergy Eur. J of Allergy Clin Immunol 1998; 

Number 44 Volume 53 

4. Stewart GE, Lockey, RE: Systemic reaction to Allergen Immunotherapy, J Allergy and 

Clin Immunol 1992:90; 567-78. 

5. Position Statement on administration of immunotherapy outside of the prescribing 

allergist facility. Drug and Anaphylaxis Committee of ACAAI. Ann Allergy Asthma and 

Immunol 1998;81:101-102 

6. Muller U, Hari Y, Berchtold E, Premedication with antihistamines may enhance 

efficacy of specific-allergen immunotherapy. J Allergy Clin Immunol 2001;107 (1):81- 

861

7. Neilson L, Johnsen C, Mosbech H, Poulsen L, Malling H Antihistamine premedication 

in specific cluster immunotherapy: A double-blind-placebo controlled study. J Allergy 

Clin Immunol 1996; 97 (6): 1207-13 

8. Nelson HS Effect of preservatives and conditions of storage on the potency of allergy 

extracts J Allergy Clin Immunol. 1981 Jan; 67(1):64-9 

9. Lieberman P et al The Diagnosis &Management of Anaphylaxis: An updated Practice 

J Allergy Clin Immunol 2004; 115 (3) (supplement) 

Other suggested references: 

Efficacy 

a. Durham et al. Long-term Clinical Efficacy of Grass-pollen Immunotherapy New 

England Journal of Medicine 1999;341 468 

Possible preventive effect of allergen immunotherapy 

a. Des Roches A, Paradis L, Menardo J-L, et al. Immunotherapy With A Standardized 

Dermatophagoides Pteronyssinus Extract VI. Specific Immunotherapy Prevents The 

Onset of New Sensitizations In Children. J Allergy Clin Immunol 1997; 99;450-3. 

b. Rurello-D'Ambrosio et al. Prevention of new sensitizations in monosensitized subjects 

submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy 

2001; 31: 1295-1302 

c. Panjno, GB et al. Prevention of new sensitization in asthmatic children monsensitized 

to house dust mites by specific immunotherapy. A six-year follow-up study. Clin Exp 

Allergy 2001; 31:1392-7 

d. Jacobsen L Dreberg S, et al. Immunotherapy as a Preventive Treatment (Abstract) J 

Allergy Clin Immunol 1996;97: 232 

e. Polosa R, Al-Delaimy WK, Russo C, Piccillo G, Sarva M. Greater risk of incident 

asthma cases in adults with allergic rhinitis and effect of allergen immunotherapy: a 

retrospective cohort study. Respir Res 2005 6:153. 

Adverse reactions: treatment 

a. Simons F, Roberts J, Gu X, Simons K. Epinephrine absorption in children with a 

history of anaphylaxis. J Allergy Clin Immunol 1998; 33-34. 

b. The diagnosis and management of anaphylaxis: an updated practice parameter. J 

Allergy Clin Immunol. 2005 Mar;115 (3 Suppl 2):S483-523. 

Systemic Reactions and Immunotherapy Fatalities 

a. Lockey RF, Benedict LM, Turkeltaub PC, and Bukantz SC J Allergy Clin Immunol 

1987; 79: 660-77 

b. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TAE. J Allergy Clin Immunol 1993; 

92: 6-15 

c. Bernstein D, et. al. Twelve-year survey of fatal reactions to allergen injections and 

skin testing: 1990-2001 J Allergy Clin Immunol 2004;113:1129-36.)





reference article

Click the ⌧ next to the heading to 

view the administrative material.

Documentation of allergen immunotherapy 

Documentation of Informed Consent 

Informed consent is a process by which a patient and physician discuss various aspects of a 

proposed treatment. A copy of the signed written consent form and any entries pertaining to the 

consenting process before the immunotherapy was initiated is/are required. The consent process 

usually consists of a record of the following: 

● Treatment proposed and its alternatives 

● Benefits expected from the treatment 

● Risks, including a fair description of how frequently adverse outcomes (including 

death) occur 

● Anticipated duration of treatment 

● Office policies that affect treatment 

Immunotherapy Content Form 

The purpose of this form is to define the contents of the vaccine in enough detail that it could be 

duplicated if necessary. 

This form should include the following: 

● Appropriate patient identifiers, including name, social security number, and birth date 

● Vaccine contents, including common name or genus and species of individual 

allergens and a description of all mixtures 

● Prescription number (USACAEL) 

● Volume of individual components and final concentration of each 

● Type of diluent used (if any) 

● Immunotherapy expiration date (for each vial) 

Immunotherapy Vaccine Administration Form 

This form should be used to document the administration of vaccine to a patient. Its design 

should be clear enough so that the person administering an injection is unlikely to make an error 

in administration. It also should permit documentation in enough detail to allow later 

determination of what was done. The form should contain the following: 

● Appropriate patient identifiers, including name, social security number, and birth date. 

Placement of the patient’s picture on the form may be helpful, particularly when more 

than 1 patient has the same name. If 2 or more patients have the same name, that fact 

should be noted on the form as well, as should a means of distinguishing the 2 

individuals. 

● Name of the vaccine, including an indication of the dilution from the maintenance 

concentrate in volume per volume. Other identifiers, such as cap color, number, or 

letter, may help to reduce the risk of an administration error. 

● Dates and times of vaccine injection 

● Volume of vaccine administered in milliliters (mL) with each injection. During the 

buildup phase, the dose can be determined using a standard (provided) schedule. 

● Arm in which the injection was given (left or right). This may facilitate determination 

of which vaccine causes local reactions. Because local reactions do not correlate 

reliably with systemic reactions, the presence of an immediate local reaction may not 

be a useful way to determine which vaccine caused a systemic reaction. Although it is

a common practice to alternate the arm into which a particular vaccine is given, there 

is no evidence that this is necessary. 

● In patients with asthma (unstable asthma in particular), peak expiratory flow rate 

measurements may be considered before an injection. If a patient’s peak expiratory 

flow rate is significantly below baseline, the clinical condition of the patient should be 

evaluated before administration of the injection. 

● Description of any reactions. Dose adjustments may be necessary if reactions are 

frequent or severe. 

● Details of any treatment given in response to a reaction should be documented in the 

medical record and referenced on the administration form. 

● Any adjustment from the standard schedule and the reason for the adjustment (e.g., 

missed appointments). 

● Clinical status of the patient before the injection. In general, patients who have high 

fever or any significant systemic illness should not receive an injection. It is desirable 

to document the patient’s clinical condition before each injection, particularly if the 

patient is symptomatic. 

● Whether the patient has taken an antihistamine that day 

● Whether any new medication has been taken since the last immunotherapy injection 

Labels for Vaccine Vials 

Each vial of vaccine should be labeled in a way that permits easy identification. Each label 

should include the following information: 

● Appropriate patient identifiers, including patient name, prescription or social security 

number, or birth date 

● General description of the vaccine contents. Because of space limitations, it may be 

necessary to abbreviate the antigens. Possible abbreviations are as follows: tree, T; 

grass, G; bermuda, B; weeds, W; ragweed, R; mold, M; Alternaria, Alt; 

Cladosporium, Cla; Penicillium, Pcn; cat, C; dog, D; cockroach, Cr; dust mite, DM; D. 

farinae, Df; D. pteronyssinus, Dp; mixture, Mx. A full and detailed description of vial 

contents should be recorded on the prescription/content form. 

● The dilution from the maintenance concentrate in volume per volume. If colors, 

numbers, or letters are used to identify the dilution, they also should be included. 

● Vaccine expiration date 

Instruction Form for Use at an Outside Facility 

An instruction form should accompany all patients who go to an outside facility for 

immunotherapy injections. It should include: 

● General instructions for administration of immunotherapy 

● Directions for adjusting the dose if there is a reaction 

● Directions for adjusting the dose after an unexpected interval between injections 

● Instructions for treating reactions if they occur 

● Name and contact information of the prescribing Allergist.





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ALLERGY IMMUNOTHERAPY (AIT) PROBLEM LIST / PATIENT QUESTIONNAIRE 

AIT Start Date:________ Information Reviewed:________, ________, ________, ________ 

Patient Name ________________________ Phone (H) _______________ 

SSN:_________________________________ 

Address (W) _______________ 

_____________________________________ Fax # _______________ 

_____________________________________ 

Next of Kin Phone (H) _______________ 

Emergency Contact ___________________ (W) _______________ 

Primary Care Physician _______________ Phone # _______________ 

Prescribing Allergist ________________ Phone # _______________ 

PROBLEM LIST 

Please check any of the following medical problems if applicable: 

Allergic rhinitis / hay fever Emphysema Eczema 

Asthma Migraines Stroke 

Diabetes (sugar problems) Cancer High Blood Pressure 

Immunodeficiency Sinusitis Restrict shots to L/R arm only 

Coronary Artery Disease 

Neurological problems (i.e. seizures) 

Please list any other medical problem not listed above: 

CURRENT MEDICATIONS 

Please list all medications (name and dose) that you are taking to include prescription, 

over-the-counter, and herbal formulations, vitamins and food supplements: 

Do you take any of the following? 

• Nonsteroidal anti-inflammatory medications (pain, arthritis, anti-inflammatory) 

Aspirin Indomethacin Oxaprozin Naproxen Nabumetone 

Ketoprofen Piroxicam Diclofenac Ketorolac Trilisate 

Salsalate Diflunisal Meclofenamate Sulindac 

Etodolac Tolmetin Flurbiprofen Ibuprofen

• Beta-Blockers (heart disease, high blood pressure, glaucoma) 

Acebutolol Carvedilol Pindolol Atenolol 

Laberalol Propranolol Betaxolol Metoprolol 

Timolol Bisoprolol Nadolol Cartcolol 

• ACE inhibitors / Angiotensis Receptor Blockers (High blood pressure, kidney) 

Benazepril Lisinopril Ranipril Captopril 

Losartan Trandolapril Enalapril Moexipril 

Fosinopril Quinapril 

• Corticosteroids (pills, liquids, or shots) 

Betamethosone Hydrocortisone Prednisone Cortisone 

Triamcinolone Methylprednisolones Dexamethaxone Prednisolons 

DRUG ALLERGIES 

Please list any allergies or adverse reactions to any medications that you may have: 

GENERAL QUESTIONS 

Please circle the best answer for each of these questions concerning your allergy shots: 

1. During the last year my symptoms on allergy shots have: 

a) worsened b) stayed the same c) improved d) disappeared completely e) don't know 

2. How many times have you visited a health care provider for allergy problems in the 

last year (not including allergy shot visits)? 

0 1 2 3 4 5 6 7 8 9 10 >10 

3. How many workdays were missed during the last year that were all or partly due to 

allergies? 

0 1 2 3 4 5 6 7 8 9 10 >10 

4. Comments:____________________________________________________________________________ 

_________________________________________________________________________________________ 

Reviewed by Physician:_____________________________ 

Date:___________________________





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MEMORANDUM FOR: Allergy Immunotherapy Patients 

SUBJECT: Allergy Patient Consent / Instruction Sheet 

1. As a service to our patients, the ________ clinic administers 

Allergy Immunotherapy (AIT) for pollens, molds, and animal dander, and 

stinging insects as directed by your Allergist. 

2. An Allergy specialist must evaluate your medical condition, 

prescribe a course of AIT, and supply the allergen extract vials. Your 

first shot of any new prescription must be given at your Allergist's 

office. The site for the first shot of a refill vial will be at your 

Allergist’s discretion. 

3. We will maintain your allergen vials in our medication 

refrigerator. This will ensure your extract is maintained at the 

proper conditions. All vials must be labeled with name, vial number or 

v/v concentration, prescription number, contents, and expiration date 

in accordance with ACAAI standards of care. 

4. Before treatment begins, you will be required to have a completed 

AIT patient questionnaire on file. 

5. "Allergy shots" will be given in room _____, on weekdays from 9:00- 

11:00 and 1:00-3:00 [modify times as appropriate]. A fully credentialed 

health care provider and nurse must be present to administer your 

allergy shots. Availability of Medical staff may be limited on rare 

occasions due to other primary duties, and you may not be able to 

receive your shot. A brief delay in receiving your AIT will not pose a 

health risk, but may result in a subsequent dose adjustment. 

6. You are receiving injections of the materials to which you are most 

allergic. You may have very significant local or generalized reactions 

that require prompt treatment. 

7. Nearly all of the serious and rapidly progressive reactions begin 

within 30 minutes after the shot. 

8. We require a 30 minute waiting period after all allergy injections. 

You must wait in _______ after your injections and be checked by a 

staff member before leaving. If your schedule does not permit you to 

wait the required 30 minutes, you will not be able to receive your shot 

at that time. 

9. Promptly inform the staff if you are having any significant 

increase in itching, hay fever, asthma, hives, shortness of breath, 

throat clearing, or other discomforts you did not arrive with.

10. Those patients having their doses increased towards maintenance 

are most likely to have reactions, but even long term patients 

occasionally have serious reactions. 

11. Serious local or generalized reactions may require prompt 

treatment. If you should experience a serious reaction (hives, trouble 

breathing or swallowing) while in the clinic we will implement 

treatment as far as possible to stabilize or resolve the problem. Be 

aware that should this situation occur, you would be required to be 

observed for several hours to be sure that you do not develop a delayed 

reaction to your allergens requiring further treatment. You may be 

observed in this clinic, or you may be transferred emergently to a 

higher level of care for ongoing treatment depending on the severity of 

your reaction. 

12. Should you have a history of systemic reactions, you need to 

inform the staff promptly. Please make the staff aware if you do not 

have an epinephrine autoinjector (Epi-Pen or TwinJect) or do not have a 

ready knowledge of when and how to use it. 

13. If you should experience a delayed reaction after leaving the 

clinic, notify the staff on your next visit. This is required to 

assure that you receive the correct amount of extract and prevent 

worsening reactions. 

14. If you have started on any new medications, notify the staff 

immediately. The medications we use to treat a severe allergic 

reaction may NOT work as efficiently if you are on a class of drugs 

known as beta-blockers or ACE inhibitors. This could be a lifethreatening 

situation. If your primary physician feels you absolutely 

must be on beta blockers, your prescribing Allergist must review this 

fact with you and your primary care provider/specialist before we can 

continue your allergy shots. 

15. Significant illness with fevers over 100 degrees, respiratory 

illnesses, and worsened asthma symptoms are all conditions that require 

you notify staff of before receiving your allergy shot. These 

conditions may precipitate serious reactions after allergy shots. It 

is best to wait until these conditions resolve or stabilize before 

continuing. 

I understand the above information and will comply with the clinic 

policies. 

_____________________________ 

Patient's Signature 

____________________ 

Date 

_____________________________ 

Witness 

____________________ 

Date





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SPECIFIC INSTRUCTIONS 

A. PHYSICIAN MUST ALWAYS BE IMMEDIATELY AVAILABLE IN THE CLINIC AREA. 

B. ALL PATIENTS MUST REMAIN IN THE CLINIC AT LEAST 30 MINUTES AFTER AN INJECTION. 

C. Use a 26-28 gauge needle and give the subcutaneous injection into the lower deltoid area. 

D. Record data, dosage, and any reaction on a separate immunotherapy form. 

E. GRADING AND MANAGEMENT OF REACTIONS: 

1. Negative (swelling up to 15 mm, i.e. dime size) – progress according to schedule. 

2. “A” swelling 15-20 mm, i.e. dime to nickel size) – repeat the same dosage. 

3. “B” (swelling 20-25mm, i.e. nickel to quarter size – return to the last dosage which caused no reaction. 

4. “C” (swelling persisting more than 12 hours or over 25mm, i.e. quarter size or larger – decrease dosage by 50%. 

5. Systemic reactions (hives, sneezing, generalized itching, asthma, difficulty breathing, or shock) may be controlled by 

immediately placing a tourniquet above the injection site, and giving up to 0.01 ml/kg of 1:1000 epinephrine, up to 0.50 ml, 

every 10-20 minutes subcutaneously. NOTIFY THE PHYSICIAN. For the average adult, give 0.10 ml of 1:1000 epinephrine 

subcutaneously in the injection site and 0.20 ml of 1:1000 epinephrine in the other arm. Generally the allergen extract dose is 

reduced to 1/3 the last dosage that caused no systemic reaction and repeated 3 times before increasing dose. If the injections 

cause repeated reactions or are suspected of causing delayed symptoms repeatedly, or if reactions prevent progression of 

treatment, please contact the medical facility below for further instructions. 

F. IF THE PATIENT MISSSED THE SCHEDULED INJECTION BY: 

Up to 7 days late, increased according to schedule 22 to 28 days late, reduce dose by 50% 

8 to 14 days late, repeat the last dose 29 to 42 days late, reduce dose by 75% 

15 to 21 days late, reduce dose by 25% 43 to 56 days late, reduce dose by 90% 

In a patient with a history of previous shot reactions, severe asthma, or severe cardiac disease, the dose may need to be decreased even more. If in 

doubt, contact the medical facility below. If patient misses his/her scheduled injection by over 8 weeks, contact the medical facility below. 

G. If newly informed that patient is pregnant or on beta-blockers, notify medical facility below for instruction. 

H. REFILL EXTRACT PRESCRIPTIONS. When starting a new treatment vial, recommend a minimum of 50% reduction in initial dose. 

RECOMMENDED TREATMENT INSTRUCTION: Progress treatment using one vial at a time starting with the lowest numbered vial. When the 

schedule for each vial is completed, go to the next higher vial. 

13. VIAL # 13 A. CONTENT 

W/V 

CONTENT 

BAU/ML 

CONTENT 

AU/ML 

13B. DAYS BETWEEN 

SHOTS 

13C. SCHEDULE 

(SEE BELOW) 

1 1:2000000 1.1 0.2 3-7 A 

2 1:200000 11 2 3-7 B 

3 1:20000 110 20 3-7 C 

4 1:2000 1,100 200 3-7 D 

5 1:200 11,000 2,000 3-7 E 

13D. When the maximum tolerated 

dose or a dose of _0.5___ ml of vial 

___#5___ has been achieved, injections 

should be administered every __ 

2-4_____ weeks. An exception to 

this is during the period of 1 st year of AIT 

when injections should be 

administered every __1-4__weeks. 

SCHEDULE A SCHEDULE B SCHEDULE C SCHEDULE D SCHEDULE E SCHEDULE F/CUSTOM SCHEDULE 

0.05 ml 0.05 ml 0.05 ml 0.05 ml 0.05 ml 0.30 ml 

0.10 ml 0.10 ml 0.10 ml 0.10 ml 0.07 ml 0.35 ml 

0.25 ml 0.20 ml 0.20 ml 0.15 ml 0.10 ml 0.40ml 

0.60 ml 0.40 ml 0.30 ml 0.20 ml 0.15 ml 0.45 ml 

0.60 ml 0.40 ml 0.30 ml 0.20 ml 0.50 ml 

0.50 ml 0.40 ml 0.25 ml 

0.50 ml 

CUSTOM EXTRACT LABEL OR REMARKS: 

THE PRESCRIPTION MUST BE SIGNED BY THE ORDERING PHYSICIAN 

SIGNATURE, RANK, AND DEGREE DATE: January 12, 2007___ 

14A. NAME OF MEDICAL FACILITY Capt. J.R. Montgomery MC, USN 14B. TELEPHONE NUMBER 

NATIONAL NAVAL MEDICAL CENTER Chief, Allergy & Immunology Service (301) 295-4510 

ALLERGY/IMMUNOLOGY CLINIC 

BLDG. 9, 1 ST FLOOR 

BETHESDA, MD 20853





reference article

ALLERGY IMMUNOTHERAPY RECORD 

NNMC, BETHESDA, MD 

Immunotherapy Start Date: 

Immunotherapy Re-evaluation Date: 

SINGLE EXTRACT 

RX # Extract Contents: Trees Grasses Weeds Molds 

Prior Systemic Allergy Shot Reactions: YES / NO Roach Dust Mites Cat Dog Other:____________ 

Peak Flow: 

DATE 

Peak Flow Parameters: 

Beta Blockers: YES / NO Consent Signed YES / NO Education Given: YES / NO 

V/V 

EPI-PEN? 

Y / N / N/A 

C 

Health Status: 

PEAK 

O DILUTION SCD 

Any Illness? 

FLO 

L 

Y / N 

DOSE TIME GIVEN BY VERIF'D BY ARM (L /R) RXN-NOW RXN-DEL TIME CHKD CHKD BY 

O 

Any Fever? 

R 

Y / N 

NURSE/TECH/PT’S SIGNATURE & INITIALS 

NAME: NAME INITIALS 

_________________________________________ 

_________ 

RANK: _________________________________________ _________ 

_________________________________________ 

_________ 

SSN: DOB: _________________________________________ _________ 

HYDROCORTISONE/CLOBETASOL: Y / N (CIRCLE WHICH IF YES) 

ICE: Y/N ANESTHETIC: Y/N BANDAID: Y/N 

Special Instructions





reference article

Immunotherapy Pre-Injection Questionnaire 

Patient Name:____________________________________ 

Date:____________________ 

This questionnaire is designed to optimize safety precautions already in place for your 

allergen immunotherapy injection (s) (allergy shot). Please review and answer the 

following questions. The nursing staff will review your responses and notify your 

physician if they have any questions or concerns whether you should receive your 

injection(s) today. 

If you are pregnant or have been diagnosed with a new medical condition, please 

notify the staff. 

1. 

2. 

3. 

4. 

5. 

(Please check appropriate box.) YES 

Have you had increased asthma symptoms (chest tightness, increased 

cough, wheezing, or felt short of breath) in the past week? 

Have you had increased allergy symptoms (itching eyes or nose, 

sneezing, runny nose, post-nasal drip, or throat-clearing) in the past 

week? 

Have you had a cold, respiratory tract infection, or flu-like symptoms in 

the past two weeks? 

Did you have any problems such as increased allergy or asthma 

symptoms, hives, or generalized itching within 12 hours of receiving 

your last injection or swelling that persisted into the next day? 

Are you on any new medications since your last allergy injection? 

New blood pressure or heart medications, eyedrops, etc.? 

Please specify: 

NO 

Staff intervention/office visit: 

________________________________________________________________________ 

________________________________________________________________________ 

________________________________________________________________________ 

________________________________________________________________________ 

Staff Signature: __________________________________________________________





reference article

Aeroallergen Dose Adjustment Schedule 

Build up phase (1-2/ wk) 

7-13 days late 







> 56 days late 

Maintenance phase (q30 day) 




28-34 days (1 month) late 



> 56 days (2 months) late 

Repeat last dose 


Go back 1 dose from last given 

Go back 2 doses from last given 


Call office 

Call office 

Call office 






Call office 

Call office 

Special Note: 

If ‘going back’ crosses into the 

previous vial, go back 1 extra dose 

Reaction, local 

< dime size (15mm) 

nickel size (20mm) 

quarter size (25mm) 

> quarter size or lasts > 12 hr 

Reaction, systemic 

Advance per schedule 

Advance per schedule 

Go back 1 dose from last given. Consider split dose, pre-Rx: H1, NSAIDs, etc. 

Go back 2 doses from last given. Call office if intervention not effective. 

Rx emergently. Call office for follow up appointment before resuming protocol.





reference article

NATIONAL NAVAL MEDICAL CENTER: Allergy and Immunology 

ON-GOING COMPETENCY ASSESSMENT OF SPECIFIC SKILLS AND PROCEDURES FOR SPECIALTY CARE PATIENTS 

Performance Standards: Care of Patients-----------Continuum of Care-------------Screening--------------Assessment----------------Education 

Demonstrates clinical competency related to specific skills and procedures IAW appropriate standards for care and within defined scope of 

practice and established guidelines. 

CRITICAL BEHAVIOR 

(SOURCE OF PERFORMANCE STANDARD) 

*Self 

Assess 

+Eval 

Method 

Validator’s Signature Day/Month/Year Comments 

1. Patient Screening CRITICAL THINKING: Identifies situations where obtaining vital signs is in the best interest of the patient (even if not 

requested by the provider) and alerts the RN or Health Care Provider (HCP) to the results and the patient’s presenting 

situation. Recognizes abnormal value, takes appropriate action in a timely manner, and documents findings appropriately. 

Recognizes unique age and language appropriate communication needs of patients and responds appropriately. 

Recognizes normal variations in vital signs parameters associated with the aging process from toddlers to older adults. 

A. Obtains VS (pulse, BP, temp, respiration, pulse ox ) as 

requested by the specialty provider and recognizes normal & 

abnormal values for: 

(1) toddlers (18 months to 3 years) 

(2) preschool age (3-6 years) 

(3) school age (6-10 years) 

(4) adolescents (10-17 years) 

(5) adults (18-64 years) 

(6) geriatric (65 and older) 

B. Obtains weight for allergy and immunology patients and 

compares to previous visit. Brings significant weight loss/gain to 

the attention of HCP. (10 pounds change in past 6mos.) 

C. Inquires about presence of pain and uses appropriate pain 

scales (Wong and Baker FACES Scale, 0-10, etc.) and documents 

per protocol 

D. Inquires about pertinent safety practices (i.e., inability to 

perform daily activities due to injuries or disabilities) and alerts 

RN/HCP for patients who might require additional interventions 

and documents. 

E. Inquires about increased asthma symptoms, allergy 

symptoms, respiratory tract symptoms, or any symptom(s) 

occurring within 12 hrs of previous allergy shot or vaccination. 

CRITICAL THINKING: Recognizes the influence of age, language, and culture on the perception of pain. Realizes that 

pain perception often changes with normal aging to include the minimizing normally acute symptoms (i.e., chest pain 

associated with myocardial infarction or discomforts associated with anaphylactic reactions) in the geriatric population. 

Inquires as to how the patient manages pain at home (medications, home remedies, restricting activities, etc.) and 

documents. Alerts nursing staff and/or HCP to presence of pain. . 

*Self Assessment: E = Experienced NP = Needs Practice ND = Never Done NA = Not Applicable (Based on Scope of Practice) 

+Evaluation Method: V = Verbal D = Demonstrated PE = Practical Exercise L = Lecture or Video 

I understand that I will be allowed to perform only those tasks listed for my skill level/Scope of Practice, after I have successfully demonstrated competency in those tasks. 

Signature: _________________________________________Date: ______________________ Signature of Supervisor: _____________________________________ Date: ________________

ONGOING COMPETENCY ASSESSMENT OF UNIT SPECIFIC SKILLS & PROCEDURES: Allergy and Immunology 



*Self 

Assess 

+Eval 

Method 


2. Patient Education CRITICAL THINKING: Recognizes unique needs of toddlers to geriatric patients and performs procedures accordingly. 

Gathers age and diagnosis appropriate supplies and equipment. Explains all procedures in an age appropriate manner 

according to the level of understanding of the patient and family. Approaches patient in non-threatening manner and 

demonstrates acceptance of their coping mechanisms. Provides teaching and reassurance throughout the entire process. 

A. Greets patient/family and establishes a rapport. 

B. Screens for learning needs, barriers to learning and preferred 

learning method(s). 

C. Provide information to meet educational needs or refers to 

appropriate resources (i.e. VIS, handouts, immunotherapyspecific 

patient education class, Nurse Educator or HCP) 

D. Documents education provided on progress note, order form, 

screening questionnaire or electronically. 

(1) Toddlers (18 months-3 years) CRITICAL THINKING FOR TODDLERS: Encourages parent to provide child with a security item (blanket, toy) and 

have parent stay with child. Gives toddler one step directions at their eye level and maintains eye contact during 

examination. Speaks in slow and calm manner and praises toddler at completion of examination. 

(2) Pre-School age (3-6 years) CRITICAL THINKING FOR PRE-SCHOOL AGE: Involves child and parent in all decisions and encourages child to 

participate in examination as much as possible (i.e., handling equipment to reduce fear and satisfy curiosity).Provides a 

safe environment, explains all steps using simple words the child can understand, and uses distraction technique such as 

songs or asking questions about favorite activities or pets. Provides for minimal exposure due to particular modesty of this 

age group. Praises child at the completion of the examination. 

(3) School age (6-10 years) CRITICAL THINKING FOR SCHOOL AGE: Involves child and parent in all decisions and encourages child to 

participate in n examination as much as possible. Provides a safe environment and maintains modesty. Allows child to 

choose whether parent remains present if appropriate. Praises child at the completion of the examination. 

(4) Adolescents (10-17 years) CRITICAL THINKING FOR ADOLESCENTS: Involves adolescent and parent in all decisions and encourages the 

adolescent to participate in examination as much as possible. Supplements explanations with rationale. Provides a safe 

environment and maintains modesty. Allows adolescent to choose whether parent remains present if appropriate. 

Encourages adolescent to ask questions and express concerns/fears regarding illness. Talks directly to the adolescent and 

allows them to answer questions even if a parent is present. Does not treat adolescent like a child. 

(5) Adults (18-64 years) CRITICAL THINKING FOR ADULTS (18-64): Addresses patient by name and/or rank per their preference. Explains 

examinations/ procedures in clear and simple terms using correct terminology. Maintains safety and provides reassurance. 

(6) Geriatric (64 plus) CRITICAL THINKING FOR OLDER ADULTS: Shows respect for patient and family and addresses patient by name 

and/or rank per their preference avoiding such terms as “honey, sweetie, or cutie”. Involves patient and family in all 

decisions and encourages the patient to participate in procedure as much as possible. Recognizes that older patients may 

demonstrate a delayed response to questions and allows them time to phrase an answer. Also adjusts explanations to 

accommodate short-term memory loss. Explains examinations/procedures in clear and simple terms using correct 

terminology. Allows patient to describe their mobility capabilities and limitations in regard to positioning. Maintains safety 

and provides reassurance. Minimizes exposure to ensure modesty and avoid unnecessary heat loss. 

Name: ____________________________________ 

2 


+Evaluation Method: V = Verbal D = Demonstrated PE = Practical Exercise L = Lecture or Video




*Self 

Assess 

+Eval 

Method 


3. Patient Care: 

IMMUNOTHERAPY/IMMUNIZATIONS 

A. Assures a physician order is available prior to administering 

immunotherapy/immunizations. 

B. Screens patient’s records for required immunotherapy/ 

immunization(s). 

C. Documents date, vial/lot number, amount, manufacturer and 

site of vaccine to be given as appropriate for vaccination. 

D. Measures pulmonary function IAW clinic policy. 

E. Assures educational needs are met IAW clinic policy. 

F. Obtains appropriate vaccine(s) and gathers supplies for 

administration. 

G. Checks expiration date on vaccines and diluents. 

H. Dilutes appropriately and draws up right vaccine and dose. 

I. Explains the procedure to patient. 

J. Reviews and clarifies screening questions (immunodeficiency, 

allergies, pregnancy, worsening symptoms, new medications). 

K. Appropriately refers to HCP, if needed. 

L. Washes or sanitizes hands between patient contacts and uses 

proper aseptic technique. 

M. Carefully check and administer vaccine(s) utilizing the five 

(5) rights to giving medications. 

N. Cleanses the site “center to outward”, approximately 2” 

around it. Allows the site to dry. 

O. Inserts the needle at the correct angle to the skin for SC or for 

IM as appropriate to the immunotherapy/vaccine. 

P. Aspirates prior to injecting vaccine. 

Q. Applies gentle pressure to injection site for several seconds 

after each injection. Does NOT rub immunotherapy site. 

R. Properly disposes of needle, syringe and empty vials in 

sharps container. 

CRITICAL THINKING: Recognizes unique needs of toddlers through geriatric patients and performs 

examinations/procedures accordingly. Gathers age and diagnosis appropriate supplies and equipment. Explains all 

examinations/procedures in an age appropriate manner according to the level of understanding of the patient and the 

family. Approaches patient in professional and non-threatening manner. Serves as a chaperone for physical exams as 

needed. Provides reassurance to patient and family. 

CRITICAL THINKING: Recognizes appropriate size needle gauge and length based on patient’s age and size considering 

the route of administration. 

CRITICAL THINKING: Focus on the right medication (age specific vaccine, IT prescription#, allergen contents, 

concentration), right dose (age/dose specific, VIT vs AIT), via the right route to the right patient at the right time interval. 

Name: ____________________________________ 

3 






*Self 

Assess 

+Eval 

Method 


S. Explains some post injection comfort measures and instructs 

the patient to wait in the clinic lobby for 30 minutes for JEV and 

immunotherapy injections, and 15 minutes for all other vaccines. 

T. Advises the patient to contact any nurse, technician, or doctor 

in the clinic if they began to feel “different” than prior to shot. 

U. Documents local reaction at site of injection prior to departing 

the clinic and any delayed reaction prior to administering next 

shot. 

CRITICAL 

ADVERSE REACTIONS 

THINKING: Understands the purpose of the medication and its intended effect. Recognizes systemic 

reactions to vaccines. (Anaphylaxis vs vasovagal) 

A. Recognizes adverse systemic reactions CRITICAL THINKING: Patients with post-shot vasovagal reactions tend to be lightheaded, pale, and have slower 

pulses, while patients suffering post-shot allergic anaphylaxis tend to be flushed and tachycardic, and may have hives, 

shortness of breath, cough, wheeze, and/or GI cramping. 

B. Calls for Help 

C. Positions patient (supine, Trendelenburg) 

D. Administers age-appropriate dose of epinephrine IM 

(1) Less than 60 pounds = 0.15 cc of 1:1,000 Epinephrine 

(2) Greater than 60 pounds = 0.30 cc of 1:1,000 Epinephrine 

E. Assesses ABC’s and continually monitors vital signs 

F. Administers Oxygen 

G. Appropriately annotates medical record 

H. Arranges follow up appointment with Allergist. 

I. Provides patient with epinephrine autoinjector 

(1) Instructs patient/parent in indication(s) for use 

(2) Instructs patient/parent in correct technique for use 

(3) Monitors for compliance 

Name: ____________________________________ 

4 







reference article

Allergy immunotherapy administration by licensed nursing staff 

By Arline M. Gerard, RN, Kaiser Orange County, CA 

It is within the scope of practice of licensed nurses to administer allergy immunotherapy medications for 

the purpose of treatment of allergy patients. 

Authority for nurses to administer medications derives from varying sections of their states’ Nurse 

Practice Act (NPA). Most states place few limits on the type of medication or route of administration; 

there is often only a requirement that the drug be ordered by one lawfully authorized to prescribe it. Other 

relevant sections of some NPA’s do impose additional requirements, but these generally do not pertain to 

allergy immunotherapy extract vaccines. Specifically, the nurse should be competent to perform the 

function of administering medications, and this task must be performed in a manner consistent with the 

standard of practice expected of a diligent nurse, in that state. 

In administering medication/extracts for treatment of allergy patients, the nurse is required to have the 

same knowledge and skills as for any other medication that she/he administers. This knowledge base 

includes, but is not limited to: 

• Effects of the medication/extract 

• Potential side effects of the medication/extract 

• Contraindications for the administration of the medication/extract 

• Amount of the medication/extract to be administered 

• Dilution of the medication/extract to be administered 

The requisite skills include the ability to competently and safely administer the medication/extract by the 

specified route, anticipate and recognize potential complications of the medication/extract, recognize 

emergency situations, and institute emergency procedures. Thus, the nurse would be held accountable for 

knowledge of the medication/extract and for ensuring that the proper safety measures are followed. 

As of March 2003, safety considerations for allergy immunotherapy administration include the standards 

embodied in the Practice Parameters. These national standards were issued jointly by the American 

Academy of Allergy, Asthma & Immunology with the American College of Allergy, Asthma & 

Immunology. The Practice Parameters should be consulted in establishing and maintaining allergy office 

policies and procedures. 

The nurse administering allergy immunotherapy should conduct a brief nursing assessment to determine 

that administration of the medication/extract is in the patient's best interest, for that visit. The nurse would 

also ensure that all safety measures are enforced, including back-up personnel skilled and trained in 

airway management, resuscitation and emergency intubation, should complications occur. Nurses 

managing the care of patients receiving allergy immunotherapy shall expect the patient to wait, post 

injection. The nurse should not engage in tasks that would seriously compromise monitoring of the 

patient by the nurse. The nurse must have knowledge of signs and symptoms of a reaction to the 

medication/extract, and must be empowered to give epinephrine and other treatments, immediately, when 

determined to be necessary. 

A nurse is held accountable for any act of nursing provided to a patient. The nurse has the right and 

obligation to act as the patient's advocate by refusing to administer or continue to administer any 

medication/extract not in the patient's best interest; this includes medication/extracts which may cause the 

patient to have an anaphylactic event, especially when given in error. Basic immunotherapy forms

eflecting current robust documentation standards, as well as office policy and procedure manuals should 

be reviewed and updated at reasonable intervals. 

All nursing and support staff should have in-services to reflect knowledge changes, as the profession of 

the allergy nurse evolves. As offices transition to computerized systems, the nurse is still responsible for 

the actual administration of the medication/extract, and should be engaged in finding and reducing errors, 

and potential errors which may be inherent within their computerized programming. He/she should never 

knowingly give a medication/extract which he/she reasonably deems to be improper, for that patient. 

The institution or employer should have in place a process for evaluating and documenting the nurse’s 

demonstration of the knowledge, skills, and abilities for management of patients receiving allergy 

immunotherapy. Evaluation and documentation of these competency skills should occur on a regular 

basis. 

Immediate availability of epinephrine and of an emergency cart, which contains resuscitative and 

antagonist medications, airway and ventilator adjunct equipment, defibrillator, suction, and a source for 

administration of oxygen are commonly included in current standards for giving allergy immunotherapy. 

Registered nurse practitioners, by virtue of advanced education and practice in their area of allergy 

specialty, may, or should have met, these requirements to safely administer allergy immunotherapy, but 

only if properly trained to do so.





reference article

Allergen immunotherapy: A practice parameter 

second update 

Supplement Editor: Linda Cox, MD 

Co-editors: James T. Li, MD, Harold Nelson, MD, and Richard Lockey, MD 

These parameters were developed by the Joint Task Force on 

Practice Parameters, representing the American Academy of 

Allergy, Asthma and Immunology; the American College of Allergy, 

Asthma and Immunology; and the Joint Council of Allergy, Asthma 

and Immunology. 

The American Academy of Allergy, Asthma and Immunology 

(AAAAI) and the American College of Allergy, Asthma and 

Immunology (ACAAI) have jointly accepted responsibility for 

establishing the ‘‘Allergen immunotherapy: a practice parameter 

second update.’’ This is a complete and comprehensive document at 

the current time. The medical environment is a changing 

environment, and not all recommendations will be appropriate for 

all patients. Because this document incorporated the efforts of 

many participants, no single individual, including those who served 

on the Joint Task Force, is authorized to provide an official AAAAI 

or ACAAI interpretation of these practice parameters. Any request 

for information about or an interpretation of these practice 

Disclosure of potential conflict of interest: L. Cox has consulting arrangements 

with Allergy Therapeutics, Genentech/Novartis, and Greer Laboratories and 

is on the speakers’ bureau for Genentech/Novartis, GlaxoSmithKline, and 

AstraZeneca. R. Lockey has received grant support from Greer Laboratories; 

served as chairman of an advisory committee for ALK-Abelló for over 

7 years; and has served as an expert witness for allergen immunotherapy 

death for both plaintiff and defendant. H. Nelson has consulting arrangements 

with Genentech/Novartis, Curalogic, GlaxoSmithKline, Inflazyme 

Pharmaceuticals, Dey Laboratories, Dynavax Technologies, Altana, and 

Schering-Plough; has received grant support from Dey Laboratories, 

IVAX, MediciNova, Wyeth, Sepracor, Genentech, Schering-Plough, Novartis, 

AstraZeneca, SkyPharma, Altana, and Roche; and is on the speakers’ 

bureau for GlaxoSmithKline and AstraZeneca. D. Bernstein has consulting 

arrangements with ALK-Abelló and has received grant support from 

Dynavax and ALK-Abelló. J. Blessing-Moore has received grant support 

from Novartis-Genentech and AstraZeneca and is on the speakers’ bureau 

for Schering-Plough, Merck, Aventis, Novartis/Genentech, AstraZeneca. 

D. M. Lang has consulting arrangements with, has received grant support 

from, and is on the speakers’ bureau for GlaxoSmithKline, Merck, Astra- 

Zeneca, Centocor, Sanofi-Aventis, Schering-Plough, Verus, and Dey. J. 

Oppenheimer has consulting arrangements with GlaxoSmithKline, Astra- 

Zeneca, Sepracor, and Merck; has received grant support from AstraZeneca, 

Sepracor, and Merck, Boehringer Ingelheim, Novartis/Genentech, and 

Schering-Plough; and is on the speakers’ bureau for GlaxoSmithKline, 

AstraZeneca, Sepracor, and Merck. J. M. Portnoy has consulting arrangements 

with Greer and GlaxoSmithKline; has received grant support from 

Clorox; and is on the speakers’ bureau for Schering-Plough, Merck, Aventis, 

Secpracor, and AstraZeneca. S. A. Tilles has consulting arrangements with 

Genentech, Schering-Plough, and GlaxoSmithKline; has received grant support 

from AstraZeneca, Novartis, Medpoint, Apieron, and ALK-Abelló; and 

is on the speakers’ bureau for GlaxoSmithKline, Pfizer, Genentech, and 

Alcon. The rest of the authors have declared that they have no conflict of 

interest. 

Reprint requests: Joint Council of Allergy, Asthma and Immunology, 50 N 

Brockway St, #3-3, Palatine, IL 60067. 

J Allergy Clin Immunol 2007;120:S25-85. 

0091-6749/$32.00 

Ó 2007 American Academy of Allergy, Asthma & Immunology 

doi:10.1016/j.jaci.2007.06.019 

parameters by the AAAAI or the ACAAI should be directed to the 

Executive Offices of the AAAAI, the ACAAI, and the Joint Council 

of Allergy, Asthma and Immunology. These parameters are not 

designed for use by pharmaceutical companies in drug promotion. 

Published practice parameters of the Joint Task Force 

on Practice Parameters for Allergy and Immunology 

include the following: 

1. Practice parameters for the diagnosis and treatment 

of asthma. J Allergy Clin Immunol 1995;96(suppl): 

S707-S870. 

2. Practice parameters for allergy diagnostic testing. 

Ann Allergy 1995;75:543-625. 

3. Practice parameters for the diagnosis and management 

of immunodeficiency. Ann Allergy 1996;76:282-94. 

4. Practice parameters for allergen immunotherapy. 

J Allergy Clin Immunol 1996;98:1001-11. 

5. Disease management of atopic dermatitis: a practice 

parameter. Ann Allergy 1997;79:197-211. 

6. The diagnosis and management of anaphylaxis. 

J Allergy Clin Immunol 1998;101(suppl):S465-S528. 

7. Algorithm for the diagnosis and management of 

asthma: a practice parameter update. Ann Allergy 

1998;81:415-20. 

8. Diagnosis and management of rhinitis: parameter 

documents of the Joint Task Force on Practice 

parameters in Allergy, Asthma and Immunology. 

Ann Allergy 1998;81(suppl):S463-S518. 

9. Parameters for the diagnosis and management of 

sinusitis. J Allergy Clin Immunol 1998;102(suppl): 

S107-S144. 

10. Stinging insect hypersensitivity: a practice parameter. 


11. Disease management of drug hypersensitivity: a 

practice parameter. Ann Allergy 1999;83(suppl): 

S665–S700. 

12. Diagnosis and management of urticaria: a practice 

parameter. Ann Allergy 2000;85(suppl):S521-S544. 

13. Allergen immunotherapy: a practice parameter. Ann 

Allergy 2003;90(suppl):SI-S540. 

14. Symptom severity assessment of allergic rhinitis: 

part I. Ann Allergy 2003;91:105-14. 

15. Disease management of atopic dermatitis: an updated 

practice parameter. Ann Allergy 2004;93(suppl): 

S1-S21. 

16. Stinging insect hypersensitivity: a practice parameter 

update. J Allergy Clin Immunol 2004;114:869-86. 

17. The diagnosis and management of anaphylaxis: an 

updated practice parameter. J Allergy Clin Immunol 

2005;115(suppl):S483-S523. 

S25

S26 Cox et al 

J ALLERGY CLIN IMMUNOL 

SEPTEMBER 2007 

18. Practice parameter for the diagnosis and management 

of primary immunodeficiency. Ann Allergy 2005; 

94(suppl):S1-S63. 

19. Attaining optimal asthma control: a practice parameter. 


20. The diagnosis and management of sinusitis: a practice 

parameter update. J Allergy Clin Immunol 2005; 

116(suppl):S13-S47. 

21. Food allergy: a practice parameter. Ann Allergy 

Asthma Immunol 2006;96(suppl 2):S1-S68. 

22. Contact dermatitis: a practice parameter. Ann Allergy 

Asthma Immunol 2006;97(suppl 2):S1-S38. 

These parameters are also available on the internet at 

http://www.jcaai.org. 

CONTRIBUTORS 

The Joint Task Force has made a concerted effort to 

acknowledge all contributors to this parameter. If any 

contributors have been excluded inadvertently, the Task 

Force will ensure that appropriate recognition of such 

contributions is made subsequently. 

The Joint Task Force gratefully acknowledges the 

American Academy of Allergy, Asthma and Immunology 

Board of Directors and the American College of Allergy, 

Asthma and Immunology Board of Regents for their 

review and support of this document. 

SUPPLEMENT EDITOR 

Linda Cox, MD 

Department of Medicine 

Nova Southeastern University College of Osteopathic 

Medicine 

Davie, Fla 

CO-EDITORS 

James T. Li, MD, PhD 

Division of Allergic Diseases 

Mayo Clinic 

Rochester, Minn 

Richard Lockey, MD 

Departments of Medicine, Pediatrics, and Public Health 

Division of Allergy and Immunology 

University of South Florida College of Medicine 

James A. Haley Veterans’ Hospital 

Tampa, Fla 

Harold Nelson, MD 


National Jewish Medical and Research Center 

Denver, Colo 

JOINT TASK FORCE REVIEWERS 

David Bernstein, MD 

Department of Medicine and Environmental Health 

University of Cincinnati College of Medicine 

Cincinnati, Ohio 

I. Leonard Bernstein, MD 

Departments of Medicine and Environmental Health 



David A. Khan, MD 

Department of Internal Medicine 

University of Texas Southwestern Medical Center 

Dallas, Tex 

Joann Blessing-Moore, MD 

Departments of Medicine and Pediatrics 

Stanford University Medical Center 

Department of Immunology 

Palo Alto, Calif 

David M. Lang, MD 

Allergy/Immunology Section 

Division of Medicine 

Allergy and Immunology Fellowship Training Program 

Cleveland Clinic Foundation 

Cleveland, Ohio 

Richard A. Nicklas, MD 


George Washington Medical Center 

Washington, DC 

John Oppenheimer, MD 


New Jersey Medical School 

Pulmonary and Allergy Associates 

Morristown, NJ 

Jay M. Portnoy, MD 

Section of Allergy, Asthma & Immunology 

The Children’s Mercy Hospital 

Department of Pediatrics 

University of Missouri-Kansas City School of Medicine 

Kansas City, Mo 

Diane E. Schuller, MD 


Pennsylvania State University Milton S. Hershey 

Medical College 

Hershey, Pa 

Sheldon L. Spector, MD 


UCLA School of Medicine 

Los Angeles, Calif 

Stephen A. Tilles, MD 


University of Washington School of Medicine 

Redmond, Wash 

Dana V. Wallace, MD 

Nova Southeastern University 

Davie, Fla 

INVITED REVIEWERS 

Don Aaronson, MD, Chicago, Ill 

David Golden, MD, Baltimore, Md 

Moises Calderon, MD, London, United Kingdom (UK)


VOLUME 120, NUMBER 3 

Cox et al S27 

Stephen Durham, MD, London, UK 

Ira Finegold, MD, New York, NY 

Stephen Kemp, Jackson, Miss 

Brian Smart, MD, Glen Ellyn, Ill 

Mark L. Vandewalker, MD, Columbia, Mo 

Richard Weber, MD, Denver, Colo 

David Weldon, MD, College Station, Tex 

REVIEWERS OF ALLERGEN EXTRACT 

SECTION 

Robert Esch, PhD, Lenoir, NC 

Larry Garner, CPT, BA, Spokane, Wash 

Richard Lankow, PhD, Round Rock, Tex 

Greg Plunkett, PhD, Round Rock, Tex 

Tom Willoughby, Liberty, Miss 

The authors and editors gratefully acknowledge Susan 

Grupe for her administrative assistance. 

Allergen immunotherapy: A practice parameter 

second update 

Preface 

S27 

Algorithm and annotations for immunotherapy S28 

Immunotherapy glossary 

S31 

Introduction 

S33 

Summary statements 

S33 

Mechanisms of immunotherapy 

S38 

Allergen extracts 

S38 

Efficacy of immunotherapy 

S41 

Safety of immunotherapy 

S43 

Patient selection 

S46 

Allergen selection and handling 

S48 

Immunotherapy schedules and doses 

S53 

Location of allergen immunotherapy 

administration 

S61 

Special considerations in immunotherapy S63 

Alternative routes of immunotherapy S64 

Future trends in immunotherapy 

S66 

References 

S67 

PREFACE 

This document was developed by the Joint Task Force 

on Practice Parameters, which represents the American 

Academy of Allergy, Asthma and Immunology (AAAAI); 

the American College of Allergy, Asthma and Immunology 

(ACAAI); and the Joint Council of Allergy, Asthma 

and Immunology (JCAAI). 

The objective of ‘‘Allergen immunotherapy: A practice 

parameter second update’’ is to optimize the practice of 

allergen immunotherapy for patients with allergic rhinitis, 

allergic asthma, and Hymenoptera sensitivity. This parameter 

is intended to establish guidelines for the safe and 

effective use of allergen immunotherapy, while reducing 

unnecessary variation in immunotherapy practice. These 

guidelines have undergone an extensive peer-review 

process consistent with recommendations of the 

American College of Medical Quality’s ‘‘Policy on development 

and use of practice parameters for medical 

quality decision-making’’ (Appendix 1). 1 

This document builds on the previous Joint Task Force 

document, ‘‘Allergen immunotherapy: a practice parameter’’ 

published in the Annals of Allergy, Asthma and 

Immunology in 2003. 2 The updated practice parameters 

draft was prepared by Drs Linda Cox, James Li, Hal 

Nelson, and Richard Lockey. The Joint Task Force 

reworked the initial draft into a working draft of the 

document. The project was exclusively funded by the 3 

allergy and immunology societies noted above. 

In preparation for the 2003 ‘‘Allergen immunotherapy: 

a practice parameter’’ and the second update, a comprehensive 

search of the medical literature was conducted with 

various search engines, including PubMed; immunotherapy, 

allergic rhinitis, asthma, stinging insect allergy, and 

related search terms were used. Published clinical studies 

were rated by category of evidence and used to establish 

the strength of a clinical recommendation (Table I). 3 

Laboratory-based studies were not rated. 

The working draft of ‘‘Allergen immunotherapy: a 

practice parameter second update’’ was reviewed by a 

large number of experts in immunotherapy, allergy, and 

immunology. These experts included reviewers appointed 

by the ACAAI, AAAAI, and JCAAI. In addition, the draft 

was posted on the ACAAI and AAAAI Web sites with an 

invitation for review and comments from members of the 

sponsoring organizations. The authors carefully considered 

all of these comments in preparing the final version. 

An annotated algorithm in this document summarizes the 

key decision points for the appropriate use of allergen 

immunotherapy (Fig 1). 

The section on efficacy summarizes the evidence 

demonstrating that allergen immunotherapy is effective in 

the management of properly selected patients with allergic 

rhinitis, allergic asthma, and stinging insect hypersensitivity. 

This document also contains recommendations for 

the safe practice of allergen immunotherapy, including 

specific recommendations on the prevention and management 

of systemic reactions. 

Specific recommendations guide the physician in 

selecting those patients for whom allergen immunotherapy 

is appropriate. Aeroallergen immunotherapy should be 

considered for patients who have symptoms of allergic 

rhinitis or asthma with natural exposure to allergens and 

who demonstrate specific IgE antibodies to the relevant 

allergen or allergens. Symptoms of allergic conjunctivitis 

(eg, itchy watery eyes) are often considered part of allergic 

rhinitis or are included in the diagnosis of rhinoconjunctivitis. 

Particularly good candidates for immunotherapy are 

patients whose symptoms are not controlled adequately by 

medications and avoidance measures, those in whom it is 

important to avoid the potential adverse effects of medications, 

and those who wish to reduce the long-term use of 

medications. Immunotherapy is recommended for patients 

with a history of systemic reaction to Hymenoptera stings 

and specific IgE antibodies to Hymenoptera venom.

S28 Cox et al 



TABLE I. Classification of evidence and 

recommendations* 

Category of evidence 

Ia Evidence from meta-analysis of randomized 

controlled trials 

Ib Evidence from at least 1 randomized controlled 

trial 

IIa Evidence from at least 1 controlled study without 

randomization 

IIb Evidence from at least 1 other type of 

quasiexperimental study 

III Evidence from nonexperimental descriptive 

studies, such as comparative studies, 

correlation studies, and case-control studies 

IV Evidence from expert committee 

reports or opinions, clinical experience 

of respected authorities, or both 

LB Evidence from laboratory-based studies 

NR Not rated 

Strength of recommendation 

A 

Directly based on category I evidence 

B 

Directly based on category II evidence 

or extrapolated from category I evidence 

C 

Directly based on category III evidence or 

extrapolated from category I or II evidence 

D 

Directly based on category IV evidence or 

extrapolated from category I, II, or III evidence 

NR Not rated 

*Adapted with permission from Shekelle PG, Woolf SH, Eccles M, 

Grimshaw J. Clinical guidelines: developing guidelines. BMJ 

1999;318:593-6. 3 

The selection of allergens for immunotherapy is based 

on clinical history, the presence of specific IgE antibodies, 

and allergen exposure. This parameter offers suggestions 

and recommendations derived from known patterns of 

allergen cross-reactivity. Recognizing that the immunotherapy 

terminology used to describe extract dilutions is 

sometimes ambiguous, the 2003 ‘‘Allergen immunotherapy: 

a practice parameter’’ established standardized terminology 

for describing allergen immunotherapy extract 

dilutions. These parameters also provided specific recommendations 

for immunotherapy maintenance doses for 

some standardized allergens and a suggested dosing range 

for nonstandardized allergen extracts. The therapeutic 

preparations for allergen immunotherapy are extracted 

from source materials, such as pollen, mold cultures, and 

pelt, hence the traditional term allergen extract. The terms 

allergen extract or extract refer to solutions of proteins or 

glycoproteins extracted from source material not yet incorporated 

into a therapeutic allergen immunotherapy extract. 

The term maintenance concentrate should be used to identify 

the allergen immunotherapy extract that contains a therapeutic 

effective dose for each of its individual constituents 

(see the Immunotherapy schedules and doses section). 

The term manufacturer’s extract refers to the allergy 

extract purchased from the manufacturer. The terms 

stock, full-strength, and concentrate are ambiguous and 

should not be used. All dilutions should be referenced 

to the maintenance concentrate and should be noted as a 

volume-to-volume dilution (eg, 1:100 vol/vol dilution of 

a maintenance concentrate). 

Allergen immunotherapy is effective when appropriate 

doses of the allergens are administered. ‘‘Allergen immunotherapy: 

A practice parameter’’ recommends that vials of 

allergen immunotherapy extracts should be prepared individually 

for each patient to enhance the individualization 

of therapy, reduce the risk of allergen cross-contamination, 

and reduce the risk of error in administration. 4,5 This 

parameter recommends the use of standardized allergen 

immunotherapy prescription and administration forms to 

improve the safety, uniformity, and standardization of 

allergen immunotherapy practice. 4,5 The suggested forms 

are found in the Appendix (Appendices 7, 8, 11, 12, and 

14) and in the members’ section of the www.aaaai.org 

Web site. The routine use of these standardized forms 

should improve the quality of immunotherapy practice. 

Members’ feedback comments on the recommended 

allergen extract dilution dating in the 2003 ‘‘Allergen 

immunotherapy: A practice parameter’’ led to an allergen 

immunotherapy extract dilution stability study designed 

by the AAAAI Immunotherapy and Allergy Diagnostics 

Committee and funded by the AAAAI Board of Directors. 

The study was designed to investigate the effect of time, 

temperature, and dilution of standardized allergen extract 

potency, and the results of this study were considered in 

this update. 

This document was approved by the sponsoring organizations 

and represents an evidence-based, broadly accepted 

consensus opinion. These clinical guidelines are 

designed to assist clinicians by providing a framework for 

the evaluation and treatment of patients and are not intended 

to replace a clinician’s judgment or establish a protocol for 

all patients. Not all recommendations will be appropriate 

for all patients. Because this document incorporates the 

efforts of many participants, no individual, including 

anyone who served on the Joint Task Force, is authorized 

to provide an official AAAAI or ACAAI interpretation 

of these guidelines. Recognizing the dynamic nature of 

clinical practice and practice parameters, the recommendations 

in this document should be considered applicable 

for 3 years after publication. Requests for information 

about or an interpretation of these practice parameters 

should be directed to the Executive Offices of the AAAAI, 

ACAAI, and JCAAI. These parameters are not designed 

for use by pharmaceutical companies in drug promotion. 

ALGORITHM AND ANNOTATIONS FOR 

IMMUNOTHERAPY 

Fig 1 provides an algorithm for the appropriate use of 

allergen immunotherapy. Given below are annotations 

for use with the algorithm. 

Box 1 

Immunotherapy is effective in the management of 

allergic asthma, allergic rhinitis/conjunctivitis, and 

stinging insect hypersensitivity. Allergen immunotherapy



Cox et al S29 

FIG 1. Algorithm for allergen immunotherapy.

S30 Cox et al 



might prevent the development of asthma in individuals 

with allergic rhinitis. 6-9 Evaluation of a patient with suspected 

allergic rhinitis, allergic rhinoconjunctivitis, allergic 

asthma, or stinging insect allergy includes a detailed 

history, an appropriate physical examination, and selected 

laboratory tests. A definitive diagnosis of allergic asthma, 

allergic conjunctivitis, allergic rhinitis, or stinging insect 

hypersensitivity depends on the results of allergy testing 

(immediate hypersensitivity skin tests or in vitro tests for 

specific IgE antibody). 10 

Box 2 

Immediate hypersensitivity skin testing is generally the 

preferred method of testing for specific IgE antibodies, 

although in vitro testing for specific IgE antibodies is useful 

under certain circumstances. Immunotherapy should 

be considered when positive test results for specific IgE 

antibodies correlate with suspected triggers and patient 

exposure. 

Box 3 

Immunotherapy should not be given to patients with 

negative test results for specific IgE antibodies or those 

with positive test results for specific IgE antibodies that do 

not correlate with suspected triggers, clinical symptoms, 

or exposure. This means that the presence of specific IgE 

antibodies alone does not necessarily indicate clinical 

sensitivity. There is no evidence from well-designed 

studies that immunotherapy for any allergen is effective 

in the absence of specific IgE antibodies. 

Box 4 

Management of complex medical conditions, such as 

allergic asthma, allergic rhinitis/conjunctivitis, and stinging 

insect hypersensitivity, should include the careful 

evaluation of management options. Each of the 3 major 

management approaches (allergen immunotherapy, allergen 

exposure reduction, and pharmacotherapy) has benefits, 

risks, and costs. Furthermore, the management plan 

must be individualized, with careful consideration given 

to patient preference. Disease severity and response (or 

lack of response) to previous treatment are important 

factors. 

Box 5 

The physician and patient should discuss the benefits, 

risks, and costs of the appropriate management options 

and agree on a management plan. On the basis of clinical 

considerations and patient preference, allergen immunotherapy 

might or might not be recommended. Patients with 

allergic rhinitis/conjunctivitis or allergic asthma whose 

symptoms are not well controlled by medications or 

avoidance measures or require high medication doses, 

multiple medications, or both to maintain control of their 

allergic disease might be good candidates for immunotherapy. 

Patients who experience adverse effects of medications 

or who wish to avoid or reduce the long-term use 

of medications are good candidates for immunotherapy. 

However, asthma must be controlled at the time the 

immunotherapy injection is administered. In general, 

patients with stinging insect hypersensitivity who are at 

risk for anaphylaxis should receive venom immunotherapy 

(VIT). 

Box 6 

After careful consideration of appropriate management 

options, the physician and patient might decide not to 

proceed with immunotherapy. 

Box 7 

Before immunotherapy is started, patients should understand 

its benefits, risks, and costs. Counseling should 

also include the expected onset of efficacy and duration of 

treatment, as well as the risk of anaphylaxis and importance 

of adhering to the immunotherapy schedule. 

Box 8 

The physician prescribing immunotherapy should be 

trained and experienced in prescribing and administering 

immunotherapy. The prescribing physician must select the 

appropriate allergen extracts on the basis of that particular 

patient’s clinical history and allergen exposure history and 

the results of tests for specific IgE antibodies. The quality 

of the allergen extracts available is an important consideration. 

When preparing mixtures of allergen extracts, the 

prescribing physician must take into account the crossreactivity 

of allergen extracts and the potential for allergen 

degradation caused by proteolytic enzymes. The prescribing 

physician must specify the starting immunotherapy 

dose, the target maintenance dose, and the immunotherapy 

schedule (see the Immunotherapy schedules and doses 

section). In general, the starting immunotherapy dose is 

1000-fold to 10,000-fold less than the maintenance dose. 

For highly sensitive patients, the starting dose might be 

lower. The maintenance dose is generally 1000 to 4000 

arbitrary units (AU; eg, for dust mite) or bioequivalent 

allergy units (BAU; eg, for grass) for standardized allergen 

extracts. For nonstandardized extracts, a suggested maintenance 

dose is 3000 to 5000 protein nitrogen units (PNU) 

or 0.5 mL of a 1:100 wt/vol dilution of manufacturer’s 

extract. If the major allergen concentration of the extract is 

known, a range between 5 and 20 mg of major allergen is 

the recommended maintenance dose for inhalant allergens 

and 100 mg for Hymenoptera venom. Immunotherapy 

treatment can be divided into 2 periods, which are commonly 

referred to as the build-up and maintenance phases. 

The immunotherapy build-up schedule (also referred to 

as up-dosing, induction, or the dose-increase phase) entails 

administration of gradually increasing doses during 

a period of approximately 14 to 28 weeks. In conventional 

schedules a single dose increase is given on each visit, and 

the visit frequency can vary from 1 to 3 times a week. 

Accelerated schedules, such as rush or cluster immunotherapy, 

entail administration of several injections at increasing 

doses on a single visit. Accelerated schedules 

offer the advantage of achieving the therapeutic dose earlier 

but might be associated with increased risk of systemic 

reaction in some patients.



Cox et al S31 

Box 9 

Immunotherapy should be administered in a setting that 

permits the prompt recognition and management of adverse 

reactions. The preferred location for such administration is 

the prescribing physician’s office. However, patients can 

receive immunotherapy injections at another health care 

facility if the physician and staff at that location are trained 

and equipped to recognize and manage immunotherapy 

reactions, in particular anaphylaxis. Patients should wait at 

the physician’s office for at least 30 minutes after the 

immunotherapy injection or injections so that reactions 

can be recognized and treated promptly, if they occur. 

In general, immunotherapy injections should be withheld 

if the patient presents with an acute asthma exacerbation. 

For patients with asthma, consider measuring peak 

expiratory flow rate before administering an immunotherapy 

injection and withholding an immunotherapy injection 

if the peak expiratory flow rate is considered low for 

that patient. Some physicians recommend providing certain 

patients with epinephrine for self-administration in 

case of severe late reactions to immunotherapy injections. 

Box 10 

Injections of allergen immunotherapy extract can cause 

local or systemic reactions. Most severe reactions develop 

within 30 minutes after the immunotherapy injection, but 

reactions can occur after this time. 

Box 11 

Local reactions can be managed with local treatment 

(eg, cool compresses or topical corticosteroids) or antihistamines. 

Systemic reactions can be mild or severe 

(anaphylaxis). Epinephrine is the treatment of choice in 

anaphylaxis, preferably when administered intramuscularly, 

11 although subcutaneous administration is 

acceptable. 12 

Antihistamines and systemic corticosteroids are secondary 

medications that might help to modify systemic 

reactions but should never replace epinephrine in the 

treatment of anaphylaxis. Intravenous saline or supplemental 

oxygen might be required in severe cases. 

For additional details, see the practice parameters for 

anaphylaxis. 12 

The immunotherapy dose and schedule, as well as the 

benefits and risks of continuing immunotherapy, should 

be evaluated after any immunotherapy-induced systemic 

reaction. After a severe systemic reaction, careful evaluation 

by the prescribing physician is recommended. For 

some patients, the immunotherapy maintenance dose 

might need to be reduced because of repeated systemic 

reactions to immunotherapy injections. The decision to 

continue immunotherapy should be re-evaluated after 

severe or repeated systemic reactions to allergen immunotherapy 

extracts. 

Box 12 

Patients receiving maintenance immunotherapy should 

have follow-up visits at least every 6 to 12 months. 

Periodic visits should include a reassessment of symptoms 

and medication use, the medical history since the previous 

visit, and an evaluation of the clinical response to immunotherapy. 

The immunotherapy schedule and doses, 

reaction history, and patient compliance should also be 

evaluated. The physician can at this time make adjustments 

to the immunotherapy schedule or dose, as clinically 

indicated. 

There are no specific markers that will predict who will 

remain in clinical remission after discontinuing effective 

allergen immunotherapy. Some patients might sustain 

lasting remission of their allergic symptoms after discontinuing 

allergen immunotherapy, 13 but others might 

experience a recurrence of their symptoms after discontinuation 

of allergen immunotherapy. 14 As with the decision 

to initiate allergen immunotherapy, the decision to discontinue 

treatment should be individualized, taking into account 

factors such as the severity of the patient’s illness 

before treatment, the treatment benefit sustained, and the 

inconvenience immunotherapy represents to a specific patient 

and the potential effect a clinical relapse might have 

on the patient. Ultimately, the duration of immunotherapy 

should be individualized on the basis of the patient’s clinical 

response, disease severity, immunotherapy reaction 

history, and patient preference. 

IMMUNOTHERAPY GLOSSARY 

For more information on immunotherapy definitions, 

see the article by Kao. 15 

The allergen immunotherapy extract is defined as the 

mixture of the manufacturer’s allergen extract or extracts 

that is used for allergen immunotherapy. Allergen extracts 

used to prepare the allergen immunotherapy extract can be 

complex mixtures containing multiple allergenic and nonallergenic 

macromolecules (proteins, glycoproteins, and 

polysaccharides) and low-molecular-weight compounds 

(pigments and salts; see the Allergen selection and handling 

section). Other terms used to describe the allergen 

immunotherapy extract include allergen product, 16 

allergy serum, allergen vaccine, 17 and allergen solution. 

Allergen immunotherapy is defined as the repeated 

administration of specific allergens to patients with IgEmediated 

conditions for the purpose of providing protection 

against the allergic symptoms and inflammatory 

reactions associated with natural exposure to these allergens. 

18 Other terms that have been used for allergen immunotherapy 

include hyposensitization, allergen-specific 

desensitization, and the lay terms allergy shots or allergy 

injections. 15 

Anaphylaxis is an immediate systemic reaction often 

occurring within minutes and occasionally as long as an 

hour or longer after exposure to an allergen. It can be 

IgE mediated, as can occur with allergen immunotherapy, 

or non–IgE mediated, as occurs with radiocontrast media. 

It is caused by the rapid release of vasoactive mediators 

from tissue mast cells and peripheral blood basophils. 

The build-up phase involves receiving injections with 

increasing amounts of the allergen. The frequency of

S32 Cox et al 



TABLE II. Allergen immunotherapy dose-calculation table 

d Express weight per volume as a fraction: 1 N 

or 1:N. 

d Calculate concentration of individual allergens in mixtures. If a mixture is made of equal amounts of N individual allergens to make a total 

concentration (C), the final concentration of an individual allergen (Ca) can be calculated by using the following equation: 

Ca 5 C 3 1 N 5 C N 

or C:N. 

For example, if a mixture of equal amounts of 5 (N) allergens has a total concentration (C) of 100,000 BAU/mL, then the final concentration 

of each individual allergen (Ca) is: Ca 5 C N 5 100;000 

5 

5 20; 000 BAU=mL 

Likewise, if C 5 1:10 (wt/vol), then: Ca 5 C N 5 1=10 

5 5 0:1 

5 5 0:02 or 1 50 

or 1:50. 

d Dilution of individual allergen: If an initial volume, Vi (in milliliters), of an individual antigen with concentration, Ci, is added to an 

allergen extract to make a final volume of Vf (in milliliters), the final allergen concentration (Ca) in the allergen extract mixture will 

be: Ca 5 Ci 3 Vi 

Vf . 

d Final concentration of an allergen in a mixture of mixtures is determined by multiplying the initial concentration by the dilution factors from 

each mixing step. 

For example, consider a mixture containing equal amounts of 5 (N) allergens with a total concentration (C) of 100,000 BAU/mL (first dilution). 

If an initial volume (Vi) of 0.5 mL of this mixture is further mixed with other components and diluent to make a final allergen extract 

mixture volume (Vf) of 5.0 mL (second dilution), the final concentration of an individual allergen (Ca) will be: 

Ca 5 C 3 

1 Vi 

N 

3 

Vf 

5 100; 000 3 1 5 

|{z} |{z} 

3 0:5 

5:0 5 100;000 

50 

5 2000 BAU=mL 

Mixture dilution Allergen extract dilution 

Likewise, if C 5 1:10 (wt/vol), then: Ca 5 1 

10 3 1 5 3 0:5 

5:0 5 1 

500 or 1:500. 

injections during this phase generally ranges from 1 to 3 

times a week, although more rapid build-up schedules 

are sometimes used. The duration of this phase depends 

on the frequency of the injections but generally ranges 

from 3 to 6 months (at a frequency of 2 times and 1 time 

per week, respectively). 

Cluster immunotherapy is an accelerated build-up 

schedule that entails administering several injections at increasing 

doses (generally 2-3 per visit) sequentially in 

a single day of treatment on nonconsecutive days. The 

maintenance dose is generally achieved more rapidly than 

with a conventional (single injection per visit) build-up 

schedule (generally within 4 to 8 weeks). 

Desensitization is the rapid administration of incremental 

doses of allergens or medications by which effector 

cells are rendered less reactive or nonreactive to an IgEmedicated 

immune response. Desensitization can involve 

IgE-mediated or other immune mechanisms. The positive 

skin test response to the allergens might diminish or actually 

convert to a negative response in some cases after this 

procedure. Tolerance to medications can be achieved 

through desensitization. 

The dose is the actual amount of allergen administered 

in the injection. The volume and concentration can vary 

such that the same delivered dose can be given by changing 

the volume and concentration (ie, 0.05 mL of a 1:1 vol/vol 

allergen would equal 0.5 mL of a 1:10 vol/vol allergen). 

The dose can be calculated by using the following formula: 

concentration of allergen multiplied by volume of administered 

dose (see Table II for a dose-calculation table). 

The effective therapeutic dose or maintenance dose is 

the dose that provides therapeutic efficacy without significant 

adverse local or systemic reactions. The effective 

therapeutic dose might not be the initially calculated projected 

effective dose (eg, cat, 1000 BAU, [highest tolerated 

dose] vs 2000 BAU [projected effective dose]). 

Hyposensitization is a term formerly used interchangeably 

with allergen immunotherapy. It was introduced to 

distinguish allergen immunotherapy from classical desensitization. 

Hyposensitization denotes a state of incomplete 

desensitization because complete desensitization is rarely 

accomplished with allergen immunotherapy. 

Immunomodulation is a term that denotes a wide variety 

of drug or immunologic interventions that alter normal or 

abnormal immune responses by deletion of specific T 

cells, B cells, or both; immune deviation; induction of 

peripheral/central tolerance; or modification of various 

inflammatory pathways (eg, chemotaxis, adhesions, or 

intracytoplasmic signaling). 

Immunotherapy is a treatment modality that appeared 

soon after adaptive immune responses were discovered 

and has gradually evolved to encompass any intervention 

that might benefit immune-induced aberrant conditions by 

a variety of immunologic transformations. Early definitions 

of the term immunotherapy included active and passive 

immunization for the purpose of improving a host’s 

defenses against microorganisms. Allergen immunotherapy 

was originally conceived as a form of active immunization, 

the purpose of which was to alter the host’s 

abnormal immune responses and not augment the host’s 

defenses against microorganisms. The modern rubric of 

immunotherapy includes all methods used to overcome abnormal 

immune responses by means of induction of clonal 

deletion, anergy, immune tolerance, or immune deviation. 

The maintenance concentrate is a preparation that 

contains individual or mixtures of manufacturer’s allergen 

extracts intended for allergen immunotherapy treatment. 

A maintenance concentrate can be composed of 

a concentrated dose of a single allergen or a combination 

of concentrated allergens to prepare an individual 

patient’s customized allergen immunotherapy extract 

mixture. Subsequent dilutions can be prepared from the



Cox et al S33 

maintenance concentrate for the build-up phase or if the 

patient cannot tolerate the maintenance concentrate. 

The maintenance dose (or effective therapeutic dose)is 

the dose that provides therapeutic efficacy without significant 

adverse local or systemic reactions. The effective 

therapeutic dose may not be the initially calculated projected 

effective dose. 

The maintenance goal (or projected effective dose) is 

the allergen dose projected to provide therapeutic efficacy. 

The maintenance goal is based on published studies, but a 

projected effective dose has not been established for allergens. 

Not all patients will tolerate the projected effective 

dose, and some patients experience therapeutic efficacy 

at lower doses. 

The maintenance phase begins when the effective therapeutic 

dose is reached. Once the maintenance dose is 

reached, the intervals between the allergy injections are 

increased. The dose generally is the same with each injection, 

although modifications can be made based on several 

variables (ie, new vials or a persistent large local reaction 

causing discomfort). The intervals between maintenance 

immunotherapy injections generally ranges from 4 to 8 

weeks for venom and every 2 to 4 weeks for inhalant allergens 

but can be advanced as tolerated if clinical efficacy is 

maintained. 

A major allergen is an antigen that binds to the IgE sera 

from 50% or more of a clinically allergic group of patients. 

Such allergens are defined either by means of immunoblotting 

or crossed allergoimmunoelectrophoresis. 

For a definition of projected effective dose, see maintenance 

goal. 

Rush immunotherapy is an accelerated immunotherapy 

build-up schedule that entails administering incremental 

doses of allergen at intervals varying between 15 and 60 

minutes over 1 to 3 days until the target therapeutic dose 

is achieved. Rush immunotherapy schedules for inhalant 

allergens can be associated with a greater risk of systemic 

reactions, particularly in high-risk patients (eg, those with 

markedly positive prick/puncture test responses), and 

premedication with antihistamines and corticosteroids 

appears to reduce the risk associated with rush immunotherapy. 

However, rush protocols for administration of 

Hymenoptera VIT have not been associated with a similar 

high incidence of systemic reactions. 

Off the board into one syringe is a phrase that describes a 

method of allergen immunotherapy preparation and administration 

that involves specifically mixing the patient’s 

allergenimmunotherapy injectionina single syringe,which 

is not recommended. This syringe might be inserted into 

more than one allergen extract vial, and this poses a risk of 

cross-contamination of the allergen extracts and might dull 

the needle with repeated penetration of the rubber stopper. 

Shared specific patient vials is a method of allergen immunotherapy 

preparation and administration in which the 

allergy immunotherapy extract is withdrawn from a shared 

vial (eg, mixed vespids or dust mite mix). This is sometimes 

referred to as off the board, but it is distinct from 

the method of off the board into one syringe in that the 

syringe enters only one allergen extract vial. 

INTRODUCTION 

Immunity has been defined as protection against certain 

diseases. The initial immunotherapeutic interventions, 

which included the use of preventive vaccines and xenogenic 

antisera by Jenner, Pasteur, Koch, and von 

Behring, were effective for disease prevention. These 

initial efforts in immune modulation served as a model for 

later developments in the field of allergen immunotherapy. 

From its humble empiric emergence in 1900, when 

ragweed injections were proposed as therapy for autumnal 

hay fever, allergen immunotherapy has progressed in both 

theory and practice from the passive immunologic approach 

to the active immunologic procedures pioneered 

by Noon 19 and Freeman. 20,21 Advances in allergen immunotherapy 

have depended on the improved understanding 

of IgE-mediated immunologic mechanisms, the characterization 

of specific antigens and allergens, and the standardization 

of allergen extracts. Proof of the efficacy of 

allergen immunotherapy has accumulated rapidly during 

the past 10 years. Numerous well-designed controlled 

studies have demonstrated that allergen immunotherapy 

is efficacious in the treatment of allergic rhinitis, allergic 

asthma, and stinging insect hypersensitivity. Some studies 

have suggested that allergen immunotherapy might prevent 

the development of asthma in individuals with allergic 

rhinitis. 6-9 

Effective subcutaneous allergen immunotherapy appears 

to correlate with administration of an optimal 

maintenance dose in the range of 5 to 20 mg of major 

allergen for inhalant allergens, 22-26 and it should be differentiated 

from unproved methods, such as neutralizationprovocation 

therapy and low-dose subcutaneous regimens 

based on the Rinkel technique, which have been found 

to ineffective in a double-blind placebo-controlled 

study. 27,28 

SUMMARY STATEMENTS 

Mechanisms of immunotherapy 

Summary Statement 1: Immunologic changes during 

immunotherapy are complex. D 

Summary Statement 2: Successful immunotherapy is 

associated with a change toward a T H 1 CD4 1 cytokine 

profile. A 

Summary Statement 3: Allergen immunotherapy is also 

associated with immunologic tolerance, defined as a 

relative decrease in allergen-specific responsiveness and 

by the generation of CD4 1 CD25 1 regulatory T lymphocytes. 

A 

Summary Statement 4: Efficacy from immunotherapy 

is not dependent on reduction in specific IgE levels. A 

Summary Statement 5: Increases in allergen-specific 

IgG antibody titers are not predictive of the duration and 

degree of efficacy of immunotherapy. However, alterations 

in the allergen-specific IgG specificity with immunotherapy 

might play a role in determining clinical 

efficacy. A

S34 Cox et al 



Allergen extracts 

Summary Statement 6: When possible, standardized 

extracts should be used to prepare the allergen immunotherapy 

extract treatment sets. A 

Summary Statement 7: Nonstandardized extracts might 

vary widely in biologic activity and, regardless of a 

particular wt/vol or PNU potency, should not be considered 

equipotent. B 

Summary Statement 8: In choosing the components for 

a clinically relevant allergen immunotherapy extract, the 

physician should be familiar with local and regional 

aerobiology and indoor and outdoor allergens, paying 

special attention to potential allergens in the patient’s own 

environment. D 

Cross-reactivity of allergen extract. Summary 

Statement 9: Knowledge of allergen cross-reactivity is 

important in the selection of allergens for immunotherapy 

because limiting the number of allergens in a treatment 

vial is necessary to attain optimal therapeutic doses for the 

individual patient. B 

Efficacy of immunotherapy 

Allergic rhinitis, allergic asthma, and stinging insect 

hypersensitivity. Summary Statement 10: Immunotherapy 

is effective for treatment of allergic rhinitis, allergic conjunctivitis, 

allergic asthma, and stinging insect hypersensitivity. 

Therefore immunotherapy merits consideration in 

patients with these disorders as a possible treatment option. A 

Food allergy, urticaria, and atopic dermatitis. 

Summary Statement 11: Clinical studies do not support 

the use of allergen immunotherapy for food hypersensitivity 

or chronic urticaria, angioedema, or both at this time. 

Therefore allergen immunotherapy for patients with food 

hypersensitivity or chronic urticaria, angioedema, or both 

is not recommended. D 

Summary Statement 11b: There are limited data indicating 

that immunotherapy might be effective for atopic 

dermatitis when this condition is associated with aeroallergen 

sensitivity. C 

Summary Statement 11c: The potential for benefit in 

symptoms related to oral allergy syndrome with inhalant 

immunotherapy directed at the cross-reacting pollens has 

been observed in some studies but not in others. For this 

reason, more investigation is required to substantiate that a 

benefit in oral allergy symptoms will occur with allergen 

immunotherapy. C 

Measures of efficacy. Summary Statement 12: Clinical 

parameters, such as symptoms and medication use, might 

be useful measures of the efficacy of immunotherapy in a 

clinical setting; however, repetitive skin testing of patients 

receiving immunotherapy is not recommended. A 

Safety of immunotherapy 

Reaction rates. Summary Statement 13: Published 

studies indicate that individual local reactions do not 

appear to be predictive of subsequent systemic reactions. 

However, some patients with greater frequency of large 

local reactions might be at an increased risk for future 

systemic reactions. C 

Summary Statement 14: Although there is a low risk of 

severe systemic reactions with appropriately administered 

allergen immunotherapy, life-threatening and fatal reactions 

do occur. C 

Summary Statement 15: An assessment of the patient’s 

current health status should be made before administration 

of the allergy immunotherapy injection to determine 

whether there were any recent health changes that might 

require modifying or withholding that patient’s immunotherapy 

treatment. Risk factors for severe immunotherapy 

reactions include symptomatic asthma and injections 

administered during periods of symptom exacerbation. 

Before the administration of the allergy injection, the 

patient should be evaluated for the presence of asthma or 

allergy symptom exacerbation. One might also consider 

an objective measure of airway function (eg, peak flow) 

for the asthmatic patient before allergy injections. B 

Timing of anaphylactic reactions to immunotherapy 

injections. Summary Statement 16: Because most systemic 

reactions that result from allergen immunotherapy occur 

within 30 minutes after an injection, patients should remain in 

the physician’s office at least 30 minutes after an injection. C 

b-Adrenergic blocking agents. Summary Statement 

17: b-Adrenergic blocking agents might make allergen 

immunotherapy–related systemic reactions more difficult 

to treat and delay the recovery. Therefore a cautious 

attitude should be adopted toward the concomitant use of 

b-blocker agents and inhalant allergen immunotherapy. 

However, immunotherapy is indicated in patients with 

life-threatening stinging insect hypersensitivity who also 

require b-blocker medications because the risk of the 

stinging insect hypersensitivity is greater than the risk of 

an immunotherapy-related systemic reaction. C 

Contraindications. Summary Statement 18: Medical 

conditions that reduce the patient’s ability to survive the 

systemic allergic reaction or the resultant treatment are 

relative contraindications for allergen immunotherapy. 

Examples include severe asthma uncontrolled by pharmacotherapy 

and significant cardiovascular disease. C 

Reducing the risk of anaphylaxis to immunotherapy 

injections. Summary Statement 19: Allergen immunotherapy 

should be administered in a setting where procedures 

that can reduce the risk of anaphylaxis are in place 

and where the prompt recognition and treatment of 

anaphylaxis is ensured. C 

Patient selection 

Clinical indications. Summary Statement 20: Allergen 

immunotherapy should be considered for patients who have 

demonstrable evidence of specific IgE antibodies to clinically 

relevant allergens. The decision to begin allergen 

immunotherapy depends on the degree to which symptoms 

can be reduced by avoidance and medication, the amount 

and type of medication required to control symptoms, and 

the adverse effects of medications. A 

Special precautions in patients with asthma. Summary 

Statement 21: Allergen immunotherapy in asthmatic 

patients should not be initiated unless the patient’s asthma 

is stable with pharmacotherapy. C



Cox et al S35 

Clinical indications for VIT. Summary Statement 22: 

VIT should be strongly considered if the patient has had a 

systemic reaction to a Hymenoptera sting, especially if 

such a reaction was associated with respiratory symptoms, 

cardiovascular symptoms, or both and if the patient has 

demonstrable evidence of specific IgE antibodies. A 

Summary Statement 23: Patients selected for immunotherapy 

should be cooperative and compliant. D 

Allergen selection and handling 

Clinical evaluation. Summary Statement 24: The selection 

of the components of an allergen immunotherapy 

extract that are most likely to be effective should be based 

on a careful history of relevant symptoms with knowledge 

of possible environmental exposures and correlation with 

positive test results for specific IgE antibodies. A 

Clinical correlation. Summary Statement 25: The 

allergen immunotherapy extract should contain only clinically 

relevant allergens. A 

Skin tests and in vitro IgE antibody tests. Summary 

Statement 26: Skin testing has been the primary diagnostic 

tool in clinical studies of allergen immunotherapy. 

Therefore in most patients, skin testing should be used 

to determine whether the patient has specific IgE antibodies. 

Appropriately interpreted in vitro tests for specific 

IgE antibodies can also be used. A 

Specific allergens. Summary Statement 27: Immunotherapy 

is effective for pollen, mold, animal allergens, 

cockroach, dust mite, and Hymenoptera hypersensitivity. 

Therefore immunotherapy should be considered as part of 

the management program in patients who have symptoms 

related to exposure to these allergens, supported by the 

presence of specific IgE antibodies. A 

Principles of mixing. Summary Statement 28: 

Consideration of the following principles is necessary 

when mixing allergen extract: (1) cross-reactivity of 

allergens, (2) optimization of the dose of each constituent, 

and (3) enzymatic degradation of allergens. B 

Mixing cross-reactive extracts. Summary Statement 

29: The selection of allergens for immunotherapy should 

be based (in part) on the cross-reactivity of clinically 

relevant allergens. Many botanically related pollens contain 

allergens that are cross-reactive. When pollens are 

substantially cross-reactive, selection of a single pollen 

within the cross-reactive genus or subfamily might suffice. 

When pollen allergens are not substantially cross-reactive, 

testing for and treatment with multiple locally prevalent 

pollens might be necessary. B 

Dose selection. Summary Statement 30: The efficacy of 

immunotherapy depends on achieving an optimal therapeutic 

dose of each of the constituents in the allergen 

immunotherapy extract. A 

Proteolytic enzymes and mixing. Summary Statement 

31: Separation of extracts with high proteolytic enzyme 

activities, such as mold/fungi and cockroach, from other 

extracts, such as pollens, is recommended. B 

Summary Statement 32: Allergen immunotherapy 

extract preparation should be performed by individuals 

experienced and trained in handling allergenic products. D 

Allergen immunotherapy extract handling 

STORAGE 

Summary Statement 33a: Allergen immunotherapy 

extracts should be stored at 48C to reduce the rate of 

potency loss. B 

Summary statement 33b: Extract manufacturers conduct 

stability studies with standardized extracts that 

expose them to various shipping conditions. It is the 

responsibility of each supplier or manufacturer to ship 

extracts under validated conditions that are shown not to 

adversely affect the product’s potency or safety. C 

STORING DILUTE EXTRACTS 

Summary Statement 34a: More dilute concentrations of 

allergen immunotherapy extracts (diluted greater than 

1:10 vol/vol) are more sensitive to the effects of temperature 

and lose potency more rapidly than more concentrated 

allergen immunotherapy extracts. The expiration 

date for more dilute concentrations should reflect this 

shorter shelf life. B 

Summary Statement 34b: In determining the allergen 

immunotherapy extract expiration date, consideration 

must be given to the fact that the rate of potency loss 

over time is influenced by a number of factors separately 

and collectively, including (1) storage temperature, (2) 

presence of stabilizers and bactericidal agents, (3) concentration, 

(4) presence of proteolytic enzymes, and (5) 

volume of the storage vial. B 

Immunotherapy schedules and doses 

Summary Statement 35: A customized individual 

allergen immunotherapy extract should be prepared from 

a manufacturer’s extract or extracts in accordance to the 

patient’s clinical history and allergy test results and might 

be based on single or multiple allergens. D 

Maintenance concentrate. Summary Statement 36: 

The highest-concentration allergy immunotherapy vial 

(eg, 1:1 vol/vol vial) that is used for the projected effective 

dose is called the maintenance concentrate vial. The 

maintenance dose is the dose that provides therapeutic 

efficacy without significant adverse local or systemic 

reactions and might not always reach the initially calculated 

projected effective dose. This reinforces that allergy 

immunotherapy must be individualized. D 

Recommended doses. Summary Statement 37: The 

maintenance concentrate should be formulated to deliver 

a dose considered to be therapeutically effective for each of 

its constituent components. The projected effective dose is 

referred to as the maintenance goal. Some individuals 

unable to tolerate the projected effective dose will experience 

clinical benefits at a lower dose. The effective 

therapeutic dose is referred to as the maintenance dose. A 

Effect of dilution on dose. Summary Statement 38: 

Dilution limits the number of antigens that can be added to 

a maintenance concentrate if a therapeutic dose is to be 

delivered. A 

Dilutions of the maintenance concentrate. Summary 

Statement 39: Serial dilutions of the maintenance concentrate 

should be made in preparation for the build-up phase 

of immunotherapy. D

S36 Cox et al 



Labeling dilutions. Summary Statement 40: A consistent 

uniform labeling system for dilutions from the 

maintenance concentrate might reduce errors in administration 

and therefore is recommended. D 

Individualized treatment vials. Summary Statement 41: 

Administration of an incorrect injection is a potential risk 

of allergen immunotherapy. An incorrect injection is an 

injection given to the wrong patient or a correct patient 

receiving an injection of an incorrect dose. 

A customized individual maintenance concentrate of 

the allergen immunotherapy extract and serial dilutions, 

whether a single extract or a mixture of extracts, prepared 

and labeled with the patient’s name and birth date might 

reduce the risk of incorrect (ie, wrong patient) injection. 

The mixing of antigens in a syringe is not recommended 

because of the potential for cross-contamination of 

extracts. C 

Starting doses. Summary Statement 42: The starting 

dose for build-up is usually a 1000- or 10,000-fold dilution 

of the maintenance concentrate, although a lower starting 

dose might be advisable for highly sensitive patients. D 

Summary Statement 43: The frequency of allergen 

immunotherapy administration during the build-up phase 

is usually 1 to 2 injections per week. D 

Dose adjustments for systemic reactions. Summary 

Statement 44: The dose of allergen immunotherapy extract 

should be appropriately reduced after a systemic reaction 

if immunotherapy is continued. D 

Reductions during periods of exacerbation of symptoms. 

Summary Statement 45: Immunotherapy given 

during periods when the patient is exposed to increased 

levels of allergen to which they are sensitive might be 

associated with an increased risk of a systemic reaction. 

Consider not increasing or even reducing the immunotherapy 

dose in highly sensitive patients during the time 

period when they are exposed to increased levels of 

allergen, especially if they are experiencing an exacerbation 

of their symptoms. C 

Dose adjustments for late injections. Summary 

Statement 46: It is customary to reduce the dose of 

allergen immunotherapy extract when the interval between 

injections is prolonged. D 

Cluster schedules. Summary Statement 47: With cluster 

immunotherapy, 2 or more injections are administered 

per visit to achieve a maintenance dose more rapidly than 

with conventional schedules. C 

Rush schedules. Summary Statement 48: Rush schedules 

can achieve a maintenance dose more quickly than 

weekly schedules. A 

Systemic reactions and rush schedules. Summary 

Statement 49: Rush schedules are associated with an 

increased risk of systemic reactions. However, rush protocols 

for administration of Hymenoptera VIT have not 

been associated with a similarly high incidence of systemic 

reactions. A 

Premedication and weekly immunotherapy. Summary 

Statement 50: Premedication might reduce the frequency 

of systemic reactions caused by conventional immunotherapy. 

A 

Premedication with cluster and rush immunotherapy. 

Summary Statement 51: Premedication should be given 

before cluster and rush immunotherapy with aeroallergens 

to reduce the rate of systemic reactions. A 

Maintenance schedules. Summary Statement 52: Once 

a patient reaches a maintenance dose, the interval between 

injections often can be progressively increased as tolerated 

up to an interval of up to 4 weeks for inhalant allergens and 

up to 8 weeks for venom. Some individuals might tolerate 

longer intervals between maintenance dose injections. A 

Continuing care 

TIME COURSE OF IMPROVEMENT 

Summary Statement 53: Clinical improvement can be 

demonstrated very shortly after the patient reaches a 

maintenance dose. A 

FOLLOW-UP VISITS 

Summary Statement 54: Patients should be evaluated at 

least every 6 to 12 months while they receive immunotherapy. 

D 

DURATION OF TREATMENT 

Summary Statement 55a: At present, there are no 

specific tests or clinical markers that will distinguish 

between patients who will relapse and those who will 

remain in long-term clinical remission after discontinuing 

effective inhalant allergen immunotherapy, and the duration 

of treatment should be determined by the physician 

and patient after considering the benefits and risks associated 

with discontinuing or continuing immunotherapy. D 

Summary Statement 55b: Although there are no specific 

tests to distinguish which patients will relapse after 

discontinuing VIT, there are clinical features that are 

associated with a higher chance of relapse, notably a history 

of very severe reaction to a sting, a systemic reaction during 

VIT (to a sting or a venom injection), honeybee venom 

allergy, and treatment duration of less than 5 years. C 

Summary Statement 55c: The patient’s response to 

immunotherapy should be evaluated on a regular basis. A 

decision about continuation of effective immunotherapy 

should generally be made after the initial period of up to 

5 years of treatment. D 

Summary Statement 55d: The severity of disease, 

benefits sustained from treatment, and convenience of 

treatment are all factors that should be considered in 

determining whether to continue or stop immunotherapy 

for any individual patient. D 

Summary Statement 55e: Some patients might experience 

sustained clinical remission of their allergic disease after 

discontinuing immunotherapy, but others might relapse. B 

DOCUMENTATION AND RECORD KEEPING 

Summary Statement 56: The allergen immunotherapy 

extract contents,informed consent for immunotherapy, and 

administration of extracts should be carefully documented. D 

INJECTION TECHNIQUES 

Summary Statement 57: Allergen immunotherapy extract 

injections should be administered with a 1-mL syringe 

with a 26- to 27-gauge half-inch nonremovable needle. D 

Summary Statement 58: The injection should be administered 

subcutaneously in the posterior portion of the 

middle third of the upper arm. D



Cox et al S37 

Location of allergen immunotherapy 

administration 

Physician’s office. Summary Statement 59: The preferred 

location for administration of allergen immunotherapy 

is in the office of the physician who prepared the 

patient’s allergen immunotherapy extract. D 

Summary Statement 60: Patients at high risk of systemic 

reactions, where possible, should receive immunotherapy 

in the office of the physician who prepared the patient’s 

allergen immunotherapy extract. D 

Other locations. Summary Statement 61: Regardless of 

the location, allergen immunotherapy should be administered 

under the supervision of an appropriately trained 

physician and personnel. D 

Home administration. Summary Statement 62: In rare 

and exceptional cases, when allergen immunotherapy 

cannot be administered in a medical facility and withholding 

this therapy would result in a serious detriment to the 

patients’ health (eg, VIT for a patient living in a remote 

area), very careful consideration of potential benefits and 

risks of at-home administration of allergen immunotherapy 

should be made on an individual patient basis. If this 

approach is used, informed consent should be obtained 

from the patient, and the person administering the injection 

to the patient must be educated about how to administer 

immunotherapy and recognize and treat anaphylaxis. D 

Summary Statement 63: If a patient receiving immunotherapy 

transfers from one physician to another, a decision 

must be made by the physician to whom the patient has 

transferred as to whether to continue immunotherapy. If 

immunotherapy is continued, a decision must then be 

made about whether to continue an unchanged immunotherapy 

program initiated by the previous physician or to 

prepare a new immunotherapy program. D 

Summary Statement 64: If a patient transfers from one 

physician to another and continues on an immunotherapy 

program without changes to either the schedule or allergen 

immunotherapy extract, the risk of a systemic reaction is 

not substantially increased. D 

Summary Statement 65: A full, clear, and detailed 

documentation of the patient’s schedule must accompany 

a patient when he or she transfers responsibility for his or 

her immunotherapy program from one physician to 

another. In addition, a record of previous response to 

and compliance with this program should be communicated 

to the patient’s new physician. D 

Summary Statement 66: An allergen immunotherapy 

extract must be considered different from a clinical standpoint 

if there is any change in the constituents of the 

extract. These include changes in the lot, manufacturer, 

allergen extract type (eg, aqueous, glycerinated, standardized, 

and nonstandardized), and/or components or relative 

amounts in the mixture. D 

Summary Statement 67: There is an increased risk of a 

systemic reaction in a patient who transfers from one 

physician to another if the immunotherapy extract is 

changed because of the significant variability in content 

and potency of allergen extracts. The risk of a systemic 

reaction with a different extract might be greater with 

nonstandardized extracts and with extracts that contain 

mixtures of allergens. D 

Summary Statement 68: Immunotherapy with a different 

extract should be conducted cautiously. If there is 

inadequate information to support continuing with the 

previous immunotherapy program, re-evaluation might be 

necessary, and a new schedule and allergen immunotherapy 

extract might need to be prepared. D 

Special considerations in immunotherapy 

Allergen immunotherapy in children. Summary 

Statement 69: Immunotherapy for children is effective 

and often well tolerated. Therefore immunotherapy should 

be considered (along with pharmacotherapy and allergen 

avoidance) in the management of children with allergic 

rhinitis, allergic asthma, and stinging insect hypersensitivity. 

It might prevent the new onset of allergen sensitivities 

or progression to asthma. A 

Summary Statement 70: Children under 5 years of age 

can have difficulty cooperating with an immunotherapy 

program. Therefore the physician who evaluates the 

patient must consider the benefits and risks of immunotherapy 

and individualize treatment in patients under the 

age of 5 years. A 

Pregnancy. Summary Statement 71: Allergen immunotherapy 

can be continued but is usually not initiated in 

the pregnant patient. C 

Immunotherapy in the elderly patient. Summary 

Statement 72: Comorbid medical conditions and certain 

medication use might increase the risk from immunotherapy 

in elderly patients. Therefore special consideration 

must be given to the benefits and risks of immunotherapy 

in this patient population. D 

Immunotherapy in patients with immunodeficiency 

and autoimmune disorders. Summary Statement 73: 

Immunotherapy can be considered in patients with immunodeficiency 

and autoimmune disorders. D 

Alternative routes of immunotherapy 

Sublingual and oral immunotherapy. Summary 

Statement 74: Optimal high-dose sublingual swallow 

and oral immunotherapies are under clinical investigation 

in the United States. Studies of oral immunotherapy have 

demonstrated conflicting results. High-dose sublingual 

immunotherapy has been found to be effective in many 

studies of adults and children with allergic rhinitis and 

asthma, but a consistent relationship among allergen dose, 

treatment duration, and clinical efficacy has not been 

established. However, there is no US Food and Drug 

Administration (FDA)–approved formulation for sublingual 

or oral immunotherapy in the United States. 

Therefore sublingual and oral immunotherapy should be 

considered investigational at this time. A 

Summary Statement 75: Intranasal immunotherapy is 

undergoing evaluation in children and adults with allergic 

rhinitis, but there is no FDA-approved formulation for this 

modality in the United States. B

S38 Cox et al 



Immunotherapy techniques that are not recommended. 

Summary Statement 76: Low-dose immunotherapy, enzyme-potentiated 

immunotherapy, and immunotherapy 

(parenteral or sublingual) based on provocation-neutralization 

testing are not recommended. D 

MECHANISMS OF IMMUNOTHERAPY 

Summary Statement 1: Immunologic changes during 

immunotherapy are complex. D 

Summary Statement 2: Successful immunotherapy is 

associated with a change toward a T H 1 CD4 1 cytokine 

profile. A 

Summary Statement 3: Allergen immunotherapy is also 

associated with immunologic tolerance, which is defined 

as a relative decrease in allergen-specific responsiveness, 

and by the generation of CD4 1 CD25 1 regulatory T lymphocytes. 

A 

Summary Statement 4: Efficacy from immunotherapy 

is not dependent on reduction in specific IgE levels. A 

Summary Statement 5: Increases in allergen-specific IgG 

antibody titers are not predictive of the duration and degree 

of efficacy of immunotherapy. However, alterations in the 

allergen-specific IgG specificity with immunotherapy 

might play a role in determining clinical efficacy. A 

The immunologic changes associated with immunotherapy 

are complex, and the exact mechanism or mechanisms 

responsible for its’ clinical efficacy are continually 

being elucidated. Data support the concept that successful 

immunotherapy is associated with a change to a T H 1CD4 1 

cytokine profile. 29-34 Data indicate that increased production 

of IL-12, a strong inducer of T H 1 responses, contributes 

to this shift. 33 Clinically successful immunotherapy 

has been reported to be associated with immunologic tolerance, 

which is defined as a relative decrease in antigenspecific 

responsiveness, immune deviation, or anergy. For 

example, lymphoproliferative responses to allergen are 

reduced with immunotherapy. 32 Successful immunotherapy 

results in generation of a population of T regulatory 

cells, which are CD4 1 CD25 1 T lymphocytes producing 

IL-10, TGF-b, or both. 35-39 Regulatory T-cell release has 

been described in allergen immunotherapy with Hymenoptera 

venom, 35 grass pollen extract, 37 and house dust 

mites. 38 IL-10 reduces B-cell antigen-specific IgE and 

increases IgG4 levels; reduces proinflammatory cytokine 

release from mast cells, eosinophils, and T cells; and 

elicits tolerance in T cells by means of selective inhibition 

of the CD28 costimulatory pathway. 36,37 

Allergen immunotherapy has been shown to block both 

the immediate and late-phase allergic response. 40 Allergen 

immunotherapy has been shown to decrease the recruitment 

of mast cells, basophils, and eosinophils in the 

skin, nose, eye, and bronchial mucosa after provocation 

or natural exposure to allergens. 41 

In patients receiving immunotherapy, initially there is an 

increase in specific IgE antibody levels, followed by a 

gradual decrease to a level that is still higher than that present 

before treatment. Clinical improvement in many patients 

develops before decreases in their IgE antibody levels occur 

or in other patients whose IgE antibody levels never 

decrease, thereby demonstrating that efficacy is not dependent 

on reductions in specific IgE levels. 42,43 Immunotherapy 

does diminish the seasonal increase in specific IgE 

levels. 44 Despite the persistence of significant levels of specific 

IgE antibody levels, immunotherapy usually causes a 

reduction in release of mediators, such as histamine, from basophils 

and mast cells, a phenomenon most relevant to the 

immediate phase of allergic reactions. Suppression of latephase 

inflammatory responses in the skin and respiratory 

tract generally also occur with allergen immunotherapy. 45-48 

An increase in serum allergen-specific IgA and IgG 

levels, particularly of the IgG4 isotype, has also been 

associated with immunotherapy. The properties of allergen-specific 

IgA have yet to be determined, and there is a 

weak correlation between the increase in allergen-specific 

IgG levels and immunotherapy’s clinical efficacy. 30,49,50 

Immunotherapy might alter the affinity and specificity 

of allergen-specific IgG. 51,52 During the initial phase of ultrarush 

VIT, a change in IgG specificity (ie, a change in the 

set of epitopes dominantly recognized by IgG on wasp 

venom antigens) occurred concomitantly with early clinical 

tolerance and was seen within 12 hours of ultrarush 

VIT (P



Cox et al S39 

the biologic activity is more consistent, and therefore the 

risk of an adverse reaction caused by extract potency 

variability should be diminished. 

United States–licensed extracts can be obtained in aqueous, 

glycerinated, lyophilized, and acetone-precipitated 

and alum-precipitated formulations. Some commonly 

used allergens are standardized. These include extracts 

for cat hair, cat pelt, Dermatophagoides pteronyssinus, 

Dermatophagoides farinae, short ragweed, Bermuda grass, 

Kentucky bluegrass, perennial rye grass, orchard grass, 

timothy grass, meadow fescue, red top, sweet vernal 

grass, and Hymenoptera venoms (yellow jacket, honeybee, 

wasp, yellow hornet, and white-faced hornet). 

However, most allergen extracts are not yet standardized. 

Allergen standardization comprises 2 components: (1) 

selection of a reference extract and (2) selection of an 

assay or procedure to compare the manufactured extract 

with the reference extract. Allergen standardization in 

the United States is based on assessment of the potency 

of allergen extracts by using quantitative skin tests and 

reported as BAU values. The quantitative test method is 

called the intradermal dilution for 50 mL sum of erythema 

(ID 50 EAL) system for determining BAU values. 57 The 

ID 50 EAL method entails preparing a series of 3-fold dilutions 

of a candidate reference extract and injecting 0.05 mL 

intradermally to 15 to 20 ‘‘highly sensitive’’ allergic 

subjects. The dilution that results in an erythema with the 

sum of the longest diameter and midpoint (orthogonal) 

diameter equaling 50 mm is considered the end point 

(D 50 ). The mean D 50 is calculated, and the potency of 

the extract is assigned. 

Most standardized extracts are labeled in BAU. Short 

ragweed potency units were originally based on the 

content of the major allergen Amb a 1. Ragweed potency 

is reported in FDA units and BAU. One FDA unit of Amb 

a 1 equals 1 mg of Amb a 1, and 350 units of Amb a 1/mL 

is equivalent to 100,000 BAU/mL. Cat extracts were also 

originally standardized based on the content of major 

allergen (Fel d 1), with 100,000 arbitrary units (AU) per 

milliliter containing between 10 to 19.9 FDA units of Fel d 

1 per milliliter (1 FDA unit of Fel d 1 equals 2 to 4 mg of 

Fel d 1). 55,58,59 Subsequently, ID 50 EAL testing suggested 

that 100,000 AU/mL was equal to 10,000 BAU/mL. 60 

Approximately 22% of individuals with cat allergy have 

specific IgE antibodies to cat albumin. 61 Cat pelt extracts 

have a greater amount of albumin than cat hair extracts. 60 

Dust mites were originally standardized in AU by 

means of inhibition radioimmunoassay (RIA), and subsequent 

ID 50 EAL testing indicated that the AU was bioequivalent 

to the BAU, and the original AU nomenclature was 

kept. Dust mite extracts are still labeled in AU. 

Summary Statement 7: Nonstandardized extracts can 

vary widely in biologic activity and, regardless of a 

particular wt/vol or PNU potency, should not be considered 

equipotent. B 

Nonstandardized extracts are labeled as wt/vol, which 

expresses weight in grams per volume in milliliters; that is, 

a potency of 1:100 indicates that 1 g of dry allergen (eg, 

ragweed) was added to 100 ml of a buffer for extraction. 

Nonstandardized extracts can also be labeled in PNU, 

where 1 PNU equals 0.01 g of protein nitrogen. Neither 

method confers any direct or comparative information 

about an extract’s biologic potency. Nonstandardized 

extracts can have a wide range of potencies. Extracts 

with a particular wt/vol or PNU potency can have widely 

varying biologic activities. 62-64 Therefore they should not 

be considered equipotent. 

Summary Statement 8: In choosing the components for 

a clinically relevant allergen immunotherapy extract, the 

physician should be familiar with local and regional 

aerobiology and indoor and outdoor allergens, paying 

special attention to potential allergens in the patient’s own 

environment. D 

Because North America is botanically and ecologically 

diverse, it is not possible to devise a common list of 

appropriate allergen extracts for each practice location. 

The major clinically relevant aeroallergens of North 

America are listed in Table III. Furthermore, nonrelevant 

allergens in such mixtures could act as sensitizers rather 

than as tolerogens. 65,66 The physician must therefore 

select only those aeroallergens for testing and treatment 

that are clinically relevant in a particular geographic area. 

The clinical relevance of an aeroallergen depends on 

certain key properties: (1) its intrinsic allergenicity, (2) its 

aerodynamic properties, (3) whether it is produced in large 

enough quantities to be sampled, (4) whether it is sufficiently 

buoyant to be carried long distances, and (5) 

whether the plant releasing the pollen is widely and 

abundantly prevalent in the region. The primary allergens 

used for immunotherapy are derived from plant (grasses, 

trees, and weeds), arthropod (house dust mites), fungus, 

animal (cat, dog), insect (cockroach), and Hymenoptera 

venom source materials. 

Cross-reactivity of allergen extract 

Summary Statement 9: Knowledge of allergen crossreactivity 

is important in the selection of allergens for 

immunotherapy because limiting the number of allergens 

in a treatment vial is necessary to attain optimal therapeutic 

doses for the individual patient. B 

Cumulative data, both in vitro and in vivo, concerning 

cross-reactivity offer a practical advantage in the selection 

of several categories of pollen allergens for immunotherapy. 

However, because cross-reactivity is variable for 

many grass and weed pollens, their intrinsic allergenicity, 

prevalence, and aerobiologic characteristics within a specific 

region should be considered. A summary of cross-reactivity 

patterns of the clinically relevant North American 

aeroallergens can be found in Fig 2. Because many temperate 

pasture grasses (subfamily Pooideae; eg, fescue, 

rye, timothy, blue, and orchard), which are widely distributed 

throughout the United States, share major allergens, 67 

inclusion of a representative member (eg, perennial rye, 

meadow fescue, or timothy) generally provides efficacy 

against the entire group. 68-75 Grasses in other subfamilies 

(eg, Bermuda, Bahia, and Johnson) show greater diversity 

and should be evaluated separately. 76-78 Bermuda and 

Johnson grasses are increasingly important in the South,

S40 Cox et al 



TABLE III. The major clinically relevant aeroallergens of 

North America* 

Tree pollen 

Chinese elm (Ulmus parvifolia) à; Siberian elm (Ulmus 

pumila) à; American elm (Ulmus Americana) à 

Red oak (Quercus rubra) ; White oak (Quercus alba) 

Paper birch (Betula papyrifera) 

Alder (Alnus rubra) 

Box elder (Acer negundo) ; Red maple (Acer rubra) 

Eastern cottonwood (Populus deltoides) 

Sycamore (Platanus occidentalis) 

White ash (Fraxinus americana) ; Olive (Olea europaea) à 

Black walnut (Juglans nigra) 

Mulberry (Morus rubra) 

Mountain cedar (Juniperus ashei) 

Pecan (Carya illinoensis) 

Grass pollen 

Rye (Lolium perenne)§k 

Timothy (Phleum pratense)§k 

Meadow fescue (Festuca elatior)§k 

Bermuda (Cynodon dactylon)k 

Johnson (Holcus halepensis) 

Bahia (Paspalum notatum) 

Weed pollen 

Short ragweed (Ambrosia artemisiifolia)k 

English (narrow leaf) plantain (Plantago lanceolata) 

Mugwort (Artemisia vulgaris) 

Russian thistle (Salsola kali) 

Burning bush (Kochia scoparia) 

Sheet (red) sorrel (Rumex asetosella) 

Red root pigweed (Amaranthus retroflexus) 

Indoor aeroallergens 

Cat epithelium (Felis domesticus)k 

Dog epithelium (Canis familiaris) 

Arthropods (domestic mites: Dermatophagoides farinae, 

Dermatophagoides pteronyssinus)k 

Insects (German cockroach: Blattella germanica) 

Fungi 

Alternaria alternata{ 

Cladosporium (C cladosporioides, C herbarum){ 

Penicillium (P chrysogenum, P expansum){ 

Aspergillus fumigatus{ 

Epicoccum nigrum, Drechslera or Bipolaris type 

(eg, Helminthosporium solani){ 

*Compiled and selected in collaboration with the AAAAI Immunotherapy 

Committee Allergen Subcommittee for the identification of 35 key 

allergens of North America. 

Extensive cross-reaction of species within the genus. 

àApart from regional prevalence, they are limited to local sites with 

substantial stands of these trees. 

§Extensively cross-react with one another and bluegrass, orchard, red top, 

and sweet vernal. 

kAllergens for which standardized extracts are commercially available. 

{Species that are widely distributed and clinically important. 

and Bahia has become an important allergenic grass in the 

lower southern states. Because it is uncertain whether 

palms, sedges, and cattails have the ability to trigger allergy 

symptoms, immunotherapy with these allergens is 

generally not recommended. 

Although cross-reactivity among tree pollens is not as 

pronounced as that among grass or ragweed pollens, it 

does occur. Pollen from members of the cypress family 

(Cupressaceous; eg, juniper, cedar, and cypress) strongly 

cross-react. 79-82 Therefore pollen from one member of this 

family should be adequate for skin testing and immunotherapy. 

The closely related birch family (Betulaceae; 

eg, birch, alder, hazel, hornbeam, and hop hornbeam) 

and oak (Fagaceae; eg, beech, oak, and chestnut) have 

strong cross-allergenicity. 83-85 Significant cross-reactivity 

between Betulaceae pollens and oak of the Fagaceae 

family has been demonstrated with percutaneous skin 

testing. 75 RAST inhibition studies have shown cross-inhibition 

between oaks and other Fagales species. 86 IgE 

immunoblot inhibition experiments have demonstrated 

that the Fagales species might be strongly inhibited by 

birch species. 87 The use of one of the locally prevalent 

members (eg, birch and alder) should be adequate. 88 

Ash and European olive trees are strongly cross-reactive; 

the extract that is the most prevalent in the region and best 

correlates with symptoms could be used. 89,90 Maple and 

box elder trees are found throughout the United States, 

except for the arid southwest. Although in the same genus 

as maple, Acer, box elders appear different and should 

be considered separately. Oaks and elms (eg, Chinese, 

Siberian, some American) are prevalent in eastern and 

central states but have a more limited distribution west of 

the continental divide. The distribution of other trees is 

variable enough to require botanical observation in a given 

locale. 

There is strong cross-reactivity between major allergens 

of common ragweed species (eg, short, giant, false, 

and western). However, southern and slender ragweed do 

not cross-react as well, 91,92 and there are allergenic differences 

between major and minor allergens of short and 

giant ragweed that might be clinically significant. 93 

Weeds other than ragweed, such as marsh elders, sages, 

and mugwort, have an abundant distribution, predominantly 

in the western states. These weeds and sages 

(Artemisia species) must be treated separately from the 

ragweeds. Sages are strongly cross-reactive, and a single 

member can provide adequate coverage of the group. 94 

Similarly, Chenopod-Amaranth families have wide ranges 

in the western regions but are present throughout North 

America. 95 Current information on cross-reactivity of 

these families is limited. 96-98 Skin testing suggests strong 

cross-reactivity across Chenopod and Amaranth family 

boundaries. The Amaranth family also seems to have 

strong cross-reactivity by means of RAST inhibition and 

immunodiffusion. 99 The use of a single Amaranth extract 

should be sufficient to cover this family. 100,101 Similarly, 

Atriplex species (eg, saltbushes and scales) show near 

identity, and use of a single member is adequate. Among 

other subfamily Chenopod members, Russian thistle 

appears to have the most cross-allergenicity. 

The most prevalent house dust mites, D pteronyssinus 

and D farinae, are ubiquitous except in arid or semiarid 

climates and regions of higher altitudes. D pteronyssinus 

and D farinae are members of the same family and genus. 

They have allergens with extensive cross-reacting epitopes, 

as well as unique allergenic epitopes. Generally,



Cox et al S41 

FIG 2. Patterns of allergen cross-reactivity. 

D pteronyssinus and D farinae are considered individually. 

Establishing the practical importance of various 

allergenic fungi involves many of the same problems 

encountered in treating pollen allergy. In general, the genera 

of deuteromycetes occur in all but the coldest regions. 

For clinical purposes, molds often are characterized as outdoor 

(eg, Alternaria, Cladosporium, and Drechslera 

[Helminthosporium] species) or indoor (eg, Aspergillus 

and Penicillium). 

Immunotherapy with standardized extracts of cat hair 

(Fel d 1 only) or pelt (Fel d 1 plus cat albumin) is available 

for cat allergy. Although German cockroaches are most 

likely to occur in American homes, an extract representing 

an equal mixture of German and American cockroaches 

might be appropriate for immunotherapy. 102,103 Stinging 

Hymenoptera insects occur throughout the United States; 

the fire ant is found only in Gulf Coast states, Texas, and 

some other southern and western states. Commercial 

venom extracts are available for some Hymenoptera species, 

except the fire ant, for which only whole-body extract 

is available. 

EFFICACY OF IMMUNOTHERAPY 

Allergic rhinitis, allergic asthma, and stinging 

insect hypersensitivity 

Summary Statement 10: Immunotherapy is effective for 

treatment of allergic rhinitis, allergic conjunctivitis, allergic 

asthma, and stinging insect hypersensitivity. Therefore 

immunotherapy merits consideration in patients with these 

disorders as a possible treatment option. A 

Many double-blind, placebo-controlled, randomized 

clinical trials demonstrate a beneficial effect of immunotherapy 

under a variety of conditions. 104-111 Immunotherapy 

is effective for the treatment of allergic rhinitis 107 

(including ocular symptoms 112,113 ), allergic 

asthma, 104,109,111,114,115 and stinging insect hypersensitivity 

108,116 and is effective in both adults and children. 117-124 

Its efficacy is confirmed for the treatment of inhalant 

allergy caused by pollens, 13,125-132 fungi, 133-138 animal 

allergens, 22,25,26,139-143 dust mite, 114,115,144-153 and cockroach. 

154 There have been no controlled trials of fire ant 

whole-body extract, but it does appear to be effective in

S42 Cox et al 



TABLE IV. Improvement of symptoms and reduction in 

medication and bronchial hyperresponsiveness after 


Outcome measure 

House 

dust mite 

Other 

allergens*y 

Symptomatic improvement 2.7 (1.7-4.4) 4.8 (2.3-10.1) 

Reduction in medication 4.2 (2.2-7.9) ND 

Reduction in bronchial 

hyperresponsiveness 

13.7 (3.8-50) 5.5 (2.8-10.7) 

Data are used with permission from Abramson et al. 104 

ND, Not done. 

*Odds ratio (95% CI). 

Pollen, mold, or animal dander. 

uncontrolled trials. 155-157 A variety of different types of 

extracts have been evaluated in these clinical trials, including 

aqueous and modified extracts. Outcome measures 

used to measure the efficacy of immunotherapy include 

symptom and medication scores, organ challenge, and immunologic 

changes in cell markers and cytokine profiles. 

A number of studies have also demonstrated a significant 

improvement in quality of life, as measured by using standardized 

questionnaires. 24,158-161 The magnitude of the 

effect depends on the outcome that is used (Table IV). 

For dust mite, the effect size ranges from a 2.7-fold 

improvement in symptoms to a 13.7-fold reduction in 

bronchial hyperresponsiveness. Although many studies 

demonstrate the efficacy of immunotherapy, some do not. 

A review of the studies that do not demonstrate efficacy 

failed to identify a systematic deficiency. 110 Instead, this 

review notes that many studies evaluating immunotherapy 

are only marginally powered to show efficacy, making it 

likely that some would fail to demonstrate efficacy by 

chance alone, even when it is present (a type II error). 

Meta-analyses of the efficacy of immunotherapy both 

for rhinitis 107 and asthma 104,109,111 have been performed 

to deal with the issue of power. One review of 75 trials involving 

3188 asthmatic patients found that, overall, there 

was a significant reduction in asthma symptoms and medication 

and improvement in bronchial hyperreactivity after 

immunotherapy, and it would have been necessary to treat 

4 patients (95% CI, 3-5) with immunotherapy to avoid 

1 deterioration in asthma symptoms and 5 (95% CI, 4-6) 

patients to avoid 1 requiring increased medication. 111 

These meta-analyses strongly support the efficacy of allergen 

immunotherapy. Allergen immunotherapy for allergic 

rhinitis might have persistent benefits after immunotherapy 

is discontinued 13,162,163 and might reduce the risk 

for the future development of asthma in patients with allergic 

rhinitis. 6,9,122,162-165 Allergen immunotherapy might 

also prevent the development of new allergen sensitivities 

in monosensitized patients. 120,166,167 

Food allergy, urticaria, and atopic dermatitis 

Summary Statement 11: Clinical studies do not support 

the use of allergen immunotherapy for food hypersensitivity 

or chronic urticaria, angioedema, or both at this time. 

Therefore allergen immunotherapy for patients with food 

hypersensitivity or chronic urticaria, angioedema, or both 

is not recommended. D 

Summary Statement 11b: There are limited data indicating 

that immunotherapy can be effective for atopic 

dermatitis when this condition is associated with aeroallergen 

sensitivity. C 

Summary Statement 11c: The potential for benefit in 

symptoms related to oral allergy syndrome with inhalant 

immunotherapy directed at the cross-reacting pollens has 

been observed in some studies but not in others. For this 

reason, more investigation is required to substantiate that a 

benefit in oral allergy symptoms will occur with allergen 

immunotherapy. C 

The use of allergen immunotherapy for individuals with 

the potential for IgE-mediated (anaphylaxis) reactions to 

foods should be regarded as investigational at this 

time. 168-171 There have been 2 investigational studies 

demonstrating efficacy in food hypersensitivity, the first 

using aqueous subcutaneous injections to peanut and the 

second using sublingual immunotherapy to hazelnut. 171-173 

In the subcutaneous peanut immunotherapy study there 

was increased tolerance to oral peanut challenge in all of 

the treated patients, but there were repeated systemic 

reactions in most patients, even during maintenance 

injections, and the authors concluded a modified peanut 

extract is needed for clinical application of this method of 

treatment. 171 There is currently no FDA-approved formulation 

for sublingual immunotherapy, and this route of 

allergen immunotherapy is currently considered investigational 

at this time (see Summary Statement 73). 

At the present time, there is not enough evidence to 

support food immunotherapy. 

There is no evidence supporting the efficacy of immunotherapy 

for individuals with chronic urticaria, angioedema, 

or both. 

There are limited data indicating that immunotherapy 

might be effective for atopic dermatitis when this condition 

is associated with aeroallergen sensitivity. 174-176 One 

randomized, double-blind study of adults with atopic dermatitis 

demonstrated a dose-response effect of dust mite 

immunotherapy on atopic dermatitis severity, as measured 

by using the SCORAD score (P 5 .0379) and topical 

corticosteroid use (P 5 .0007). 174 

The potential for benefit in symptoms related to oral 

allergy syndrome with the cross-reacting inhalant immunotherapy, 

which includes cross-reacting pollens, has been 

observed in some studies but not in others. One controlled 

prospective study demonstrated the potential to decrease 

oral allergy syndrome symptoms with subcutaneous 

immunotherapy directed against birch tree, 177 whereas 

another double-blind, double-dummy, placebo-controlled 

study comparing the effect of subcutaneous immunotherapy 

with sublingual immunotherapy demonstrated no significant 

effect on the severity of apple allergy symptoms 

with either method compared with the placebo group, despite 

a significant effect on seasonal hay fever symptoms, 

medication use, and decrease in IgE reactivity. 178 More investigation 

is required to substantiate the contention that 

benefits in oral symptoms will occur with immunotherapy.



Cox et al S43 

Measures of efficacy 

Summary Statement 12: Clinical parameters, such as 

symptoms and medication use, might be useful measures 

of the efficacy of immunotherapy in a clinical setting; 

however, repetitive skin testing of patients receiving 

immunotherapy is not recommended. A 

Whether immunotherapy is effective can be determined 

by measuring objective and subjective parameters. 

Objective measures, such as increase in allergen-specific 

IgG levels and decreased skin test reactivity, as measured 

by skin test titration, are changes generally associated with 

effective immunotherapy but, at present, are not practical 

for routine clinical use. 147 Nonquantitative skin testing or 

in vitro IgE antibody testing of patients during immunotherapy 

is not recommended because it has not been 

demonstrated that skin test reactivity (to a single dilution) 

or specific IgE antibody levels correlate closely with a 

patient’s clinical response. For that reason, most allergists 

rely on subjective assessments, such as a patient’s report 

that he or she is feeling better during a season previously 

causing symptoms. Although subjective assessments are 

the most common means by which physicians judge the 

result of immunotherapy, they are not very reliable given 

the strong placebo-like effect (Hawthorne effect) associated 

with any treatment. A more objective means for determining 

efficacy as validated in controlled clinical studies 

is the use of clinical symptom scores and the amount of 

medication required to control symptoms and maintain 

peak flow rates or pulmonary function tests within acceptable 

limits. Successful immunotherapy often results in 

a reduction in medication. Sequential measurement of 

disease-specific quality of life also might be helpful. 

SAFETY OF IMMUNOTHERAPY 

Reaction rates 

Summary Statement 13: Published studies indicate that 

individual local reactions do not appear to be predictive of 

subsequent systemic reactions. However, some patients 

with greater frequency of large local reactions might be at 

an increased risk for future systemic reactions. C 

Large local reactions associated with allergen immunotherapy 

are fairly common, with a frequency ranging from 

26% to 86% of injections. 179 Two retrospective studies 

compared the effect of not adjusting immunotherapy dose 

based on large local reactions on the immunotherapy systemic 

reaction rate with dose-adjustment protocols. 179,180 

There was a total of 12,464 injections administered with 

a dose-adjustment protocol in the 2 studies compared 

with 9542 injections administered with a no-dose-adjustment 

protocol. Both studies found no statistical difference 

between the dose-adjustment and no-dose-adjustment protocols 

in terms of immunotherapy-induced systemic reactions. 

Both authors concluded that local reactions were 

poor predictors for subsequent systemic reactions, and 

dose reductions for most local reactions are unnecessary. 

However, a retrospective review of a large, multicenter, 

allergy practice group’s database comparing the frequency 

of large local reactions, defined as 25 mm or larger, in 

patients who had experienced systemic reactions with age-, 

sex-, and allergen sensitivity–matched control subjects 

who had not had allergen immunotherapy systemic reactions 

found the rate of large local reactions was 4 times 

higher among the 258 patients who had subsequently 

experienced a systemic reaction compared with those who 

had never experienced a systemic reaction. 181 Patients who 

had experienced systemic reactions had 1573 large local 

reactions in 4460 visits (ie, 35.2% of visits) and 8081 injections 

(ie, 19.5% of injections) compared with the matched 

control group without systemic reactions who had 1388 

large local reactions in 15,540 visits (8.9% per visit) and 

26,259 injections (5.3% per injection; difference between 

groups, P

S44 Cox et al 



Five patients experienced more than 3 systemic reactions 

(total of 36 reactions), and the authors noted that 40% of 

the systemic reactions (21 reactions) would have been 

avoided if patients experiencing the third systemic reaction 

had been withdrawn. 

In the previously mentioned AAAAI physician members’ 

survey of fatal reactions and NFRs, there were 41 

fatalities identified in the initial brief survey (20 directly 

reported and 17 with completed detailed questionnaire) 

from immunotherapy injections. 188 The estimated fatality 

rate was 1 per 2.5 million injections, (average of 3.4 deaths 

per year), which is similar to 2 previous surveys of AAAAI 

physician members. 189,190 Therefore although severe systemic 

reactions to allergen immunotherapy are not common, 

serious systemic reactions (some fatal) can occur. 

Summary Statement 15: An assessment of the patient’s 

current health status should be made before administration 

of the allergy immunotherapy injection to determine 

whether there were any recent health changes that might 

require modifying or withholding that patient’s immunotherapy 

treatment. Risk factors for severe immunotherapy 

reactions include symptomatic asthma and injections 

administered during periods of symptom exacerbation. 

Before the administration of the allergy injection, the 

patient should be evaluated for the presence of asthma or 

allergy symptom exacerbation. One might also consider 

an objective measure of airway function (eg, peak flow) 

for the asthmatic patient before allergy injections. B 

In the AAAAI survey of physician members on immunotherapy 

and skin testing, fatal reactions, and NFRs 

during the period of 1990-2001, 15 of the 17 fatalities had 

asthma, and in 9 patients asthma was considered the 

susceptibility factor that contributed to the fatal 

outcome. 188 

The most severe NFR, respiratory failure, occurred 

exclusively in asthmatic patients, and 4 (57%) of 7 

asthmatic patients had a baseline FEV 1 of less than 70% 

of predicted value. 184 

Administration during the peak pollen season (3 patients) 

and previous systemic reactions (4 patients) were 

cited as other contributing factors. Five fatalities occurred 

in outside medical facilities, and 2 fatalities occurred at 

home. No patients were receiving b-blockers; 1 patient 

was taking an angiotensin-converting enzyme inhibitor. In 

the most comprehensive evaluation of fatalities associated 

with allergen immunotherapy, from 1945-1987, there 

were 40 fatalities during allergen immunotherapy and 6 

fatalities during skin testing. 189 Ten fatalities occurred 

during seasonal exacerbation of the patient’s disease, 4 

in patients who had been symptomatic at the time of the 

injection, 2 of whom had been receiving b-adrenergic 

blockers. Of the 24 fatalities associated with immunotherapy, 

4 had experienced previous reactions, 11 manifested 

a high degree of sensitivity, and 4 had been injected with 

newly prepared extracts. In a prospective study of 125 

asthmatic patients with mite allergy that used a 3-day 

rush immunotherapy protocol, FEV 1 was identified as a 

predictor for systemic reactions, with 73.3% of patients 

with an FEV 1 of less than 80% of predicted value 

experiencing an asthma reaction during rush immunotherapy, 

whereas only 12.6% of patients with an FEV 1 of 

greater than 80% of predicted value had asthmatic reactions 

(P



Cox et al S45 

minutes after the injection, but treatment was initiated 20 

minutes after the onset of symptoms. The timing of the 

reaction was unknown in 4 of the fatal reactions. 

In an earlier AAAAI survey, 17 fatalities associated 

with allergen immunotherapy were reported for the years 

1985-1989. 190 Onset of anaphylaxis occurred within 20 

minutes in 11 patients, within 20 to 30 minutes in 1 patient, 

and after more than 30 minutes in 1 patient. Four patients 

did not wait after the injection, and the onset of their systemic 

reaction symptoms is not known. 

In a prospective study a total of 20,588 extract injections 

were administered to 628 patients, resulting in 52 

systemic reactions in 42 patients, with 38% of the systemic 

reactions occurring from 30 minutes to 6 hours after the 

allergy vaccine administration. 192 In another prospective 

study 8% of systemic reactions occurred more than 2 

hours after injection. 193 

Most of the extract manufacturers’ package inserts 

recommend a wait period of either 20 to 30 minutes or 30 

minutes after administration of the immunotherapy injection. 

The European Academy of Allergy and Clinical 

Immunology’s recommended observation period after an 

allergen immunotherapy injection is 30 minutes. 194 

Because most reactions that resulted from allergen 

immunotherapy occurred within 30 minutes after an 

injection, patients should remain in the physician’s office 

for at least 30 minutes after receiving an injection, but 

longer waits are reasonable, as directed by the physician. 

In addition, patients who are at increased risk of a systemic 

reaction might need to carry injectable epinephrine. Such 

patients might also need to remain in the physician’s office 

more than 30 minutes after an injection. These patients 

should be instructed in the use of epinephrine to treat a 

systemic reaction that occurs after they have left the 

physician’s office or other location where the injection 

was given. The risks and benefits of continuing allergen 

immunotherapy in patients who have had a severe systemic 

reaction should be carefully considered. 

b-Adrenergic blocking agents 

Summary Statement 17: b-Adrenergic blocking agents 

might make allergen immunotherapy–related systemic 

reactions more difficult to treat and delay the recovery. 

Therefore a cautious attitude should be adopted toward 

the concomitant use of b-blocker agents and inhalant 

allergen immunotherapy. However, immunotherapy is 

indicated in patients with life-threatening stinging insect 

hypersensitivity who also require b-blocker medications 

because the risk of the stinging insect hypersensitivity is 

greater than the risk of an immunotherapy-related systemic 

reaction. C 

b-Blockade enhances pulmonary, cardiovascular, and 

dermatologic end-organ effects of mediators and increases 

mortality associated with experimental anaphylaxis induced 

by either immunologic or nonimmunologic mechanisms. 

Patients who are receiving b-adrenergic blocking 

medications might be at increased risk if they experience a 

systemic reaction to an allergen immunotherapy injection 

because the b-receptor blockade might attenuate the 

response to epinephrine. 195-202 Patients who are receiving 

b-blocking drugs were almost 9 times more likely to be 

hospitalized after an anaphylactoid reaction from radiocontrast 

media. 198 Although topical b-blockers have 

markedly less systemic b-antagonist effects than oral 

b-blockers, they still might exhibit some systemic 

b-antagonist effects. Whether topical b-blockers pose 

the same or a smaller risk than oral b-blockers in regard 

to the treatment of allergen immunotherapy–related systemic 

reactions is not known. 

There have been very few studies that have examined 

the effect of b-blocker medications on allergen immunotherapy. 

A prospective 1-year study designed to determine 

whether patients taking b-blocker drugs were at increased 

risk of immunotherapy-induced systemic reactions found 

that there were 166 systemic reactions out of 56,105 

injection visits in 3178 patients (68 were receiving a 

b-blocker). 203 The systemic reactions occurred in 144 

(4.5%) patients, and only 1 of these patients was receiving 

a b-blocker medication. The authors calculated that by 

chance, 3.08 patients receiving the b-blocker medications 

drugs were expected to have had an systemic reaction and 

concluded that b-blocker medications did not increase the 

frequency of allergen immunotherapy systemic reactions 

(P >.95). 

In another study of 1389 patients prescribed immunotherapy 

for Hymenoptera venom hypersensitivity who 

were followed for 34 months, there were 25 patients who 

received concomitant b-blocker medications. 204 Three 

(12%) of the 25 patients receiving b-blocker medications 

experienced systemic reactions during immunotherapy 

compared with 23 (16.7%) of 117 patients with cardiovascular 

disease not receiving b-blockers. Systemic reactions 

after a field sting or challenge occurred in 1 (14.3%) of 7 

cardiovascular patients receiving b-blocker medications 

compared with 4 (13.8%) of 29 cardiovascular patients 

not receiving b-blocker medications. No severe reactions 

to immunotherapy or sting re-exposure were observed in 

patients receiving b-blockers medications. 

Immunotherapy is indicated in patients with life-threatening 

stinging insect hypersensitivity who also require 

b-blocker medications because the risk of the stinging 

insect hypersensitivity is greater than the risk of an 

immunotherapy-related systemic reaction. In such cases, 

intravenous glucagon, which might reverse the refractory 

bronchospasm and hypotension by activating the adenyl 

cyclase directing and bypassing the b-adrenergic receptor, 

might be used if epinephrine has not been effective. 205,206 

Prospective studies are necessary to clarify the magnitude 

of the risk of systemic reactions to allergens in patients 

who are receiving concomitant therapy with b-blockers, 

and a cautious attitude should be adopted toward the concomitant 

use of b-blocker agents and inhalant allergen 

immunotherapy. 

Contraindications 

Summary Statement 18: Medical conditions that reduce 

the patient’s ability to survive the systemic allergic reaction 

or the resultant treatment are relative contraindications

S46 Cox et al 



TABLE V. Actions to reduce the risk of anaphylaxis 

d 

d 

d 

d 

d 

d 

d 

d 

Assess the patient’s general medical condition at the time of injection (eg, asthma exacerbation). 

Consider obtaining a PEFR before administration of the injection. If the PEFR is significantly less than the patient’s baseline value, the 

clinical condition of the patient should be evaluated before administration of the injection. 

Adjust the immunotherapy dose or injection frequency if symptoms of anaphylaxis occur and immunotherapy is continued. 

Use appropriately diluted initial allergen immunotherapy extract in patients who appear to have increased sensitivity on the basis of history 

or tests for specific IgE antibodies. 

Instruct patients to wait in the physician’s office/medical facility for 30 minutes after an immunotherapy injection. Patients at greater risk 

of reaction from allergen immunotherapy (eg, patients with increased allergen sensitivity or those who have previously had a systemic 

reaction) might need to wait longer. 

Carefully evaluate any patient with a late reaction (eg, persistent large local reaction lasting >24 hours, systemic reaction occurring more 

than 30 minutes after the immunotherapy injection). 

Ensure procedures to avoid clerical or nursing errors (eg, careful checking of patient identification). 

Recognize that dosage adjustments downward are usually necessary with a newly prepared allergen immunotherapy extract or a patient who 

has had a significant interruption in the immunotherapy schedule. 

PEFR, Peak expiratory flow rate measurement. 

TABLE VI. Recommended equipment and medications to treat anaphylaxis 

Adequate equipment and medications should be immediately available to treat anaphylaxis, should it occur. This should include at least the 

following equipment and medications: 

d stethoscope and sphygmomanometer; 

d tourniquet, syringes, hypodermic needles, and large-bore needles (14-gauge); 

d aqueous epinephrine HCL 1:1000 wt/vol; 

d equipment to administer oxygen by mask. 

d intravenous fluid set-up; 

d antihistamine for injection (second-line agents for anaphylaxis, but H 1 and H 2 antihistamines work better together than either one alone); 

d corticosteroids for intravenous injection; 

d vasopressor; 

d equipment to maintain an airway appropriate for the supervising physician’s expertise and skill. 

for allergen immunotherapy. Examples include severe 

asthma uncontrolled by pharmacotherapy and significant 

cardiovascular disease. C 

Alternatives to allergen immunotherapy should be 

considered in patients with any medical condition that 

reduces the patient’s ability to survive a systemic allergic 

reaction. Examples include patients with markedly compromised 

lung function (either chronic or acute), poorly 

controlled asthma, unstable angina, recent myocardial 

infarction, significant arrhythmia, and uncontrolled hypertension. 

Under some circumstances, immunotherapy 

might be indicated for high-risk patients, such as those 

with Hymenoptera venom hypersensitivity and cardiac 

disease being treated with b-blocker medications. 

Reducing the risk of anaphylaxis to 

immunotherapy injections 


should be administered in a setting where procedures 

that can reduce the risk of anaphylaxis are in place and 

where the prompt recognition and treatment of anaphylaxis 

is ensured. C 

The major risk of allergen immunotherapy is anaphylaxis, 

which in extremely rare cases can be fatal, despite 

optimal management. Therefore allergen immunotherapy 

should be administered in a setting where anaphylaxis will 

be promptly recognized and treated by a physician or other 

health care professional appropriately trained in emergency 

treatment. 

The health care professional who administers immunotherapy 

injections should be able to recognize and treat 

the early symptoms and signs of anaphylaxis and administer 

emergency treatment, if necessary. Epinephrine is the 

first-line treatment for anaphylaxis. Health care professionals 

should know the potential pharmacologic benefits, 

risks, and routes of administration of epinephrine, as well 

as the potential reasons for lack of response. 12,207-213 It is 

important to administer epinephrine early in the management 

of anaphylaxis. Appropriate personnel, equipment, 

and medications should be immediately available to treat 

anaphylaxis, should it occur. Suggested actions to reduce 

the risk of anaphylaxis and recommended equipment and 

medications to treat anaphylaxis are listed in Tables V and 

VI, respectively. Before allergen immunotherapy is chosen 

as a treatment, the physician should educate the patient 

about the benefits and risks of immunotherapy, as well as 

methods for minimizing risks. The patient also should be 

told that despite appropriate precautions, reactions might 

occur without warning signs or symptoms. Informed consent 

should include a discussion of the potential immunotherapy 

adverse reactions, and this discussion should be 

documented in the patient’s medical record. 

PATIENT SELECTION 

Clinical indications 


should be considered for patients who have demonstrable



Cox et al S47 

TABLE VII. Clinical indications for allergen immunotherapy 

Indications for allergen immunotherapy in patients with allergic rhinitis, allergic conjunctivitis, or both: 

d symptoms of allergic rhinitis after natural exposure to aeroallergens and demonstrable evidence of clinically relevant specific IgE 

AND (one of the following) 

d poor response to pharmacotherapy, allergen avoidance, or both; 

d unacceptable adverse effects of medications; 

d wish to reduce or avoid long-term pharmacotherapy and the cost of medication; 

d coexisting allergic rhinitis and asthma; 

d possible prevention of asthma in patients with allergic rhinitis 

Symptoms of asthma after natural exposure to aeroallergens and demonstrable evidence of clinically relevant specific IgE 

AND (one of the following) 

d poor response to pharmacotherapy, allergen avoidance, or both; 

d unacceptable adverse effects of medication; 

d wish to reduce or avoid long-term pharmacotherapy and the cost of medications; 

d coexisting allergic rhinitis and allergic asthma. 

Indications for allergen immunotherapy in patients with reactions to Hymenoptera stings: 

d patients with a history of a systemic reaction to a Hymenoptera sting (especially if such a reaction is associated with respiratory 

symptoms, cardiovascular symptoms, or both) and demonstrable evidence of clinically relevant specific IgE antibodies; 

d patients older than 16 years with a history of a systemic reaction limited to the skin and demonstrable evidence of clinically relevant 

specific IgE antibodies (patients

S48 Cox et al 



immunotherapy were more common in symptomatic subjects 

with asthma. 188,189 Thus allergen immunotherapy 

should not be initiated in patients with poorly controlled 

asthma symptoms. 2,217 

Clinical indications for VIT 

Summary Statement 22: VIT should be strongly considered 

if the patient has had a systemic reaction to a 

Hymenoptera sting, especially if such a reaction was 

associated with respiratory symptoms, cardiovascular 

symptoms, or both and if the patient has demonstrable 

evidence of specific IgE antibodies. A 

Systemic reactions to Hymenoptera stings, especially 

when associated with respiratory symptoms, cardiovascular 

symptoms, or both and positive skin test or in vitro test 

results for specific IgE antibodies, are a strong indication 

for allergen immunotherapy. 218 In the United States patients 

older than 16 years with a systemic reaction limited 

to the skin are also candidates for allergen immunotherapy. 

Several studies of patients with imported fire ant 

allergy have demonstrated the effectiveness of immunotherapy 

with whole-body extracts of fire ants. 155,156,219 

Adults and children with a history of systemic reactions 

to the imported fire ant (Solenopsis species) who have positive 

skin test results or venom-specific IgE antibodies 

should be treated with allergen immunotherapy. Patients 

younger than 16 years of age who present only with a 

cutaneous reaction to imported fire ant or Hymenoptera 

stings might not require immunotherapy. 218,220-222 In addition 

to allergen immunotherapy, patients with imported 

fire ant and Hymenoptera venom sensitivity should be instructed 

in how to best avoid insect stings, be prescribed 

epinephrine, and be taught how to inject it. 

Venom skin test results are positive in more than 65% 

of patients with a history of a systemic reaction to a 

Hymenoptera sting compared with 15% of the population 

that has not had a systemic reaction. 223 In patients with 

negative venom skin test results who have a severe systemic 

reaction, further evaluation for the presence of 

venom-specific IgE is recommended. 218 If the venom-specific 

IgE test result is also negative, it is recommended that 

the skin tests, venom-specific IgE tests, or both be repeated 

3 to 6 months later. Approximately 5% to 10% of 

patients with negative venom skin test results with a history 

of a systemic reaction have a positive venom-specific 

IgE test result. 224 There are no published results of the effectiveness 

of allergen immunotherapy in patients with 

negative skin test results and positive venom-specific 

IgE test results who have experienced systemic reactions 

resulting from a Hymenoptera sting. There are data to indicate 

that these patients might have another episode of 

anaphylaxis if they are re-stung. The chance of another 

systemic reaction to a sting is relatively small (5% to 

10%) in adults with negative venom skin test results 

with a history of systemic reactions compared with the 

risk associated with positive venom skin test results 

(25% to 70%). 225 However, even though the risk is small, 

the reaction can be severe, and VIT is recommended for 

patients with negative venom skin test results and positive 

venom-specific IgE test results who have had severe 

anaphylaxis to an insect sting. 

Some patients who have negative venom skin test 

results and negative venom-specific IgE test results are 

reported to have had subsequent systemic reactions to 

stinging insects. 225-227 Controlled studies designed to 

evaluate the efficacy of immunotherapy in these patients 

have not been performed. There are very few anecdotal 

reports of patients with negative venom skin 

test results and negative venom-specific IgE test results 

being successfully treated with VIT if the selected 

venom is based on the results of a sting challenge. 

Generally, there are not sufficient data on the efficacy 

of immunotherapy in these patients to form conclusive 

recommendations. 

The AAAAI Insect Committee’s modified working 

guidelines state that a negative venom skin test result or 

in vitro assay result is not a guarantee of safety, and patients 

with suspected higher risk should be counseled 

about avoidance strategies, use of epinephrine injectors, 

and the emergency and follow-up care of the acute allergic 

reaction. 226 The AAAAI Insect Committee also acknowledged 

that the management of patients with a positive history 

and negative venom skin test results requires clinical 

judgment and ongoing research. 

Summary Statement 23: Patients selected for immunotherapy 

should be cooperative and compliant. D 

Patients who are mentally or physically unable to 

communicate clearly with the physician and patients 

who have a history of noncompliance might be poor 

candidates for immunotherapy. If a patient cannot communicate 

clearly with the physician, it will be difficult for 

the patient to report signs and symptoms, especially early 

symptoms, suggestive of systemic reactions. 

ALLERGEN SELECTION AND HANDLING 

Allergen selection 

Clinical evaluation. Summary Statement 24: The selection 

of the components of an allergen immunotherapy 

extract that are most likely to be effective should be based 

on a careful history of relevant symptoms with knowledge 

of possible environmental exposures and correlation with 

positive test results for specific IgE antibodies. A 

A careful history, noting environmental exposures and 

an understanding of the local and regional aerobiology of 

suspected allergens, such as pollen, fungi (mold), animal 

dander, dust mite, and cockroach, is required in the 

selection of the components for a clinically relevant 

allergen immunotherapy extract. Although the relationship 

between day-to-day outdoor pollen and fungi exposure 

and the development of clinical symptoms is not 

always clear, symptoms that occur during periods of 

increased exposure to allergens, in association with positive 

skin or in vitro test results for specific IgE antibodies, 

provide good evidence that such exposures are relevant. 

Information concerning regional and local aerobiology is 

available on various Web sites or through the National 

Allergy Bureau at http://www.aaaai.org/nab. There are



Cox et al S49 

no data to support allergen immunotherapy as a treatment 

for non–IgE-mediated symptoms of rhinitis or asthma. As 

is the case in interpreting positive immediate hypersensitivity 

skin test results, there must be a clinical correlation 

with the demonstration of in vitro allergen-specific IgE 

levels and clinical history of an allergic disease. 

There is no evidence to support the administration of 

immunotherapy based solely on results of specific in vitro 

testing, as is being done by both commercial laboratories 

and some physician’s offices. This is promoting the remote 

practice of allergy, which is not recommended. 

Clinical correlation. Summary Statement 25: The 

allergen immunotherapy extract should contain only clinically 

relevant allergens. A 

The omission of clinically relevant allergens from an 

allergic patient’s allergen immunotherapy extract contributes 

to decreased effectiveness of allergen immunotherapy. 

The inclusion of all allergens to which IgE antibodies 

are present, without establishing the possible clinical 

relevance of these allergens, might dilute the content of 

other allergens in the allergen immunotherapy extract and 

can make allergen immunotherapy less effective. 

Knowledge of the total allergenic burden facing a 

patient and the realistic possibility of avoidance is important 

in determining whether allergen immunotherapy 

should be initiated. A patient’s lifestyle can produce 

exposure to a wide variety of aeroallergens from different 

regions, necessitating inclusion in the extract of multiple 

allergens from different geographic areas. Many individuals 

travel extensively for business or pleasure into 

different regions, and symptoms might worsen at these 

times. However, inclusion of allergens to which IgE 

antibodies are present but that are not clinically relevant 

might dilute the essential allergen components of the 

allergen immunotherapy extract so that immunotherapy 

might be less effective. Determination of the significance 

of indoor allergens for a particular patient is harder 

because it is difficult to determine exposure in the home, 

school, and/or workplace. Historical factors, such as the 

presence of a furry animal in the home, a history of water 

damage and subsequent fungal exposure, or a history of 

insect infestation, might be helpful. However, such information 

is subjective and is often of uncertain reliability. 

In addition, some studies have demonstrated significant 

indoor levels of cat and dog allergen in households 

without pets 228 and significant levels of mouse allergen 

in suburban 229 and inner-city 230 homes of asthmatic children. 

In the National Cooperative Inner-City Asthma 

Study, 33% of the homes had detectable rat allergen 

(Rat n 1), and a correlation between rat allergen sensitization 

with increased asthma morbidity in inner-city children 

was found. 231 Fur-bearing pets and the soles of 

shoes are also conduits by which molds and other ‘‘outdoor’’ 

allergens can enter the home. 

Several commercial immunoassays to measure the 

presence of indoor allergens (eg, dust mite, cat, cockroach, 

and dog) in settled house dust samples are available and 

might provide useful estimates of indoor allergen exposure. 

Nevertheless, for most patients, determination of the 

clinical relevance of an allergen requires a strong correlation 

between the patient’s history and evidence of 

allergen-specific IgE antibodies. 

Skin tests and in vitro IgE antibody tests. Summary 

Statement 26: Skin testing has been the primary diagnostic 

tool in clinical studies of allergen immunotherapy. 

Therefore in most patients, skin testing should be used 

to determine whether the patient has specific IgE antibodies. 

Appropriately interpreted in vitro tests for specific 

IgE antibodies can also be used. A 

The use of standardized allergens has greatly increased 

the consistency of skin test results for these antigens. 

Controlled studies in which the clinical history has 

correlated with the skin test results have demonstrated 

the efficacy of immunotherapy for relevant allergens. 

25,26,112,130,134,135,140,141,149,154 Skin testing can 

also provide the physician with useful information about 

the appropriate starting dose of selected allergens. On 

rare occasions, systemic reactions can occur from skin 

testing in a highly sensitive individual. 232,233 In addition, 

skin tests might be difficult to perform in patients with 

dermatographism or atopic dermatitis. In vitro tests are 

particularly useful in such patients. 

Studies indicate that skin testing is generally more 

sensitive than in vitro tests in detecting allergen-specific 

IgE. 234,235 Based on inhalation challenge test results, 

skin tests have shown specificity and sensitivity generally 

superior to those of in vitro tests. The comparability of 

skin tests and in vitro tests for specific IgE antibodies depends 

on the allergen being tested. For all of these reasons, 

skin testing is preferable as a method for selection of allergens 

for inclusion in immunotherapy and determining the 

starting dose for an immunotherapy program. Among 

the skin testing techniques available, a properly applied 

percutaneous (prick/puncture) test consistently produces 

reproducible results. Generally, prick testing is sensitive 

enough to detect clinically relevant IgE antibodies when 

potent extracts, such as grass 236 and cat, 237 are used. 

Intradermal/intracutaneous skin testing might be required 

for some allergen extracts. It is appropriate in some patients 

to use in vitro tests for specific IgE antibody as an 

alternative to skin tests in the diagnosis of allergic rhinitis, 

allergic rhinoconjunctivitis, allergic asthma, and stinging 

insect hypersensitivity. In vitro tests can also be used to 

define the allergens that should be used in allergen immunotherapy. 

If the allergy skin test result is negative and the 

in vitro test result is positive, a controlled challenge can be 

performed, and if the latter is positive, immunotherapy can 

be considered. In the case of Hymenoptera venom, immunotherapy 

can be started even without a live sting challenge 

in patients with negative skin test results and 

positive in vitro test results. However, there are no published 

results of the effectiveness of Hymenoptera VIT 

in patients with negative skin test results and positive 

in vitro test results. 

Specific allergens 

Summary Statement 27: Immunotherapy is effective for 

pollen, mold, animal allergens, cockroach, dust mite, and

S50 Cox et al 



Hymenoptera hypersensitivity. Therefore immunotherapy 

should be considered as part of the management program 

in patients who have symptoms related to exposure to 

these allergens, as supported by the presence of specific 

IgE antibodies. A 

Pollen. Pollen extracts have been shown to be safe and 

effective in many controlled clinical trials. 17,104,106,107,109 

It seems reasonable to extrapolate information about pollen 

extracts that have been studied to those that have not 

been subjected to rigorous investigation and to assume 

that the latter are also safe and effective. Less information 

is available with respect to mixtures of pollen extracts. 

However, those studies that have been conducted with 

mixtures have demonstrated clinical effectiveness. 112,122 

Because a particular pollen extract is a mixture of multiple 

glycoproteins, this suggests that mixing pollen allergens 

does not alter biologic activity. 

Fungi (molds). Several studies with Alternaria and 

Cladosporium species suggest that allergen immunotherapy 

with fungi might be effective. 133-138 The allergen content 

of most mold extracts is highly variable. 238,239 

However, there is evidence that proteolytic enzymes present 

in some mold extracts could digest other antigens, 

such as pollens, when combined in a mixture. 240 For this 

reason, it might be desirable to separate all pollen extracts 

from mold extracts when using mixtures. 

Unfortunately, extracts for some potentially clinically 

important fungi are not available. 241 For example, there 

are no commercially available extracts for many fungal ascospores, 

even though they frequently are the dominant 

type of airborne bioparticulate during certain seasons. 

Another example is the lack of basidiospore (mushroom) 

extracts, especially given the evidence that such exposures 

can be associated with epidemics of asthma in the late fall. 

It is important that the practicing physician distinguish between 

molds that are predominantly found indoors (eg, 

Penicillium and Aspergillus genera) and many other 

molds that are found either exclusively outdoors or both 

indoors and outdoors and be able to assess the potential 

clinical effect of each. 

Animal dander. Although the best treatment for animal 

allergy is avoidance, this is not always possible. Exposure 

to both dog and cat allergen has been shown to be 

ubiquitous and can occur even without an animal in the 

home, making avoidance even more difficult. 

Because immunotherapy has been shown to be effective 

for cat 22,26,139-143,242 and dog, 25,141 the decision to include 

dog or cat allergen in an allergen immunotherapy 

extract should be considered in those circumstances in 

which there is exposure. 

Dust mites and cockroach allergens. Crude house dust 

extract is generally an inappropriate substitute for house 

dust mite extract because the protein content measured is 

not restricted to dust mite allergens, nor does it necessarily 

guarantee inclusion of dust mite protein. Immunotherapy 

with standardized dust mite is generally more effective 

than that with crude house dust allergens. The house dust 

mites D farinae and D pteronyssinus contain 2 major allergen 

groups that are immunologically cross-reactive: Der p 

1 and Der f 1 and Der p 2 and Der f 2. Sixty percent or more 

of mite-sensitive patients react to these 2 major allergen 

dust mite groups. Allergens from other species of mites, 

such as Blomia tropicalis and Euroglyphus maynei, partially 

cross-react with allergens from Dermatophagoides 

species. Only 50% of the projected amounts of each of 

the 2 house dust mites (D pteronyssinus and D farinae) 

need to be included when preparing an allergen immunotherapy 

extract based on the high degree of cross-allergenicity 

between the major allergens in these 2 species. 

Immunotherapy for dust mites is effective 144,147-149,151 

and should be considered in conjunction with avoidance 

measures in patients who have symptoms consistent 

with dust mite allergy and specific IgE antibodies for 

dust mite allergens. Dust mite hypersensitivity should particularly 

be considered in patients who have perennial 

symptoms exacerbated by a dusty environment at home, 

work, or both and periods of high humidity. 

The most common species of cockroach identified in 

dwellings are the German cockroach, Blatella germanica, 

and the American cockroach, Periplaneta americana. 

Allergens derived from B germanica include Bla g 2, 

Bla g 4, and Bla g 5. The major allergen of P americana 

is Per a 1. Partial cross-reactivity between cockroach 

allergens exists, but each regionally relevant species 

should be represented in the immunotherapy extract. 243 

Immunotherapy with cockroach allergens is effective 154 

and should be considered in conjunction with aggressive 

avoidance measures, particularly in patients living in the 

inner city who have perennial allergic symptoms and 

specific IgE antibodies to cockroach allergens. 

Hymenoptera venom. Randomized, double-blind, placebo-controlled 

studies show that immunotherapy with 

Hymenoptera venom is effective in dramatically reducing 

the risk of anaphylaxis to honeybee, yellow jacket, hornet, 

and wasp stings. 108,116,244 Efficacy has also been demonstrated 

with immunotherapy by using whole-body extracts 

of imported fire ants. 155,156 

Foods. Only a single clinical study accessing the 

efficacy and safety of subcutaneous immunotherapy with 

foods has been performed. 171,173 This study, which evaluated 

immunotherapy with peanut, found the incidence of 

systemic reactions, even during maintenance, was unacceptable. 

Thus there is no evidence to support the use of 

immunotherapy with food extracts. Currently, strict avoidance 

of the offending food is advisable, and subcutaneous 

immunotherapy for food allergy is not recommended. 

Mixing of extracts 

Principles of mixing. Summary Statement 28: 

Consideration of the following principles is necessary 

when mixing allergen extract: (1) cross-reactivity of 

allergens, (2) optimization of the dose of each constituent, 

and (3) enzymatic degradation of allergens. B 

Once the relevant allergens for each patient are identified, 

it is necessary to prepare a mixture that contains 

each of these allergens. Standardized extracts should be 

used, when available, and can be mixed with nonstandardized 

extracts. A number of factors need to be considered



Cox et al S51 

when combining extracts, including (1) cross-reactivity of 

allergens, (2) the need to include the optimal dose for each 

constituent, and (3) potential interactions between different 

types of allergens, when mixed, that could lead to 

degradation or unmasking of epitopes on exposure to 

proteolytic enzymes. 

Mixing cross-reactive extracts. Summary Statement 

29: The selection of allergens for immunotherapy should 

be based (in part) on the cross-reactivity of clinically 

relevant allergens. Many botanically related pollens contain 

allergens that are cross-reactive. When pollens are 

substantially cross-reactive, selection of a single pollen 

within the cross-reactive genus or subfamily might suffice. 

When pollen allergens are not substantially cross-reactive, 

testing for and treatment with multiple locally prevalent 

pollens might be necessary. B 

Immunologic and allergenic cross-reactivity is the 

recognition by the patient’s immune system of different 

extracts’ constituents as the same or similar. When one 

allergen elicits the same immunologic responses as another 

cross-reacting allergen, it is not necessary or even 

desirable to include both in the same mixture. 71 Such a 

practice might result in the addition of too much of a given 

allergen, which could lead to an adverse reaction, as well 

as the unnecessary dilution of other allergens, with a resultant 

reduction in efficacy. A knowledge of each allergen’s 

classification according to species and the fact that there is 

immunologic cross-reactivity within allergens of the same 

genera or subfamily allows one to select components of 

the allergen immunotherapy extract that are maximally 

effective. In general, the patterns of allergenic crossreactivities 

among pollens follow their taxonomic relationships 

(see the Allergen extract section, Fig 2, and the 

allergens and allergy diagnostic tests practice parameters). 

Dose selection. Summary Statement 30: The efficacy of 

immunotherapy depends on achieving an optimal therapeutic 

dose of each of the constituents in the allergen 

immunotherapy extract. A 

The maintenance dose of allergen immunotherapy must 

be adequate. 22-26,128,149,245 Low maintenance doses are 

generally not effective (eg, dilutions of 1:1,000,000 vol/ 

vol). 28 A consideration when mixing extract is the need 

to deliver an optimal therapeutically effective dose of 

each of the constituents in the allergen immunotherapy 

vaccine. Failure to do so might reduce the efficacy of immunotherapy. 

This occurs because of a dilution effect; that 

is, as one mixes multiple extracts, the concentration of 

each in the final mixture will be decreased (see the 

Immunotherapy schedules and doses section for further 

discussion and for recommended maintenance doses). 

Proteolytic enzymes and mixing. Summary Statement 

31: Separation of extracts with high proteolytic enzyme 

activities, such as fungi (mold) and cockroach, from other 

extracts, such as pollens, is recommended. B 

Many allergen extracts contain mixtures of proteins and 

glycoproteins. Proteolytic enzymes can degrade other 

allergenic proteins. There have been reports of interactions 

between extracts when mixed together. 240,246,247 Extracts 

such as Alternaria species have been shown to reduce the 

IgE-binding activity of timothy grass extract when mixed 

together. Studies designed to investigate the effect of combining 

mold/fungi extracts with pollen extracts have demonstrated 

a significant loss of potency of grass pollen, cat, 

birch, white oak, box elder, and some weeds. 240,246,247 

Cockroach had a similar deleterious effect on pollen extract 

potency. 246,248 Short ragweed appeared resistant to 

the effects of the proteolytic enzymes in one study, 240 

but another study found short ragweed Amb a 1 was susceptible 

to proteases present in Penicillium and Alternaria 

species extracts at relatively low (10%) glycerin levels. 247 

Dust mite extracts do not appear to have a deleterious 

effect on pollen extracts. 240,246,248 These studies suggest 

that pollen, dust mite, and cat extracts can be mixed together. 

The effect of the combination of high proteolytic-containing 

extracts on each other or the extent of 

self-degradation of allergenic proteins has not been extensively 

studied. The evidence on mixing cockroach extract 

with other extracts is conflicting, and the clinical relevance 

of the changes is also unclear; therefore the clinician has 

the option of separating cockroach or not. 

Because such interactions between extracts have not 

been fully delineated, consideration should be given to 

keeping extracts that tend to have high proteolytic enzyme 

activities, such as fungi and cockroach extracts, separate 

from those with lesser activities, such as pollen extracts. 

It is not recommended to mix venoms together (eg, 

wasps or honeybee with yellow jacket), even though 

yellow jacket and hornet venom are available premixed as 

a mixed-vespid extract. 

In this regard the number of separate injections that 

need to be given at each patient visit depends on whether 

all of the relevant extracts mixed into a single vial still 

deliver an optimal dose of each allergen. If mixing causes 

excessive dilution or if there are advantages to separating 

allergens into separate vials, then more than one vial might 

be necessary for successful immunotherapy. 


extract preparation should be performed by individuals 

experienced and trained in handling allergenic products. D 

Allergen immunotherapy extracts are high-alert products 

that carry the risk for anaphylaxis. Policies, procedures, 

and processes intended for conventional drugs and 

medications might be highly inappropriate for allergenic 

products. For example, substitution with differing lots, 

manufacturers, or dose formulations might be routine for 

conventional drugs and medications but could lead to 

fatal anaphylactic reactions with allergenic products. 

Prepared allergenic products usually have expiration 

dates of 3 to 12 months from the date of preparation but 

should not extend beyond the shortest expiration date of 

the individual components. There are no reports of 

infection associated with allergen immunotherapy injections. 

Allergen vaccines are prepared by using sterile 

manufacturer’s extracts and sterile diluents containing 

antibacterial constituents (usually phenol). A summary of 

the AAAAI/ACAAI/JCAAI proposed USP allergen immunotherapy 

extract preparation guidelines can be found 

in Table VIII.

S52 Cox et al 



TABLE VIII. AAAAI/ACAAI/JCAAI-proposed USP Allergen Immunotherapy Extract Preparation Guidelines 

1. Qualifications of extract preparation personnel: 

d Compounding personnel must pass a written test on aseptic technique and extract preparation. 

d Compounding personnel must be trained in preparation of allergenic products. 

d Compounding personnel must annually pass a media-fill test, as described below.* 

d Compounding personnel who fail written or media-fill tests would be reinstructed and re-evaluated. 

d Compounding personnel must be able to demonstrate understanding of antiseptic hand cleaning and disinfection of mixing surfaces. 

d Compounding personnel must be able to correctly identify, measure, and mix ingredients. 

2. Physician responsibility: A physician with training and expertise in allergen immunotherapy is responsible for ensuring that compounding 

personnel are instructed and trained in the preparation of immunotherapy using an aseptic technique as defined below and that they meet the 

requirements of these guidelines. Evidence of such compliance shall be documented and maintained in personnel files. 

3. Bacteriostasis: Allergen extract dilutions must be bacteriostatic, meaning that they must contain phenol concentrations of at least 0.25%, 

or if phenol concentration is less than 0.25%, the extract must have a glycerin concentration of at least 20%. 

4. Dilutions prepared in accordance with manufacturer’s instructions: Allergen extracts must be diluted in accordance with the antigen 

manufacturer’s instructions. 

5. Potency: The manufacturer’s expiration dates must be followed. Beyond-use dates for allergy extract dilutions should be based on the best 

available clinical data. 

6. Mixing of extracts with high and low proteolytic enzymes—cross-reactivity of antigens: Separation of aqueous extracts with high 

proteolytic enzyme activities from other extracts is recommended. 

7. Storage: Extracts should be stored at 48C to reduce the rate of potency loss or according to the manufacturer’s directions. Extracts beyond 

the expiration date of the manufacturer are to be discarded. Storage must be in a designated refrigerator for medications and not used for 

food or specimens. 

8. Subcutaneous injection: Allergen extracts can only be administered intradermally or through subcutaneous injection unless the 

FDA-approved package insert or accepted standards of clinical practice permit another route of administration. 

9. Aseptic technique: Preparation of allergy immunotherapy shall follow aseptic manipulations defined as follows: 

d The physician must designate a specific site, such as a countertop, in an area of the practice facility where personnel traffic is restricted 

and activities that might contribute to microbial contamination (eg, eating, food preparation, and placement of used diagnostic devices 

and materials and soiled linens) are prohibited. 

d The extract preparation area must be sanitized with 70% isopropanol that does not contain added ingredients, such as dyes and glycerin. 

d Extract preparation personnel must thoroughly wash hands to wrists with detergent or soap and potable water. Substitution of hand 

washing by treatment with sanitizing agents containing alcohol and/or 70% isopropanol is acceptable. 

d Necks of ampules to be opened and stoppers of vials to be needle punctured must be sanitized with isopropanol. 

d Direct contact contamination of sterile needles, syringes, and other drug-administration devices and sites on containers of manufactured 

sterile drug products from which drugs are administered must be avoided. Sources of direct contact contamination include, but are not 

limited to, touch by personnel and nonsterile objects, human secretions, blood, and exposure to other nonsterile materials. 

d After mixing is complete, visual inspection is to be performed for the physical integrity of the vial. 

10. Labeling: Immunotherapy vials are to be clearly labeled with the patient’s name and beyond-use date of the vial. 

11. Mixing log: A mixing log is to be kept with information on the patient’s name, extract used for mixing, mixing date, and expiration date 

and lot numbers. 

12. Policy and procedure manual: Practices preparing allergy extracts must maintain a policy and procedure manual for the procedures to be 

followed in mixing, diluting, or reconstituting of sterile products and for the training of personnel in the standards described above. 

*Example of a media-fill test procedure: This or an equivalent test is performed at least annually by each person authorized to compound allergen 

immunotherapy extracts under conditions that closely simulate the most challenging or stressful conditions encountered during compounding of allergen 

immunotherapy extracts. Once begun, this test is completed without interruption. 

A double-concentrated media, such as from Valiteq (http://www.valiteq.com), is transferred in ten 0.5-mL increments with a sterile syringe to a sterile 10-mL vial. 

Five milliliters of sterile water (preservative free) is added. This is the concentrate. The vial is incubated within a range of 208Cto358C for 14 days. Failure is indicated 

by visible turbidity in the medium on or before 14 days. 

Allergen immunotherapy extract handling 

Storage. Summary Statement 33a: Allergen immunotherapy 

extracts should be stored at 48C to reduce the rate 

of potency loss. B 

Summary statement 33b: Extract manufacturers conduct 

stability studies with standardized extracts that 

expose them to various shipping conditions. It is the 

responsibility of each supplier or manufacturer to ship 

extracts under validated conditions that are shown not to 

adversely affect the product’s potency or safety. C 

Because the efficacy and safety of immunotherapy depend 

on the use of allergen immunotherapy extracts with reasonably 

predictable biologic activity, it is important that they be 

stored under conditions that preserve such activity. The 

potency of allergen immunotherapy extracts is affected by a 

number of factors, including the passage of time, temperature, 

concentration, number of allergens in a vial, volume of the 

storage vial, and presence of stabilizers and preservatives. 

Allergen immunotherapy extract, including reconstituted 

lyophilized extracts, should be stored at 48C to minimize 

the rate of potency loss because storage at higher temperatures 

(eg, room temperature) can result in rapid deterioration. 249 

Extract manufacturers conduct stability studies with 

standardized extracts that expose them to various shipping 

conditions (personal communication). These studies include 

actual shipments made by their carriers to places like



Cox et al S53 

Phoenix in the summer and Alaska in the winter. The 

results of these studies are on file under each manufacturer’s 

product licenses. Each study is specific to each 

manufacturer because the packaging (eg, use of insulation) 

varies from company to company. It is the responsibility 

of each supplier or manufacturer to ship allergen 

extracts under validated conditions that have been shown 

not to adversely affect the product’s potency or safety. 

Storing dilute extracts. Summary Statement 34a: More 

dilute concentrations of allergy immunotherapy extracts 

(diluted greater than 1:10 vol/vol) are more sensitive to the 

effects of temperature and lose potency more rapidly than 

do more concentrated allergen immunotherapy extracts. 

The expiration date for more dilute concentrations should 

reflect this shorter shelf life. B 

Summary Statement 34b: In determining the allergy 

vaccine expiration date, consideration must be given to the 

fact that the rate of potency loss over time is influenced by 

a number of factors separately and collectively, including 

(1) storage temperature, (2) presence of stabilizers and 

bactericidal agents, (3) concentration, (4) presence of 

proteolytic enzymes, and (5) volume of the storage vial. D 

The potency of concentrated allergen immunotherapy 

extracts (1:1 vol/vol up to 1:10 vol/vol) when kept at 48Cis 

relatively constant and allows the allergen immunotherapy 

extract to be used until the expiration date that is present on 

the label. Less concentrated allergen immunotherapy 

extracts are more sensitive to the effects of temperature 

and might not maintain their potency until the listed 

expiration date. 249,250 

The mixing of other allergens might decrease the loss of 

potency with time because the additional allergens might 

prevent adherence of proteins to the vial’s glass wall. Thus 

highly concentrated extracts are more stable than diluted 

ones. Extracts are prepared as aqueous, glycerinated, freezedried, 

and alum formulations. Aqueous and glycerin diluents 

are compatible for mixing standardized with nonstandardized 

products. Lyophilization is used to maintain the 

strength of the dry powder, but once the allergen immunotherapy 

extract is reconstituted, stabilizing agents, such 

as human serum albumin (0.03%) or 50% glycerin, are 

needed to maintain potency. 250 Phenol is a preservative 

added to extracts to prevent growth of microorganisms. 

Phenol can denature proteins in allergen extracts. 251,252 

Human serum albumin might protect against the deleterious 

effect of phenol on allergen extracts. 251 Human serum 

albumin might also prevent the loss of potency within storage 

vials by preventing absorption of allergen on the inner 

surface of the glass vial. Glycerin is also a preservative. At 

a concentration of 50%, glycerin appears to prevent loss of 

allergenic potency, 250,253 possibly through inhibition of 

the activity of proteolytic and glycosidic enzymes that 

are present in certain extracts. However, it is irritating 

when injected and should be diluted before beginning immunotherapy. 

Recommendations for extract stability are 

found in the manufacturers’ product insert sheets. The extract 

manufacturers’ package insert advises care when administering 

a volume greater than 0.2 mL of an extract in 

50% glycerin because of the potential discomfort and pain 

TABLE IX. Potency of selected manufacturer’s extracts 

currently available 

Extract 

Potency 

Cat hair and pelt 5000 and 10,000 BAU/mL 

Dust mite 

3000, 5000, 10,000, and 30,000 AU/mL 

Bermuda grass 10,000 AU/mL 

Short ragweed 1:10-1:20 wt/vol or 100,000 AU/mL 

Other grasses* 10,000 and 100,000 BAU/mL 

Other pollen 

1:10 to 1:40 (wt/vol) or 10,000 PNU/mL 

Molds 1:10 to 1:40 (wt/vol) or 20,000 

to 100,000 PNU/mL 

AU, Allergy unit; BAU, bioequivalent allergy unit; PNU, protein nitrogen unit. 

*Perennial rye, Kentucky blue/June, timothy, sweet vernal, redtop, orchard, 

and meadow. 

it might cause. The pain associated with glycerin increases 

in proportion to the glycerin concentration and injection 

volume, and the pain is proportional to the total injected 

dose of glycerin. 254 However, individual pain perception 

can vary substantially. Total glycerin doses of less than 

0.05 mL rarely produce clinically important pain. 

There have been few studies that have investigated the 

potency of dilutions of allergen extract mixture over time. 

Expiration dates for allergen extract dilutions are somewhat 

empiric and not strongly evidence based. A study 

undertaken by the AAAAI Immunotherapy and Allergy 

Diagnostic committee designed to study the stability of a 

mixture of standardized extracts in 4 conditions of storage 

(with and without intermittent room temperature exposure 

and diluted in normal saline or human serum albumin) 

found that short ragweed at 1:10 vol/vol dilution, as 

measured by means of radial immunodiffusion, was stable 

in all conditions of storage over 12 months. Dust mite and 

cat at 1:10 and 1:100 vol/vol dilution were also stable in all 

conditions of storage over 12 months, as measured by an 

ELISA assay using an mAb for Der p 1, Der f 1, and Fel d 1. 

The expiration date of any dilution should not exceed 

the expiration date of the earliest expiring constituent that 

is added to the mixture. 

IMMUNOTHERAPY SCHEDULES AND DOSES 

Summary Statement 35: A customized individual 

allergen immunotherapy extract should be prepared from 

a manufacturer’s extract or extracts in accordance to the 

patient’s clinical history and allergy test results and can be 

based on single or multiple allergens. D 

An allergen extract is a solution of elutable materials 

derived from allergen source materials, such as pollens or 

molds. They consist of complex mixtures of proteins and 

glycoproteins to which antibodies can bind. Animal 

dander contains between 10 and 20 antigens, 255 house 

dust mites between 20 and 40 antigens, 256 and pollens between 

30 and 50 antigens, 257,258 and fungal extract can 

contain as many as 80 antigens. 259 

Extracts obtained from extract manufacturing companies 

should be called the manufacturer’s extract. Vials of 

manufacturer’s extract contain individual or limited

S54 Cox et al 



mixtures of allergens that can be used alone as a concentrated 

dose of single allergen or combined with other 

concentrated allergens to prepare an individual patient’s 

customized allergen mixture. This is designated as the 

patient’s maintenance concentrate. 

Nonstandardized manufacturer’s extracts usually are 

available at concentrations of between 1:10 and 1:50 wt/ 

vol or 20,000 and 100,000 PNU. Standardized extracts are 

available with biologic potencies of 10,000 and 100,000 

BAU for grasses; 5000 and 10,000 BAU for cat allergen; 

5000, 10,000, or 30,000 AU for dust mite; and 100,000 

AU or 1:10 and 1:20 wt/vol for short ragweed, with the 

Amb a 1 concentration listed in FDA units on the label of 

the wt/vol extracts (Table IX). The main factor that limits 

how concentrated an allergen immunotherapy extract can 

be is the tendency of highly concentrated antigen solutions 

to develop precipitates. This is an unpredictable and 

poorly understood phenomenon. Although there is no evidence 

that such precipitates adversely affect the extract, 

the FDA does not permit a manufacturer to ship an extract 

that has a precipitate. 

Summary Statement 36: The highest-concentration allergy 

immunotherapy vial (eg, 1:1 vol/vol vial) that is used 

for the projected effective dose is called the maintenance 

concentrate vial. The maintenance dose is the dose that 

provides therapeutic efficacy without significant adverse 

local or systemic reactions and might not always reach the 

initially calculated projected effective dose. This reinforces 

that allergy immunotherapy must be individualized. D 

The highest concentration of an allergen extract mixture 

that is projected to be used as the therapeutically effective 

dose is called the maintenance concentrate. This should be 

prescribed individually for each patient by an allergist/ 

immunologist. The maintenance concentrate (if a mixture 

of extracts) should either be obtained from the manufacturer 

as a customized mixture or should be prepared by 

the physician under sterile conditions by adding an 

appropriate volume of individual manufacturer’s extracts. 

Some patients might be unable to attain the projected 

therapeutically effective dose of the maintenance concentrate 

because of local reactions, systemic reactions, or both 

(eg, cat, 1000 BAU [highest tolerated dose] vs 2000 BAU 

[projected effective dose]; see Table X for probable effective 

therapeutic dose range). Such patients might need 

weaker dilutions of their maintenance concentrate. Even 

so, the original projected maintenance concentration of 

the allergen immunotherapy extract is still referred to as 

the maintenance concentrate, and the specific patient’s 

therapeutic dose is referred to as the maintenance dose. 

The consistent use of this nomenclature system is essential 

because errors in choosing the correct vial are a common 

cause of systemic reactions, especially when the patient 

transfers from one physician to another. Therefore it is 

important that standard terminology be adopted by all 

physicians who prescribe allergen immunotherapy. 

Recommended doses 

Summary Statement 37: The maintenance concentrate 

should be formulated to deliver a dose considered to be 

therapeutically effective for each of its constituent components. 

The projected effective dose is referred to as the 

maintenance goal. Some individuals unable to tolerate the 

projected effective dose will experience clinical benefits at 

a lower dose. The effective therapeutic dose is referred to 

as the maintenance dose. A 

The effective maintenance dose of immunotherapy for a 

particular patient must be individualized. To do this, the 

allergist/immunologist who prepares the allergen immunotherapy 

extract must balance the dose necessary to 

produce efficacy and the risk of reactions if such a dose is 

reached. The allergist/immunologist might need to prepare 

more than one maintenance concentrate to provide 

a therapeutic dose of each of the allergens for the 

polysensitized patient. Therapeutically effective doses 

for immunotherapy have been reported for some allergen 

extracts. 22,24,25,128,134,135,149,246,260,261 Effective doses 

have been determined for Hymenoptera venom, dust 

mite, cat allergen, dog, grass, and short ragweed (Table X). 

Controlled studies demonstrate that the content of 

particular allergens in allergen immunotherapy extracts 

can be used to predict a therapeutic dose for those 

allergens, particularly when the extracts are standardized. 

For antigens that have not been standardized, the effective 

dose must be estimated and individualized. It is important 

to keep a separate record of the contents of each extract, 

including final dilutions of each of the constituents. The 

therapeutically effective doses used in the most recent 

controlled clinical studies are the basis of the recommended 

dosage range of standardized extracts presented in 

Table X. Although early improvement in symptoms has 

been documented with these doses, long-term benefit appears 

to be related not only to the individual maintenance 

dose but also the duration of time that it is administered. 14 

Because a full dose-response curve has not been 

determined for most allergens, it is possible (and supported 

by expert opinion) that therapeutic response can 

occur with doses lower than those that have been shown to 

be effective in controlled studies. In general, however, low 

doses are less likely to be effective, and very low doses 

usually are ineffective. 27 Although administration of a 

higher maintenance dose of immunotherapy increases 

the likelihood of clinical effectiveness, it also increases 

the risk of systemic reactions. In particular, highly sensitive 

patients might be at risk of systemic reactions to immunotherapy 

injections with higher maintenance doses. 

The maintenance concentrate should be formulated to 

deliver a full therapeutic dose of each of its constituent 

components. However, some sensitive patients might 

not tolerate the targeted therapeutic dose, and their maintenance 

dose would be lower. Individuals who have 

systemic reactions with doses that are less than the projected 

effective dose should be maintained on the highest 

tolerated dose, providing this dose is effective. The highest 

tolerated effective therapeutic dose is referred to as the 

maintenance dose. 

Regardless of dose schedule, some patients are unable 

to progress to the predetermined maintenance dose because 

of large local or systemic reactions to the allergen



Cox et al S55 

TABLE X. Probable effective dose range for allergen extracts US standardized units a 

Antigen Labeled potency or concentration a,b Probable effective dose range 

Dust mites: D farinae and D pteronyssinus c 3000, 5000, 10,000, and 30,000 AU/mL 500-2000 AU 

Cat d 5000-10,000 BAU/mL 1000-4000 BAU 

Grass, standardized e 10,000-100,000 BAU/mL 1000-4000 BAU 

Short ragweed f 1:10 to 1:20 wt/vol 100,000 AU/mL 6-12 mg of Amb a 1 

1000-4000 AU 

Concentration of Amb a 1 is on the label 

of wt/vol extracts in FDA units 358 

Nonstandardized extract, dog g 1:10 to 1:100 wt/vol 15 mg of Can f 1 

Nonstandardized extracts 1:10 to 1:40 wt/vol or 10,000-40,000 PNU/mL Highest tolerated dose 

a Multiple studies have demonstrated that the efficacious dose for allergen immunotherapy is between 5 and 20 mg of the major allergen per injection. Only 2 

extracts licensed in the United States are standardized based on major allergen content (measured by means of radial immunodiffusion): short ragweed 

(Amb a 1) and cat (Fel d 1). 

b The labeled concentrations for the nonstandardized extracts have no established standards for biologic potency. Nonstandardized extracts are labeled on the 

basis of PNU values or the weight of the source material extracted with a given volume of extracting fluid (wt/vol). 

c There have been no dose-response studies with United States–licensed dust mite extracts, and dosing recommendations in AU value are extrapolated from 

published European studies that used aqueous 349 and alum-precipitated 149,151 extracts. One study designed to investigate the effect of 3 doses of an alumprecipitated 

D pteronyssinus extract (0.7, 7, and 21 mg of Der p 1) found a dose-response effect on efficacy and side effects. 149 The authors suggested the 

optimal maintenance dose was 7 mg of Der p 1. Corresponding doses were based on specific allergen measurements of US commercially available standardized 

extracts provided by manufacturers. Extrapolating effective and safe doses in this manner might not be scientifically valid. D farinae and D pteronyssinus are 

similar in group 1 allergen content according to the FDA’s current reference standards. Appropriate dose reductions would need to be made when combining 

antigens that have a strong degree of cross-reactivity, such as D pteronyssinus and D farinae. 

d The major cat allergen Fed d 1 is reported in FDA units, with 1 Fel d 1 unit equaling approximately 2 to 4 mg of Fel d 1. 55,58,59 The amount of Fel d 1 in 10,000 

BAU/mL ranges from 10 to 19.9 U/mL. One study demonstrated clinical efficacy of a maintenance dose of 4.56 FDA units of Fel d 1 dose in terms of decreased 

cat extract PD 20 , titrated skin test results, and allergen-specific IgE and IgG levels. 350,351 In a recent study that investigated the efficacy in terms of immunologic 

changes of 3 doses of a United States–licensed cat extract (0.6, 3, and 15 mg) demonstrated that a significant effect on titrated skin prick test results, allergenspecific 

IgG4 levels, and CD4 1 /IL-4 levels was only seen in the group treated with 15 mg of Fel d 1, although the 3-mg dose group did demonstrate a significant 

change in titrated skin test response and increase in cat-specific IgG4 levels. 22 

e There have been no dose-response studies with United States–licensed standardized grass extracts. Recommended doses are extrapolated from published 

European studies that have used aqueous, 130 alum-precipitated, 24,161 and calcium phosphate–precipitated grass pollen extracts. 352 One of these studies 

compared a dose of 2 mg with 20 mg of major timothy allergen (Phl p 5) and found clinical efficacy at both doses. 24 The efficacy was greater in the 20 mg of Phl 

p 5 dose, but the systemic reaction rate was also higher in the high-dose group. The package inserts for United States–licensed grass pollen extracts contain a 

table to convert the nonstandardized units (wt/vol and PNU), for which there have been studies that have demonstrated efficacy, into BAU. Extrapolating 

effective and safe doses in this manner might not be scientifically valid. Appropriate dose reductions would need to be made when combining antigens that have 

a strong degree of cross-reactivity, such as the northern pasture grasses (subfamily Pooideae; eg, perennial rye, meadow fescue, or timothy). 

f Ragweed is reported in FDA units, with 1 U of Amb a 1 equaling 1 mg of Amb a 1. The potency units for short ragweed extracts were originally assigned based 

on their Amb a 1 content. Subsequent data suggested that 1 unit of Amb a 1 is equivalent to 1 mg of Amb a 1, and 350 Amb a 1 units/mL is equivalent to 

100,000 BAU/mL. 60 The package insert of the short ragweed 100,000 AU/mL extract states the optimal immunotherapy dose is 2000 AU, with a range of 

1000-4000 AU. One open study of patients with ragweed-induced allergic rhinitis demonstrated a significant improvement in ragweed nasal challenge in 

patients treated with a mean dose of 6 mg of Amb a 1 for 3 to 5 years compared with an untreated matched control group. 45 A ragweed dose-response study 

(0.6, 12.4, and 24.8 mg of Amb a 1) demonstrated efficacy, as measured by nasal challenge, at 12 and 24 mg of Amb a 1. 128 The efficacy of the 24-mg dose was 

not significantly better than the 12-mg dose, and the authors concluded that the optimal dose for ragweed extract was greater than 0.6 mg but not more than 

12.4 mg of Amb a 1. 

g Dog extracts are not standardized. However, one dose-response study with a United States–licensed acetone-precipitated dog extract investigated the efficacy 

of 3 doses (AP dog; Hollister-Stier, Spokane, Wash; 0.6, 3, and 15 mg) in terms of immunologic changes and found the dose of 15 mg of Can f 1 to be most 

efficacious. 25 The 3-mg dose also demonstrated significant efficacy, although not as great as the 15-mg dose. The extract used in the dosing study was assayed at 

160 mg/mL. Subsequent lots have assayed between 128 and 208 mg/mL (average Can f 1, 162 mg/mL [SD 6 26 mg/mL]; information provided by the extract 

manufacturer, Hollister-Stier). 

immunotherapy extract. The evidence is not clear whether 

large local reactions are a potential risk for subsequent 

allergen immunotherapy systemic reactions. 

Published studies do not indicate that an individual 

large local reaction is predictive of a subsequent systemic 

reaction. 179,180 However, one retrospective study found 

that individuals who have a history of repeated large local 

reactions (defined as >25 mm) might be at greater risk for 

a subsequent systemic reaction. 181 

The concept of highest tolerated dose does not apply for 

VIT, and all patients are expected to achieve the full 

recommended dose to achieve the necessary degree of 

protection. There are conflicting data over whether lower 

doses (50 mg) are less effective, but there are also data 

showing that 200 mg is more reliably effective. 245 In the 

case of VIT, patients are asked to tolerate more large local 

reactions to achieve the full dose, even though with inhalant 

immunotherapy the dose can be reduced for such large 

local reactions to minimize patient discomfort. 

Effect of dilution on dose 

Summary Statement 38: Dilution limits the number of 

antigens that can be added to a maintenance concentrate if 

a therapeutic dose is to be delivered. A 

The more antigens that are added to the maintenance 

concentrate, the more there is the potential to dilute other 

antigens in the vaccine, thereby limiting the ability to 

deliver a therapeutic effective dose for any given allergen.

S56 Cox et al 



TABLE XI. Procedure for dilutions from the maintenance concentrate (which is termed 1:1 vol/vol) 

Dilution from maintenance 

concentrate vaccine Volume Volume (mL) Diluent volume (mL) Final volume 

1:1 (vol/vol) 1.0 0.0 1.0 1:1 (vol/vol) 

1:1 (vol/vol) 2.0 8.0 10.0 1:5 (vol/vol) 

1:1 (vol/vol) 1.0 9.0 10.0 1:10 (vol/vol) 

1:10 (vol/vol) 1.0 9.0 10.0 1:100 (vol/vol) 

1:100 (vol/vol) 1.0 9.0 10.0 1:1000 (vol/vol) 

All dilutions are expressed as vol/vol from the maintenance concentrate. 

If the appropriate concentration of each allergen extract is 

added, then adding additional allergens to the maintenance 

concentration will have no effect on the concentration of 

the other allergens, as long as the additional allergens are 

replacing diluent. For example, if the desired maintenance 

concentration for cat is 2000 BAU/mL, 2 mL of the 

manufacturer’s extract (cat, 10,000 BAU/mL) can be 

added to 8 mL of diluent or 8 mL of other allergens, and 

the final concentration of cat will be 2000 BAU/mL in 

both mixtures. Once the diluent is all replaced, addition of 

further allergens will result in undesirable dilution of all 

allergens in the maintenance mixture. 

Dilutions of the maintenance concentrate 

Summary Statement 39: Serial dilutions of the maintenance 

concentrate should be made in preparation for the 

build-up phase of immunotherapy. D 

In preparation for the build-up phase of immunotherapy, 

serial dilutions should be produced from each maintenance 

concentrate. Typically, these are 10-fold dilutions, 

although other dilutions occasionally are used. These 

dilutions should be labeled in terms of vol/vol to indicate 

that they are dilutions derived from the maintenance 

concentrate. For example, serial 10-fold dilutions from 

the maintenance concentrate would be labeled as 1:10 

(vol/vol) or 1:100 (vol/vol). Alternatively, the vial dilutions 

can be labeled in actual units (eg, 1000 BAU or 100 

BAU), but this system can be complicated if allergens with 

different potency units are used (eg, wt/vol, BAU, AU, or 

PNU) and make it difficult to easily interpret the vial label. 

Instructions on how to prepare various allergen extracts 

dilutions are shown in Table XI. If the final volume of the 

diluted allergen immunotherapy extract to be produced is 

10 mL, then one tenth of that final volume, or 1.0 mL, 

should be removed from the more concentrated allergen 

immunotherapy extract and added to a new bottle containing 

9.0 mL of diluent. 

Labeling dilutions 

Summary Statement 40: A consistent uniform labeling 

system for dilutions from the maintenance concentrate 

might reduce errors in administration and therefore is 

recommended. D 

During the build-up phase of immunotherapy, a number 

of dilutions of the patient’s maintenance concentrate are 

needed. Use of one labeling system to indicate dilutions 

might help to avoid administration errors (Table XII). In 

TABLE XII. Suggested nomenclature for labeling dilutions 

from the maintenance concentrate 

Dilution from 

maintenance concentrate Vol/vol label No. Color 

Maintenance concentrate 1:1 1 Red 

10-fold 1:10 2 Yellow 

100-fold 1:100 3 Blue 

1000-fold 1:1000 4 Green 

10,000-fold 1:10,000 5 Silver 

addition to the labeled dilution from the maintenance concentrate 

(vol/vol), a numbering system, a color-coding 

system, or an alphabetical system should be used. If this 

uniform labels system is used, it is essential that it be 

used in the same way by all physicians to reduce potential 

administration errors by staff unfamiliar with the labeling 

system. If the current labeling system is different, the transition 

toward the uniform labeling system should be gradually 

phased in to reduce potential errors, and the staff 

involved with preparation and administration of allergen 

immunotherapy should be involved with the planning of 

this transition. 

If a numbering system is used, the highest concentration 

should be numbered 1. This is necessary to provide 

consistency in labeling because if larger numbers are 

used to indicate more concentrated extracts, the number of 

the maintenance concentrate would vary from patient to 

patient depending on the number of dilutions made. If a 

color-coding system is used, it should be consistent (eg, 

the highest concentration should be red, the next highest 

yellow, followed by blue, green, and silver in that order) 

(Figs 3 and 4). 

Regardless of the labeling system used for indicating 

dilutions from the maintenance concentrate, the specific 

contents of each allergen immunotherapy extract should 

be listed separately. The volume and concentration of each 

of its constituents should be listed on the immunotherapy 

prescription form. 

Consistency is essential as a basis for adoption of a 

standardized system. Some allergists/immunologists, 

however, have found it helpful to use letters for designating 

different component mixtures of extracts (eg, trees [T], 

grasses [G], and molds [M] [see Appendix 2]).



Cox et al S57 

Individualized treatment vials 

Summary Statement 41: Administration of an incorrect 

injection is a potential risk of allergen immunotherapy. An 

incorrect injection is an injection given to the wrong 

patient or a correct patient receiving an injection of an 

incorrect dose. 

A customized individual maintenance concentrate of 

the allergen immunotherapy extract and serial dilutions, 

whether a single extract or a mixture of extracts, prepared 

and labeled with the patient’s name and birth date might 

reduce the risk of incorrect (wrong patient) injection. The 

mixing of antigens in a syringe is not recommended 

because of the potential for cross-contamination of 

extracts. C 

Individually prepared and labeled vials are recommended 

because they have several potential advantages over 

shared vials (ie, vials of allergen extract used for multiple 

patients). Labels on patient-specific vials can provide at 

least 2 patient identifiers (birth date and patient name), 

which would be consistent with the recommendations of 

the Joint Commission on Accreditation of Health Care 

Organizations National Patient Safety Goals: ‘‘Goal 1: 

Improve the accuracy of patient identification by using at 

least two patient identifiers when providing care, treatment 

or services.’’ 5 The risk of errors of administration might be 

reduced because the individually prepared allergen immunotherapy 

vials labeled with the patient’s name and birth 

date will allow the person administering the extract and 

the patient an opportunity to verify the name/birth date 

on the label before administration of the injection. 4,5 

In a survey of 1717 allergists endorsed by the AAAAI 

and JCAAI, 57% of the 476 respondents reported at least 

one wrong-patient injection, and 74% of the 473 respondents 

reported at least one wrong-dose injection. 4 The 

incorrect injections resulted in 1 death, 29 hospital 

admissions, and 59 emergency department visits. In addition 

to patient identifiers on vial labels, the authors cited 

several reasons why this might reduce incorrect injection 

errors. One reason was that patient-specific vials can be 

prepared in a quiet laboratory setting, which might provide 

substantially less distraction than the nurse in a room with 

a patient who is trying to concentrate only on drawing up 

the injection correctly. In addition, the specific components 

are mixed once with the preparation of individually 

prepared patient-labeled vials, whereas the mixing would 

be repeated on every injection visit if the allergen extract is 

withdrawn from different stock solutions, as it is in the 

off-the-board method. For safety reasons and to avoid 

cross-mixing of allergens removed from the manufacturer’s 

extract, the mixing of antigens in the syringe (off 

the board) is not recommended. 

Some allergists/immunologists prefer to administer 

immunotherapy doses drawn directly from a single stock 

dilution of individual allergens or common mixes (shared 

specific patient vials). In this way the immunotherapy dose 

is transferred to the patient without cross-contamination. If 

shared-patient (eg, mixed vespids and dust mite mix) vials 

are used, it is essential that policies and procedures are 

developed to verify that the correct dose from the correct 

vial is administered to the correct patient. 

Starting doses 

Summary Statement 42: The starting dose for build-up 

is usually a 1000- or 10,000-fold dilution of the maintenance 

concentrate, although a lower starting dose might be 

advisable for highly sensitive patients. D 

There are 2 phases of allergen immunotherapy administration: 

the initial build-up phase, when the dose and 

concentration of allergen immunotherapy extract are 

slowly increased, and the maintenance phase, when the 

patient receives an effective therapeutic dose over a period 

of time. If the starting dose is too dilute, an unnecessarily 

large number of injections will be needed, resulting in a 

delay in achieving a therapeutically effective dose. On the 

other hand, if the starting dose is too concentrated, the 

patient might be at increased risk of having a systemic 

reaction. 

When choosing the starting dose, most allergists/immunologists 

start at a dilution of the maintenance concentrate 

that is appropriate based on the sensitivity of the 

patient to the allergens in the extract, which in turn is based 

on the history and skin test reactivity. 

Common starting dilutions from the maintenance concentrate 

are 1:10,000 (vol/vol) or 1:1000 (vol/vol), although 

more diluted concentrations frequently are used for 

patients who are highly sensitive, as indicated by history 

or skin test reaction (see Appendix 3 for an example of a 

conventional immunotherapy schedule). 

Frequency of build-up injections 

Summary Statement 43: The frequency of allergen 

immunotherapy administration during the build-up phase 

is usually 1 to 2 injections per week. D 

A number of schedules are used for the build-up phase 

of immunotherapy. The most commonly used schedule is 

for increasing doses of allergen immunotherapy extract to 

be administered 1 to 2 times per week. This weekly 

schedule is recommended in most of the allergen extract 

package inserts. With this schedule, a typical patient can 

expect to reach a maintenance dose in 4 to 6 months, 

depending on the starting dilution and the occurrence of 

reactions. It is acceptable for patients to receive injections 

more frequently, provided there is adequate spacing 

between injections. The interval between injections is 

empiric but might be as short as 1 day without any increase 

in the occurrence of systemic reactions 262 if there is some 

urgency to achieve a maintenance dose (eg, allergy season 

is approaching) or for practical reasons (eg, patient’s 

schedule). Alternatively, treatment schedules can be 

used that more rapidly achieve maintenance dosing. 

These cluster and rush dosing schedules are discussed in 

Summary Statements 47 through 49. 

Allergen immunotherapy extracts used during the 

build-up phase usually consist of three or four 10-fold 

dilutions of the maintenance concentrate. The volume 

generally is increased at a rate that depends on a number 

of factors, including (1) the patient’s sensitivity to the

S58 Cox et al 



extract, (2) the history of prior reactions, and (3) the 

concentration being delivered (with smaller percentage 

increments being given at higher concentrations). 

Dose adjustments for systemic reactions 

Summary Statement 44: The dose of allergen immunotherapy 

extract should be appropriately reduced after a 

systemic reaction if immunotherapy is continued. D 

It is customary to either reduce the dose if a systemic 

reaction has occurred or consider discontinuation of 

immunotherapy, especially if the reaction has been severe. 

Although there are no evidence-based guidelines on dose 

adjustment after a systemic reaction, many allergists/ 

immunologists reduce the dose to one that was previously 

tolerated or an even lower dose if the reaction was severe. 

Once the patient tolerates a reduced dose, a cautious 

increase in subsequent doses can be attempted. It is 

important for the physician who prescribed the allergen 

immunotherapy extract to review the course of immunotherapy 

to determine whether the benefit/risk ratio justifies 

continuation of immunotherapy. 

Reductions during periods of exacerbation 

of symptoms 

Summary Statement 45: Immunotherapy given during 

periods when the patient is exposed to increased levels of 

allergen to which they are sensitive might be associated 

with an increased risk of a systemic reaction. Consider not 

increasing or even reducing the immunotherapy dose in 

highly sensitive patients during the time period when they 

are exposed to increased levels of allergen, especially if 

they are experiencing an exacerbation of their symptoms. C 

Immunotherapy administered during periods of exacerbation 

of symptoms is considered a risk factor for 

immunotherapy. 17,184 Injections administered during periods 

when a patient is exposed to increased levels of allergen 

to which they are sensitive might be associated with an 

increased risk of a systemic reaction, especially if the 

patient is experiencing a significant exacerbation of symptoms 

and, in particular, asthma symptoms. 184 Therefore it 

is reasonable to consider not increasing or even reducing 

the dose of the allergen immunotherapy extract during seasons 

when the patient is exposed to increased levels of 

allergen to which they are sensitive, especially if their 

symptoms are poorly controlled. 

Dose adjustments for late injections 

Summary Statement 46: It is customary to reduce the 

dose of allergen immunotherapy extract when the interval 

between injections is prolonged. D 

During the build-up phase, it is customary to repeat or 

even reduce the dose of allergen immunotherapy extract if 

there has been a substantial time interval between injections. 

This depends on (1) the concentration of allergen 

immunotherapy extract that is to be administered, (2) 

whether there is a previous history of systemic reactions, 

and (3) the degree of variation from the prescribed interval 

of time, with longer intervals since the last injection 

leading to greater reductions in the dose to be administered 

(see Appendix 4 for an example of a dose-modification 

regimen for gaps in treatment). 

Cluster schedules 

Summary Statement 47: With cluster immunotherapy, 

2 or more injections are administered per visit to achieve a 

maintenance dose more rapidly than with conventional 

schedules. C 

Cluster schedules are designed to accelerate the buildup 

phase of immunotherapy. Cluster immunotherapy 

usually is characterized by visits for administration of 

allergen immunotherapy extract 1 or 2 times per week 

with a schedule that contains fewer total injections than 

are used with conventional immunotherapy. With cluster 

immunotherapy, 2 or more injections are given per visit on 

nonconsecutive days (see Appendix 5). 22,26 The injections 

are typically given at 30-minute intervals, but longer intervals 

have also been used in some protocols. This schedule 

can permit a patient to reach a maintenance dose in as brief 

a period of time as 4 weeks. The cluster schedule is associated 

with the same or a slightly increased frequency of 

systemic reactions compared with immunotherapy administered 

with more conventional schedules. 145,263-266 The 

occurrence of both local and systemic reactions to cluster 

immunotherapy can be reduced with administration of an 

antihistamine 2 hours before dosing. 267 

Rush schedules 

Summary Statement 48: Rush schedules can achieve a 

maintenance dose more quickly than weekly schedules. A 

Rush schedules are more rapid than cluster immunotherapy. 

An early study used a schedule that permitted 

patients to achieve a maintenance dose in 6 days; however, 

patients were required to remain in the hospital. 268 As experience 

with accelerated forms of immunotherapy was 

acquired, schedules were developed to reach a maintenance 

dose more rapidly. 191,269-272 

The most accelerated schedule that has been described 

for inhalant allergens involves administering 7 injections 

over the course of 4 hours. 273 Ultrarush immunotherapy 

schedules have been described for stinging insect hypersensitivity 

to achieve a maintenance dose in as little as 

3.5 to 4 hours. 274-276 The advantage of a cluster or rush 

schedule is that it permits patients to attain a therapeutically 

effective maintenance dose more rapidly than with a 

conventional schedule. Controlled studies have shown 

symptomatic improvement shortly after reaching maintenance 

doses by using cluster 145,266 and rush 134,277 

schedules. 

Systemic reactions and rush schedules 

Summary Statement 49: Rush schedules are associated 

with an increased risk of systemic reactions. However, 

rush protocols for administration of Hymenoptera VIT 

have not been associated with a similarly high incidence of 

systemic reactions. A 

The advantages of rush immunotherapy come at a cost 

because there is an increased risk of local and systemic 

reactions. Systemic reaction rates have been reported to be



Cox et al S59 

as high as 73% of patients, with the risk of such reactions 

reduced to 27% by premedication in one study. 272 Most 

reactions to rush immunotherapy are not severe, and the 

most common systemic reaction is usually flushing. 273 

Systemic reactions with rush schedules have been 

reported to occur up to 2 hours after the final injection. 

For that reason, individuals receiving rush immunotherapy 

should remain under physician supervision for a 

longer waiting period than the usual 30 minutes recommended 

for conventional schedules (eg, 1.5-3 hours on the 

day of allergen immunotherapy extract administration). 

Rush protocols for administration of Hymenoptera 

venom have not been associated with a similarly high 

incidence of systemic reactions. 274-276,278,279 

Premedication and weekly immunotherapy 

Summary Statement 50: Premedication can reduce the 

frequency of systemic reactions caused by conventional 

immunotherapy. A 

There is concern that antihistamines taken before each 

injection with conventional immunotherapy might mask a 

minor reaction that would otherwise alert a physician to an 

impending systemic reaction. However, one randomized 

controlled study demonstrated that premedication reduced 

the frequency of severe systemic reactions caused by 

conventional immunotherapy and increased the proportion 

of patients who achieved the target maintenance dose. 280 

One study that compared terfenadine premedication with 

placebo premedication during rush VIT demonstrated 

greater clinical efficacy in the terfenadine-premedicated 

group in terms of subsequent responses to field stings or 

sting challenge. 281 There was also a significant difference 

in the systemic reaction rate between the 2 groups: 6 

patients in the placebo-premedicated group had systemic 

reactions, whereas none of the patients in the terfenadinepremedicated 

group had systemic reactions (P 5 .012). 

Unfortunately, patients might still have life-threatening 

anaphylaxis despite premedication treatment. Because 

many patients might take an antihistamine as part of their 

overall allergy management, it is important to determine 

whether they have taken it on the day that they receive 

an allergen immunotherapy extract injection. For consistency 

in interpretation of reactions, it also might be 

desirable that they consistently either take their antihistamine 

or avoid it on days when they receive immunotherapy. 

Other attempts to reduce the occurrence of 

systemic reactions, such as the addition of epinephrine 

to the allergen immunotherapy extract or use of concomitant 

corticosteroids, are not justified and might delay the 

onset of a systemic reaction beyond the waiting time when 

the patient is in the physician’s office, thus increasing 

the risk. 

Premedication with cluster and rush 


Summary Statement 51: Premedication should be given 

before cluster and rush immunotherapy with aeroallergens 

to reduce the rate of systemic reactions. A 

Premedication with a nonsedating antihistamine (loratadine) 

2 hours before the first injection of each visit 

reduced both the number and severity of systemic reactions 

during cluster immunotherapy. 267 Premedication 

with a 3-day course of prednisone, an H 1 histamine receptor 

antagonist, and an H 2 histamine receptor antagonist before 

rush immunotherapy with inhalant allergens reduced 

the risk of a systemic reaction from approximately 73% to 

27% of patients. 272 In one study designed to investigate 

the effect of 12 weeks of premedication with a humanized 

monoclonal anti-IgE antibody (omalizumab) on the safety 

and efficacy of rush immunotherapy, there was a 5-fold 

decrease in the risk of anaphylaxis in the group premedicated 

with omalizumab compared with the placebo premedication 

group. 282 

There are anecdotal reports of reductions in systemic 

reaction rates with the addition of a leukotriene receptor 

antagonist, but there have been no published studies. 

Because the risk of a systemic reaction from rush VIT is 

relatively low, routine premedication before rush VIT is 

usually unnecessary. 274,276,278,279 In a study evaluating 

premedication with antihistamines and steroids for rush 

immunotherapy with imported fire ant venom, there was 

no statistically significant differences in the systemic reaction 

rates between the premedication and placebo premedication 

group (3.6% of the premedication group vs 6.7% of 

the placebo group, P 5 .87). 157 

Maintenance schedules 

Summary Statement 52: Once a patient reaches a 

maintenance dose, the interval between injections often 

can be progressively increased as tolerated up to an 

interval of up to 4 weeks for inhalant allergens and up to 

8 weeks for venom. Some individuals might tolerate 

longer intervals between maintenance dose injections. A 

Once a patient who is receiving inhalant allergen 

immunotherapy reaches a maintenance dose, an interval 

of 2 to 4 weeks between injections is recommended, 

provided clinical improvement is maintained. Some individuals 

might tolerate longer intervals between maintenance 

dose injections. 

The interval between venom injections can be safely 

increased up to 8 weeks in some patients without loss of 

efficacy. In other patients, greater efficacy, fewer reactions, 

or both might occur with shorter intervals between 

injections. Therefore the interval between allergen immunotherapy 

injections should be individualized to provide 

the greatest efficacy and safety for each patient. 

Continuing care 

Time course of improvement. Summary Statement 53: 

Clinical improvement can be demonstrated very shortly 

after the patient reaches a maintenance dose. A 

Clinical improvement can be demonstrated very shortly 

after the patient reaches a maintenance dose. 24,134,143,277 

Improvement might not be observed for a number of reasons, 

including (1) failure to remove significant allergenic 

exposures (eg, a cat), (2) exposure to high levels of

S60 Cox et al 



allergen (eg, pollen or molds), (3) continued exposure to 

nonallergen triggers (eg, tobacco smoke), or (4) incomplete 

identification and treatment of clinically relevant allergens. 

If clinical improvement is not apparent after 

1 year of maintenance therapy, possible reasons for lack 

of efficacy should be evaluated. If none are found, discontinuation 

of immunotherapy should be considered, and 

other treatment options should be pursued. 

Follow-up visits. Summary Statement 54: Patients 

should be evaluated at least every 6 to 12 months while 

they receive immunotherapy. D 

Patients should be evaluated at least every 6 to 12 

months while receiving immunotherapy: 

d to assess efficacy; 

d to implement and reinforce its safe administration and 

to monitor adverse reactions; 

d to assess the patient’s compliance with treatment 

d to determine whether immunotherapy can be discontinued; 

and 

d to determine whether adjustments in immunotherapy 

dosing schedule or allergen content are necessary. 

Patients might need more frequent office visits for 

evaluation and management of immunotherapy (eg, treatment 

of local reactions, systemic reactions, or both or 

changes in their immunotherapy vials or lots) or changes 

in the management of underlying allergic disease or 

comorbid conditions. 

Duration of treatment 

Summary Statement 55a: At present, there are no 

specific tests or clinical markers that will distinguish 

between patients who will relapse and those who will 

remain in long-term clinical remission after discontinuing 

effective inhalant allergen immunotherapy, and the duration 

of treatment should be determined by the physician 

and patient after considering the benefits and risks associated 

with discontinuing or continuing immunotherapy. D 

Summary Statement 55b: Although there are no specific 

tests to distinguish which patients will relapse after 

discontinuing VIT, there are clinical features that are 

associated with a higher chance of relapse, notably a history 

of very severe reaction to a sting, a systemic reaction during 

VIT (to a sting or a venom injection), honeybee venom 

allergy, and treatment duration of less than 5 years. C 

Summary Statement 55c: The patient’s response to 

immunotherapy should be evaluated on a regular basis. A 

decision about continuation of effective immunotherapy 

should generally be made after the initial period of up to 

5 years of treatment. D 

Summary Statement 55d: The severity of disease, 




for any individual patient. D 

Summary Statement 55e: Some patients might experience 

sustained clinical remission of their allergic disease 

after discontinuing immunotherapy, but others might 

relapse. B 

The patient’s response to immunotherapy should be 

evaluated on a regular basis. The severity of disease, 




for any individual patient. If allergen immunotherapy is 

effective, treatment might be continued for longer than 

3 years, depending on the patient’s ongoing response 

to treatment. Some patients experience a prolonged 

remission after discontinuation, but others might relapse 

after discontinuation of immunotherapy. Therefore the 

decision to continue or stop immunotherapy must be 

individualized. 

There have been very few studies designed specifically 

to look at the question of when to discontinue effective 

allergen immunotherapy or the duration of immunotherapy 

efficacy after termination of treatment. The duration of 

allergen immunotherapy efficacy has probably been most 

extensively studied in Hymenoptera hypersensitivity. 

Long-term follow-up studies suggest that a 5-year 

immunotherapy treatment course for Hymenoptera hypersensitivity 

might be sufficient for most allergic individuals. 

283-285 However, relapse rates as high as 15% of 

patients in the 10-year period after discontinuing VIT 

have been reported. 283,285 Nevertheless, systemic reactions 

to stings after discontinuing VIT were generally 

much milder than the pretreatment reactions and were 

rarely severe. Two studies did not find a difference in relapse 

rates between the patients treated for 3 years compared 

with those treated for 5 years, 283,286 but one of the 

studies noted that the small number of patients in the 3- 

year treatment group prevented them from making any 

conclusions about the risk of discontinuing treatment after 

3 years. 283 However, one study found that patients 

who had experienced re-sting reactions after discontinuing 

VIT had received VIT for a significantly shorter 

duration (mean, 43.35 months) than those with continued 

protection (mean, 54.65 months; P



Cox et al S61 

have reported a significant relapse rate within 3 years of 

discontinuing allergen immunotherapy. 

One prospective controlled study was designed to study 

the immunotherapy relapse rate during the 3-year period 

after discontinuation of immunotherapy in 40 asthmatic 

patients who had been treated with immunotherapy with a 

standardized dust mite (D pteronyssinus) extract for 12 to 

96 months. 14 Fifty-five percent of the patients relapsed. 

The duration of efficacy was related to the reduction of 

skin test reactivity at the end of immunotherapy treatment 

(P 5 .003) and the duration of immunotherapy treatment. 

The relapse rate was 62% in the group treated for less than 

35 months compared with 48% in the group treated for 

greater than 36 months (P 5 .04). Prolonged clinical 

efficacy was demonstrated in a double-blind, placebocontrolled 

study of patients with severe grass pollen– 

induced allergic rhinitis who had been treated for 3 to 4 

years with immunotherapy. 13 There was a switch to placebo 

in half of the group (16 patients) after 3 to 4 years 

of immunotherapy, and efficacy parameters were monitored 

over the next 3 years. Seasonal symptom scores and 

the use of rescue medication remained low for 3 to 4 years 

after the discontinuation of immunotherapy, and there was 

no significant difference between patients who continued 

and those who discontinued immunotherapy. These studies 

demonstrate the uncertainty of the long-term benefit of 

inhalant immunotherapy after discontinuation. 

Currently, there are inadequate diagnostic tools available 

to identify which patients will experience a sustained 

clinical remission after discontinuing inhalant immunotherapy, 

and the duration of treatment should be determined 

by the physician and patient after considering the 

benefits and risks associated with discontinuing or continuing 

inhalant immunotherapy. 

A form to document indication for continuation of 

immunotherapy can be found at http://www.aaaai.org or 


Documentation and record keeping. Summary 

Statement 56: The allergen immunotherapy extract contents, 

informed consent for immunotherapy, and administration 

of extracts should be carefully documented. D 

An immunotherapy injection should not be given 

unless adequate documentation is available in the patient’s 

medical record. This also means that patients who receive 

injections in a health care facility other than the office of 

the prescribing physician must have appropriate documentation. 

The recommended documentation for informed 

consent allergy immunotherapy and prescription forms 

can be found in the Appendix (Appendices 6-15), and 

these include examples of immunotherapy prescription 

and administration forms. These forms, along with examples 

of immunotherapy consent and instruction forms, can 

also be found at http://www.aaaai.org. 

Injection techniques. Summary Statement 57: Allergen 

immunotherapy extract injections should be given using a 

1-mL syringe with a 26- to 27-gauge half-inch nonremovable 

needle. C 

Immunotherapy should be given with a 26- to 27-gauge 

syringe with a half-inch nonremovable needle. Syringes 

specifically designed for immunotherapy are available 

from medical supply companies. Although recent 

Occupational Safety and Health Administration guidelines 

mandate the use of safety needles with allergy 

injections, recent publications indicate a potential increase 

in accidental needle sticks with the use of safety needles 

compared with standard syringes. 289-291 

If using shared specific patient vials (stock vials, such as 

mixed vespid or dust mite mix), a single dose should be 

drawn from each vial. Antigens from different vials should 

not be combined in a single syringe. Furthermore, extra 

care is needed to prevent using the wrong stock antigen. 

Summary Statement 58: The injection should be given 

subcutaneously in the posterior portion of the middle third 

of the upper arm. D 

Each immunotherapy injection should be given in the 

posterior portion of the middle third of the upper arm at the 

junction of the deltoid and triceps muscles. This location 

tends to have a greater amount of subcutaneous tissue than 

adjacent areas. The skin should be wiped with an alcohol 

swab before giving the immunotherapy injection. This 

does not sterilize the area, but it does remove gross 

contamination from the skin surface. 

Immunotherapy should be given subcutaneously. 

Subcutaneous injections result in formation of a reservoir 

of allergen immunotherapy extract that is slowly absorbed. 

Absorption that is too rapid, such as after an 

intramuscular injection, could lead to a systemic reaction. 

The skin should be pinched and lifted off of the muscles to 

avoid intramuscular or intravenous injection and to increase 

access to the subcutaneous tissues. 

The syringe should be aspirated to check for blood 

return in the syringe before injecting. If blood is present, 

the syringe should be removed and discarded in an 

appropriate container (‘‘sharps’’ box). Another dose of 

the allergen extract should be drawn into a new syringe 

and a different site chosen for the injection. In theory, 

removal of the syringe when blood is present reduces 

the likelihood of intravenous administration, which could 

lead to a systemic reaction. The syringe should be 

appropriately discarded. A fresh syringe and needle are 

necessary to determine whether a blood vessel has been 

entered. 

The plunger should be depressed at a rate that does not 

result in wheal formation or excessive pain. Mild pressure 

should then be applied to the injection site for about 

1 minute immediately after removal of the needle. This 

reduces the chance of leakage of the allergen extract, 

which could result in a local reaction. 

LOCATION OF ALLERGEN IMMUNOTHERAPY 

ADMINISTRATION 

Physician’s office 

Summary Statement 59: The preferred location for 

administration of allergen immunotherapy is in the office 

of the physician who prepared the patient’s allergen 

immunotherapy extract. D

S62 Cox et al 



The preferred location of allergen immunotherapy 

administration is in the office of the physician who prepared 

the patient’s allergen immunotherapy extract. The physician’s 

office should have the expertise, personnel, and 

procedures in place for the safe and effective administration 

of immunotherapy. However, in many cases it might 

be necessary to administer the allergen immunotherapy 

extract in another physician’s office. Allergen immunotherapy 

should be administered with the same care wherever 

it is administered. A physician or qualified physician 

extender to treat anaphylaxis should be in the immediate 

vicinity when immunotherapy injections are administered. 

Summary Statement 60: Patients at high risk of systemic 

reactions, where possible, should receive immunotherapy 

in the office of the physician who prepared the 

patient’s allergen immunotherapy extract. D 

Patients at high risk of systemic reactions (highly 

sensitive, severe symptoms, comorbid conditions, and 

history of recurrent systemic reactions), where possible, 

should receive immunotherapy in the allergist/immunologist’s 

office. 292 The allergist/immunologist who prepared 

the patient’s allergen immunotherapy extract and 

his or her support staff should have the experience and 

procedures in place for the administration of allergen immunotherapy 

to such patients. 184 The early signs of an allergic 

reaction are more likely to be recognized and early 

treatment initiated, which will decrease the possibility of a 

serious outcome. Modifications might be frequently necessary 

in the patient’s immunotherapy schedule, as well 

as the patients total treatment program. 

Other locations 

Summary Statement 61: Regardless of the location, 

allergen immunotherapy should be administered under the 

supervision of an appropriately trained physician and 

personnel. D 

The physician and personnel administering immunotherapy 

should be aware of the technical aspects of this 

procedure and have available appropriately trained personnel, 

resuscitative equipment/medicines, and storage 

facilities for allergen immunotherapy extract. 292 The 

health care professional and staff should be able to recognize 

early signs and symptoms of anaphylaxis and administer 

emergency medications as necessary. 

The physician and staff should be aware of situations that 

might place the patient at greater risk for systemic reactions 

(eg, concomitant medications that can interfere with 

emergency treatment, such as b-blockers, acute illness, or 

allergy/asthma exacerbations at the time of allergen immunotherapy 

extract injection or poorly controlled asthma). 

Appropriate adjustment of dose should be made as 

clinically indicated. The physician who prepared the 

patient’s allergen immunotherapy extract should provide 

adequately labeled allergen immunotherapy extract vials, 

detailed directions regarding dosage schedule for build-up 

and maintenance, and instructions on adjustments that 

might be necessary under the following circumstances: 

1. when providing patients with new vials; 

2. during seasonal exposure to allergens that are in the 

patient’s allergen vaccine, to which the patient is 

very sensitive, or both; 

3. if the patient has missed injections; and 

4. when reactions occur to the allergen immunotherapy 

extract. 

Any systemic reaction to allergen immunotherapy 

should be treated immediately, and the physician who 

prepared the allergen immunotherapy extract should be 

informed. This might require a return to the allergist/ 

immunologist’s office for treatment and re-evaluation. 

Home administration. Summary Statement 62: In rare 

and exceptional cases, when allergen immunotherapy 

cannot be administered in a medical facility and withholding 

this therapy would result in a serious detriment to 

the patients’ health (eg, VIT for a patient living in a remote 

area), very careful consideration of potential benefits and 

risks of at-home administration of allergen immunotherapy 

should be made on an individual patient basis. If this 

approach is used, informed consent should be obtained 

from the patient, and the person administering the injection 

to the patient must be educated about how to administer 

immunotherapy and recognize and treat anaphylaxis. D 

Allergen immunotherapy should be administered in a 

medical facility with trained staff and medical equipment 

capable of recognizing and treating anaphylaxis. Under 

rare circumstances, when the benefit of allergen immunotherapy 

clearly outweighs the risk of withholding 

immunotherapy (eg, patients with a history of venom 

anaphylaxis living in a remote region), at-home administration 

of allergen immunotherapy can be considered on 

an individual basis. In this instance there should be a 

discussion with the patient with very careful consideration 

of the potential benefits and risks involved in home 

administration and alternatives. Informed consent should 

be obtained from the patient and appropriate family 

members after this discussion. Under these circumstances, 

another adult person should be fully trained to administer 

the injection and to treat anaphylaxis if this should occur. 

It should be noted, however, that the package insert 

approved by the FDA that accompanies all allergen 

extracts, including venom, implies that allergy injections 

should be administered in a clinical setting under the 

supervision of a physician. Intuitively, the risk from 

administering allergenic extracts outside a clinical setting 

would appear to be greater. Recognition and treatment of 

anaphylaxis might be delayed or less effective than in a 

clinical setting in which supports (personnel, medications, 

supplies, and equipment) are more optimal for encouraging 

prompt recognition and treatment of anaphylaxis 

(Table V). Home administration should only be considered 

in the rare circumstance when the benefit of immunotherapy 

clearly outweighs the risks. Frequent or routine 

prescription of home immunotherapy is not appropriate 

under any circumstances. 

Summary Statement 63: If a patient on immunotherapy 

transfers from one physician to another, a decision must be 

made by the physician to whom the patient has transferred



Cox et al S63 

as to whether to continue immunotherapy. If immunotherapy 

is continued, a decision must then be made about 

whether to continue an unchanged immunotherapy program 

initiated by the previous physician or to prepare a 

new immunotherapy program. D 

Summary Statement 64: If a patient transfers from one 

physician to another and continues on an immunotherapy 

program without changes to either the schedule or allergen 

immunotherapy extract, the risk of a systemic reaction is 

not substantially increased. D 

Summary Statement 65: A full, clear, and detailed 

documentation of the patient’s schedule must accompany 

a patient when he or she transfers responsibility for their 

immunotherapy program from one physician to another. 

In addition, a record of previous response to and compliance 

with this program should be communicated to the 

patient’s new physician. D 

Summary Statement 66: An allergen immunotherapy 

extract must be considered different from a clinical 

standpoint if there is any change in the constituents of 

the extract. These include changes in the lot, manufacturer, 

allergen extract type (eg, aqueous, glycerinated, 

standardized, and nonstandardized), and/or components 

or relative amounts in the mixture. D 

Summary Statement 67: There is an increased risk of a 

systemic reaction in a patient who transfers from one 

physician to another if the immunotherapy extract is 

changed because of the significant variability in content 

and potency of allergen extracts. The risk of a systemic 

reaction with a different extracts might be greater with 

nonstandardized extracts and with extracts that contain 

mixtures of allergens. D 

Summary Statement 68: Immunotherapy with a different 

extract should be conducted cautiously. If there is 

inadequate information to support continuing with the 

previous immunotherapy program, re-evaluation might be 

necessary, and a new schedule and allergen immunotherapy 

extract might need to be prepared. D 

Patients often transfer from one physician (previous 

physician) to another (current physician) while receiving 

allergen immunotherapy. When this occurs, a decision must 

be made by the current physician about whether to continue 

immunotherapy and, if so, what allergen immunotherapy 

extract and schedule should be used: the one that the patient 

brought from the previous physician (ie, an unchanged 

immunotherapy program) or one to be prepared by the 

current physician (ie, a new immunotherapy program). 

If the patient transfers from one physician to another and 

continues on the previous immunotherapy program without 

changing either the schedule or allergen immunotherapy 

extract, he or she is not at substantially increased risk 

of having systemic reactions as long as there is a full, clear, 

and detailed documentation of the patient’s previous 

schedule and the contents of the allergen immunotherapy 

extract (see Appendices 7, 8, 11, 12, and 14 for examples of 

allergen immunotherapy prescription and administration 

forms and documentation guidelines for allergen immunotherapy 

forms). In addition, the patient’s previous response 

to and compliance with this program must accompany the 

patient who transfers responsibility for the immunotherapy 

program from one physician to another. This should include 

a record of any reactions to immunotherapy and how 

they were managed, as well as the patient’s response to immunotherapy. 

Under these circumstances, immunotherapy 

can be continued with the allergen immunotherapy extract 

that the patient was previously receiving if (1) the previous 

physician is willing and able to continue to provide the 

patient with a schedule and the allergen immunotherapy 

extract, (2) the patient has shown significant improvement 

on this immunotherapy program, and (3) the contents of 

the allergen immunotherapy extract are appropriate for 

the area in which the patient is now living. 

An allergen immunotherapy extract must be considered 

different from a clinical standpoint if there is any change in 

the constituents of the allergen immunotherapy extract. 

These include changes in the lot, manufacturer, vaccine 

type (eg, aqueous, glycerinated, standardized, and nonstandardized), 

and component allergens and their respective 

concentrations in the allergen immunotherapy extract. 

There is increased risk of a systemic reaction if the allergen 

immunotherapy extract is changed and the patient’s dose is 

not modified. This increased risk is due to the significant 

variability in content and potency of extracts and the 

variability in methods used by physicians to prepare the 

patient’s maintenance concentrate and its dilutions. For 

example, the strength of a given concentration of nonstandardized 

extracts might vary significantly from vial to 

vial. The risk of systemic reactions in such a situation 

might be greater with nonstandardized extracts and allergen 

immunotherapy extracts that contain mixtures of allergens. 

Therefore if the allergen immunotherapy extract is to be 

changed, the patient might need to be retested for specific 

IgE to the appropriate allergens and started on an immunotherapy 

schedule and immunotherapy extract formulation 

that is appropriate. In this situation the starting dose 

should be comparable with the initial dose that would be 

used if the patient had not previously been receiving 

immunotherapy. If the information that accompanies the 

patient is thorough, the current physician can prepare an 

allergen immunotherapy extract identical or almost identical 

to that provided by the previous physician. In such a 

case, all that might be required is a decrease in the dose 

from the patient’s previous injection provided the interval 

of time since the last injection has not been too long. For 

lot changes from the same manufacturer, the physician can 

consider decreasing the dose by 50% to 90%. For changes 

in manufacturer and nonstandardized extracts, a greater 

decrease in dose might be necessary. 

SPECIAL CONSIDERATIONS IN 

IMMUNOTHERAPY 

Allergen immunotherapy in children 

Summary Statement 69: Immunotherapy for children is 

effective and often well tolerated. Therefore immunotherapy 

should be considered (along with pharmacotherapy 

and allergen avoidance) in the management of children

S64 Cox et al 



with allergic rhinitis, allergic rhinoconjunctivitis, allergic 

asthma, and stinging insect hypersensitivity. It might 

prevent the new onset of allergen sensitivities or progression 

to asthma. A 

Immunotherapy for children has been shown to be effective 

and often well tolerated, 137,242 although at least one 

study did not show efficacy. 293 However, this study did 

not include an important allergen, cockroach, which has 

been shown to correlate with asthma severity in other studies 

of inner-city asthmatic children. 294 In general, the clinical 

indications for immunotherapy for allergic rhinitis and 

asthma are similar for adults and children (see the Patient 

selection section and Table VII). In recent studies children 

receiving allergen immunotherapy have demonstrated: 

1. improvement in symptom control for 

asthma 117,119,121,122 and allergic rhinitis 118 ; 

2. increased PC 20 to histamine 121 ; 

3. increased PC 20 to cat and house dust mite 

allergens 121,149 ; 

4. decreased risk of development of asthma 6,9,163-165 ; 

5. decreased development of new sensitivities 120,166 ; and 

6. modification in release of mediators in children receiving 

immunotherapy that correlates with decreased 

clinical symptoms. 123 

Summary Statement 70: Children under 5 years of 

age can have difficulty cooperating with an immunotherapy 

program. Therefore the physician who evaluates 

the patient must consider the benefits and risks of immunotherapy 

and individualize treatment in patients under 

the age of 5 years. A 

Although there is some disagreement about the role of 

allergen immunotherapy in children under the age of 5 

years, there have been reports of effectiveness of allergen 

immunotherapy in this age group. 117,122 In children with 

allergic rhinitis, allergen immunotherapy might prevent 

the development of asthma. 6,9,163-165 However, allergen 

immunotherapy for inhalant allergens is usually not considered 

necessary in infants and toddlers because (1) there 

is difficulty in communicating with the child regarding 

systemic reactions, and (2) injections can be traumatic to 

very young children. Therefore each case should be considered 

individually by weighing the benefits and risks. 

For children who have had a history of anaphylaxis to 

stinging insects or have severe allergic disease, the benefits 

of allergen immunotherapy might outweigh the risks. 

Immunotherapy in pregnancy 


might be continued but is usually not initiated in the 

pregnant patient. C 

The physician must be aware of the benefits and risks of 

immunotherapy in pregnant patients. The recommended 

precautions for prevention of adverse reactions are especially 

important in the pregnant patient. Allergen immunotherapy 

is effective in the pregnant patient. Thus allergen 

immunotherapy maintenance doses can be continued 

during pregnancy. Allergen immunotherapy is usually not 

initiated during pregnancy because of risks associated with 

systemic reactions and their treatment (ie, spontaneous 

abortion, premature labor, or fetal hypoxia). The initiation 

of immunotherapy might be considered during pregnancy 

when the clinical indication for immunotherapy is a highrisk 

medical condition, such as anaphylaxis caused by 

Hymenoptera hypersensitivity. When a patient receiving 

immunotherapy reports that she is pregnant, the dose of 

immunotherapy is usually not increased, and the patient is 

maintained on the dose that she is receiving at that time. 

Immunotherapy in the elderly patient 

Summary Statement 72: Comorbid medical conditions 

and certain medication use might increase the risk from 

immunotherapy in elderly patients. Therefore special 

consideration must be given to the benefits and risks of 

immunotherapy in this patient population. D 

Immunotherapy might be considered in the treatment of 

the elderly patient, but the benefit/risk assessment must be 

evaluated carefully in this population. Older patients 

might be taking medications that could make treatment 

of anaphylaxis with epinephrine more difficult, such as 

b-blockers, or might have significant comorbid medical 

conditions, such as hypertension, coronary artery disease, 

cerebrovascular disease, and/or cardiac arrhythmias. 

However, elderly patients may also benefit from allergen 

immunotherapy and age alone should not preclude the 

consideration of allergen immunotherapy. 295 

Immunotherapy in patients with 

immunodeficiency and autoimmune 

disorders 

Summary Statement 73: Immunotherapy can be considered 

in patients with immunodeficiency and autoimmune 

disorders. D 

There are no controlled studies about the effectiveness 

or risks associated with immunotherapy in patients with 

immunodeficiency or autoimmune disorders. Therefore 

the decision to begin immunotherapy in patients with 

major humoral or cellular immune defects must be individualized. 

Concern about the increased risk of immunotherapy 

in such patients is largely hypothetical. 

Although concern about the safety of allergen immunotherapy 

in patients with autoimmune disease or connective 

tissue disease has been raised in the past, there is 

no substantive evidence that such treatment is harmful in 

these diseases. Therefore the benefits and risks of allergen 

immunotherapy in patients with autoimmune or connective 

tissue must be assessed on an individual basis. 

ALTERNATIVE ROUTES OF 

IMMUNOTHERAPY 

Sublingual and oral immunotherapy 

Summary Statement 74: Optimal high-dose sublingual 

swallow and oral immunotherapies are under clinical 

investigation in the United States. Studies of oral immunotherapy 

have demonstrated conflicting results. Highdose 

sublingual immunotherapy has been found to be



Cox et al S65 

effective in many studies of adults and children with 

allergic rhinitis and asthma, but a consistent relationship 

among allergen dose, treatment duration, and clinical 

efficacy has not been established. However, there is no 

FDA-approved formulation for sublingual or oral immunotherapy 

in the United States. Therefore sublingual and 

oral immunotherapy should be considered investigational 

at this time. B 

Alternative routes of administration of allergen immunotherapy 

are ‘‘a viable alternative to parenteral injection 

therapy’’ in some cases. 106,296 Studies of oral immunotherapy 

have provided conflicting results for ragweed, 297 

birch, 298 and cat 299 immunotherapy. The present dosage of 

oral immunotherapy extract is 20 to 200 times the parenteral 

injected dosage, which requires a cost assessment for 

this type of therapy. Furthermore, adverse effects have included 

gastrointestinal and oral reactions (50% in 1 study) 

that might preclude home therapy. Oral immunotherapy 

should be considered investigational at this time. 

Optimal-dose (high-dose) sublingual swallow immunotherapy 

is effective in adults and children. 300-304 In a 

study of 855 patients with grass pollen allergy and allergic 

rhinitis randomized to placebo or one of 3 grass tablet 

doses, there was a significant reduction in symptom and 

medication scores in the highest-dose subgroup, who 

were treated for at least 8 weeks before the grass pollen 

season, compared with the placebo group (symptoms, 

21%, P 5 .0020; medication use, 29%, P 5 .0120). 303 

Sublingual allergen studies have evaluated house dust, 

olive pollen, grass pollen, ragweed, birch, cat, latex, 

Alternaria species, and Parietaria judaica. 305-313 

Sublingual immunotherapy has been shown to be effective 

in patients sensitized to 2 non–cross-reacting allergens, 

grass and birch. 314 It has been noted that the allergen is 

not degraded by saliva and that there is no direct sublingual 

absorption of allergen. Radiolabeled allergen has 

been detected after 48 hours in the sublingual region. 

315,316 Alternative protocols, such as rush and ultrarush 

(20 minutes) sublingual swallow 307,316,318 and no 

induction (build-up) phase, 301,303,317,319,320 have been 

studied. Several studies have suggested a relationship 

between dose and efficacy with sublingual immunotherapy, 

303,310,321 but a consistent relationship among allergen 

dose, treatment duration, and clinical efficacy has not been 

established. The majority of sublingual studies have demonstrated 

some evidence of clinical efficacy in the form of 

either improved symptom scores, medication scores, or 

both, but approximately 35% of the randomized, doubleblind, 

placebo-controlled studies did not demonstrate 

efficacy in either parameter during the first year of treatment. 

322 Further studies are needed to confirm the optimal 

dose for sublingual immunotherapy. 

One of the potential advantages of sublingual immunotherapy 

is that it appears to be safe, even at very high 

doses (up to 500 times the usual monthly subcutaneous 

dose), and to be associated with a lower incidence of 

serious side effects. 310,320,323 This appears to apply to 

young children (

S66 Cox et al 



FIG 4. Sample set of color-coded vials of allergen vaccine. 

There is currently no FDA-approved formulation for 

sublingual immunotherapy in the United States at this 

time, and this modality should be considered investigational. 

Current investigation of sublingual immunotherapy 

should not be confused with low-dose sublingual immunotherapy 

based on provocation neutralization testing or 

Rinkel-type skin testing. 

Intranasal immunotherapy 

Summary Statement 75: Intranasal immunotherapy is 

undergoing evaluation in children and adults with allergic 

rhinitis, but there is no FDA-approved formulation for this 

modality in the United States. B 

Based on controlled, well-designed studies, intranasal 

immunotherapy has been shown to improve the nasal 

symptoms of rhinitis. 330 Intranasal dry powder extract immunotherapy 

has been studied in grass, 330 birch, 331 P judaica, 

332-334 and house dust mite 335 allergy. Clinical 

efficacy was noted in all of these studies. Nasal reactivity 

to allergen challenge was reduced, and only minor side effects 

were noted in 2 of the above studies. A 3-year study 

with P judaica reported to provide persistent benefits for 

up to 12 months after conclusion of allergen immunotherapy. 

333 Local administration of nasal allergen in an aqueous 

solution for immunotherapy might be limited by the 

local side effects. Further studies in both pediatric and 

adult groups are needed. In human studies the antigen 

has been noted to appear in the serum within 15 to 30 minutes 

of administration, with a peak level occurring within 

2 to 3 hours. 315 Some allergens have been reported to be 

retained in the nasal mucosa for up to 48 hours after administration. 

Intranasal immunotherapy is not currently 

available in the United States but has gained some acceptance 

in other parts of the world. 

Immunotherapy techniques that are not 

recommended 

Summary Statement 76: Low-dose immunotherapy, 

enzyme-potentiated immunotherapy, and immunotherapy 

(parenteral or sublingual) based on provocation-neutralization 

testing are not recommended. D 

Low-dose regimens, including coseasonal low-dose 

immunotherapy for aeroallergens and the Rinkel lowdose 

titration techniques, are not effective. 27,28 Immunotherapy 

based on provocation–neutralization testing with 

food and aeroallergens and enzyme-potentiated desensitization 

is not effective. 336 

FUTURE TRENDS IN IMMUNOTHERAPY 

Therapy with aeroallergen extracts will become more 

uniform (as is the current practice for insect venoms) as 

greater numbers of biologically standardized allergen 

extracts become available. The actual number of commercially 

available allergen extracts will be reduced based on 

consensus agreements about the regional prevalence of 

aeroallergens, their cross-allergenicity, and the relevance of 

their effect on human health in specific locales. Novel routes 

for more effective, convenient, and safer allergen immunotherapy 

are being investigated throughout the world. 

For example, the sublingual route of administering 

allergen immunotherapy has been studied extensively in 

Europe. A meta-analysis confirmed its clinical effectiveness 

in allergic rhinitis, 302 and it has been reported to be 

effective in asthma as well. 337 Sublingual immunotherapy 

appears to have a very low risk of serious life-threatening 

systemic side effects, which might allow for home administration. 

324,338 In some studies the clinical benefits of sublingual 

immunotherapy were not significant until the 

second year of treatment, 306,339 and comparisons suggest 

that the magnitude of the clinical benefit of sublingual immunotherapy 

might not be as great as that of subcutaneous 

immunotherapy. 311 

Trials with non–IgE-binding peptides containing T-cell 

stimulating peptides have been reported. 340 Site-directed 

mutagenesis has produced allergens with decreased 

IgE-binding capacity without decreased T-cell 

responses. 341,342 

Immunostimulatory sequences mimicking bacterial 

and viral DNA have been prepared that stimulate the 

innate immune system to direct T-cell responses toward



Cox et al S67 

T H 1 rather than T H 2 phenotypes. 343 The results of clinical 

trials with a conjugate of the immunostimulatory sequence 

to the major allergen of ragweed, Amb a 1 (AIC), have 

been reported. 34,343 In a double-blind, placebo-controlled 

study of 25 adults who received 6 weekly injections of the 

AIC or placebo vaccine before ragweed season, the AIC 

group had better peak-season rhinitis scores on the visual 

analog scale (P 5 .006), peak-season daily nasal symptom 

diary scores (P 5 .02), and midseason overall quality-oflife 

scores (P 5 .05) than the placebo group during the first 

ragweed season, and this effect was observed in the subsequent 

ragweed season. 344 

Humanized anti-IgE mAb has been shown to have 

clinical effects in both allergic rhinitis and asthma. 345-348 

Theoretically, this new therapeutic modality could be 

used as protective cover for clinical applications of rapid 

forms of immunotherapy. It is possible that preadministration 

of anti-IgE could provide a more effective protective 

effect than premedication with antihistamines and therefore 

permit a rush allergen immunotherapeutic regimen 

with reduced risk of serious systemic reactions. 282 

AUTHOR’S NOTE 

Examples of allergen immunotherapy prescription and 

administration forms, immunotherapy labels, conventional 

and cluster build-up schedules, immunotherapy 

dose adjustments for unscheduled gaps in allergen immunotherapy 

injection intervals, summaries of documentation 

guidelines, systemic reaction reporting sheets, and 2 

systemic reaction grading systems (the European 

Academy of Allergy and Clinical Immunology’s grading 

of severity for systemic side effects and the Portnoy 

method for numeric grading of reactions to allergen 

immunotherapy) can be found in the Appendix section. 

These forms can also be found along with examples of 

immunotherapy instruction and consent forms, preinjection 

health questionnaires, and indications for beginning 

and continuing immunotherapy forms at www.aaaai.org. 

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307. Passalacqua G, Albano M, Riccio A, et al. Clinical and immunologic 

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for a dose-response relationship. Int Arch Allergy Immunol 2003;131: 

111-8. Ib 

311. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. 

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312. Bernardini R, Campodonico P, Burastero S, et al. Sublingual immunotherapy 

with a latex extract in paediatric patients: a double-blind, placebo-controlled 

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313. Cistero Bahima A, Sastre J, Enrique E, et al. Tolerance and effects on 

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314. Marogna M, Spadolini I, Massolo A, et al. Effects of sublingual immunotherapy 

for multiple or single allergens in polysensitized patients. 

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315. Bagnasco M, Mariani G, Passalacqua G, et al. Absorption and distribution 

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by noninjectable routes in healthy human beings. J Allergy Clin 

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316. Passalacqua G, Altrinetti V, Mariani G, et al. Pharmacokinetics of radiolabelled 

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319. Dahl R, Stender A, Rak S. Specific immunotherapy with SQ standardized 

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trial. Allergy 2006;61:181-4. Ib 

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324. Agostinis F, Tellarini L, Canonica GW, Falagiani P, Passalacqua G. 

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325. Fiocchi A, Pajno G, La Grutta S, et al. Safety of sublingual-swallow immunotherapy 

in children aged 3 to 7 years. Ann Allergy Asthma Immunol 

2005;95:254-8. III 

326. Di Rienzo V, Pagani A, Parmiani S, Passalacqua G, Canonica GW. 

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in pediatric patients. Allergy 1999;54:1110-3. III 

327. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingual immunotherapy. 

Allergy 2006;1236-7. 

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sublingual immunotherapy. Allergy 2006;61:1235. 

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pollen allergen sublingual immunotherapy. Allergy 2007;62: 

567-8. 

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evaluation of local intranasal immunotherapy with aqueous and allergoid 

grass extracts. J Allergy Clin Immunol 1984;74:694-700. IIa 

331. Andri L, Senna G, Andri G, et al. Local nasal immunotherapy for birch 

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332. Andri L, Senna GE, Betteli C, et al. Local nasal immunotherapy in allergic 

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1992;47:318-23. Ib 

333. Passalacqua G, Albano M, Pronzato C, et al. Long-term follow-up of 

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334. Passalacqua G, Albano M, Ruffoni S, et al. Nasal immunotherapy to 

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335. Andri L, Senna G, Betteli C, Givanni S, Andri G, Falagiani P. Local 

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of a powder extract. J Allergy Clin Immunol 1993;91:987-96. Ib 

336. Radcliffe MJ, Lewith GT, Turner RG, Prescott P, Church MK, Holgate ST. 

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337. Ippoliti F, De Santis W, Volterrani A, et al. Immunomodulation during 

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safety of sublingual-swallow immunotherapy: an analysis of published 

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340. Norman PS, Ohman JL Jr, Long AA, et al. Treatment of cat allergy with 

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341. Schramm G, Kahlert H, Suck R, et al. ‘‘Allergen engineering’’: variants of 

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342. Smith AM, Chapman MD, Taketomi EA, Platts-Mills TA, Sung SS. Recombinant 

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343. Jain VV, Kitagaki K, Kline JN. CpG DNA and immunotherapy of allergic 

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344. Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a 

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345. Adelroth E, Rak S, Haahtela T, et al. Recombinant humanized mAb- 

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placebo-controlled study. Clin Exp Allergy 2001;31:988-96.



Cox et al S75 

APPENDIX 1. American College of Medical Quality’s policy on the development and use of practice parameters for 

medical quality decision-making 1 

Practice parameters are strategies for patient management developed to assist health care professionals in clinical decision making. Practice 

parameters include standards, guidelines, and other patient management strategies. Standards are accepted principles for patient management. 

Guidelines are recommendations for patient management that identify a particular management strategy or a range of management strategies. 

Other strategies for patient management include practice policies and practice options. Practice parameters are to be used as screening tools to 

identify possible deviations from the applicable standards of care. Such parameters are not to be used as absolute standards or to profile or 

report on health care personnel. Parameters are designed to trigger a process in which possible deviations from the standard of care are identified 

as outlier practice patterns. Once a deviation from the parameter is identified, such a deviation should be referred to the appropriate 

qualified physician advisor or reviewer for a determination of medical necessity that conforms to the applicable standard of care. Parameters 

used in the day-to-day practice of clinical medicine should be clinically relevant. They should not be considered as substitutes for the standard 

of care but might contribute to its formulation. 

Practice parameters must be developed, designed, and implemented only by board-certified, clinically practicing, specialty-matched physician 

advisors/reviewers with unrestricted medical licenses. Qualified nonphysicians might participate in the development of these parameters 

only in the areas in which their clinical expertise based on the standard of care is applicable. The health care personnel who develop these 

parameters should sign their names and date the final version as evidence of their participation and support. Practice parameters must be based 

on sound scientific research findings, professional literature, clinical experience and appropriate well-recognized methodologies and reflect 

professionally recognized national standards of care practiced in the clinical community of medicine. The development procedures followed, 

the participants involved, the evidence used, the assumptions and rationales accepted, and the analytic methods used should be meticulously 

documented, described, and made publicly available for national peer review. Parameters should be updated as needed. 

Practice parameters are used as tools to enhance medical decision making but not as replacements for physicians’ clinical judgment. They 

can be considered as means to enhance the performance of clinical and review personnel but not to replace them. It is below the standard of 

care of the medical review process to substitute qualified physician reviewer experts with unqualified reviewers who are using parameters. 

APPENDIX 2. Examples of possible abbreviations for 

allergen immunotherapy extract components 

Tree 

Grass 

Bermuda 

Weeds 

Ragweed 

Mold 

Alternaria 

Cladosporium 

Penicillium 

Cat 

Dog 

Cockroach 

Dust mite 

D farinae 

D pteronyssinus 

Mixture 

T 

G 

B 

W 

R 

M 

Alt 

Cla 

Pcn 

C 

D 

Cr 

DM 

Df 

Dp 

Mx 

APPENDIX 3. Example of a build-up schedule for weekly 


Dilution (vol/vol) 

Volume (mL) 

1:1000 0.05 

0.10 

0.20 

0.40 

1:100 0.05 

0.10 

0.20 

0.30 

0.40 

0.50 

1:10 0.05 

0.07 

0.10 

0.15 

0.25 

0.35 

0.40 

0.45 

0.50 

Maintenance concentrate 0.05 

0.07 

0.10 

0.15 

0.20 

0.25 

0.30 

0.35 

0.40 

0.45 

0.50 

Dilutions are expressed as vol/vol from the maintenance concentrate.

S76 Cox et al 



APPENDIX 4. Example of immunotherapy dose adjustments for unscheduled gaps in allergen immunotherapy injection 

intervals (modification of the AAAAI skin testing and immunotherapy consent and instruction forms: immunotherapy 

administration instruction form, which can be found at http://www.aaaai.org) 

Build-up phase for weekly or biweekly injections (time intervals from missed injection) 

d Up to 7 days, continue as scheduled (ie, if on weekly build-up, then it would be up to 14 days after administered injection or 7 days after 

the missed scheduled injection). 

d Eight to 13 days after missed scheduled injection; repeat previous dose. 

d Fourteen to 21 days after missed scheduled injection; reduce dose 25%. 

d Twenty-one to 28 days after missed scheduled injection; reduce previous dose 50%. 

Then increase dose each injection visit as directed on the immunotherapy schedule until therapeutic maintenance dose is reached. 

This suggested approach to modification of doses of allergen immunotherapy because of gaps between treatment during the build-up 

phase is not based on retrospective or prospective published evidence, but it is presented as a sample for your consideration. The individual 

physician should use this or a similar protocol as a standard operating procedure for the specific clinical setting. A similar dosereduction 

protocol should be developed for gaps in maintenance immunotherapy. 

APPENDIX 5. Example of a cluster immunotherapy 

schedule 22,26 

Visit 

Dose (mL) 

Concentration as dilution 

of maintenance vial 

1 0.10 1:1000 vol/vol 

0.40 1:1000 vol/vol 

0.10 1:100 vol/vol 

2 0.20 1:100 vol/vol 

0.40 1:100 vol/vol 

0.07 1:10 vol/vol 

3 0.10 1:10 vol/vol 

0.15 1:10 vol/vol 

0.25 1:10 vol/vol 

4 0.35 1:10 vol/vol 

0.50 1:10 vol/vol 

5 0.07 1:1 vol/vol 

0.10 1:1 vol/vol 

6 0.15 1:1 vol/vol 

0.20 1:1 vol/vol 

7 0.30 1:1 vol/vol 

0.40 1:1 vol/vol 

8 0.50 1:1 vol/vol 

APPENDIX 6. Recommended documentation for allergen 

immunotherapy prescription forms 

The purpose of the allergen immunotherapy prescription form is to 

define the contents of the allergen immunotherapy extract in enough 

detail that it could be precisely duplicated. The following information 

should be on an immunotherapy prescription form: 

Patient information: 

d Patient name, patient number (if applicable), birth date, telephone 

number, and picture (if available) should be included. 

Preparation information: 

d Name of person and signature preparing the allergen immunotherapy 

extract should be included. 

d Date of preparation should be recorded. 

d Bottle name should be included (eg, trees and grass). If abbreviations 

are used, a legend should be included to describe the 

meaning of the abbreviations. 

Allergen immunotherapy extract content information: 

d The following information for each allergen should be included 

on the form in a separate column: 

Content of the allergen immunotherapy extract, including common 

name or genus and species of individual antigens and detail 

of all mixes, should be included. 

d Concentration of available manufacturer’s extract should be 

included. 

d Volume of manufacturer’s extract to add to achieve the projected 

effective concentration should be included. This can be 

calculated by dividing the projected effective concentration 

by the concentration of available manufacturer’s extract times 

the total volume. 

d The type of diluent (if used) should be included. 

d Extract manufacturer should be included. 

d Lot number should be included. 

d Expiration date should be recorded and should not exceed the 

expiration date of any of the individual components.



Cox et al S77 

APPENDIX 7. Allergen immunotherapy extract prescription form

S78 Cox et al 



APPENDIX 8. Maintenance concentrate prescription form



Cox et al S79 

APPENDIX 9. Labels for allergen immunotherapy extracts 

Each vial of allergen immunotherapy extract should be labeled in a way that permits easy identification. Each label should include the 

following information (example in Figs 3 and 4): 

d Appropriate patient identifiers might include the patient’s name, patient’s number, patient’s picture, and birth date. 

d The contents of the allergen immunotherapy extract in a general way should be included. The detail with which this can be identified 

depends on the size of the label and the number of allergens in the vial. Ideally, allergens should be identified as trees, grasses, weeds, 

mold, dust mite, cockroach, cat, and dog. Because of space limitations, it might be necessary to abbreviate the antigens (eg, T, G, W, M, 

DM, Cr, C, and D respectively [see Appendix 2]). A full and detailed description of vial contents should be recorded on the prescription/ 

content form. 

d The dilution from the maintenance concentrate (vol/vol) should be recorded. If colors, numbers, or letters are used to identify the dilution, 

they also should be included. 

d The expiration date should be included. 

APPENDIX 10. Allergen immunotherapy administration form recommended documentation 

The purpose of the allergen immunotherapy administration form is to document the administration of the allergen immunotherapy extract to a 

patient. Its design should be clear enough so that the person administering an injection is unlikely to make an error in administration. It also 

should provide documentation in enough detail to determine what was done on each visit. The following recommendations on allergen 

immunotherapy are taken from The Joint Task Force on Practice Parameters. 

Patient information: 

d Patient’s name, date of birth, telephone number, and patient’s picture (optional but helpful). 

Allergen immunotherapy extract information: 

d Allergen immunotherapy extract name and dilution from maintenance in vol/vol bottle letter (eg, A and B), bottle color, or number, if 

used. 

d Expiration date of all dilutions. 

Administration information in separate columns: 

d Date of injection. 

d Arm administered injection, which might facilitate determination of exact cause of local reaction. 

d Projected build-up schedule. 

d Delivered volume reported in milliliters. 

d Description of any reactions. The details of any treatment given in response to a reaction would be documented elsewhere in the medical 

record and referenced on the administration form. 

d Patient’s health before injection. This can be performed through a verbal or written interview of the patient before administering the immunotherapy 

injection. The patient should be questioned about increased asthma or allergy symptoms, b-blocker use, change in health 

status (including pregnancy and recent infections), or an adverse reaction to a previous injection (including delayed large local reactions 

persisting through the next day). Patients with significant systemic illness generally should not receive an injection. 

d Antihistamine use. Antihistamines are frequently a component of an allergy medication regimen, and it would be important to note 

whether a patient is taking an antihistamine on the day he or she receives his or her immunotherapy injection. For consistency in interpretation 

of reactions, it might be desirable for a patient to either take or avoid antihistamines on a regular basis on the days he or she 

receives immunotherapy. The physician should note on the form whether he or she recommends the patient consistently take an antihistamine 

on immunotherapy treatment days. 

d Peak flow reading. Consider obtaining a peak expiratory flow rate measurement before administering an immunotherapy injection to asthmatic 

patients. Poorly controlled asthma is considered a risk factor for immunotherapy. Obtaining a peak expiratory flow rate measurement 

before the immunotherapy injection might help identify patients with symptomatic asthma. The patient’s baseline peak expiratory 

flow rate should be provided on the form as a reference. Health care professionals administering immunotherapy injections should be 

provided with specific guidelines about the peak expiratory flow rate measurement for when an immunotherapy injection should be withheld 

and the patient referred for clinical evaluation. 

d Baseline blood pressure. It might be useful to record the patient’s blood pressure as a baseline for future reference.

S80 Cox et al 



APPENDIX 11. Allergen immunotherapy administration form



Cox et al S81

S82 Cox et al 



APPENDIX 12. Health screen record



Cox et al S83 

APPENDIX 13. Allergen immunotherapy informed consent 

d Documentation that informed consent has been obtained. d Informed consent is a process by which a patient and physician 

discuss various aspects of a proposed treatment. Although many 

allergists use a written consent form before starting immunotherapy, 

a reasonable alternative is simply to document the consent 

process in the medical record. The consent process usually consists 

of the following: 

d what the treatment is and alternatives to the treatment; 

d potential benefits to be expected from the treatment; 

d potential risks, including a fair description of how frequently 

they are likely to occur, if known, including the possibility 

of death; 

d costs associated with immunotherapy and who pays for them; 

d the anticipated duration of treatment; and 

d any specific office policies that affect treatment. 

d Since the informed consent process is complex and details might 

vary from state to state, each allergist/immunologist should decide 

how they should document informed consent. Legal advice 

might be useful.

S84 Cox et al 



APPENDIX 14. Allergen immunotherapy systemic reaction/anaphylaxis treatment record



Cox et al S85 

APPENDIX 15. Grading severity of allergen immunotherapy reactions: Two methods 

1. The European Academy of Allergy and Clinical Immunology grading of severity for systemic side effects* 

Classification of systemic reactions 

0 5 No symptoms or nonspecific symptoms 

I 5 Mild systemic reactions: symptoms—localized urticaria, rhinitis, or mild asthma (PF 15 minutes) of generalized urticaria, moderate asthma, or both (PF < 40% 

decrease from baseline). 

III 5 Severe (non–life-threatening) systemic reactions: symptoms—rapid onset ( 40% decrease from baseline). 

IV 5 Anaphylactic shock: symptoms—immediate evoked reaction of itching, flushing, erythema, generalized urticaria, stridor (angioedema), 

immediate asthma, and hypotension, for example. 

2. Portnoy method for numeric grading of reactions to allergen immunotherapy 

Local 

01 5No significant reaction or small area of erythema less than the size of a half dollar without swelling or wheal formation 

11 5Erythema greater than the size of a half dollar, swelling or wheal formation, or both 

Systemic 

21 5Systemic reactions: cutaneous only—might consist of a cutaneous eruption, such as urticaria 

31 5Systemic reaction: generalized pruritus, sneezing, or both—might consist of increased allergy symptoms, such as nasal congestion, 

sneezing, or pruritus, especially in the mouth or throat 

415Systemic reaction: pulmonary—consists of wheezing, shortness of breath, and tightness. Might be associated with decreased pulmonary 

function tests 

51 5Systemic reaction: anaphylaxis—a sensation of not feeling right is a frequent prelude; might consist of hypotension, laryngeal edema, 

severe wheezing, and cramping 

61 5Cardiopulmonary arrest 

PF, Peak expiratory flow. 

*Subcutaneous immunotherapy. Allergy 2006;61(suppl 82):5-13. 

Sharkey P, Portnoy J. Rush immunotherapy: experience with a one-day schedule. Ann Allergy Asthma Immunol 1996;76:175-80.





reference article

Immunotherapy Safety for the Primary Care Provider 

Self-Assessment Test 

1. Allergen immunotherapy is NOT indicated for: 

a. Allergic asthma 

b. Chronic urticaria 

c. Venom hypersensitivity 

d. Allergic rhinitis 

2. Anaphylaxis can be triggered by bee stings, foods, allergy shots, and vaccines. 

a. True 

b. False 

3. Patients should remain in the physician’s office at least ____ minutes after an allergen 

injection. 

a. 10 minutes 

b. 30 minutes 

c. 60 minutes 

d. 120 minutes 

4. Who can NOT initiate treatment with Epinephrine during anaphylaxis? 

a. Any trained technician (trained Corpsman/Medic) or licensed provider 

b. Any Corpsman/Medic under the “Ferris Doctrine” 

c. Any trained friend or family member under the “Good Samaritan Law” 

d. The trained patient to themselves 

5. Risk factors associated with immunotherapy include all of the following EXCEPT: 

a. Concurrent beta blocker use 

b. Poorly controlled asthma 

c. Concurrent use of antihistamines which may mask systemic reactions 

d. Injections given from a new vial 

6. When starting an AEROALLERGEN REFILL vial, by how much should you decrease the 

dose? 

a. 10% 

b. 90% 

c. 50% 

d. 25% 

7. What was the recommended color of the cap for the maintenance (1:1 v/v) AIT vial? 

a. Red 

b. Yellow 

c. Blue 

d. Silver

8. Allergy shots are administered: 

a. Intramuscular (IM) 

b. Subcutaneous (SQ) 

c. Intradermal (ID) 

d. Oral (PO) 

9. A patient reports to you 10 minutes after her allergy injection that she is sneezing, having 

itchy eyes, and chest congestion with coughing. What is the treatment of choice? 

a. Administer epinephrine intravenously 

b. Administer epinephrine intramuscularly 

c. Administer steroids by injection 

d. Administer albuterol by nebulizer 

10. A patient is on his monthly maintenance (0.5 cc of 1:1 v/v) aeroallergen immunotherapy. He 

comes 4 weeks after his last shot, but now has a new (just refilled) vial. What dose should he get 

today? 

a. 0.50 cc of the renewed maintenance (1:1) vial 

b. 0.25 cc of a diluted (1:10) step-down vial 

c. 0.05 cc of the renewed maintenance (1:1) vial 

d. 0.25 cc of the renewed maintenance (1:1) vial 

11. All of the following are ABSOLUTE contraindications for initiating venom immunotherapy 

EXCEPT: 

a. Pregnancy 

b. Severe COPD 

c. Unstable angina 

d. Patient taking a beta-blocker 

12. After the initiation of AIT, when should the patient be routinely re-evaluated by the 

Allergist? 

a. Monthly 

b. Quarterly 

c. Annually 

d. At the conclusion of his/her AIT (i.e., 3-5 years) 

13. A patient reports that he had swelling down to his elbow after the last allergy shot and it 

lasted for greater than 12 hours. What adjustments should be made? 

a. No adjustment required – advance per routine advancement protocol 

b. Make adjustments as directed by the Allergist’s dose adjustment instructions 

c. Do not give a shot today and advise the patient to return after having taken ibuprofen 

d. Treat the reaction as a systemic considering the size of the swelling 

14. Can a trained technician administer epinephrine in the absence of a physician? 

a. Yes 

b. No

15. A 12 yo male presents for his allergy injection. He has asthma and is on several medications. 

His mother stated that after his last injection, he had an increase in coughing, but no wheezing or 

other chest complaints. The coughing continued through the night but resolved the next day. 

What dose of his immunotherapy would you administer next? 

a. Repeat the last dose given since this may be the patient’s baseline 

b. Advance as per protocol since this may be the patient’s baseline 

c. Decrease or hold the dose per allergist’s dose adjusting instructions as if the patient had a 

systemic allergic reaction from the last injection 

d. Decrease by 25% after pretreating with albuterol and Benadryl before today’s shot 

16. A patient comes in for her shot. She has asthma; therefore pulmonary function testing is 

done prior to her shot. Her Peak Flow is 24% lower than her normal baseline. It is permissible to 

give her allergy shot today. 

a. Yes 

b. No 

17. You DO NOT reduce the first dose when administering venom from a refill vial. 

a. True 

b. False 

18. You have received a set of new vials for a patient. The vials have red tops and previously the 

vials had blue tops. The accompanying schedule directs that the vial progression is from green to 

blue to yellow to red tops. What should you do? 

a. Notify the prescribing allergist’s office of a possible error and do not give any further 

injections until clarified 

b. Give the recommended starting dose of 0.05 cc SQ per protocol 

c. Give ½ of the recommended starting dose 

d. Start over in the previous vials (blue tops) 

19. Your patient is 6 weeks late for his allergy shot and his Allergist has asked that you “reduce 

this shot by 75%”. His last shot was 0.50 cc from his yellow (1:10 v/v) vial. Today's dose would 

be? 

a. 0.1 cc from his yellow (1:10) vial 

b. 0.4 cc from his blue (1:100) vial 

c. 0.25 cc from his blue (1:100) vial 

d. 0.05 cc from his yellow (1:10) vial 

20. You decide in question #19 to give your patient a dose from his blue vial, but find his blue 

vial has expired. To make a blue vial from his yellow vial, you would… 

a. Add 1.0 cc of yellow vial to 10.0 cc of sterile albumin/saline diluent 

b. Add 0.05 cc of yellow vial to 4.5 cc of sterile albumin/saline diluent 

c. Add 0.2 cc of yellow vial to 1.8 cc of sterile albumin/saline diluent 

d. Add 3.0 cc of yellow vial to 9.0 cc of sterile albumin/saline diluent





reference article

Immunotherapy Safety for the Primary Care Provider 

Self-Assessment Test Answer Key 

1. B 

2. A 

3. B 

4. B 

5. C 

6. C 

7. A 

8. B 

9. B 

10. D 

11. D 

12. C 

13. B 

14. A 

15. C 

16. B 

17. A 

18. A 

19. A 

20. C





reference article

Site Under 

Construction

Anaphylactic/Anaphylactoid 

Reactions 

Capt. Jay R. Montgomery MC, USN 

Allergy and Immunology Service 

National Naval Medical Center

Introduction 

• “Anaphylaxis” 

– Word first coined by Portier and Richet in 1902. 

– While attempting to immunize dogs to sea anemone venom, 

the dogs unexpectedly died after a previously non-lethal 

dose. 

– They had unwittingly sensitized the animals. 

– This phenomenon was opposed to their goal of prophylaxis 

so they referred to it as anaphylaxis, meaning “against 

protection”.

Definition 101 

• Anaphylaxis: 

– An acute systemic reaction caused by release of 

potent chemical mediators from mast cells, basophils, 

and secondarily recruited inflammatory cells. It 

may occur within a few minutes to a few hours and 

can be life threatening. 

– Signs & symptoms may be isolated to one or involve 

several organ systems. 

– Mediated through IgE and its receptor on the cell 

• Anaphylactoid 

– Same as above, just disregard statement #3

Revised Nomenclature For 

Anaphylaxis 

Anaphylaxis 

Allergic Anaphylaxis 

Non-allergic 

anaphylaxis 

IgE- mediated 

anaphylaxis 

Immunologic, non-IgEmediated 

anaphylaxis 

Johansson SGO et al JACI 2004,113:832-6

Anaphylaxis* Is Not Rare 

Insect stings 3% of adults 

Food 1-3% of children 

Drugs 1% of adults 

RCM 0.1% of cases 

Immuno Tx 3% of patients 

Latex 1% of adults 

*urticaria/angioedema or dyspnea or hypotension

Anaphylaxis* Is Not Rare 

Estimated risk in US: 1-3% 

Fatalities per year in the US: 

- antibiotic-induced: 600 

- food-induced: 150 

- venom-induced: 50 

Kemp SF and Lockey RF, J Allergy Clin Immunol 2002;110:341-8 

*urticaria/angioedema or dyspnea or hypotension

Pathophysiology 

• Activation of mast cells and basophils result in 

secretion of preformed mediators, followed by 

synthesis and secretion of lipid mediators and 

cytokines. 

– preformed granule-associated substances = 

histamine, tryptase, chymase, carboxypeptidase, & 

cytokines 

– newly-generated lipid-derived mediators = 

prostaglandin D2, leukotriene (LT) B4, LTC4, LTD4, 

LTE4, & platelet activating factor.

Pathophysiology


• The physiologic effects of the pre-formed 

mediators define the early phase anaphylactic 

reaction, 

• While those of the synthesized cytokine IL-4, 

IL-5, IL-13, and chemokines shape the late 

phase inflammatory reaction.

Pathophysiology


• Major effects of mediators 

– Smooth muscle (bronchial/gut)spasm 

– profound myocardial depression 

– vasodilation, increase in vascular permeability can 

transfer 50% of IV fluid into EV space in 10 minutes 

Death occurs via CV collapse or respiratory 

obstruction. Death occurred in < 1 hour in 70% 

(39/56) of patients in one study


• Histamine acts through H1 and H2 receptors 

– H1: pruritus, rhinitis, tachycardia, & bronchospasm 

– H1 & H2: headache, flushing, & hypotension 

• Leukotrienes (LTB 4 ) 

– direct mast cell degranulation 

– chemotactic agents for late-phase inflammatory cells 

• Complement (C5a) 

– direct mast cell degranulation 

– Induce smooth muscle ctx, increase vascular perm

Classification of Anaphylactic 

Syndromes 

• IgE mediated 

• Direct Mast-Cell Activation 

• Complement Mediated 

• Arachidonic Cascade Mediated 

• Unknown Mechanisms

IgE Mediated Reactions 

• Most Antibiotics 

– penicillins, cephalosporins, sulfonamides... 

• Allergen Extracts 

– pollen, mold, dander, Hymenoptera & snake venom 

• Vaccines 

– contaminated with egg, gelatin... 

• Food 

– peanut, milk, egg, seafood, wheat, tree nuts 

• Miscellaneous 

– insulin, formaldehyde, latex, streptokinase, seminal 

fluid...

Direct Mast Cell Releasers 

• Opiates 

• Hypertonic solutions 

– Radiocontrast media, Mannitol 

• Polysaccharides 

– dextran, iron-dextran 

• Other Drugs 

– curare, succinylcholine, vancomycin, ciprofloxacin 

• Exercise (?) 

• Physical stimuli (?)

Complement-mediated 

• C5a, C3a, C4a (anaphylotoxins) 

– plasma 

– immunoglobulins 

– dialysis membranes 

 

Direct mast cell degranulation

Arachidonic Cascade-mediated 

• Nonsteroidal anti-inflammatory agents 

– COX1 

– COX2 (?) 

• Increase in Leukotrienes through blockade of 

prostaglandin synthesis pathway(s) 

 

Direct mast cell degranulation

Unknown Mechanisms 

• Exercise-induced anaphylaxis 

• Cholinergic urticaria w/ anaphylaxis 

• Cold-induced urticaria w/ anaphylaxis 

• Mastocytosis 

• Sulfites 

• Steroid preparations 

– progesterone, hydrocortisone

Signs and Symptoms 

• Cutaneous 

– Flushing, erythema, pruritus, urticaria, angioedema 

• Gastrointestinal 

– Abdominal cramping, nausea/vomiting,diarrhea 

• Reproductive 

– Uterine cramping 

Respiratory 

– Rhinitis, upper airway obs. from angioedema of tongue, 

oropharynx, & larynx. Lower airway obs. from bronchospasm 

Cardiovascular 

– Hypotension, arrhythmias, hypovolemic shock (severe & refrac.)

Anaphylaxis 

Summary of Signs & Symptoms 

• Flushing/urticaria/angioedema >90% 

• Upper airway symptoms 56% 

• Lower airway symptoms 47% 

• Gastrointestinal symptoms 30% 

• Cardiovascular Shock 10-30% 

• Feeling of impending doom, metallic taste 

Lieberman P. In: Middleton’s Allergy: Principles and Practice, 6th edition, Mosby Inc., St. Louis, MO, 2003

Anaphylaxis 

Summary of Signs & Symptoms 

• Uniphasic (52%) 

– Abrupt and severe with death in minutes despite treatment 

– Gradual increase in symptoms 

• Biphasic (7-20%) 

– Immediate symptoms, then an asymptomatic period from 1-8 

hours, then recurrence of severe symptoms 

• Protracted (28%) 

– Symptoms persisting for hours 

Lieberman P. Ann Allergy Asthma Immunol 2005;95:217-26

Differential Diagnosis 

• Pulmonary 

– Epiglottis, PE, foreign body aspiration, hyperventilation, 

asphyxiation 

• Cardiovascular 

– MI, arrhythmia, cardiac arrest, hypovolemic shock 

• CNS 

– Vasovagal rxn, CVA, seizures, drug overdose 

• Endocrine 

– Carcinoid, pheochromocytoma, hypoglycemia 

• Other 

– Mastocytosis, H/AAE, idiopathic urticaria, serum sickness, 

scombroid poisoning, VCD, panic attack 

Montanaro A and Bardana EJ Jr. J Investig Allergol Clin Immunol 2002;12:2-11

Anaphylaxis Grading Scale I 

• Severe Anaphylaxis (likely to progress to 

hypotension/hypoxia) 

– Confusion, fainting, unconsciousness, incontinence 

• Moderate Anaphylaxis (weakly associated with 


– Diaphoresis, vomiting, lightheadedness, dyspnea, stridor, 

wheezing, throat/chest tightness, nausea, abdominal pain 

• Mild Anaphylaxis (not associated with 


– Flushing, urticaria, erythema, angioedema (reactions 

limited to the skin alone)

Anaphylaxis Grading Scale II 

• Anaphylaxis is likely when 1 of 3 fulfilled: 

1. Acute onset with: 

a) Skin/mucosa AND 

b) Airway compromise OR 

c) Reduced BP 

2. Two or more of the following: 

a) Hx of severe reaction 

b) Skin/mucosa involvement 

c) Airway compromise 

d) Reduced BP 

e) Crampy abdominal pain, vomiting 

3. Hypotension after known exposure, angioedema 

(reactions limited to the skin alone)

Anaphylaxis 

In The Emergency Department 

• Chart review in 21 American Emergency Departments 

• Random sample of 678 pts presenting with food allergy 

• Management: 

- 72% received antihistamines 

- 48% received systemic corticosteroids 

- 16% received epinephrine (24% of those with severe reactions) 

- 33% received respiratory medication (eg. inhaled albuterol) 

- only 16% received Rx for self-injectable epinephrine at discharge 

- only 12% referred to an allergist 

Clark S et al. J Allergy Clin Immunol 2004;347-52

Laboratory Studies 

• IgE antibodies to suspected allergen by either 

skin testing or RAST 

• Histamine, plasma & urinary (max at 15 mins) 

• Tryptase (peaks at 1-2 hours) 

• Other 

– 5-HIAA, VMA, metanephrines, catecholamines

Guidelines for Treatment 

• Assessment TO BE PERFORMED 

AT THE TIME OF ADMINISTRATION 

OF EPINEPHRINE. 

– Remove or discontinue of inciting agent (Infusion, stinger, etc.) 

– Examine upper/lower airway patency, secure airway 

– Place patient in recumbent position and elevate his/her legs 

– Monitor vital signs (P, BP, RR) 

– Monitor level of consciousness/mentation


• Treatment (Airway/Breathing) 

– Maintain an open airway 

– High flow Oxygen (4-10 l/m) with pulse oximetry monitoring 

– Intubation when PaCO 2 > 65 mm Hg. / SaO 2 < 90% on O 2 

• Treatment (Circulation) 

– Keep Systolic BP > 90 mm Hg 

– Place patient in Trendelenburg position as appropriate. 

– Insertion of large-bore IV 

• 0.9% saline or lactated ringer’s 

– Severe Hypotension 

• Dextran, Hetastarch


• Treatment (Drugs - ABC) 

– EPINEPHRINE (Adrenalin) 

• α and β adrenergic effects 

• 0.3-0.5 cc 1:1,000 IM q 5-15 min 

– Antihistamines (Benadryl) 

• H1 - diphenhydramine (Benadryl): 50 - 75 mg IM/IV 

• H2 - ranitidine (Zantac): 150mg q8-12 hr PO, 50mg q6-8 IV 

– Corticosteroids 

• Methylprednisolone IV 60 - 80 mg followed by predinsone 

Kemp S and Lockey R. J Allergy Clin Immunol 2002;110:341-8 

Simons FER et al. J Allergy Clin Immunol 1998;101:33-7 

Simons FER et al. J Allergy Clin Immunol 2001;108:871-3


• Treatment (Drugs) 

– For Myocardial depression 

• Epinephrine 0.1-0.2 cc 1:1,000 diluted in 10ml NS 

• Dopamine 2-20 µg/kg/min 

– For patients on β-blockers w/ refractory shock 

• Glucagon 1-5 mg over 2-5 min IV push 

• Isoproterenol 2-10 ug/min 

• Methylprednisolone, 1- 2 mg/kg per 24 hr 

– For Bronchospasm 

• Albuterol MDI/Nebulized (2.5 - 5 mg in 3 ml normal saline)

Prevention: 

How to Reduce Incidence 

• General measures 

– Thorough history for drug, food, and other avoidable 

allergens 

– Avoid cross reacting drugs 

– Administer drugs orally 

– Check all drugs for proper labeling 

– Keep patients in office 20-30 minutes after injections 

(for immunotherapy or vaccination) 

– Evaluation by Allergist if in doubt

How the Allergist/Immunologist 

Can Help… 

• Refer patients with: 

– A severe allergic reaction 

(anaphylaxis) without an 

obvious or previously defined 

trigger. 

– Anaphylaxis attributed to food. 

– Exercise-induced anaphylaxis 

– Drug-induced anaphylaxis

Prevention: 

Who is at risk? 

• Prior history of anaphylaxis 

• β-blockade therapy 

• ACE-Inh therapy (?) 

• Multiple antibiotic sensitivity syndrome 

• Atopic background (latex anaphylaxis & possibly 

RCM anaphylactoid rxn; not venom or PCN) 

• Unstable, steroid-dependent asthma

Summary 

• Anaphylaxis: release of inflammatory mediators 

from mast cells & basophils (IgE-/non-IgE-mediated) 

• Symptoms: within minutes of exposure to 

triggering agent (less commonly can be delayed or biphasic) 

• Common triggers: drugs, foods, hymenoptera 

stings; idiopathic 

• First-line of treatment: injected epinephrine 

• Management: education and prevention





reference article

ANAPHYLAXIS 

• First reported case was in 2640 BC – pharoh died from sting of wasp 

• Occurs in 1 of every 3,000 hospitalized patients 

• Annual deaths: at least 500 

• No known epidemiologic characteristics that reliably identify those at risk 

• Most studies suggest that an atopic person is at no greater risk 

Mast Cell Mediators: 

Once stimulated, the mast cells secrete two groups of mediators: 

1) preformed mediators and 

2) newly formed mediators. 

• The preformed mediators have been synthesized in advance and stored in granules, to 

be released immediately upon stimulation of the mast cell. This group of mediators 

include histamine, proteolytic enzymes (tryptase), heparin, and chemotactic factors. 

• The newly formed mediators consists of lipids that are synthesized after the mast cell is 

stimulated. The stimulus activates phospholipase A2, which acts to break down 

phospholipids in the cell membrane to arachidonic acid. Arachidonic acid can then either 

enter the cyclo-oxygenase pathway to produce prostaglandins and thromboxanes or the 

lipoxygenase pathway, to produce the leukotrienes. 

Mediator actions: These mediators rapidly act 

• on the smooth muscle 

• in the lung to cause bronchospasm and 

• in the gastrointestinal tract to cause abdominal cramping and diarrhea. 

• on the bronchial airways to produce 

• increased mucus production and 

• an inflammatory infiltrate 

• on the circulatory system to produce 

• vasodilation and 

• increased vasculature permeability, leading to bronchial edema, urticaria, and 

hypotension. 

Tryptase. The biologic action of tryptase in anaphylactic reactions remains uncertain; however, 

it can serve as an important marker of anaphylaxis. 

• Whereas histamine is very transient and difficult to measure, tryptase doesn’t peak until 

1-2 hours after the stimulus and remains in the circulation up to 6-8 hours. The detection 

of tryptase in the serum can serve to confirm your suspicions when a patient presents 

with symptoms of anaphylaxis. 

Mast Cell Activation: Three main triggers of mast cell activation: 

1) IgE hypersensitivity. Antigen crosslinks IgE antibodies attached to mast cells through 

Fc epsilon receptors. When it crosslinks two IgE molecules, it draws the attached 

IgE receptors close to one another. Such aggregation of receptors activates the 

cell.

2) Anaphylatoxins: C3a and C5a 

3) Drugs: Certain drugs act directly on the mast cell to release its mediators. 

Classification of Anaphylaxis: Most classification systems utilize these three mechanisms of 

mediator release to classify the various types of anaphylaxis: 

1) IgE mediated anaphylaxis 

2) Complement activated anaphylaxis 

3) Mast cell/basophil activated anaphylaxis 

4) Unknown/Idiopathic anaphylaxis 

Anaphylaxis vs anaphylactoid: The term anaphylaxis is frequently used to refer only to IgEmediated, 

mast cell activation, whereas anaphylactoid reactions are used to denote the 

other non-IgE mediated responses. However, both events are clinically and 

biochemically similar; therefore, the term “anaphylaxis” is often used interchangeably for 

both clinical syndromes. 

Components of an IgE anaphylactic response: 

1) Exposure to a sensitizing antigen 

2) An IgE-class antibody response, resulting in systemic sensitization of mast cells or 

basophils 

3) Reintroduction of the sensitizing antigen 

4) Mast cell degranulation (with mediator release/generation) 

5) Pathologic responses: anaphylaxis. 

Examples of IgE-Mediated Reactions 

1) Medications 

• Penicillin: Penicillin and other beta-lactam antibiotics account for more 

than 75% of cases of anaphylaxis from medication. 

• Most frequent cause of anaphylaxis: 400-800 deaths annually. 

• 1 case/2,500 course of penicillin given. 

• Skin testing: predictive. 

• Local anesthetics: 

Reactions to local anesthetics are common; however, IgE mediated 

reactions are exceedingly rare. Most reactions are due to vasovagal, toxic, 

or idiosyncratic responses rather than true allergic reactions. 

Hypersensitivity more common with the preservatives in the anesthetic: 

parabens and sulfites. 

2) Foreign proteins (horse serum, chymopapain, latex) 

Latex: becoming especially important with the widespread use of latex gloves. It 

is particularly common in patients with spina bifida or congenital urologic 

abnormalities because of frequent exposure to urinary catheters and 

frequent operations. Should be considered whenever an intraoperative 

reaction occurs. 

3) Foods (peanuts, nuts, fish, shellfish, egg, and milk) Concomitant asthma is an 

important risk factor.

4) Hymenoptera stings 

Although almost 25% of the population may be at risk, fewer than 100 deaths 

occur each year 

5) Immunotherapy 

Despite its widespread use, fatalities from allergen immunotherapy are extremely 

rare. (45 fatalities since 1945) 

Complement mediated anaphylaxis. This type of anaphylaxis doesn’t depend on IgE, but 

rather the other antibodies: IgG, IgM, and IgA antibodies. Both the classic complement 

pathway and the alternate pathway are implicated in the generation of anaphylatoxins, 

C3a and C5a. These products are then capable of causing mast cell (and basophil) 

degranulation. 

The most classic examples of complement mediated anaphylaxis are reactions to blood and its 

products: 

• Example 1: IgG aggregates (Gamma globulin) 

Administration of gamma globulin has been associated with anaphylactoid 

reactions because it contains IgG dimers and polymers capable of activating 

complement spontaneously. 

• Cl combines with the aggregated immunoglobulins and eventually leads 

to the production of C3 convertase and CS convertase which, in turn, result in the 

release of the anaphylatoxins C3a and C5a 

• Both C3a and C5a then act on the mast cell to promote mediator release. 

• Example 2: IgG or 1gM anti-IgA 

Probably the best defined example is the anaphylaxis which can result when an 

IgA deficient patient receives blood products containing IgA. These patients 

frequently will produce IgG or 1gM anti-IgA antibodies, which will combine with 

the infused IgA in the administered blood products, and release anaphylatoxins. 

(IgA anaphylaxis can also occur through the more typical most cell 

sensitization with IgE anti -IgA) 

Mast Cell Activated Anaphylaxis. Numerous agents have been reported to be capable of 

causing direct degranulation of mast cells with histamine release. The most clinically relevant 

are: 

1. Opiates (generally limited to the skin) 

2. Muscle relaxants (curare, d-tubocurarine) 

3. Highly charged polyanionic antibiotics (polymyxin B) 

4. Radiocontrast media (Some sources suggest it might be complement mediated) 

• Initial exposure: 1-10% risk of anaphylaxis (with conventional RCM) 

• Reexposure, in those with previous reaction: 17-35% risk of anaphylaxis 

• No in-vitro or in-vivo testing available (Not IgE mediated) 

• Rx -- prevent recurrence: 

• Pretreatment (Prednisone, Benadryl, and ephedrine) 

• Low osmolality RCM

Anaphylaxis of unknown origin: 

1. Aspirin/NSAID 

2. Sulfites (Na/K sulfites, bisulfites, metabisulfites) 

3. Exercise 

4. Hormones: 

A rare subset of women have cyclic anaphylaxis - often during the luteal phase of 

their menstrual cycle. 

• They may have positive skin tests to medroxyprogesterone, and 

• They may respond favorably to ovarian suppression or oophorectomy 

5. Idiopathic: 

This group of patients experience recurrent anaphylaxis with no recognized cause. 

• The diagnosis is based on the typical signs and symptoms, as well as 

evidence of elevated urine histamine, elevated serum tryptase, and an exhaustive 

search for causative factors. 

• These patients all require an Ana-kit, and if anaphylaxis occurs 

frequently enough may require chronic steroid therapy to control their symptoms. 

• A subset of these patients even fail to respond to high-dose 

corticosteroid therapy - these patients are referred to as having malignant 

idiopathic anaphylaxis. 

Acetylsalicylic acid (aspirin) and NSAID anaphylaxis 

• Most likely mechanism is modulation of arachidonic acid metabolism by interference 

with cyclooxygenase enzyme pathways. There are two consequences of this action: 

1) reduction in the formation of prostaglandins, thromboxanes, and prostacyclin, 

2) enhanced formation of lipoxygenase products. 

• In addition to enhanced mediator release, these patients may have an increased targetorgan 

sensitivity to the leukotrienes. 

• Rx: aspirin avoidance, desensitization, leukotriene receptor antagonists/lipoxygenase 

inhibitors. 

Sulfite anaphylaxis. Should be suspected in individuals who have anaphylaxis associated with 

eating, particularly if restaurants or process foods are implicated. 

• These patients may have such profound bronchoconstriction that they cannot 

speak and have been mistaken for a choking victim, occasionally having had the 

Heimlich maneuver performed on them. 

• Sulfites are frequently utilized as preservatives and antioxidants. They are added 

to foods to prevent discoloration. 

• Foods to which these substances are added in the highest concentrations include 

• leafy salad greens (salad-bar restaurants before restrictions). 

• light-colored fruits and vegetables (esp. dried fruits and instant potatoes) 

• wine and beer 

• fish and shellfish (particularly shrimp) 

• Sulfites are also used as preservatives/antioxidants in a variety of medication. 

However, when compared with the amount of sulfite in foods, most pharmaceuticals 

contain small amounts of sulfite (0.25% to I %) However, the potential still exists, as 

these agents are either injected directly or inhaled by the patient.

• Sulfites are added to all the bronchodilator solutions of the catecholamine class 

to offset catecholamine susceptibility to inactivation by oxidation. Used primarily in the 

multidose vials -- but not in MDIs, because fluorocarbon propellant replaces sulfite as 

the preservative, and oxidation does not occur in these closed containers. 

• Bronchodilator solutions: Bronkosol (the worst), Alupent, Isuprel 

• Epinephrine 

• Dopamine, norepinephrine 

• Corticosteroids: Hydrocortisone, dexamethasone 

Exercise-induced anaphylaxis. Recently a new group of patients have been described who 

experience urticaria and anaphylaxis on vigorous exercise, an entity termed exercise-induced 

anaphylaxis. 

• This syndrome should be suspected in any person who collapses after exercise, 

particularly if flushing, urticaria, or angioedema are evident. 

• Most of these events occur only very sporadically, and it was this intermittent nature 

that served as a clue that other associated factors may be responsible for promoting the 

occurrence. 

• Many of these individuals only develop symptoms in the post-prandial period. 

In a survey of 199 patients, more than half of them felt that food ingestion 3 to 4 hours 

before exercise significantly increased their risk for anaphylaxis. 

• Others report that a specific food ingested prior to exercise was a major factor: 

shellfish, celery, cabbage, chicken, or wheat products. 

• Other associated factors: alcohol (5%) 

aspirin (6%) 

environmental factors (humidity: 63%) 

menstrual cycle (25% of women) 

Clinical manifestations of anaphylaxis 

• Onset: usually begins within minutes after exposure to the causative factor, although the 

onset may be delayed for several hours. 

• Once under way, the reaction usually progresses in an explosive manner, reaching a 

peak intensity within 1 hour. 

• The primary anaphylactic shock organs in humans are the cutaneous, gastrointestinal, 

respiratory, and cardiovascular systems, the latter two being the most critical. 

• Respiratory events: accounted for 70% of the mortality in one series, 

• Cardiovascular manifestations: accounting for an additional 24% 

• Patients typically present with generalized pruritus (though often located to their 

palms, soles, or groin area) They get hives, angioedema and frequently are noted 

to have flushing. 

• They often describe an immediate sense of impending doom - they know something is 

wrong. Other neurologic symptoms: weakness, dizziness, confusion, LOC, or 

seizures. 

• Occasionally they complain of a metallic taste in their mouth, and are noted to have 

swelling of the lips and tongue. 

• They frequently develop typical allergic symptoms 

• Itchy, watery, red eyes 

• Nasal congestion/rhinorrhea or sneezing

• In addition they may have: 

• Gastrointestinal symptoms: 

Nausea, vomiting, cramping, and diarrhea - sometimes bloody 

• Upper airway symptoms: (especially in children) 

Stridor secondary to laryngeal edema 

Early presentation may consist of 

hoarseness 

dysphonia, or 

“a lump in the throat” 

• Lower airway symptoms, typical of asthma: 

SOB, wheezing, and chest tightness 

• Cardiovascular symptoms: 

Hypotension, shock, and arrhythmias 

Differential diagnosis 

1. Loss of consciousness: In the diagnosis of sudden collapse in the absence of 

accompanying pruritus, urticaria and angioedema, one must consider several other 

disorders: 

• Cardiac arrhythmias 

• Myocardial infarction 

• Pulmonary embolism 

• Seizures 

• Asphyxiation/foreign body 

• Hypoglycemia 

• Vaso-vagal reaction: (Most common similar syndrome) 

• Patient collapses after an injection or painful situation 

• Bradycardia (rather than rapid, thready pulse of anaphylaxis) 

• Pallor (rather than flushing) 

• No respiratory difficulty nor pruritus, urticaria or angioedema 

2. Acute respiratory distress: 

• Status asthmaticus 

• Epiglottitis 

• Foreign-body aspiration 

• Pulmonary embolism 

• Hereditary angioedema 

Stridor secondary to laryngeal edema, but no pruritus or urticaria. 

Slower onset, 

Usually a history of recurrent attacks or a positive family history. 

Poor response to epinephrine 

3. Disorders with similar cutaneous manifestations. 

• Systemic mastocytosis: The mast cells may degranulate causing systemic effects 

exactly like anaphylaxis. Indeed some patients originally diagnosed as 

having idiopathic anaphylaxis have later been found to have systemic

mastocytosis on bone marrow biopsy. Both may have elevated plasma 

histamine, urinary histamine, and serum tryptase levels. Suspicion of the 

diagnosis should be raised with the recognition of the classic reddish 

brown macular-papular skin lesions with a positive Darier’s sign. 

(urticaria pigmentosa) 

• Cold urticaria. These patients can present with generalized urticaria, 

angioedema, laryngeal edema, and vascular collapse, resulting from a 

massive outpouring of histamine. The history is usually suggestive, 

especially if they have a positive past history of urticaria with cold 

stimulus. These patients are usually particularly at risk with aquatic 

activities, and the precipitating stimulus is frequently swimming in cold 

water. 

• Serum sickness. May present with urticaria, but is generally not an abrupt or 

progressive event. Associated with fever, lymphadenopathy, and arthritis 

• Carcinoid syndrome. Carcinoid symptoms may sometimes be mistaken for 

anaphylaxis, given the presence of flushing, tachycardia, hypotension, 

gastrointestinal symptoms, and bronchospasm. However, urticaria and 

angioedema are absent, and upper respiratory tract obstruction does not 

occur. Occasionally, carcinoid syndrome may have elevated 24-hour urine 

histamine; however they also have increased urinary levels of 5-HIAA. 

Nonimmunologic Risk Factors for Severe or Fatal Anaphylaxis 

• Beta-adrenergic blockade. 

• The presence of beta-adrenergic blocking drugs may increase the likelihood of 

anaphylaxis. 

• It definitely increases its severity and interferes with the use of epinephrine to 

treat anaphylaxis. 

• It acts to block the expected beta-i and beta-2 anti-anaphylactic actions of 

epinephrine, thus facilitating unopposed aipha-adrenergic effects, which 

in the presence of excess epinephrine, may constrict coronary arteries and 

dangerously exaggerate the systemic pressor effects of epinephrine. 

In addition, reflex vagotonic effects that can lead to augmented mediator 

release, bronchoconstriction, and bradycardia. 

• Even small amounts of the drug, such as that absorbed from Timoptic eye drops, 

can cause problems. 

• Asthma. Asthmatic patients appear to be twice as likely to die if anaphylaxis occurs. 

• Cardiac disease. Anaphylaxis is more likely to be severe or fatal in patients with 

congestive heart failure or arteriosclerotic coronary artery disease. 

• Parenteral administration: Oral administration appears to be the safest, while the 

parenteral route is the most hazardous. 

• Delayed anaphylaxis. 

A more prolonged period between antigen exposure and onset of symptoms 

(latent period) has been thought to be associated with a more benign outcome; however, a 

recent prospective study of anaphylaxis in 25 consecutive patients by Sullivan (Dallas, 

Texas) suggests that patients with delayed onsets may be at greater risk of a fatal

outcome. He found that recurrent or prolonged reactions were 2.8 fold more likely if the 

onset was 30 or more minutes after exposure to the stimulus. 

General therapeutic measures: 

• Close monitoring: PFT’s, oxygen saturation, cardiac monitor, serial BPs 

• Initial evaluation and treatment should be directed to maintenance of an effective 

airway and circulatory system. 

• Epinephrine: Nearly an ideal drug. It suppresses mediator release from mast cells and 

basophils and reverses many of the end organ effects of the mediators. It both 

relaxes bronchial smooth muscle and produces peripheral vasoconstriction 

• Dosage: 1:1,000 concentration 

Adult: 0.3 to 0.5 ml, SC or IM (Asthma: 0.5 ml) 

Child: 0.01ml/kg (up to 0.3 ml), SC or IM 

Repeat: after 10 minutes 

Avoid: IV bolus administration (arrhythmias) 

Caution: elderly or underlying cardiovascular or cerebrovascular disease 

• If anaphylaxis from injection/sting (except head, neck, hands, feet) 

• Administer 0.1 to 0.2 ml in the injection/sting site 

• Apply a tourniquet (released 1-2 minutes every 10 minutes) 

• Remove stinger 

• Intravenous infusion (1 mg diluted in 500 ml of D5W) 

Adult: 2-4 ug/minute (1-2 mi/minute) Child: 0.1 ugfkg/minute (0.05 mI/kg/min) 

• Prompt recognition and treatment is critical -- early use is the key. The longer initial 

therapy is delayed, the greater the incidence of fatality. 

Expansion of Intravascular Volume 

• Trendelenburg position 

• Normal saline or Plasmanate can be administered (Child: 10-30 ml/kg) 

Vasopressor infusion 

• Norepinephrine (Levophed) appears to be the most consistently effective pressor in 

anaphylaxis 

• Dopamine hydrochloride (Intropin): 

• Primarily a beta-adrenergic stimulant. 

• May be useful in the presence of cardiac failure. 

• Glucagon: IV glucagon has been effective in patient on beta-blockers who are in shock 

and unresponsive to beta-agonists. This may reflect a direct action of glucagon on 

cardiac that is independent of the beta-receptor. 

(It is probably not indicated for bronchospasm). 

• Initial dose of 1-5 mg, followed by infusion of 5-15 mg/minute titrated against 

blood pressure.

Antihistamines 

H1 antihistamines (Benadryl) Further therapy can be provided by an Hi antihistamine; 

however this drug is not a substitute for epinephrine. 

• Dose: 1-2 mg/kg (Max:’ 50 mg) 

IV (slowly over 5-10 minutes), IM, or P0 (depending on the severity) 

• Other antihistamines (Atarax) can be substituted for oral therapy. 

H2 antihistamines. (Cimetidine/Ranitidine) Although pruritus, wheal and flare reactions, 

and angioedema reactions are primarily Hi receptor mediated, histamine induced 

hypotension and cardiac arrhythmias can be mediated by both Hi and H2. receptors. 

Therefore, though has not been proven to be of benefit for anaphylaxis, H2 

antihistamine can be added. 

• Dose: 4 mg/kg Cimetidine IV (slowly over 5 minutes) 

• Exception: beta-blockers. In this setting, cimetidine could decrease clearance of 

the beta-blocker and thus perpetuate its action. 

Upper Airway Obstruction 


• Oxygen 

• Racemic epinephrine: 0.3 ml in 3 ml saline (or nebulized epinephrine) 

• Intubation or cricothyrotomy 

Lower Airway Obstruction 

Managed with a stepwise approach similar to that used for severe asthma. 


• Oxygen 

• Nebulized beta-agonists 

• Aminophylline bolus/infusion 

• Endotracheal intubation 

Late-phase reactions It is important to realize that some patients will resolve their anaphylaxis 

only to have a spontaneous recrudescence 8 to 24 hours later. This is the so-called late 

phase response. 

• Bronchodilators prevents the early, but not the late phase. 

• Corticosteroids prevents the late, but not the early phase. 

• Cromolyn prevents both the early and late phase. 

• The prospective study by Dr. Sullivan of anaphylaxis in 25 consecutive patients noted 

three distinct clinical patters: 

Uniphasic: 52% 

Biphasic: 20% 

Protracted: 28% (hypotension or respiratory distress lasting 5 to 32 hours despite 

aggressive therapy). 

• Contrary to expectations, glucocorticoid therapy introduced during the initial phase of 

anaphylaxis did not prevent the appearance of recurrent or protracted anaphylaxis.

Steroids may indeed lessen the chances or decrease the intensity of a recurrence, 

but they cannot be relied upon to eliminate it. 

• Therefore, individuals who have experienced a significant episode of anaphylaxis 

require at least 12 -24 hours of additional observation, and may require admission 

for overnight observation. 

Corticosteroids 

Disposition 

• Corticosteroids are not helpful in the acute management of anaphylaxis, 

• In moderate or severe reactions they should be started early to modify or perhaps 

prevent protracted or reèurrent symptoms. 

• Dosage: 

Methyiprednisolone: 2 mg/kg, followed by 1 mg/kg q 6 hours 

Hydrocortisone: 10 mg/kg, followed by 5 mg/kg q 6 hours. 

(Hydrocortisone sodium succinate) 

• In the elderly patient, the patient with cardiovascular disease, and the patient with 

severe or protracted hypoxia: observe for myocardial ischemia and 

cerebrovascular complications. 

• Identify the stimulus to anaphylaxis for future avoidance 

• Exercise, cold, stinging insects, drugs, and - frequently forgotten - foods 

• Arrange for immunotherapy whenever possible 

• Hymenoptera: 98% effective 

• Discuss desensitization (penicillin, sulfa) and premedication with corticosteroids and 

H1 antihistamines (radiocontrast studies) 

• Medic-alert bracelet or necklace 

• Continue oral prednisone and H1 antihistamines (6 to 48 hours) 

• Ana-kit. Self-administered epinephrine should be provided for patients who are likely to 

experience anaphylaxis outside a medical facility. The patient should be taught the 

indications and details of self-administration.





reference article





reference article

The diagnosis and management of anaphylaxis: 

An updated practice parameter 

Chief Editors: Phillip Lieberman, MD, Stephen F. Kemp, MD, John Oppenheimer, MD, 

David M. Lang, MD, I. Leonard Bernstein, MD, and Richard A. Nicklas, MD * 

Workgroup Contributors: John A. Anderson, MD, David I. Bernstein, MD, Jonathan A. 

Bernstein, MD, Jordan N. Fink, MD, Paul A. Greenberger, MD, Dennis K. 

Ledford, MD, James Li, MD, PhD, Albert L. Sheffer, MD, Roland Solensky, MD, and 

Bruce L. Wolf, MD 

Task Force Reviewers: Joann Blessing-Moore, MD, David A. Khan, MD, Rufus E. 

Lee, MD, Jay M. Portnoy, MD, Diane E. Schuller, MD, Sheldon L. Spector, MD, and 


These parameters were developed by the Joint Task Force on Practice 

Parameters, representing the American Academy of Allergy, Asthma 

and Immunology; the American College of Allergy, Asthma and 

Immunology; and the Joint Council of Allergy, Asthma and 

Immunology. 

The American Academy of Allergy, Asthma and Immunology 

(AAAAI) and the American College of Allergy, Asthma and 

Immunology (ACAAI) have jointly accepted responsibility for 

establishing ‘‘The diagnosis and management of anaphylaxis: an 

updated practice parameter.’’ This is a complete and comprehensive 

document at the current time. The medical environment is 

a changing environment, and not all recommendations will be 

appropriate for all patients. Because this document incorporated 

the efforts of many participants, no single individual, including 

those who served on the Joint Task force, is authorized to provide 

an official AAAAI or ACAAI interpretation of these practice 

parameters. Any request for information about or an interpretation 

of these practice parameters by the AAAAI or ACAAI should 

be directed to the Executive Offices of the AAAAI, the ACAAI, and 

the Joint Council of Allergy, Asthma and Immunology. These 

parameters are not designed for use by pharmaceutical companies 

in drug promotion. 

This is a complete and comprehensive document at 

the current time. The medical environment is a 

changing environment, and not all recommendations 

will be appropriate for all patients. 

Published practice parameters of the Joint Task Force 

on Practice Parameters for Allergy & Immunology 

include the following: 

1. Practice parameters for the diagnosis and treatment 

of asthma. J Allergy Clin Immunol 1995;96(suppl): 

S707-S870. 

2. Practice parameters for allergy diagnostic testing. 

Ann Allergy 1995;75:543-625. 

3. Practice parameters for the diagnosis and management 

of immunodeficiency. Ann Allergy 1996;76: 

282-94. 

4. Practice parameters for allergen immunotherapy. 


5. Disease management of atopic dermatitis: a practice 

parameter. Ann Allergy 1997;79:197-211. 

6. The diagnosis and management of anaphylaxis. 


7. Algorithm for the diagnosis and management of 

asthma: a practice parameter update. Ann Allergy 

1998;81:415-20. 

8. Diagnosis and management of rhinitis: parameter 

documents of the Joint Task Force on Practice Parameters 

in Allergy, Asthma and Immunology. Ann 

Allergy 1998;81(suppl):S463-S518. 

*This parameter was edited by Dr Nicklas in his private capacity and not in his 

capacity as a medical officer with the Food and Drug Administration. No 

official support or endorsement by the Food and Drug Administration is 

intended or should be inferred. 

Disclosure of potential conflict of interest: P. Lieberman—none disclosed. S. F. 

Kemp has consultant arrangements with MedPointe Pharmaceuticals. J. 

Oppenheimer—none disclosed. D. M. Lang—none disclosed. I. L. 

Bernstein—none disclosed. R. A. Nicklas—none disclosed. J. A. 

Anderson—none disclosed. D. I. Bernstein—none disclosed. J. Bernstein 

is on the Speakers’ Bureau for Merck, GlaxoSmithKline, AstraZeneca, 

Aventis, Medpointe, Pfizer, Schering-Plough, and IVAX. J. N. Fink—none 

disclosed. P. A. Greenberger—none disclosed. D. K. Ledford—none 

disclosed. J. Li—none disclosed. A. L. Sheffer—none disclosed. 

R. Solensky—none disclosed. B. L. Wolf—none disclosed. J. Blessing- 

Moore—none disclosed. D. A. Khan has consultant arrangements with 

Pfizer; receives grants/research support from AstraZeneca; and is on the 

Speakers’ Bureau for Pfizer, Merck, Aventis, and GlaxoSmithKline. R. E. 

Lee—none disclosed. J. M. Portnoy—none disclosed. D. E. Schuller is on 

the Speakers’ Bureau for Boehringer-Ingelheim. S.L. Spector has had 

consultant arrangements with, has received grants/research support from, 

and has been on the Speakers’ Bureau for Abbott, Allen & Hanburys, 

AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Fisons, Forest, 

ICN, Key, Eli-Lilly, 3M, Miles, Muro, Pfizer, Purdue Frederick, 

Schering-Plough, Wallace, and Witby. S. A. Tilles—none disclosed. 

Reprint requests: Joint Council of Allergy, Asthma & Immunology, 50 N 

Brockway St, #3-3, Palatine, IL 60067. 

J Allergy Clin Immunol 2005;115:S483-523. 

0091-6749/$30.00 

Ó 2005 American Academy of Allergy, Asthma and Immunology 

doi:10.1016/j.jaci.2005.01.010 

S483

S484 Lieberman et al 


MARCH 2005 

9. Parameters for the diagnosis and management of 

sinusitis. J Allergy Clin Immunol 1998;102(suppl) 

S107-S144. 

10. Stinging insect hypersensitivity: a practice parameter. 


11. Disease management of drug hypersensitivity: a practice 

parameter. Ann Allergy 1999;83(suppl):S665- 

S700. 

12. Diagnosis and management of urticaria: a practice 

parameter. Ann Allergy 2000;85(suppl):S521-S544. 

13. Allergen immunotherapy: a practice parameter. Ann 

Allergy 2003;90(suppl):SI-S540. 

14. Symptom severity assessment of allergic rhinitis: 

Part I. Ann Allergy 2003;91:105-114. 

15. Stinging insect hypersensitivity: a practice parameter 

update. J Allergy Clin Immunol 114;4:869-86. 

These parameters are also available on the Internet at 


CONTRIBUTORS 

The Joint Task Force has made a concerted effort to 

acknowledge all contributors to this parameter. If any 

contributors have been excluded inadvertently, the Task 

Force will ensure that appropriate recognition of such 

contributions is made subsequently. 

CHIEF EDITORS 

Phillip Lieberman, MD 


University of Tennessee 

College of Medicine 

Memphis, Tennessee 

Stephen F. Kemp, MD 


University of Mississippi Medical Center 

Jackson, Mississippi 

John Oppenheimer, MD 


New Jersey Medical School 

Pulmonary and Allergy Associates 

Morristown, New Jersey 

David M. Lang, MD 

Allergy/Immunology Section 

Division of Medicine 

Director, Allergy and Immunology Fellowship 

Training Program 

Cleveland Clinic Foundation 

Cleveland, Ohio 

I. Leonard Bernstein, MD 

Departments of Medicine and Environmental Health 



Richard A. Nicklas, MD 


George Washington Medical Center 

Washington, DC 

WORKGROUP CONTRIBUTORS 

John Anderson, MD 

Aspen Medical Center 

Fort Collins, Colorado 

David I. Bernstein, MD 

Department of Clinical Medicine 

Division of Immunology 



Jonathan A. Bernstein, MD 



Division of Immunology/Allergy Section 


Jordan N. Fink, MD 

Allergy-Immunology 

Departments of Pediatrics and Medicine 

Medical College of Wisconsin 

Milwaukee, Wisconsin 

Paul A. Greenberger, MD 

Division of Allergy and Immunology 

Northwestern University Feinberg School of 

Medicine 

Chicago, Illinois 

Dennis K. Ledford, MD 


University of South Florida College of Medicine and 

the James A. Haley V.A. Hospital 

Tampa, Florida 

James T. Li, MD, PhD 

Mayo Clinic 

Rochester, Minnesota 

Albert L. Sheffer, MD 

Brigham and Women’s Hospital 

Boston, Massachusetts 

Roland Solensky, MD 

The Corvallis Clinic 

Corvallis, Oregon 

Bruce L. Wolf, MD 

Vanderbilt University 

Nashville, Tennessee 

TASK FORCE REVIEWERS 

Joann Blessing-Moore, MD 

Department of Immunology 

Stanford University Medical Center 

Palo Alto, California 

David A. Khan, MD 


University of Texas Southwestern Medical Center 

Dallas, Texas



Lieberman et al S485 

The diagnosis and management of anaphylaxis: 

An updated practice parameter 

Preface 

S485 

Algorithm for initial evaluation and 

management of a patient with a 

history of anaphylaxis (Fig 1) 

S486 

Algorithm for the treatment of acute 

anaphylaxis (Fig 2) 

S489 

Summary statements 

S494 

Evaluation and management of the patient 

with a history of episodes of anaphylaxis S497 

Management of anaphylaxis 

S500 

Anaphylaxis to foods 

S506 

Latex-induced anaphylaxis 

S508 

Anaphylaxis during general anesthesia, the 

intraoperative period, and the postoperative 

period 

S509 

Seminal fluid–induced anaphylaxis S511 

Exercise-induced anaphylaxis 

S513 

Idiopathic anaphylaxis 

S514 

Anaphylaxis and allergen immunotherapy 

vaccines 

S515 

Anaphylaxis to drugs 

S516 

Prevention of anaphylaxis 

S518 

Rufus E. Lee, MD 

Private Practice 

Dothan, Alabama 

Jay M. Portnoy, MD 

Section of Allergy, Asthma & Immunology 

The Children’s Mercy Hospital 

Professor of Pediatrics 

University of Missouri-Kansas City School of 

Medicine 

Kansas City, Missouri 

Diane E. Schuller, MD 


Pennsylvania State University Milton S. Hershey 

Medical College 

Hershey, Pennsylvania 

Sheldon L. Spector, MD 


UCLA School of Medicine 

Los Angeles, California 



University of Washington School of Medicine 

Redmond, Washington 

REVIEWERS 

Mary C. Tobin, MD, Oak Park, Illinois 

Jeffrey A. Wald, MD, Overland Park, Kansas 

Dana V. Wallace, MD, Fort Lauderdale, Florida 

Stephen Wasserman, MD, La Jolla, California 

CLASSIFICATION OF RECOMMENDATIONS 

AND EVIDENCE 

Category of evidence 

Ia Evidence from meta-analysis of randomized controlled 

trials 

Ib Evidence from at least one randomized controlled 

trial 

IIa Evidence from at least on controlled study without 

randomization 

IIb Evidence from at least one other type of quasiexperimental 

study 

III Evidence from nonexperimental descriptive studies, 

such as comparative studies 

IV Evidence from expert committee reports or opinions 

or clinical experience of respected authorities 

or both 

Strength of recommendation 

A Directly based on category I evidence 

B Directly based on category II evidence or extrapolated 

recommendation from category I evidence 

C Directly based on category III evidence or extrapolated 

recommendation from category I or II 

evidence 

D Directly based on category IV evidence or extrapolated 

recommendation from category I, II, or III 

evidence 

NR Not rated 

PREFACE 

Anaphylaxis is defined for the purposes of this document 

as a condition caused by an IgE-mediated reaction. 

Anaphylactoid reactions are defined as those reactions that 

produce the same clinical picture as anaphylaxis but are 

not IgE mediated. Where both IgE-mediated and non–IgEmediated 

mechanisms are a possible cause, the term 

‘‘anaphylactic’’ has been used to describe the reaction. 

Anaphylactic reactions are often life-threatening and 

almost always unanticipated. Even when there are mild 

symptoms initially, the potential for progression to 

a severe and even irreversible outcome must be recognized. 

Any delay in the recognition of the initial signs and 

symptoms of anaphylaxis can result in a fatal outcome 

either because of airway obstruction or vascular collapse. 

Most patients who have experienced anaphylaxis 

should be evaluated by a specialist in allergy-immunology. 

Such a consultation is appropriate because individuals 

trained in allergy-immunology possess particular 

training and skills to evaluate and appropriately treat 

individuals at risk of anaphylaxis. 

The objective of this parameter, ‘‘The diagnosis and 

management of anaphylaxis: an updated practice parameter,’’ 

is to improve the care of patients by providing the 

practicing physician with an evidence-based approach to 

the diagnosis and management of anaphylactic reactions.



MARCH 2005 

‘‘The diagnosis and management of anaphylaxis: an 

updated practice parameter’’ was developed by the Joint 

Task Force on Practice Parameters, which has published 

11 practice parameters for the field of allergy-immunology 

(see list of publications). The 3 national allergy 

and immunology societies—the American College of 

Allergy, Asthma and Immunology (ACAAI); the American 

Academy of Allergy, Asthma and Immunology 

(AAAAI); and the Joint Council of Allergy, Asthma and 

Immunology (JCAAI)—have given the Joint Task Force 

the responsibility for both creating new parameters and 

updating existing parameters. This parameter builds on 

‘‘The diagnosis and management of anaphylaxis,’’ which 

was published in 1998 by the Joint Task Force on Practice 

Parameters. It was written and reviewed by specialists in 

the field of allergy and immunology and was exclusively 

funded by the 3 allergy and immunology organizations 

noted above. 

A workgroup chaired by Phillip Lieberman, MD, 

prepared the initial draft. The Joint Task Force then 

reworked the initial draft into a working draft of the 

document. A comprehensive search of the medical 

literature was conducted with various search engines, 

including PubMed, using appropriate search terms. 

Published clinical studies were rated by category of 

evidence and used to establish the strength of the clinical 

recommendations (see ‘‘Classification of rating and 

evidence’’ above). The working draft of this updated 

parameter was reviewed by a large number of experts on 

anaphylaxis selected by the sponsoring organizations. 

This document represents an evidence-based and broadly 

accepted consensus viewpoint on the diagnosis and management 

of anaphylaxis. 

‘‘The diagnosis and management of anaphylaxis: an 

updated practice parameter’’ contains annotated algorithms 

that present the major decision points for the initial 

evaluation and management of a patient with a history 

of a previous episode of anaphylaxis and for the acute 

management of anaphylaxis. These are followed by a list 

of summary statements that represent the key points to 

consider in the evaluation and management of anaphylaxis. 

These summary statements can also be found before 

each section in this document followed by the text that 

supports the summary statements, which are, in turn, 

followed by graded references that support the statements 

in the text. In addition to sections on the diagnosis and 

management of anaphylaxis, this updated parameter 

contains sections on anaphylaxis to foods, latex, seminal 

fluid, allergen immunotherapy, and medications, as well as 

exercise-induced anaphylaxis, idiopathic anaphylaxis, and 

anaphylaxis occurring during general anesthesia, both 

during the intraoperative and postoperative periods. 

Among the objectives of this updated parameter are the 

development of an improved understanding of anaphylaxis 

among health care professionals, medical students, 

interns, residents, and fellows, as well as managed care 

executives and administrators. The parameter is intended 

to provide guidelines and support for the practicing 

physician and to improve the quality of care for patients 

who experience anaphylaxis. The Joint Task Force on 

Practice Parameters recognizes that there are different, 

although appropriate, approaches to the diagnosis and 

management of anaphylactic reactions that often require 

flexible recommendations. Therefore the diagnosis and 

management of anaphylactic reactions must be individualized 

on the basis of unique features in particular patients. 

Throughout this document, we will rely on anaphylaxis 

to imply anaphylactic (IgE-mediated) and anaphylactoid 

(non–IgE-mediated) reactions. 

The Joint Task Force on Practice Parameters wishes 

to thank the ACAAI, AAAAI, and JCAAI, who have 

supported the preparation of this updated parameter, and 

the large number of individuals who have so kindly 

dedicated their time and effort to the review of this 

document. 

ALGORITHM FOR INITIAL EVALUATION AND 

MANAGEMENT OF A PATIENT WITH 

A HISTORY OF ANAPHYLAXIS (Fig 1) 

Annotation 1: Is the history consistent with 

a previous episode of anaphylaxis? 

All individuals who have had a known or suspected 

anaphylactic episode require a careful and complete 

review of their clinical history. This history might elicit 

manifestations, such as urticaria, angioedema, flushing, 

pruritus, upper airway obstruction, gastrointestinal symptoms, 

syncope, hypotension, lower airway obstruction, 

and/or dizziness. 

Of primary importance is the nature of the symptoms 

characterizing the event. Essential questions to be asked 

are as follows: 

1. Were there cutaneous manifestations, specifically 

pruritus, flush, urticaria, and angioedema? 

2. Was there any sign of airway obstruction involving 

either the upper airway or the lower airway? 

3. Were there gastrointestinal symptoms (ie, nausea, 

vomiting, or diarrhea)? 

4. Were syncope or presyncopal symptoms present? 

At this point, it should be noted that the absence of 

cutaneous symptoms puts the diagnosis in question 

because the majority of anaphylaxis includes cutaneous 

symptoms, but their absence would not necessarily rule 

out an anaphylactic or anaphylactoid event. 

The history should concentrate on agents encountered 

before the reaction. Whenever appropriate, the information 

should be obtained from not only the patient but also 

family members or other witnesses. The complete sequence 

of events must be reviewed, with special attention 

paid to the cardiorespiratory symptoms. Medical records, 

including medication records, can often be useful in 

evaluating the history, physical findings, and treatment 

of the clinical event. In addition, the results of any 

previous laboratory studies (eg, serum tryptase levels) 

might be helpful in making the diagnosis of anaphylaxis or 

distinguishing it from other entities.




FIG 1. Algorithm for the initial evaluation and management of a patient with a history of an episode of 

anaphylaxis. ACE, Angiotensin-converting enzyme. 

Annotation 1A: Consider consultation with 

an allergist-immunologist 

Patients with anaphylaxis might be first seen with 

serious and life-threatening symptoms. Evaluation and 

diagnosis, as well as long-term management, can be 

complex. The allergist-immunologist has the training 

and expertise to obtain a detailed allergy history, coordinate 

laboratory and allergy testing, evaluate the 

benefits and risks of therapeutic options, and counsel the 

patient on avoidance measures. For these reasons, patients 

with a history of anaphylaxis should be considered for 

referral to an allergy-immunology specialist. 

Annotation 2: Pursue other diagnoses or 

make appropriate referral 

Other conditions that should be considered in the differential 

diagnosis include the following: (1) vasodepressor 

(vasovagal-neurocardiogenic) syncope; (2) syndromes 

that can be associated with flushing (eg, metastatic carcinoid); 

(3) postprandial syndromes (eg, scombroid poisoning); 

(4) systemic mastocytosis; (5) psychiatric disorders 

that can mimic anaphylaxis, such as panic attacks or vocal 

cord dysfunction syndrome; (6) angioedema (eg, hereditary 

angioedema); (7) other causes of shock (eg, cardiogenic); 

and (8) other cardiovascular or respiratory events.



MARCH 2005 

Annotation 3: Is cause readily identified 

by history? 

The history is the most important tool to establish the 

cause of anaphylaxis and takes precedence over diagnostic 

tests. A detailed history of all ingestants (both foods and 

drugs) several hours before the episode should be 

obtained. In addition, the labels for all packaged foods 

ingested by the patient in this period of time should 

be reviewed because a substance added to the food 

(eg, carmine) could be responsible. A history of any 

preceding bite or sting should be obtained. The patient’s 

activities (eg, exercise, sexual activity, or both) preceding 

the event should be reviewed. Patient diaries might be 

a useful adjunct in confirming and identifying the cause of 

anaphylaxis. 

Annotation 4: Consider idiopathic 

anaphylaxis 

Idiopathic anaphylaxis is a diagnosis of exclusion 

that should be made only after other causes of anaphylaxis 

and other differential diagnoses have been considered. 

Annotation 5: Are further diagnostic tests 

indicated: immediate hypersensitivity or 

in vitro tests, challenge tests? 

Immediate hypersensitivity tests or in vitro specific IgE 

tests and/or challenge tests might be appropriate to help 

define the cause of the anaphylactic episode. However, the 

history might be so specific that none of the above tests are 

necessary. 

Annotation 6: Diagnosis established on 

basis of history, risk of testing, limitation of 

tests, patient refuses test, other 

management options available, 

management 

There might be circumstances in which allergy skin 

tests, in vitro specific IgE tests, and/or challenge tests 

might not be warranted. In general, this might apply when 

the clinician (with the consent of the patient) decides to 

proceed with management on the basis of the history and 

physical examination. 

For example, the clinical history of anaphylaxis to a 

specific agent might be so strong that testing is unnecessary 

(or dangerous). Conversely, the medical history 

of anaphylaxis might be sufficiently mild or weak that 

management can proceed in the absence of testing. If 

avoidance can be easily and safely accomplished, testing 

might not be necessary. 

Furthermore, testing or challenge with reagents to a 

suspected allergen might not be available, or the accuracy 

of the test might be in question. In addition, for patients 

with a history of anaphylaxis, challenge tests (and, to 

a lesser extent, skin tests) might be hazardous. 

Annotation 7: Testing identifies specific 

cause of anaphylaxis 

Skin tests or in vitro tests that determine the presence of 

specific IgE antibodies can identify specific causes of 

anaphylaxis. Causes of anaphylaxis that can be defined in 

this way include foods, medications (eg, penicillin and 

insulin), and stinging insects. For the majority of medications, 

standardized testing either by in vivo or in vitro 

means is not available. Such tests are only valid when the 

reaction is due to a true anaphylactic event (IgE-mediated 

reaction) and not as a result of an anaphylactoid (non–IgEmediated) 

reaction. 

In general, skin testing is more sensitive than in vitro 

testing and is the diagnostic procedure of choice for 

evaluation of most potential causes of anaphylaxis (eg, 

penicillin, insect stings, and foods). It is essential that the 

correct technique for skin testing be used to obtain 

meaningful data regarding causative agents of anaphylaxis. 

When possible, standardized extracts should be used 

(occasionally fresh food extracts will be superior to 

available standardized extracts). If the skin testing extract 

has not been standardized (eg, latex, protamine, or antibiotics 

other than penicillin), the predictive value is 

uncertain. If skin testing is performed, it should be done 

under the supervision of a physician who is experienced in 

the procedure in a setting with appropriate rescue 

equipment and medication. 

The accuracy of in vitro testing depends on the 

reliability of the in vitro method, the ability to interpret 

the results, and the availability of reliable testing material. 

The clinical significance of skin test or in vitro test results 

depends on the ability to correlate such results with the 

patient’s history. 

If tests for specific IgE antibodies (ie, skin tests, in vitro 

tests, or both) do not provide conclusive evidence of the 

cause of anaphylaxis, challenge with the suspected agent 

can be considered. Challenge procedures might also 

be appropriate in patients with anaphylactoid reactions 

(eg, reactions to aspirin or other nonsteroidal antiinflammatory 

drugs). Challenges with suspected agents 

must be done carefully by individuals knowledgeable 

in the challenge procedure and with expertise in managing 

reactions to the challenge agent if they should 

occur. 

Annotation 8: Reconsider clinical diagnosis, 

reconsider idiopathic anaphylaxis, consider 

other triggers, consider further testing, 

management 

At this stage in the patient’s evaluation, it is particularly 

important to consider other trigger factors and diagnoses. 

The medical history and laboratory test results should be 

reviewed. Further testing for specific IgE antibodies 

should be considered. Laboratory studies that might be 

helpful include serum tryptase measurement, as well as 

urinary 5-hydroxyindoleacetic acid, methylhistamine, and 

catecholamine measurement. Idiopathic anaphylaxis is 

a diagnosis of exclusion (see ‘‘Idiopathic anaphylaxis’’).




Management of anaphylaxis episodes should follow annotation 

10 (see algorithm). 

Annotation 9: Diagnosis made of specific 

cause of anaphylaxis 

The diagnosis of a specific cause of anaphylaxis might 

be supported by the results of skin tests, in vitro IgE tests, 

and/or challenge tests (particularly double-blind, placebocontrolled 

challenge tests). 

Annotation 10: Management of anaphylaxis 

When anaphylaxis has occurred because of exposure to 

a specific agent (eg, food, medication, or insect sting), 

patients should be educated about agents or exposures that 

would place them at risk for future reactions and be 

counseled on avoidance measures that might be used to 

reduce risk for such exposures. Patients who have had 

anaphylactic reactions to food should be instructed on how 

to read food ingredient labels to identify foods that they 

should avoid. Patients with anaphylaxis to medications 

should be informed about all cross-reacting medications 

that should be avoided. Should there be a future essential 

indication for use of incriminated medications, it might be 

helpful to educate patients about applicable management 

options (eg, medication pretreatment and use of lowosmolarity 

agents in patients with a history of reactions to 

radiographic contrast media or desensitization for drugs, 

such as antibiotics). Patients who have had anaphylactic 

reactions to insect stings should be advised about avoidance 

measures to reduce the risk of insect stings are candidates 

for insect venom immunotherapy (see ‘‘Stinging insect 

hypersensitivity: a practice parameter update’’). Patients 

who have had anaphylaxis should carry self-injectable 

epinephrine for use if anaphylaxis develops. There might 

be exceptions to this (eg, anaphylaxis to penicillin). 

Patients should also carry identification indicating that 

they are prone to anaphylaxis and indicating the responsible 

agent. Patients taking b-blockers are at increased risk 

during anaphylaxis. 

ALGORITHM FOR THE TREATMENT OF 

ACUTE ANAPHYLAXIS (Fig 2) 

Annotation 1. Anaphylaxis preparedness 

It is important to stress that management recommendations 

are subject to physician discretion and that 

variations in sequence and performance rely on physician 

judgment. Additionally, a determination of when a patient 

should be transferred to an emergency facility depends on 

the skill, experience, and clinical decision making of the 

individual physician. Preparedness, prompt recognition, 

and appropriate and aggressive treatment are integral 

to parts of successful management of anaphylaxis. A 

treatment log will assist in accurately recording progress 

(Fig 3). 

Recommendations depend on practice resources and 

the proximity to other emergency assistance. Stocking and 

maintaining anaphylaxis supplies with regular written 

documentation of contents and expiration dates and ready 

availability of injectable epinephrine, intravenous fluids 

and needles, oxygen and mask cannula, airway adjuncts, 

and stethoscope and sphygmomanometer are bare essentials. 

(An example of a supply checklist is included in 

‘‘Management of anaphylaxis’’ [Fig 4]. Not all items need 

to be present in each office.) 

Regular anaphylaxis practice drills, the contents of 

which are left to the discretion and qualifications of 

the individual physician, are strongly recommended. 

Essential ingredients are identification of a person who 

will be responsible for calling emergency medical services 

and the person who will document treatment and time each 

is rendered. The emergency kit should be up to date and 

complete. Everyone who will be directly involved in 

patient care should, for example, be able to easily locate 

necessary supplies and rapidly assemble fluids for intravenous 


Annotation 2. Patient presents with 

possible-probable acute anaphylaxis 

Anaphylaxis is an acute life-threatening reaction, 

usually but not always mediated by an immunologic 

mechanism (anaphylactoid reactions are IgE independent), 

that results from the sudden systemic release of mast 

cells and basophil mediators. It has varied clinical 

presentations, but respiratory compromise and cardiovascular 

collapse cause the most concern because they are the 

most frequent causes of fatalities. Urticaria and angioedema 

are the most common manifestations of anaphylaxis 

but might be delayed or absent in rapidly progressive 

anaphylaxis. The more rapidly anaphylaxis occurs after 

exposure to an offending stimulus, the more likely the 

reaction is to be severe and potentially life-threatening. 

Anaphylaxis often produces signs and symptoms 

within minutes of exposure to an offending stimulus (see 

comments in text), but some reactions might develop later 

(eg, >30 minutes after exposure). Late-phase or biphasic 

reactions, which occur 8 to 12 hours after the initial attack, 

have also been reported. Protracted and severe anaphylaxis 

might last up to 32 hours, despite aggressive 

treatment. 

Increased vascular permeability, a characteristic feature 

of anaphylaxis, allows transfer of as much as 50% of the 

intravascular fluid into the extravascular space within 10 

minutes. As a result, hemodynamic collapse might occur 

rapidly with little or no cutaneous or respiratory manifestations. 

Annotation 3. Initial assessment supports 

potential anaphylaxis 

Initial assessment should determine whether history 

and physical findings are compatible with anaphylaxis. 

The setting of the episode and the history might suggest or 

reveal the source of the reaction. Evaluation should 

include level of consciousness (impairment might reflect 

hypoxia), upper and lower airways (dysphonia, stridor, 

cough, wheezing, or shortness of breath), cardiovascular 

system (hypotension with or without syncope and/or



MARCH 2005 

FIG 2. Algorithm for the treatment of acute anaphylaxis. ICU, Intensive care unit; CPR, cardiopulmonary 

resuscitation; ACLS, advanced cardiac life support. 

cardiac arrhythmias), the skin (diffuse or localized 

erythema, pruritus, urticaria, and/or angioedema), and 

the gastrointestinal system (nausea, vomiting, or diarrhea). 

In addition, some patients might have symptoms of 

lightheadedness, headache, uterine cramps, feeling of 

impending doom, and unconsciousness. 

The vasodepressor (vasovagal) reaction probably is the 

condition most commonly confused with anaphylactic 

and anaphylactoid reactions. In vasodepressor reactions, 

however, urticaria is absent, the heart rate is typically 

bradycardic, bronchospasm or other breathing difficulty is 

generally absent, the blood pressure is usually normal or 

increased, and the skin is typically cool and pale. 

Tachycardia is the rule in anaphylaxis, but it might be 

absent in patients with conduction defects, with increased 

vagal tone caused by a cardioinhibitory (Bezold-Jarisch) 

reflex, or who take sympatholytic medications. 

Annotation 4. Consider other diagnosis 

Other diagnoses that might present with signs and/or 

symptoms characteristic of anaphylaxis should be excluded. 

Like anaphylaxis, several conditions might cause 

abrupt and dramatic patient collapse. Among conditions to 

consider are vasodepressor (vasovagal) reactions, acute 

anxiety (eg, panic attack or hyperventilation syndrome), 

myocardial dysfunction, pulmonary embolism, systemic 

mast cell disorders, foreign-body aspiration, acute poi-




FIG 3. Anaphylaxis treatment record. 

soning, hypoglycemia, and seizure disorder. Specific 

signs and symptoms of anaphylaxis might present singly 

in other disorders. Examples are urticaria-angioedema, 

hereditary angioedema, and asthma. 

Annotation 5. Immediate intervention 

The clinician should remember that anaphylaxis occurs 

as part of a continuum. Symptoms not immediately lifethreatening 

might progress rapidly unless treated 

promptly. Treatment recommendations are subject to 

physician discretion, and variations in sequence and 

performance rely on physician judgment. Additionally, 

a determination of when a patient should be transferred to 

an emergency or intensive care facility depends on 

available resources and the skill, experience, and clinical 

decision making of the individual physician. 

1. Assess airway, breathing, circulation, and level of 

consciousness (altered mentation might suggest the 

presence of hypoxia). 

2. Administer epinephrine. Aqueous epinephrine 

1:1000 dilution (1 mg/mL), 0.2 to 0.5 mL (0.01 

mg/kg in children, maximum 0.3-mg dosage) intramuscularly 

or subcutaneously every 5 minutes, as 

necessary, should be used to control symptoms and 

increase blood pressure. Consider dose-response 

effects. Note: If the clinician deems it appropriate, 

the 5-minute interval between injections can be 

liberalized to permit more frequent injections. Intramuscular 

epinephrine injections into the thigh 

have been reported to provide more rapid absorption 

and higher plasma epinephrine levels in both children 

and adults than intramuscular or subcutaneous 

injections administered in the arm. However, similar 

studies comparing intramuscular injections with subcutaneous 

injections in the thigh have not yet been 

done. Moreover, these studies were not performed in 

patients experiencing anaphylaxis. For this reason, 

the generalizability of these findings to the clinical 

setting of anaphylaxis has not been established. 

Although intuitively more rapid absorption and 

higher epinephrine levels would seem desirable, the 

clinical significance of this finding is not known. No 

data support the use of epinephrine in anaphylaxis 

through a nonparenteral route. However, alternative 

routes of administration have been anecdotally



MARCH 2005 

FIG 4. Suggested anaphylaxis supply check sheet 

successful. These include, for example, inhaled 

epinephrine in the presence of laryngeal edema or 

sublingual administration if an intravenous route 

cannot be obtained. Endotracheally administered 

dosages have also been proposed for use when intravenous 

access is not available in intubated patients 

experiencing cardiac arrest. 

Annotation 6. Subsequent emergency care 

that might be necessary depending on 

response to epinephrine 

1. Place patient in the recumbent position and elevate 

the lower extremities, as tolerated symptomatically. 

This slows progression of hemodynamic compromise, 

if present, by preventing orthostatic hypotension 

and helping to shunt effective circulation from 

the periphery to the head and to the heart and kidneys. 

2. Establish and maintain airway. Ventilatory assistance 

through a 1-way valve facemask with an oxygen 

inlet port (eg, Pocket-Mask [LaerdalÒ, Preparedness 

Industries, Ukiah, Calif] or similar device) might be 

necessary. Ambubags of less than 700 mL are 

discouraged in adults in the absence of an endotracheal 

tube because ventilated volume will not overcome 

150 to 200 mL of anatomic dead space to 

provide effective tidal volume. (Ambubags can be 

used in children, provided the reservoir volume of 

the device is sufficient.) Endotracheal intubation or 

cricothyroidotomy might be considered where appropriate 

and provided that clinicians are adequately 

trained and proficient in this procedure. 

3. Administer oxygen. Oxygen should be administered 

to patients with anaphylaxis who have prolonged 

reactions, have pre-existing hypoxemia or myocardial 

dysfunction, receive inhaled b-agonists as part of




therapy for anaphylaxis, or require multiple doses of 

epinephrine. Continuous pulse oximetry and/or arterial 

blood gas determination (where available) should 

guide oxygen therapy where hypoxemia is a concern. 

4. Consider a normal saline intravenous line for fluid 

replacement and venous access. Lactated Ringer’s 

solution might potentially contribute to metabolic 

acidosis, and dextrose is rapidly extravasated from 

the intravascular circulation to the interstitial tissues. 

Increased vascular permeability in anaphylaxis might 

permit transfer of 50% of the intravascular fluid into 

the extravascular space within 10 minutes. Crystalloid 

volumes (eg, saline) of up to 7 L might be 

necessary. One to 2 L of normal saline should be 

administered to adults at a rate of 5 to 10 mL/kg in 

the first 5 minutes. Patients with congestive heart 

failure or chronic renal disease should be observed 

cautiously to prevent volume overload. Children 

should receive up to 30 mL/kg in the first hour. 

Adults receiving colloid solution should receive 500 

mL rapidly, followed by slow infusion. Aqueous 

epinephrine 1:1000, 0.1 to 0.3 mL in 10 mL of 

normal saline, can be administered intravenously 

over several minutes and repeated as necessary in 

cases of anaphylaxis not responding to epinephrine 

injections and volume resuscitation. Alternatively, an 

epinephrine infusion can be prepared by adding 1 mg 

(1 mL) of a 1:1000 dilution of epinephrine to 250 

mL of D5W to yield a concentration of 4.0 mg/mL. 

This solution is infused at a rate of 1 to 4 mg/min (15 

to 60 drops per minute with a microdrop apparatus 

[60 drops per minute = 1 mL = 60 mL/h]), increasing 

to a maximum of 10.0 mg/min. If an infusion pump 

is available, an alternative 1:100,000 solution of 

epinephrine (1 mg [1 mL] in 100 mL of saline) can 

be prepared and administered intravenously at an 

initial rate of 30 to 100 mL/h (5-15 mg/min), titrated 

up or down depending on clinical response or 

epinephrine side effects (toxicity). A dosage of 

0.01 mg/kg (0.1 mL/kg of a 1:10,000 solution; 

maximum dose, 0.3 mg) is recommended for 

children. Alternative pediatric dosage by the ‘‘rule 

of 6’’ is as follows: 0.63 body weight (in kilograms) 

= the number of milligrams diluted to a total 

of 100 mL of saline; then 1 mL/h delivers 0.1 mg/kg/ 

min. Note: Because of the risk for potentially lethal 

arrhythmias, epinephrine should be administered 

intravenously only during cardiac arrest or to profoundly 

hypotensive patients who have failed to 

respond to intravenous volume replacement and 

several injected doses of epinephrine. In situations 

in which hemodynamic monitoring is available (eg, 

emergency department or intensive care facility), continuous 

hemodynamic monitoring is essential. However, 

use of intravenous epinephrine should not be 

precluded in a scenario in which such monitoring is 

unavailable if the clinician deems administration is 

essential after failure of several epinephrine injections. 

If intravenous epinephrine is considered 

essential under these special circumstances, monitoring 

by available means (eg, every-minute blood 

pressure and pulse measurements and electrocardiographic 

monitoring, if available) should be conducted. 

5. Consider diphenhydramine, 1 to 2 mg/kg or 25 to 50 

mg per dose (parenterally). Note: H 1 antihistamines 

are considered second-line therapy to epinephrine 

and should never be administered alone in the 

treatment of anaphylaxis. 

6. Consider ranitidine, 50 mg in adults and 12.5 to 50 

mg (1 mg/kg) in children, which might be diluted in 

5% dextrose to a total volume of 20 mL and injected 

intravenously over 5 minutes. Cimetidine (4 mg/kg) 

can be administered intravenously to adults, but no 

pediatric dosage in anaphylaxis has been established. 

Note: In the management of anaphylaxis, a combination 

of diphenhydramine and ranitidine is superior to 

diphenhydramine alone. However, these agents have 

a much slower onset of action than epinephrine and 

should never be used alone in the treatment of 

anaphylaxis. Both alone and in combination, these 

agents are second-line therapy to epinephrine. 

7. Bronchospasm resistant to adequate doses of epinephrine: 

consider inhaled b-agonist (eg, nebulized 

albuterol, 2.5 to 5 mg in 3 mL of saline and repeat as 

necessary). 

8. Hypotension refractory to volume replacement and 

epinephrine injections: consider vasopressor infusion. 

Continuous hemodynamic monitoring is essential. 

For example, dopamine (400 mg in 500 mL of 

5% dextrose) can be infused at 2 to 20 mg/kg/min 

and titrated to maintain systolic blood pressure of 

greater than 90 mm Hg. 

9. Consider glucagon infusion when concomitant b- 

adrenergic blocking agent complicates treatment. 

Glucagon dosage is 1 to 5 mg (20-30 mg/kg 

[maximum dose, 1 mg] in children) administered 

intravenously over 5 minutes and followed by an 

infusion (5 to 15 mg/min) titrated to clinical response. 

10. Consider systemic glucocorticosteroids for patients 

with a history of idiopathic anaphylaxis or asthma 

and patients who experience severe or prolonged 

anaphylaxis. Glucocorticosteroids usually are not 

helpful acutely but potentially might prevent recurrent 

or protracted anaphylaxis. If given, intravenous 

glucocorticosteroids should be administered 

every 6 hours at a dosage equivalent to 1.0 to 2.0 

mg/kg/d. Oral administration of glucocorticosteroids 

(eg, prednisone, 0.5 mg/kg) might be sufficient for 

less critical anaphylactic episodes. 

11. Consider transportation to emergency department or 

intensive care facility. 

Annotation 7. Cardiopulmonary arrest 

during anaphylaxis 

1. Cardiopulmonary resuscitation and advanced cardiac 

life support measures. 

2. High-dose epinephrine administered intravenously (ie, 

rapid progression to high dose). A common sequence



MARCH 2005 

is 1 to 3 mg (1:10,000 dilution) slowly administered 

intravenously over 3 minutes, 3 to 5 mg administered 

intravenously over 3 minutes, and then a 4 to 10 mg/ 

min infusion. For children, the recommended initial 

resuscitation dosage is 0.01 mg/kg (0.1 mL/kg of 

a 1:10,000 solution up to 10 mg/min rate of infusion) 

repeated every 3 to 5 minutes for ongoing arrest. 

Higher subsequent dosages (0.1-0.2 mg/kg; 0.1 mL/ 

kg of a 1:1,000 solution) might be considered for 

unresponsive asystole or pulseless electrical activity. 

3. Rapid volume expansion. 

4. Atropine and transcutaneous pacing if asystole and/or 

pulseless electrical activity are present. 

5. Prolonged resuscitation is encouraged, if necessary, 

because efforts are more likely to be successful in 

anaphylaxis. 

6. Transport to emergency department or intensive care 

facility, as setting dictates. 

Annotation 8. Observation and subsequent 

follow-up 

Observation periods must be individualized because 

there are no reliable predictors of biphasic or protracted 

anaphylaxis on the basis of initial clinical presentation. 

Follow-up accordingly must be individualized and 

based on such factors as clinical scenario and distance 

from the patient’s home to the closest emergency 

facility. After resolution of the acute episode, patients 

should be provided with an epinephrine syringe and 

receive proper instruction for self-administration in case 

of a subsequent episode. In circumstances in which an 

allergist-immunologist is not already involved, it is 

strongly recommended that individuals who have experienced 

acute anaphylaxis should receive consultation 

from an allergist-immunologist regarding diagnosis, 

prevention, and treatment. 

Annotation 9. Consider consultation with an 

allergist-immunologist 

After acute anaphylaxis, patients should be assessed for 

future risk for anaphylaxis. The allergist-immunologist can 

obtain a detailed history, coordinate allergy diagnostic 

testing, evaluate the risks and benefits of therapeutic 

options, train and retrain in self-administration of epinephrine, 

and provide counseling on avoidance measures (the 

most effective treatment for most causes of anaphylaxis). 

Consultation with an allergist-immunologist is recommended 

when: 

1. the diagnosis is doubtful or incomplete; 

2. the symptoms are recurrent or difficult to control; 

3. help is needed in evaluation and management of 

medication use or side effects; 

4. help is needed in medical management or adherence 

to treatment; 

5. help is needed in the diagnosis or management of 

IgE-mediated reactions or identification of allergic 

triggers; 

6. the patient is a candidate for desensitization (eg, 

penicillin) or immunotherapy (eg, venom-specific 

immunotherapy); 

7. the patient requires daily medications for prevention; 

8. the patient requires intensive education regarding 

avoidance or management; 

9. help is needed with new or investigative therapy; 

10. treatment goals have not been met; 

11. anaphylaxis is complicated by one or more comorbid 

conditions or concomitant medications; or 

12. the patient has requested a subspecialty consultation. 

SUMMARY STATEMENTS 

Evaluation and management of the patient 

with a history of episodes of anaphylaxis 

1. The history is the most important tool to determine 

whether a patient has had anaphylaxis and the cause 

of the episode. C 

2. A thorough differential diagnosis should be considered, 

and other conditions should be ruled out. C 

3. Laboratory tests can be helpful to confirm a diagnosis 

of anaphylaxis or rule out other causes. Proper 

timing of studies (eg, serum tryptase) is essential. B 

4. In the management of a patient with a previous 

episode, education is necessary. Emphasis on early 

treatment, specifically the self-administration of 

epinephrine, is essential. C 

5. The patient should be instructed to wear and/or carry 

identification denoting his or her condition (eg, 

Medic Alert jewelry). C 


6. Medical facilities should have an established protocol 

to deal with anaphylaxis and the appropriate 

equipment to treat the episode. In addition, telephone 

numbers for paramedical rescue squads and ambulance 

services might be helpful to have on hand. B 

7. Anaphylaxis is an acute, life-threatening systemic 

reaction with varied mechanisms, clinical presentations, 

and severity that results from the sudden 

systemic release of mediators from mast cells and 

basophils. B 

8. Anaphylactic (IgE-dependent) and anaphylactoid 

(IgE-independent) reactions differ mechanistically, 

but the clinical presentations are identical. C 

9. The more rapidly anaphylaxis develops, the more 

likely the reaction is to be severe and potentially lifethreatening. 

C 

10. Prompt recognition of signs and symptoms of 

anaphylaxis is crucial. If there is any doubt, it is 

generally better to administer epinephrine. C 

11. Any health care facility should have a plan of action 

for anaphylaxis should it occur. Physicians and 

office staff should maintain clinical proficiency in 

anaphylaxis management. D 

12. Epinephrine and oxygen are the most important therapeutic 

agents administered in anaphylaxis. Epinephrine 

is the drug of choice, and the appropriate




dose should be administered promptly at the onset of 

apparent anaphylaxis. A/D 

13. Appropriate volume replacement either with colloid 

or crystalloids and rapid transport to the hospital is 

essential for patients who are unstable or refractory to 

initial therapy for anaphylaxis in the office setting. B 

Anaphylaxis to foods 

14. Severe food reactions have been reported to involve 

the gastrointestinal, cutaneous, respiratory, and cardiovascular 

systems. D 

15. The greatest number of anaphylactic episodes in 

children has involved peanuts, tree nuts (ie, walnuts, 

pecans, and others), fish, shellfish, milk, and eggs 

(C). The greatest number of anaphylactic episodes in 

adults is due to shellfish (C). Clinical cross-reactivity 

with other foods in the same group is unpredictable 

(B). Additives can also cause anaphylaxis (C). 

16. Anaphylactic reactions to foods almost always occur 

immediately. Symptoms might then subside, only to 

recur several hours later. A 

17. The most useful diagnostic tests include skin tests 

and food challenges. In vitro testing with foods 

might be appropriate as an alternative screening 

procedure. C 

18. Double- or single-blind placebo-controlled food 

challenges can be done in patients with suspected 

food allergy in a medical facility by personnel 

experienced in performing the procedure and prepared 

to treat anaphylaxis. B 

19. Patient education should include discussion about 

avoidance and management of accidental ingestion. C 

20. Schools might present a special hazard for the 

student with food allergy. Epinephrine should be 

available for use by the individuals in the school 

trained to respond to such a medical emergency. C 

Latex-induced anaphylaxis 

21. Latex (rubber) hypersensitivity is a significant medical 

problem, and 3 groups are at higher risk of 

reaction: health care workers, children with spina 

bifida and genitourinary abnormalities, and workers 

with occupational exposure to latex. B 

22. Skin prick tests with latex extracts should be considered 

for patients who are members of high-risk 

groups or who have a clinical history of possible 

latex allergy to identify IgE-mediated sensitivity. 

Although a standardized, commercial skin test reagent 

for latex is not available in the United States, 

many allergy centers have prepared latex extracts 

from gloves to be used for clinical testing. It should 

be noted, however, that such extracts prepared from 

gloves demonstrate tremendous variability in content 

of latex antigen. In vitro assays for IgE to latex might 

also be useful, although these tests are generally less 

sensitive than skin tests. C 

23. Patients with spina bifida (regardless of a history of 

latex allergy) and other patients with a positive history 

of latex allergy ideally should have all medicalsurgical-dental 

procedures performed in a latex-safe 

environment and as the first case of the day. D 

24. A latex-safe environment is an environment in which 

no latex gloves are used in the room or surgical suite 

and no latex accessories (catheters, adhesives, tourniquets, 

and anesthesia equipment) come into contact 

with the patient. D 

25. In health care settings general use of latex gloves 

with negligible allergen content, powder-free latex 

gloves, and nonlatex gloves and medical articles 

should be considered in an effort to minimize 

exposure to latex allergen. Such a combined approach 

might minimize latex sensitization of health 

care workers and patients and should reduce the risk 

of inadvertent reactions to latex in previously 

sensitized individuals. C 

Anaphylaxis during general anesthesia, 

the intraoperative period, and the 

postoperative period 

26. The incidence of anaphylaxis during anesthesia has 

been reported to range from 1 in 4000 to 1 in 25,000. 

Anaphylaxis during anesthesia can present as cardiovascular 

collapse, airway obstruction, flushing, 

and/or edema of the skin. C 

27. It might be difficult to differentiate between immune 

and nonimmune mast cell–mediated reactions and 

pharmacologic effects from the variety of medications 

administered during general anesthesia. B 

28. Thiopental allergy has been documented by using 

skin tests. B 

29. Neuromuscular blocking agents, such as succinylcholine, 

can cause nonimmunologic histamine release, 

but there have been reports of IgE-mediated 

mechanisms in some cases. B 

30. Reactions to opioid analgesics are usually caused by 

direct mast cell–mediator release rather than IgEdependent 

mechanisms. B 

31. Antibiotics that are administered perioperatively can 

cause immunologic or nonimmunologic generalized 

reactions. B 

32. Protamine can also cause severe systemic reactions 

through IgE-mediated or nonimmunologic mechanisms. 

B 

33. Latex is a potent allergen, and IgE-mediated reactions 

to latex during anesthesia have been clearly 

documented. Patients with multiple surgical procedures 

(eg, patients with spina bifida) and health 

care workers are at greater risk of latex sensitization. 

Precautions for latex-sensitive patients include 

avoiding the use of latex gloves and latex blood 

pressure cuffs, as well as latex intravenous 

tubing ports and rubber stoppers from medication 

vials. B 

34. Blood transfusions can elicit a variety of systemic 

reactions, some of which might be IgE mediated or 

mediated through other immunologic mechanisms. B



MARCH 2005 

35. Methylmethacrylate (bone cement) has been associated 

with hypotension and various systemic reactions, 

although no IgE mechanism has yet been 

documented. C 

36. The evaluation of IgE-mediated reactions to medications 

used during anesthesia can include skin 

testing to a variety of anesthetic agents. B 

37. The management of anaphylactic or anaphylactoid 

reactions that occur during general anesthesia is 

similar to the management of anaphylaxis in other 

situations. B 

Seminal fluid-induced anaphylaxis 

38. Anaphylaxis caused by human seminal fluid has 

been shown to be due to IgE-mediated sensitization 

by proteins of varying molecular weights. B 

39. Localized seminal plasma hypersensitivity has been 

well described and is likely IgE mediated on the 

basis of successful response to rapid seminal plasma 

desensitization. C 

40. History of atopic disease is the most consistent risk 

factor. However, anecdotal case reports have been 

associated with gynecologic surgery, injection of 

anti-RH immunoglobulin, and the postpartum 

state. C 

41. The diagnosis is confirmed by means of skin and/or 

in vitro tests for serum-specific IgE by using proper 

reagents obtained from fractionation of seminal fluid 

components. C 

42. Prevention of reactions to seminal fluid can be 

accomplished by barrier use of condoms. C 

43. Immunotherapy to properly fractionated seminal 

fluid proteins has been universally successful in 

preventing anaphylaxis to seminal fluid, provided 

the sensitizing seminal fluid fractions are used as 

immunogens. Successful intravaginal graded challenge 

with unfractionated seminal fluid has been 

reported in a few cases, but the duration of protection 

is unknown. C 

44. Localized and/or systemic seminal plasma hypersensitivity 

is not associated with infertility. D 

Exercise-induced anaphylaxis 

45. Exercise-induced anaphylaxis is a form of physical 

allergy. Premonitory symptoms can include diffuse 

warmth, itching, and erythema. Urticaria generally 

ensues, with progression to confluence and often 

angioedema. Episodes can progress to include gastrointestinal 

symptoms, laryngeal edema, and/or 

vascular collapse. B 

46. Factors that have been associated with exerciseinduced 

anaphylaxis include medications (eg, aspirin 

and other nonsteroidal anti-inflammatory drugs) or 

food ingestion before and after exercise. C 

47. Patients with exercise-induced anaphylaxis might 

have a higher incidence of personal and/or family 

history of atopy. C 

48. Medications used prophylactically are not useful in 

preventing exercise-induced anaphylaxis. C 

49. If exercise-induced anaphylactic episodes have been 

associated with the ingestion of food, exercise 

should be avoided in the immediate postprandial 

period. C 

50. Patients with exercise-induced anaphylaxis should 

carry epinephrine and should wear and/or carry 

Medic Alert identification denoting their condition. 

They should have a companion with them when 

exercising. This companion should be versed in the 

use of an EpiPen. D 


51. The symptoms of idiopathic anaphylaxis are identical 

to those of episodes related to known causes. C 

52. Patients with idiopathic anaphylaxis should receive 

an intensive evaluation, including a meticulous history 

to rule out a definite cause of the events. C 

53. There might be a need for specific laboratory studies 

to exclude systemic disorders, such as systemic 

mastocytosis. This might include a serum tryptase 

level when the patient is asymptomatic, a ratio of 

b-tryptase to total tryptase during an event, and 

selective allergy skin testing. C 

Anaphylaxis and allergen immunotherapy 

vaccines 

54. There is a small risk of near-fatal and fatal anaphylactic 

reactions to allergen immunotherapy injections. C 

55. Patients with asthma, particularly poorly controlled 

asthma, are at higher risk for serious systemic 

reactions to allergen immunotherapy injections (C). 

Patients taking b- adrenergic blocking agents are at 

higher risk for serious systemic reactions to allergen 

immunotherapy injections (B). 

56. Allergen immunotherapy vaccines should be administered 

only by health care professionals trained in 

the recognition and treatment of anaphylaxis, only in 

health care facilities with the proper equipment for 

the treatment of anaphylaxis, and in clinics with 

policies and procedures that minimize the risk of 

anaphylaxis. D 

Anaphylaxis to drugs 

57. Low-molecular-weight medications induce an 

IgE-mediated reaction only after combining with a 

carrier protein to produce a complete multivalent 

antigen. B 

58. Penicillin is the most common cause of drug-induced 

anaphylaxis. C 

59. Penicillin spontaneously degrades to major and 

minor antigenic determinants, and skin testing with 

reagents on the basis of these determinants yields 

negative results in about 90% of patients with 

a history of penicillin allergy. B 

60. The negative predictive value of penicillin skin 

testing (for immediate-type reactions) is between 

97% and 99% (depending on the reagents used), and 

the positive predictive value is at least 50%. B




61. The extent of allergic cross-reactivity between 

penicillin and cephalosporins is unknown but appears 

to be low. Four percent of patients proved to 

have penicillin allergy by means of penicillin skin 

testing react to cephalosporin challenges. C 

62. Patients with a history of penicillin allergy who have 

negative penicillin skin test responses might safely 

receive cephalosporins. B 


positive penicillin skin test responses might (1) 

receive an alternate (non–b-lactam) antibiotic, (2) 

receive a cephalosporin through graded challenge, or 

(3) receive a cephalosporin through rapid desensitization. 

F 

64. Aztreonam does not cross-react with other b- 

lactams, except ceftazidime, with which it shares a 

common R-group side chain. B 

65. Carbapenems should be considered cross-reactive 

with penicillin. C 

66. Diagnosis of IgE-mediated reactions to non– 

b-lactam antibiotics is limited by a lack of knowledge 

of the relevant allergenic determinants and/or 

metabolites. C 

67. Aspirin and nonsteroidal anti-inflammatory drugs are 

the second most common cause of drug-induced 


68. Anaphylactic reactions to aspirin and nonsteroidal 

anti-inflammatory drugs appear to be medication 

specific and do not cross-react with structurally 

unrelated aspirin or other nonsteroidal anti-inflammatory 

drugs. D 

Prevention of anaphylaxis 

69. Major risk factors related to anaphylaxis include, but 

are not limited to, prior history of such reactions, 

concomitant b-adrenergic blocker therapy, exposure, 

or atopic background. Atopic background might be 

a risk factor for venom- and latex-induced anaphylaxis 

and possibly anaphylactoid reactions to radiographic 

contrast material but not for anaphylactic 

reactions to medications. 

70. Avoidance measures are successful if future exposure 

to drugs, foods, additives, or occupational 

allergens can be prevented. Avoidance of stinging 

and biting insects is also possible in many cases. 

Prevention of systemic reactions during allergen 

immunotherapy is dependent on the specific circumstances 

involved. 

71. Avoidance management should be individualized, 

taking into consideration factors such as age, 

activity, occupation, hobbies, residential conditions, 

access to medical care, and the patients’ level of 

personal anxiety. 

72. Pharmacologic prophylaxis should be used to prevent 

recurrent anaphylactoid reactions to radiographic 

contrast material, fluorescein, as well as to 

prevent idiopathic anaphylaxis. Prophylaxis with 

glucocorticosteroids and antihistamines markedly 

reduces the occurrence of subsequent reactions. 

TABLE I. Frequency of occurrence of signs and 

symptoms of anaphylaxis*y 

Signs and symptoms 

Cutaneous 90% 

Urticaria and angioedema 85%-90% 

Flushing 45%-55% 

Pruritus without rash 2%-5% 

Respiratory 40%-60% 

Dyspnea, wheeze 45%-50% 

Upper airway angioedema 50%-60% 

Rhinitis 15%-20% 

Dizziness, syncope, hypotension 30%-35% 

Abdominal 

Nausea, vomiting, diarrhea, cramping pain 25%-30% 

Miscellaneous 

Headache 5%-8% 

Substernal pain 4%-6% 

Seizure 1%-2% 

*On the basis of a compilation of 1865 patients reported in references 1 

through 14. 

Percentages are approximations. 

73. Allergen immunotherapy with the appropriate stinging 

insect venom should be recommended for patients 

with systemic sensitivity to stinging insects because 

this treatment is highly (90% to 98%) effective. 

74. Desensitization to medications that are known to 

have caused anaphylaxis can be effective. In most 

cases the effect of desensitization is temporary, and 

if the medication is required some time in the future, 

the desensitization process must be repeated. 

75. Patient education might be the most important 

preventive strategy. Patients should be carefully 

instructed about hidden allergens, cross-reactions to 

various allergens, unforeseen risks during medical 

procedures, and when and how to use self-administered 

epinephrine. Physicians should educate patients 

about the risks of future anaphylaxis, as well 

as the benefits of avoidance measures. 

EVALUATION AND MANAGEMENT OF THE 

PATIENT WITH A HISTORY OF EPISODES 

OF ANAPHYLAXIS 

Summary Statements 

1. The history is the most important tool to determine 

whether a patient has had anaphylaxis and the cause 

of the episode. C 

2. A thorough differential diagnosis should be considered, 

and other conditions should be ruled out. C 

3. Laboratory tests can be helpful to confirm a diagnosis 

of anaphylaxis or rule out other causes. Proper timing 

of studies (eg, serum tryptase is essential). B 

4. In the management of a patient with a previous 

episode, education is necessary. Emphasis on early 

treatment, specifically the self-administration of epinephrine, 

is essential. C



MARCH 2005 

TABLE II. Types of anaphylaxis and the differential 

diagnosis of anaphylaxis and anaphylactoid reactions 

Types of anaphylaxis and anaphylactoid reactions 

Anaphylaxis (anaphylactoid reactions) to exogenous agents 

Anaphylaxis and anaphylactoid reactions to physical factors 

Exercise 

Cold 

Heat 

Sunlight 


Anaphylaxis and anaphylactoid reactions caused by the excess 

endogenous production of histamine 

Systemic mastocytosis 

Urticaria pigmentosa 

Basophilic leukemia 

Acute promyelocytic leukemia with tretinoin treatment 

Hydatid cyst 

Vasodepressor (vasovagal) reactions 

Other forms of shock 

Hemorrhagic 

Hypoglycemic 

Cardiogenic 

Endotoxic 

Flushing syndromes 

Carcinoid 

Red man syndrome caused by vancomycin 

Postmenopausal 

Alcohol induced 

Unrelated to drug ingestion 

Related to drug ingestion 

Medullary carcinoma thyroid 

Autonomic epilepsy 

Vasointestinal peptide and other vasoactive peptide–secreting 

gastrointestinal tumors 

Ingestant-related reactions mimicking anaphylaxis (restaurant 

syndromes) 

Monosodium glutamate 

Sulfites 

Scombroidosis 

Nonorganic diseases 

Panic attacks 

Vocal cord dysfunction syndrome 

Miscellaneous 

C1 esterase deficiency syndromes (acquired and hereditary 

angioedema) 

Pheochromocytoma 

Neurologic (seizure, stroke) 

Capillary leak syndrome 

5. The patient should be instructed to wear and/or carry 

identification denoting his or her condition (eg, Medic 

Alert jewelry). C 

Performing the history 

To interpret the history adequately, it is essential to 

know the manifestations of anaphylaxis. These can best be 

ascertained by a review of published series. 1-14 A 

summary of the signs and symptoms as reported in these 

series, totaling 1865 patients, is seen in Table I. These 

series include patients with exercise-induced anaphylaxis, 

patients with idiopathic anaphylaxis, patients of all age 

ranges, and reviews of patients with anaphylaxis from 

various causes. The most frequent manifestations of 

anaphylaxis are cutaneous, occurring in more than 90% 

of reported series. The absence of cutaneous symptoms 

speaks against a diagnosis of anaphylaxis but does not rule 

it out. Severe episodes characterized by rapid cardiovascular 

collapse and shock can occur without cutaneous 

manifestations. 15,16 Friends and/or family members present 

during the event should be interviewed to better assess 

the signs and symptoms of the reaction. Anaphylaxis can 

present with unusual manifestations (eg, syncope without 

any other sign or symptom). 17,18 

The history and the record should include the time(s) of 

the occurrence of the attack(s), any treatment required 

during the attack(s), and the duration of the episode(s). A 

detailed history of all potential causes should be obtained. 

This includes a list of ingestants consumed before the 

event, including both foods and drugs; any possible stings 

or bites occurring before the event; whether the event 

occurred during exercise; location of the event (eg, work 

versus home); and whether the event was related to 

exposure to heat or cold or sexual activity. The patient’s 

atopic status should be noted because food-induced and 

idiopathic anaphylaxis are more common in atopic than 

nonatopic individuals. Also, in women the history should 

include any relationship between the attack(s) and their 

menstrual cycle. Return of symptoms after a remission 

should be noted because this might indicate a late-phase 

reaction, 6 which might require a prolonged period of 

observation if subsequent events occur. 

Differential diagnosis 

The vast majority of patients presenting with a history 

consistent with anaphylaxis will have experienced an 

anaphylactic event. Nonetheless, it is important not 

to immediately accept this diagnosis. The differential 

diagnosis must be considered when the history is taken, 

even in patients with a previous history of anaphylaxis. 

Comprehensive differential diagnoses are seen in Table II. 

Special attention in the differential diagnosis should 

be given to vasodepressor (vasovagal) reactions. Characteristic 

features of this reaction include hypotension, 

pallor, weakness, nausea, vomiting, and diaphoresis. 

Such reactions can often be distinguished from anaphylaxis 

by a lack of characteristic cutaneous manifestations 

(urticaria, angioedema, flush, and pruritus) and the 

presence of bradycardia during the vasodepressor reaction 

instead of the tachycardia usually seen with anaphylaxis. 

However, it should be noted that bradycardia can occur 

during anaphylaxis as well. 19 This is probably due to the 

Bezold-Jarisch reflex, a cardioinhibitory reflex that has its 

origin in sensory receptors in the inferoposterior wall of 

the left ventricle. Unmyelinated vagal C fibers transmit the 

reflex. 

Flushing episodes can mimic anaphylactic events. As 

noted, the history should include all of the drugs that the




patient was taking before the event. Several drugs and 

ingestants, including niacin, nicotine, catecholamines, 

angiotensin-converting enzyme inhibitors, and alcohol, 

can induce flushing. 20 Other conditions that cause flushing 

must be considered, including gastrointestinal and 

thyroid tumors, the carcinoid syndrome, pheochromocytoma, 

hyperglycemia, postmenopausal flush, alcoholinduced 

flushing, and the red man syndrome caused by 

the administration of vancomycin. Laboratory analysis 

(see below) can be helpful in establishing the cause of 

flushing. 

There are a group of postprandial syndromes that can 

mimic anaphylaxis, such as monosodium glutamate– 

induced reaction and reactions to scombroid fish (see 

‘‘Food allergy: a practice parameter’’). The latter is 

increasing in frequency, 21 and because it is caused by 

histamine produced by histidine-decarboxylating bacteria 

that cleave histamine from histidine in spoiled fish, the 

symptoms can be identical to those that occur in 

anaphylaxis. However, the cutaneous manifestation can 

be more of a flush (sunburn-like) than urticaria. Symptoms 

might affect more than one individual if others also 

ingested the fish causing the reaction and serum tryptase 

levels are normal. 

Nonorganic disease, such as vocal cord dysfunction and 

panic attacks, should be considered in the differential 

diagnosis. 

Laboratory studies 

Laboratory studies to be considered are shown in Table 

III. Serum tryptase and plasma and urinary histamine 

metabolites might be helpful in establishing the diagnosis 

of anaphylaxis. 22,23 Plasma histamine levels begin to 

increase within 5 to 10 minutes of the onset of symptoms 

of anaphylaxis and remain increased for 30 to 60 

minutes. 24,25 Therefore they are not of help if the patient 

is seen as long as an hour or more after the onset of the 

event. 24 However, urinary methyl-histamine levels are 

increased for a longer duration of time. 26 Serum tryptase 

levels peak 1 to 1½ hours after the onset of anaphylaxis 

and can persist for as long as 5 hours after the onset of 

symptoms. 25 The best time to measure serum tryptase 

levels is between 1 to 2 hours but no longer than 6 hours 

after the onset of symptoms. 25 The best time to measure 

plasma histamine levels is between 10 minutes and 1 hour 

after the onset of symptoms. 25 It should be noted that there 

can be a disconnection between histamine and tryptase 

levels, with some patients exhibiting increase of only one 

of these mediators. 25 

There are 2 forms of tryptase, a and b. 22 a-Tryptase is 

secreted constitutively, and b-tryptase is released only 

during degranulation episodes. This observation is useful 

in distinguishing between systemic anaphylaxis per se and 

a degranulation of mast cells related to mastocytosis. The 

distinction between these 2 disorders rests on the fact that 

patients with mastocytosis, because of their increased 

mast cell burden, constitutively produce larger amounts 

of a-tryptase (compared with normal subjects), whereas 

patients who have true anaphylactic events of other causes 

TABLE III. Laboratory tests to be considered in the 

differential diagnosis of anaphylaxis 

To be measured 

Serum tryptase 

Plasma histamine 

24-h Urinary 

histamine metabolite 

(methyl histamine) 

Plasma-free metanephrine 

Urinary vanillylmandelic acid 

Serum serotonin 

Urinary 5-hydroxyindoleacetic 

acid 

Serum vasointestinal 

hormonal polypeptide panel, 

including pancreastatin, 

pancreatic hormone, 

vasointestinal polypeptide 

(VIP), and substance P 

Comment 

Serum tryptase levels peak 

60-90 min after the onset of 

anaphylaxis and persist to 

6 hours. Ideally, the 

measurement should be 

obtained between 1 and 2 hours 

after the initiation of symptoms. 

Plasma histamine levels begin to 

increase within 5-10 min and 

remain increased only for 

30-60 min. They are of little 

help if the patient is seen as 

long as an hour or more after 

the onset of the event. 

Urinary histamine and its 

metabolites are increased for a 

longer period of time, up 

to 24 hours. 

To rule out a paradoxical response 

to a pheochromocytoma. 

Also useful in ruling out a 

paradoxical response to a 

pheochromocytoma. 

To rule out carcinoid syndrome. 

Also to rule out carcinoid 

syndrome. 

Useful to rule out the presence of 

a vasoactive polypeptide 

secreting gastrointestinal tumor 

or a medullary carcinoma of the 

thyroid, which also can secrete 

vasoactive peptides. 

will have normal baseline levels of a-tryptase. During 

anaphylactic events, b-tryptase is secreted in large 

amounts in both groups. Therefore the ratio of total 

tryptase (a plus b) to b-tryptase can be useful in 

distinguishing degranulation episodes in patients with 

mastocytosis from anaphylactic events in patients without 

this disorder. In addition, constitutively increased levels of 

a-tryptase are helpful in making a diagnosis of mastocytosis. 

A ratio of total tryptase (a plus b)tob-tryptase of 10 

or less is indicative of an anaphylactic episode not related 

to systemic mastocytosis, whereas a ratio of 20 or greater 

is consistent with systemic mastocytosis. 22 This distinction 

is made possible because of the fact that the 

immunoassay for tryptase using a B12 mAb or a G4 

mAb recognizes both a- and b-tryptase, whereas an assay 

using a G5 mAb recognizes only b-tryptase. 22 

It has been proposed that an increase of postmortem 

serum tryptase level be used to establish anaphylaxis as 

a cause of death. 27 However, it should be clearly noted that 

postmortem increase of serum tryptase concentrations is 

not a specific finding and therefore cannot be considered 

diagnostic of an anaphylactic death. There are reports 

detailing nonanaphylactic deaths exhibiting increased



MARCH 2005 

postmortem serum tryptase levels. 28-30 Thus the presence 

of an increased postmortem tryptase level cannot be 

considered pathognomonic for a death caused by anaphylaxis 

or an anaphylactoid event. Neither can an absence of 

an increased serum tryptase level postmortem be considered 

sufficient to rule out anaphylaxis or an anaphylactoid 

event as the cause of death. 28 

In search of the culprit in patients with possible 

anaphylaxis to food, leftover or vomited food might be 

useful as a source of antigen for the creation of a custom 

RAST reagent. 27 

In the management of a patient with a previous episode, 

education is necessary, including emphasis on early 

treatment, specifically the self-administration of epinephrine. 

Patients who have experienced an episode of 

anaphylaxis should also be equipped with identification 

denoting their possible susceptibility to future episodes. 

This can consist of a card and/or identification jewelry (eg, 

Medic Alert). 

Medical facilities should have an established protocol 

to deal with anaphylactic episodes and the appropriate 



services should be on hand. 

MANAGEMENT OF ANAPHYLAXIS 


6. Medical facilities should have an established protocol 

to deal with anaphylaxis and the appropriate 



services might be helpful to have on hand. B 

7. Anaphylaxis is an acute life-threatening systemic 

reaction with varied mechanisms, clinical presentations, 

and severity that results from the sudden 

systemic release of mediators from mast cells and 

basophils. B 

8. Anaphylactic (IgE-dependent) and anaphylactoid 

(IgE-independent) reactions differ mechanistically, 

but the clinical presentations are identical. C 

9. The more rapidly anaphylaxis develops, the more 

likely the reaction is to be severe and potentially lifethreatening. 

C 

10. Prompt recognition of signs and symptoms of 

anaphylaxis is crucial. If there is any doubt, it is 

generally better to administer epinephrine. C 

11. Any health care facility should have a plan of action 

for anaphylaxis should it occur. Physicians and 

office staff should maintain clinical proficiency in 

anaphylaxis management. D 

12. Epinephrine and oxygen are the most important 

therapeutic agents administered in anaphylaxis. Epinephrine 

is the drug of choice, and the appropriate 

dose should be administered promptly at the onset of 

apparent anaphylaxis. A/D 

13. Appropriate volume replacement either with colloid 

or crystalloids and rapid transport to the hospital is 

essential for patients who are unstable or refractory 

to initial therapy for anaphylaxis in the office 

setting. B 

Signs and symptoms of anaphylaxis 

There is no universally accepted clinical definition of 

anaphylaxis. 31,32 Anaphylaxis is an acute life-threatening 

reaction that results from the sudden systemic release of 

mast cells and basophil mediators. It has varied clinical 

presentations, but respiratory compromise and cardiovascular 

collapse cause the most concern because they are the 

most frequent causes of anaphylactic fatalities. 32 

Anaphylactic (IgE-dependent) and anaphylactoid (IgEindependent) 

reactions differ mechanistically, but the 

clinical presentations are identical. Anaphylaxis might 

affect the level of consciousness (impairment might reflect 

hypoxia), the upper and lower airways (dysphonia, stridor, 

cough, wheezing, or shortness of breath), the cardiovascular 

system (hypotension with or without syncope and/or 

cardiac arrhythmias), the skin (diffuse or localized 

erythema, pruritus, urticaria, and/or angioedema), and 

the gastrointestinal system (nausea, vomiting, or diarrhea). 

In addition, some patients might have symptoms of 

lightheadedness, headache, uterine cramps, feeling of 

impending doom, or unconsciousness. 

Urticaria and angioedema are the most common 

manifestations of anaphylaxis 2,8,33 and often occur as 

the initial signs of severe anaphylaxis. However, cutaneous 

findings might be delayed or absent in rapidly 

progressive anaphylaxis. The more rapidly anaphylaxis 

develops, the more likely the reaction is to be severe and 

potentially life-threatening. Moreover, symptoms not 

immediately life-threatening might progress rapidly unless 

treated promptly and appropriately. 

Anaphylaxis often produces signs and symptoms within 

seconds to minutes of exposure to an offending stimulus, 

but some reactions might develop later (eg, greater 

than 30 minutes after exposure). Late-phase or biphasic 

reactions, which occur 8 to 12 hours after the initial attack, 

have also been reported. 34-36 Some protracted reactions 

can last up to 32 hours, despite aggressive treatment. 35,36 

Increased vascular permeability, a characteristic feature 

of anaphylaxis, allows transfer of 50% of the intravascular 

fluid into the extravascular space within 10 minutes. 37,38 

As a result, hemodynamic collapse can occur rapidly, with 

little or no cutaneous or respiratory manifestations. 15,16 

Differential diagnosis in anaphylaxis 

The differential diagnosis of anaphylaxis is reviewed 

elsewhere in this parameter (see ‘‘Evaluation and management 

of the patient with a history of episodes of 

anaphylaxis’’ and Table II). Like anaphylaxis, several 

conditions can cause abrupt and dramatic patient collapse. 

Among conditions to consider are vasodepressor (vasovagal) 

reactions, acute anxiety (eg, panic attack or 

hyperventilation syndrome), myocardial dysfunction, 

pulmonary embolism, systemic mast cell disorders, 

foreign-body aspiration, acute poisoning, hypoglycemia, 

and seizure disorder. Specific signs and symptoms of




anaphylaxis can present singly in other disorders. 

Examples are urticaria-angioedema, hereditary angioedema, 

and asthma. 

The vasodepressor (vasovagal) reaction probably is 

the condition most commonly confused with anaphylactic 

and anaphylactoid reactions. In vasodepressor reactions, 

however, urticaria is absent, the heart rate is typically 

bradycardic, bronchospasm or other breathing difficulty is 

generally absent, the blood pressure is usually normal or 

increased, and the skin is typically cool and pale. 

Tachycardia is the rule in anaphylaxis, but it might be 

absent in patients with conduction defects, patients 

with increased vagal tone caused by a cardioinhibitory 

(Bezold-Jarisch) reflex, or patients who take sympatholytic 

medications. 

It should be recognized that urticaria and angioedema 

might be part of the continuum of anaphylaxis but in 

isolation are not anaphylaxis. 


The management of anaphylactic and anaphylactoid 

reactions is identical. A sequential approach to management 

is outlined in Table I, and a sample treatment flow 

sheet is presented in Fig 1. The following equipment 

supplies should be available for the treatment of anaphylaxis 

in medical settings in which allergen immunotherapy 

is administered or in which other medications or biologic 

agents are administered by means of injection 39,40 : (1) 

stethoscope and sphygmomanometer; (2) tourniquets, 

syringes, hypodermic needles, and large-bore needles 

(14-gauge needles); (3) injectable aqueous epinephrine 

1:1000; (4) equipment for administering oxygen; (5) 

equipment for administering intravenous fluids; (6) oral 

airway; (7) diphenhydramine or similar injectable antihistamine; 

(8) corticosteroids for intravenous injection; and 

(9) a vasopressor (eg, dopamine or norepinephrine). 

Glucagon, an automatic defibrillator, and a 1-way valve 

facemask with an oxygen inlet port (eg, Pocket-Mask or 

similar device) are other materials that some clinicians 

might find desirable, depending on the clinical setting. 

Fig 2 provides a sample checklist to track supplies 

needed to treat anaphylaxis and expiration dates for 

medications-fluids. Not all items need to be present in 

each office. 

Evaluation and treatment in a latex-safe environment is 

optimal for patients with concomitant latex allergy. It is 

important to stress that these steps are subject to physician 

discretion and that variations in sequence and performance 

rely on physician judgment. Additionally, when a patient 

should be transferred to an emergency facility depends 

on the skill, experience, and clinical decision making of 

the individual physician. Medical offices in which anaphylaxis 

is likely to occur (eg, in which allergen immunotherapy 

is administered) should consider periodic 

anaphylaxis practice drills tailored to local emergency 

medical service capabilities and response times. Essential 

ingredients to such drills are identification of a person who 

will be responsible for calling emergency medical services 

and a person who will document treatment and time each 

is rendered. The emergency kit should be up to date and 

complete. Everyone who will be directly involved in 

patient care should, for example, easily be able to locate 

necessary supplies and rapidly assemble fluids for intravenous 


Assessment and maintenance of airway, breathing, 

and circulation are necessary before proceeding to other 

management steps. Measurement of peak expiratory flow 

rate and pulse oximetry might be useful in patients with 

dyspnea, bronchospasm, or both. Epinephrine administration 

and the maintenance of adequate oxygenation and 

intravascular volume have high priority. 

Epinephrine. Epinephrine is the treatment of choice for 

acute anaphylaxis. 31,41,42 Aqueous epinephrine 1:1000 

dilution, 0.2 to 0.5 mL (0.01 mg/kg in children; maximum 

dose, 0.3 mg) administered intramuscularly or subcutaneously 

every 5 minutes, as necessary, should be used to 

control symptoms and increase blood pressure. Consider 

dose-response effects. Note: If the clinician deems it 

appropriate, the 5-minute interval between injections can 

be liberalized to permit more frequent injections. 

Subsequent therapeutic interventions depend on the 

severity of the reaction and the initial response to 

epinephrine. No data support the use of epinephrine in 

anaphylaxis through a nonparenteral route. However, 

alternative routes of administration have been anecdotally 

successful. These include, for example, inhaled epinephrine 

in the presence of laryngeal edema or sublingual 

injection if an intravenous route cannot be obtained. 

Endotracheally administered dosages have also been 

proposed for use when intravenous access is not available 

in intubated patients experiencing cardiac arrest. 43 

Fatalities during anaphylaxis usually result from delayed 

administration of epinephrine and from severe 

respiratory complications, cardiovascular complications, 

or both. There is no absolute contraindication to epinephrine 

administration in anaphylaxis. 44,45 

Absorption is more rapid and plasma levels are higher 

in children not experiencing anaphylaxis who receive 

epinephrine intramuscularly in the thigh with an autoinjector. 

46 Intramuscular injection into the thigh (vastus 

lateralis) in adults not experiencing anaphylaxis is also 

superior to intramuscular or subcutaneous injection into 

the arm (deltoid), neither of which achieves increased 

plasma epinephrine levels compared with endogenous 

levels. 47 Spring-loaded (eg, EpiPen) automatic epinephrine 

devices administered intramuscularly and intramuscular 

epinephrine injections through a syringe into the 

thigh in adults not experiencing anaphylaxis provide doseequivalent 

plasma levels. 46,47 However, similar studies 

comparing intramuscular injections to subcutaneous injections 

in the thigh have not yet been done. 

The UK consensus panel on emergency guidelines and 

the international consensus guidelines for emergency 

cardiovascular care both recommend intramuscular epinephrine 

injections for anaphylaxis. 31,41 Both publications 

also propose that epinephrine can be repeated every 

5 minutes, as clinically needed, in both adults and 

children. 31,41 It seems reasonable to infer that the 5-minute



MARCH 2005 

interval between injections can be liberalized to permit 

more frequent injections if the clinician deems it appropriate. 

Development of toxicity or inadequate response to 

epinephrine injections indicates that additional therapeutic 

modalities are necessary. 

No established dosage or regimen for intravenous 

epinephrine in anaphylaxis is recognized. Inferences can 

be drawn from the emergency cardiac care consensus 

guidelines for intravenous epinephrine for adults and 

children. 41,48 An epinephrine infusion might be prepared 

by adding 1 mg (1 ml) of a 1:1000 dilution of epinephrine 

to 250 mL of D5W to yield a concentration of 4.0 mg/ml. 

This 1:250,000 solution is infused at a rate of 1 to 4 mg/ 

min (15-60 drops per minute with a microdrop apparatus 

[60 drops per minute = 1 mL = 60 mL/h]), increasing to 

a maximum of 10.0 mg/min for adults and adolescents. A 

dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 solution 

up to 10 mg/min; maximum dose, 0.3 mg) is recommended 

for children. Alternative pediatric dosage by the ‘‘rule 

of 6’’ is as follows: 0.6 3 body weight (in kilograms) = 

numbers of milligrams diluted to total 100 mL of saline; 

then 1 mL/h delivers 0.1 mg/kg/min. 48 (See Table II for 

infusion guidelines in children.) 

An alternative epinephrine infusion protocol has been 

suggested for adults with anaphylaxis. Brown and colleagues 

conducted a prospective, randomized, doubleblind, 

placebo-controlled, crossover study of Myrmecia 

pilosula (jack jumper ant) venom immunotherapy in 

which 21 otherwise healthy adults experienced systemic 

reactions after diagnostic sting challenge. 19 Two individuals 

experienced urticarial reactions and received no 

epinephrine. The remaining 19 patients (8 of whom had 

systolic blood pressure of less than 90 mm Hg) received 

a 1:100,000 solution of epinephrine (1 mg [1 mL] in 100 

mL of saline) intravenously by means of infusion pump at 

an initial rate of 30 to 100 mL/h (5-15 mg/min) titrated up 

or down depending on clinical response or epinephrine 

side effects (toxicity). This infusion was discontinued 30 

minutes after resolution of all signs and symptoms of 

anaphylaxis. 

Five of the 8 patients with hypotension also received 

a 1-L bolus of normal saline during the first few minutes of 

treatment. Eighteen of the 19 patients who received 

epinephrine infusions had symptomatic improvement 

and systolic blood pressures of greater than 90 mm Hg 

within 5 minutes. The remaining individual required an 

additional 2 L of saline (3 L total). 

Note: Because of the risk for potentially lethal 

arrhythmias, epinephrine should be administered intravenously 

only during cardiac arrest or to profoundly 

hypotensive subjects who have failed to respond to 

intravenous volume replacement and several injected 

doses of epinephrine. In situations in which hemodynamic 

monitoring is available (eg, emergency department or 

intensive care facility), continuous hemodynamic monitoring 

is essential. 32 However, use of intravenous epinephrine 

should not be precluded in a scenario in which 

such monitoring is not available if the clinician deems its 

administration is essential after failure of several epinephrine 

injections in the thigh. If intravenous epinephrine is 

considered essential under these special circumstances, 

monitoring by available means (eg, every-minute blood 


monitoring) should be conducted. 

H 1 and H 2 antagonists. Antihistamines (H l and H 2 

antagonists) are supportive in the treatment of anaphylaxis. 

However, these agents have a much slower onset of 

action than epinephrine and should never be administered 

alone as treatment for anaphylaxis. Thus antihistamine use 

in anaphylaxis should be considered second-line treatment 

after the administration of epinephrine. 

However, antihistamines are useful in the treatment 

of urticaria-angioedema or pruritus when they appear as 

manifestations of the anaphylactic episode. Diphenhydramine, 

25 to 50 mg for adults and 1 mg/kg (up to 50 mg) for 

children, slowly might be administered intravenously. 

Oral diphenhydramine, in identical dosages, might be 

sufficient for milder attacks. 

The role of H 2 antagonists, such as ranitidine and 

cimetidine, is more controversial, but several reports have 

demonstrated that a treatment with a combination of H l 

and H 2 antagonists is more effective in anaphylaxis than 

treatment with H l antagonists alone. 49-56 For example, an 

emergency department–based study involving 91 adult 

patients demonstrated that a combination of diphenhydramine 

and ranitidine provided superior resolution of 

cutaneous symptoms and tachycardia compared with 

diphenhydramine and saline. 55 

No controlled studies support use of one H 2 antagonist 

over another. Most studies have used either cimetidine or 

ranitidine. Ranitidine might be the drug of choice because 

it has fewer potential drug interactions. The recommended 

administration for ranitidine is 1 mg/kg in adults and 12.5 

to 50 mg in children infused over 10 to 15 minutes. 57 

Ranitidine also can be diluted in 5% dextrose to a total 

volume of 20 mL and injected over 5 minutes. Cimetidine, 

4 mg/kg in adults, should be administered slowly because 

rapid intravenous administration might produce hypotension. 

58 Cimetidine should not be administered to children 

with anaphylaxis because no dosages have been established. 

Corticosteroids. Systemic corticosteroids have no role 

in the acute management of anaphylaxis because they 

might have no effect for 4 to 6 hours, even when administered 

intravenously. Although corticosteroids traditionally 

have been used in the management of anaphylaxis, their 

effect has never been evaluated in placebo-controlled 

trials. However, if their effects on other allergic diseases, 

such as asthma, are extrapolated, corticosteroids might 

potentially prevent protracted or biphasic anaphylaxis. 

They also form an essential part of the preventive management 

of frequent idiopathic anaphylaxis. 59 Corticosteroids 

administered during anaphylaxis might provide additional 

benefit for patients with asthma or other conditions 

recently treated with corticosteroids. 45 

If given, intravenous corticosteroids should be administered 

early in the treatment of anaphylaxis at a dosage 

equivalent to 1.0 to 2.0 mg/kg/d of methylprednisolone




every 6 hours. Oral administration of prednisone, 0.5 mg/ 

kg, might be sufficient for milder attacks. 

Oxygen and adrenergic agonists. Oxygen should be 

administered to patients with anaphylaxis who have 

prolonged reactions, have pre-existing hypoxemia or 

myocardial dysfunction, receive inhaled b 2 -agonists, or 

require multiple doses of epinephrine. Arterial blood gas 

determination (where available) or continuous pulse 

oximetry should guide oxygen therapy where hypoxemia 

is a concern. Inhaled b 2 -agonists, such as albuterol (0.5 

mL or 2.5 mg of a 5% solution), might be administered for 

bronchospasm refractory to epinephrine. 

Persistent hypotension–potential contributory factors 

and appropriate roles of volume replacement and vasopressors. 

Numerous cases of unusually severe or refractory 

anaphylaxis have been reported in patients 

receiving b-adrenergic blockers. 36,60-72 Although the 

pharmacology of provocation or exacerbation of bronchospasm 

with use of b-blockers is well known, the 

pharmacodynamics that contribute to greater risk for more 

serious anaphylaxis are not as widely recognized. 73,74 

That b-blockade can influence the severity of anaphylaxis 

is supported by evidence from both human and animal 

studies. 73-78 Greater severity of anaphylaxis observed in 

patients receiving b-blockers might relate, in part, to 

a blunted response to epinephrine commonly administered 

to treat anaphylaxis. 73 Epinephrine might paradoxically 

worsen anaphylaxis through facilitating unopposed a- 

adrenergic and reflex vagotonic effects. In patients receiving 

b-blockers, increased propensity not only for 

bronchospasm but also decreased cardiac contractility 

with perpetuation of hypotension and bradycardia might 

exist. 78-80 For these reasons, b-blocker–related anaphylaxis 

might be more likely to be refractory to management. 

Evidence suggests that more serious anaphylaxis might 

also be promoted in the setting of b-blocker exposure 

because of the action of b-blockers on cyclic nucleotides, 

which can lead to heightened mediator release. 73,78 There 

are no epidemiologic studies that indicate that anaphylaxis 

occurs more frequently in patients receiving b-blockers. 

The observed risk for more serious anaphylaxis in patients 

receiving b-blockers has promoted caution regarding 

casual use of b-blockers in patients who might or will 

be exposed to an anaphylactogenic stimulus, including but 

not limited to (1) patients receiving allergen immunotherapy 

or undergoing immediate hypersensitivity skin testing, 

81,82 (2) patients receiving infusion of radiographic 

contrast media, 75 and (3) patients with anaphylactic 

potential to hymenoptera venom. 64,73 Suspension of b- 

blocker treatment in such patients might be appropriate; 

however, in view of b-blocker withdrawal syndromes 

observed in selected cases and the clear benefits that will 

accrue from use of b-blockers in patients for whom these 

drugs are indicated, 63-65,83-85 this determination must be 

considered carefully from an individualized risk-benefit 

standpoint. 

The contention that increased risk for more severe 

anaphylaxis with b-blockers also includes cardioselective 

agents is supported by reports of unusually severe 

anaphylaxis described in association with b 1 -selective 

antagonists 60-64 and in vitro histamine release demonstrated 

with either b 1 -orb 2 -antagonists. 65,66 Systemic 

effects, including potential for bronchospasm and bradycardia, 

are well described with use of ophthalmic 

b-blockers. 86 For the above reasons, until more data are 

available, absence of greater risk for anaphylaxis with 

b-blocker exposure in patients receiving cardioselective 

or ophthalmic b-blockers cannot be assumed. 

In summary, patients taking b-adrenergic antagonists 

might be more likely to experience severe anaphylactic 

reactions characterized by paradoxical bradycardia, profound 

hypotension, and severe bronchospasm. Use of 

selective b 1 -antagonists does not reduce the risk of 

anaphylaxis because both b 1 - and b 2 -antagonists can 

inhibit the b-adrenergic receptor. 

Epinephrine administered during anaphylaxis to patients 

taking b-adrenergic antagonists might be ineffective. 

In this situation both glucagon administration and 

isotonic volume expansion (in some circumstances up to 7 

L of crystalloid are necessary) might be necessary. 72,87-89 

Glucagon might reverse refractory bronchospasm and 

hypotension during anaphylaxis in patients receiving 

b-adrenergic antagonists by activating adenyl cyclase 

directly and bypassing the b-adrenergic receptor. 90 The 

recommended dosage for glucagon is 1 to 5 mg (20-30 mg/ 

kg [maximum dose, 1 mg] in children) administered 

intravenously over 5 minutes and followed by an infusion 

(5-15 mg/min) titrated to clinical response. Protection of 

the airway is important because glucagon might cause 

emesis and risk aspiration in severely drowsy or obtunded 

patients. Placement in the lateral recumbent position might 

be sufficient airway protection for many of these patients. 

Fluid resuscitation. Changes in vascular permeability 

during anaphylaxis might permit transfer of 50% of the 

intravascular fluid into the extravascular space within 10 

minutes. 37,38 This effective shift of blood volume is 

countered by compensatory vasopressor mechanisms 

that involve the release of norepinephrine and epinephrine, 

91 as well as activation of the angiotensin system. 92,93 

Resulting increases in catecholamines might produce 

varied effects. Some patients during anaphylaxis experience 

abnormal increases in peripheral resistance (reflecting 

maximal vasoconstriction), 94 whereas others have 

decreased systemic vascular resistance, despite increased 

endogenous catecholamine levels. 91 These variable 

effects of internal compensatory mechanisms might 

explain why epinephrine injections sometimes fail to 

help in anaphylaxis. In contrast, these patients might 

respond to fluid replacement. (See Table IV for agedependent 

criteria for hypotension, as defined by international 

consensus guidelines for pediatric advanced life 

support.) 

The patient whose hypotension persists despite epinephrine 

injections should receive intravenous crystalloid 

solutions or colloid volume expanders. Of available 

crystalloid solutions, saline is generally preferred in 

distributive shock (eg, anaphylactic shock) because it 

stays in the intravascular space longer than dextrose and



MARCH 2005 

TABLE IV. Special considerations for anaphylaxis in 

children 22 

A. When is it hypotension? 

Age 

Systolic blood pressure (mm Hg) 

Term neonates (0-28 d) ,60 

Infants (1-12 mo) ,70 

Children (>1 y to 10 y) ,70 1 (23 age in y) 

Beyond 10 y ,90 

B. Infusion rates for epinephrine and dopamine in children with 

cardiac arrest or profound hypotension 

Medication Dose range Preparation* 

Dopamine 2-20 mg/kg/min 63 body weight (in kg) = no. of mg 

diluted to total 100 mL of saline; 

then 1 mL/h delivers 1 mg/kg/min 

Epinephrine 0.1 mg/kg/min 0.63 body weight (in kg) = no. of 

mg diluted to total 100 mL of 

saline; then 1 mL/h delivers 

0.1 mg/kg/min 

*Infusion rates shown use the ‘‘rule of 6.’’ An alternative is to prepare a 

more diluted or more concentrated drug solution on the basis of a standard 

drug concentration, in which case an individual dose must be calculated for 

each patient and each infusion rate as follows: Infusion rateðmL=hÞ ¼ 

ðWeight½kgŠ3Dose½mg=kg=minŠ360 min=hÞ=Concentrationðmg=mLÞ: 

contains no lactate, which might potentially exacerbate 

metabolic acidosis. One to 2 L of normal saline might need 

to be administered to adults at a rate of 5 to 10 mL/kg in the 

first 5 minutes. Children should receive up to 30 mL/kg in 

the first hour. Adults receiving colloid solution should 

receive 500 mL rapidly, followed by slow infusion. 19 

Large volumes are often required, but it might be appropriate 

to monitor patients with underlying congestive heart 

failure or chronic renal disease for signs of volume 

overload once the effective fluid deficit is replaced. 

Vasopressors. Vasopressors, such as dopamine (400 

mg in 500 mL of 5% dextrose), administered at 2 to 20 mg/ 

kg/min and titrated to maintain systolic blood pressure 

greater than 90 mm Hg, should be administered if 

epinephrine injections and volume expansion fail to 

alleviate hypotension. (See Table II for pediatric dosing 

of dopamine.) Dopamine will frequently increase blood 

pressure while maintaining or enhancing blood flow to the 

renal and splanchnic circulation. A critical care specialist 

might need to be consulted for any patient with intractable 

hypotension. 95 These agents would not be expected to 

work as well in those patients who have experienced 

maximal vasoconstriction as their internal compensatory 

response to anaphylaxis. 

After promising results in various animal models for 

cardiopulmonary resuscitation, vasopressin has been investigated 

for potential benefit in human cardiac arrest in 

3 randomized controlled trials, 96-98 and one case report 

investigated its effects on hypotension in 2 adults who 

experienced insect sting anaphylaxis. 99 Wenzel et al 98 

proposed that ‘‘vasopressin was superior to epinephrine in 

patients with asystole’’ on the basis of post hoc statistical 

analysis (1 of 29 statistical comparisons), did not correct 

statistically for multiple comparisons, and included no 

sensitivity analysis for 33 subjects excluded from analysis. 

100 The other 2 randomized controlled trials concluded 

there were no significant differences in survival to discharge 

or neurologic function when vasopressin was 

compared with epinephrine in cardiac arrest. 

In summary, high-quality randomized control trials 

performed to date have not demonstrated that vasopressin 

efficacy equals or exceeds that of epinephrine in clinical 

outcomes of treatment for cardiac arrest. No controlled 

studies have been performed to evaluate the potential 

efficacy of vasopressin alone in anaphylaxis or in combination 

with epinephrine. 

Analysis of anaphylaxis outcomes 

and procedures 

After treatment for any episode of acute anaphylaxis, 

the clinician should consider an analysis of event and 

possible precipitating cause, particularly with respect to 

those steps that could or should be done to prevent future 

episodes. (See ‘‘Anaphylaxis and immunotherapy’’ on 

prevention of anaphylaxis and specific scenario of anaphylaxis.) 

The clinical staff should also critique its 

approach to the management of anaphylaxis after each 

episode in regard to what worked well and what needs 

improvement. 

Guide to physician-supervised management 

of anaphylaxis 

I. Immediate intervention 

a. Assessment of airway, breathing, circulation, and 

adequacy of mentation 

b. Administer aqueous epinephrine 1:1000 dilution, 

0.2 to 0.5 mL (0.01 mg/kg in children, max 0.3 mg 

dosage) intramuscularly or subcutaneously into the 

arm (deltoid) every 5 minutes, as necessary, to 

control symptoms and blood pressure. The arm 

permits easy access for administration of epinephrine, 

although intramuscular injection into the 

anterolateral thigh (vastus lateralis) produces 

higher and more rapid peak plasma levels compared 

with injections administered intramuscularly 

or subcutaneously in the arm. Similar studies 

comparing intramuscular injections with subcutaneous 

injections in the thigh have not yet been 

done. Although intuitively higher and more 

rapid peak plasma levels seen with intramuscular 

injection in the thigh would appear desirable, 

the clinical significance of these data is not 

known. Alternatively, an epinephrine autoinjector 

(eg, EpiPen [0.3 mg] or EpiPen Jr [0.15 mg]) 

might be administered through clothing into the 

lateral thigh. Repeat every 5 minutes as necessary 

(avoid toxicity). Note: Some guidelines suggest 

that the 5-minute interval between injections 

can be liberalized to permit more frequent injections 

if the clinician deems it appropriate. There 

is no absolute contraindication to epinephrine 

administration in anaphylaxis. However, several 

anaphylaxis fatalities have been attributed to injudicious 

use of intravenous epinephrine.




II. Subsequent measures that might be necessary depending 

on response to epinephrine 

a. Place patient in recumbent position and elevate 

lower extremities. 

b. Establish and maintain airway (endotracheal tube 

or cricothyrotomy can be performed if required 

and if clinicians are adequately trained and proficient). 

c. Administer oxygen at 6-8 L/min. 

d. Establish venous access. 

e. Use normal intravenous saline for fluid replacement. 

Might require large volumes of crystalloid 

(1-2 L of normal saline to adults can be administered 

at 5-10 mL/kg in first 5 minutes; children 

can receive up to 30 mL/kg in the first hour). If 

hypotension persists, rapid infusion of volume 

expanders (colloid-containing solutions) might be 

necessary. 

III. Where appropriate, specific measures to consider 

after epinephrine injections 

a. An epinephrine infusion might be prepared by 

adding 1 mg (1 mL) of 1:1000 dilution of 

epinephrine to 250 mL of D5W to yield a concentration 

of 4.0 mg/mL. This solution is infused 

intravenously at a rate of 1 to 4 mg/min (15 to 60 

drops per minute with a microdrop apparatus 

[60 drops per minute = 1 mL = 60 mL/h]), increasing 

to a maximum of 10.0 mg/min for adults 

and adolescents. If an infusion pump is available, 

an alternative 1:100,000 solution of epinephrine 

(1 mg [1 mL] in 100 mL saline) can be prepared 

and administered intravenously at an initial rate of 

30 to 100 mL/h (5-15 mg/min), titrated up or 

down depending on clinical response or epinephrine 

side effects (toxicity). A dosage of 0.01 mg/ 

kg (0.1 mL/kg of a 1:10,000 solution; maximum 

dose, 0.3 mg) is recommended for children. 

Alternative pediatric dosage by the ‘‘rule of 6’’ 

is as follows: 0.6 3 body weight (in kilograms) 

= number of milligrams diluted to total 

100 mL of saline; then 1 mL/h delivers 0.1 mg/kg/ 

min. Note: Because of the risk for potentially 

lethal arrhythmias, epinephrine should be administered 

intravenously only during cardiac arrest 

or to profoundly hypotensive subjects who have 

failed to respond to intravenous volume replacement 

and several injected doses of epinephrine. In 

situations in which hemodynamic monitoring is 

available (eg, emergency department or intensive 

care facility), continuous hemodynamic monitoring 

is essential. However, use of intravenous epinephrine 

should not be precluded in a scenario in 

which such monitoring is not available if the 

clinician deems its administration is essential after 

failure of several epinephrine injections in the 

thigh. If intravenous epinephrine is considered essential 

under these special circumstances, monitoring 

by available means (eg, every-minute blood 


monitoring, if available) should be 

conducted. 

b. Diphenhydramine, 1-2 mg/kg or 25-50 mg/dose 

(parenterally). 

c. Consider ranitidine, 1 mg/kg, which can be 

diluted in 5% dextrose (D5W) to a total volume 

of 20 mL and injected intravenously over 5 

minutes. Cimetidine (4 mg/kg) can be administered 

intravenously to adults, but no pediatric 

dosage in anaphylaxis has been established. 

Note: In the management of anaphylaxis, a combination 

of diphenhydramine and ranitidine is 

superior to diphenhydramine alone. 

d. For bronchospasm resistant to epinephrine, use 

nebulized albuterol, 2.5-5 mg in 3 mL of saline, 

and repeat as necessary. 

e. For hypotension refractory to volume replacement 

and epinephrine injections, dopamine, 

400 mg in 500 mL D5W, can be administered 

intravenously at 2 to 20 mg/kg/min, with the rate 

titrated to maintain adequate blood pressure. 

Continuous hemodynamic monitoring is essential. 

f. Where b-blocker therapy complicates treatment, 

consider glucagon, 1-5 mg (20-30 mg/kg [maximum, 

1 mg] in children), administered intravenously 

over 5 minutes followed by an infusion 

(5-15 mg/min). Aspiration precautions should be 

observed because glucagon can cause nausea and 

emesis. 

g. Consider systemic glucocorticosteroids for patients 

with a history of idiopathic anaphylaxis and 

asthma and patients who experience severe or 

prolonged anaphylaxis. Glucocorticosteroids usually 

are not helpful acutely, but potentially might 

prevent recurrent or protracted anaphylaxis. If 

given, intravenous steroids should be administered 

every 6 hours at a dosage equivalent to methylprednisolone 

(1.0-2.0 mg/kg/day). Oral administration 

of prednisone, 0.5 mg/kg, might be 

sufficient for less critical anaphylactic episodes. 

h. Consider transportation to the emergency department 

or an intensive care facility. 

IV. Key additional interventions for cardiopulmonary 

arrest occurring during anaphylaxis 

a. Cardiopulmonary resuscitation and advanced cardiac 

life support measures. 

b. High-dose intravenous epinephrine (ie, rapid progression 

to high dose). A commonly used sequence 

is 1 to 3 mg (1:10,000 dilution) slowly administered 

intravenously over 3 minutes, 3 to 5 mg 

administered intravenously over 3 minutes, and 

then a 4 to 10 mg/min infusion. The recommended 

initial resuscitation dosage in children is 0.01 mg/ 

kg (0.1 mL/kg of a 1:10,000 solution up to 

a maximum of 0.3 mg) repeated every 3 to 5 

minutes for ongoing arrest. Another option is to 

start an epinephrine infusion and deliver up to 10 

mg/min. Higher subsequent dosages (0.1-0.2



MARCH 2005 

mg/kg; 0.1 ml/kg of a 1:1,000 solution) might be 

considered for unresponsive asystole or pulseless 

electrical activity. These arrhythmias are often 

observed during cardiopulmonary arrest that occurs 

in anaphylaxis. 

c. Rapid volume expansion is mandatory. 

d. Atropine and transcutaneous pacing should be 

considered if asystole and/or pulseless electrical 

activity are present. 

e. Prolonged resuscitation efforts are encouraged, 

if necessary, because efforts are more likely to 

be successful in anaphylaxis when the patient 

is young and has a healthy cardiovascular 

system. 

f. Transport to the emergency department or an 

intensive care facility, as the setting dictates. 

VI. Observation and subsequent follow-up 

a. Observation periods must be individualized because 

there are no reliable predictors of biphasic 

or protracted anaphylaxis on the basis of initial 

clinical presentation. Follow-up accordingly must 

be individualized and based on such factors as 

clinical scenario and distance from the patient’s 

home to the closest emergency facility. After 

resolution of the acute episode, patients should be 

provided with an epinephrine syringe and receive 

proper instruction for self-administration in case 

of a subsequent episode. All individuals experiencing 

anaphylaxis require a careful history and 

targeted diagnostic evaluation in consultation 

with an allergist-immunologist. 

ANAPHYLAXIS TO FOODS 


14. Severe food reactions have been reported to involve 

the gastrointestinal, cutaneous, respiratory, and 

cardiovascular systems. D 

15. The greatest number of anaphylactic episodes in 

children has involved peanuts, tree nuts (ie, walnuts, 

pecans, and others), fish, shellfish, milk, and 

eggs (C). The greatest number of anaphylactic 

episodes in adults is due to shellfish (C). Clinical 

cross-reactivity with other foods in the same group 

is unpredictable (B). Additives can also cause 

anaphylaxis (C). 

16. Anaphylactic reactions to foods almost always 

occur immediately. Symptoms might then subside 

only to recur several hours later. A 

17. The most useful diagnostic tests include skin tests 

and food challenges. In vitro testing with foods 

might be appropriate as an alternative screening 

procedure. C 

18. Double- or single-blind placebo-controlled food 

challenges can be done in patients with suspected 

food allergy in a medical facility by personnel 

experienced in performing the procedure and prepared 

to treat anaphylaxis. B 

19. Patient education should include discussion about 

avoidance and management of accidental ingestion. 

C 

20. Schools might present a special hazard for the 

student with food allergy. Epinephrine should be 

available for use by the individuals in the school 

trained to respond to such a medical emergency. C 

The true incidence of fatal or near-fatal anaphylaxis 

to food is unknown. One estimate, about a thousand 

severe episodes per year, has been extrapolated from 

emergency department reporting. 101 In 3 recent surveys 

food allergy was reported to be the most commonly 

identified cause of anaphylaxis, accounting for 35% to 

55% of cases. 2,3,102 

Severe adverse food reactions can involve several 

major systems. Respiratory manifestations might include 

oral and pharyngeal swelling, hoarseness and laryngeal 

edema, wheezing, cough, breathlessness, and/or chest 

tightness. Cardiovascular manifestations might include 

cardiac ischemia, arrhythmias, and hypotension, which 

might produce loss of consciousness. Gastrointestinal 

signs and symptoms include nausea, bloating, diarrhea, 

and severe abdominal pain. It should be noted that in some 

female subjects, abdominal pain involves the lowest 

portion of the abdomen and might be due to uterine 

contractions. Cutaneous manifestations have included 

urticaria, angioedema, and erythema. Angioedema and 

erythema can occur without urticaria. Angioedema of the 

eyelids and involvement of the conjunctiva is possible. 

Individuals might also experience a metallic taste and 

a sense of impending doom. 

Etiology 

Many foods have been reported to cause anaphylaxis. 

103,104 The greatest number of anaphylactic reactions 

to foods in the United States have been reported after 

exposure to peanuts, tree nuts, milk, and eggs in children, 

and shellfish, peanuts, and fish in adults. 105-108 

It should not be assumed that a reaction to one member 

of a food family necessarily incriminates any or all other 

members. 109-111 Certain foods contain epitopes that crossreact 

immunologically (eg, peanut and soy) but might not 

cross-react in terms of the clinical response. 112 

History 

Obtaining a thorough history from patients who have 

experienced a life-threatening reaction that might have 

been caused by a food is crucial. The history might be 

unequivocal, as in the individual who eats a single food 

(eg, peanut) and shortly thereafter has anaphylaxis. It 

should be remembered that highly sensitive patients might 

experience anaphylaxis after inhalation (eg, cooking fish) 

exposure. However, in many patients with anaphylaxis, a 

food offender cannot be immediately identified. If anaphylaxis 

occurs repeatedly and food allergy is suspected, it 

might be possible to assemble a list of ingredients from 

foods associated with these events by searching for 

common constituents. 104




The time from ingestion to symptom onset in food 

allergy is typically rapid, usually within minutes, but 

might be delayed up to an hour and in some instances up 

to a few hours. 111,113 Symptoms might then subside only 

to recur several hours later (biphasic reaction). 

Fatal food anaphylaxis might begin with mild symptoms, 

sometimes involving the skin, and then progress 

to shock with cardiovascular collapse over a 1- to 3-hour 

period. 107 

In evaluating suspected food allergy, it is important to 

consider associated factors, such as exercise after food 

ingestion (see section on exercise-induced anaphylaxis 

and ‘‘Food allergy: a practice parameter’’). 13 

Diagnostic testing 

Presently, the most useful diagnostic tests for food 

allergy include skin tests, in vitro serum specific IgE 

assays, and oral food challenges. The test of choice is the 

skin test. It should be recognized that although many food 

allergens have been well characterized, standardized food 

extracts are not currently available, and skin tests might 

need to be performed to fresh food extracts. 103 If skin 

testing is done, the challenge solution should be diluted, 

and testing should be performed by a physician experienced 

in the procedure in a setting with appropriate rescue 

equipment and medications available. In certain instances 

in vitro serum specific IgE determinations can be helpful. 

Food challenges 

The degree to which the history and diagnostic testing 

confirm that a single specific food is responsible for the 

reaction that the patient has experienced will determine the 

need for a food challenge. If the history and diagnostic 

testing give an unequivocal answer, no challenge is 

necessary. Inadvertent ingestion of a food will often 

confirm that the initial suspicion about that food was 

correct. 

However, if a definite food has not been identified as the 

cause of the reaction but foods are still suspected, food 

challenge might be necessary because identification of the 

food might be life-saving. 107 Double- or single-blind 

placebo-controlled food challenges can be performed 

safely in individuals with a history of food-induced 

anaphylaxis. 104-108 Open and nonblinded challenge can 

also be performed. It might be especially helpful when it is 

unlikely that the suspect food was responsible for the 

reaction and the patient needs to be reassured that it is safe 

to ingest the particular agent used. However, it might be 

necessary to begin with a minute amount of the suspected 

food, and the challenge should be stopped when the first 

symptoms occur. Often, but not always, pruritus of the oral 

tissues or nausea is the initial complaint after challenge 

with the suspected food. It is important to remember that 

even a small amount of food allergen can precipitate 

anaphylaxis. 103 

Patient education 

Education regarding avoidance and management of 

accidental ingestion of foods known to produce anaphylaxis 

is crucial because neither presently available medications 

nor immunotherapy has been shown to 

consistently prevent such reactions, and epinephrine has 

not always been effective in reversing anaphylaxis. In 

addition to attempting to identify the food that is causing 

anaphylaxis, it is important to teach patients about situations 

in which accidental ingestion might occur. 114-116 

Patients with food hypersensitivity should be taught to 

effectively read and interpret labels on foods and to inquire 

about ingredients in restaurant meals. In addition, patients 

should be educated about foods that might cross-react with 

the identified offender (eg, various shellfish). There are 

educational materials available from dietitians, as well as 

organizations such as the Food Allergy Network (10400 

Eaton Place, #107, Fairfax, VA 22030-2208; phone, 703- 

691-3179; fax, 703-691-2713). Fortunately, the food 

industry is becoming more responsive about labeling of 

food allergens and providing information to the public 

about accidental contamination of food products with 

known allergens. 

Exposure to foods at school, daycare, camps, and 

restaurants constitutes a special hazard for individuals 

with food allergy. If a child has a history of severe 

reactions to foods, the foods that caused the reaction 

should be identified for school personnel. School personnel 

should be informed about a student’s history of 

anaphylaxis and the specific food (or foods) to which the 

child is allergic. An allergen-free environment should be 

constructed for the child at mealtime to prevent inadvertent 

ingestion such as might occur with shared food. There 

should be a written response plan available that can be 

initiated immediately if a reaction occurs. Unfortunately, 

not all school policy allows children to have ready access 

to epinephrine at school. However, youngsters allergic to 

foods are covered by the Americans with Disabilities Act, 

which should make it easier to arrange an emergency 

medical response for accidental severe food reactions. 

Individuals with a history of a life-threatening reaction to 

a food should carry epinephrine. This includes individuals 

who have had any respiratory symptoms or a decrease in 

blood pressure during a reaction to a food. Patients at risk 

should carry identification, such as a Medic Alert jewelry. 

If epinephrine is prescribed for the patient, the patient 

must understand that it should be available at all times. 

This instruction might require constant reinforcement. 

Compliance is more likely in young children, for whom 

adults are responsible. Compliance is the most difficult in 

adolescents and young adults. If a reaction is of such 

severity that epinephrine is required, the patient should be 

transported to the nearest emergency facility by ambulance 

for monitoring after epinephrine has been administered. 

Ongoing evaluation 

It is recommended that patients be instructed in the 

importance of reporting any and all anaphylactic reactions 

to their physician as soon as possible after they occur. If 

the exact cause of these reactions has not been identified, 

discussing the reaction with the physician while it is still



MARCH 2005 

fresh in the patient’s mind might help to define the specific 

food causing the reaction. If the cause of the patient’s 

reactions is known, this interaction can re-establish that 

the food responsible for these reactions was correctly 

identified and that the appropriate treatment response was 

initiated. 

LATEX-INDUCED ANAPHYLAXIS 


21. Latex (rubber) hypersensitivity is a significant medical 

problem, and 3 groups are at higher risk of 

reaction: health care workers, children with spina 

bifida and genitourinary abnormalities, and workers 

with occupational exposure to latex. B 

22. Skin prick tests with latex extracts should be 

considered for patients who are members of highrisk 

groups or who have a clinical history of possible 

latex allergy to identify IgE-mediated sensitivity. 

Although a standardized commercial skin test reagent 

for latex is not available in the United States, 

many allergy centers have prepared latex extracts 

from gloves to be used for clinical testing. It should 

be noted, however, that such extracts, prepared from 

gloves, demonstrate tremendous variability in the 

content of latex antigen. In vitro assays for IgE to 

latex might also be useful, although these tests are 

generally less sensitive than skin tests. C 

23. Patients with spina bifida (regardless of a history of 

latex allergy) and other patients with a positive 

history of latex allergy ideally should have all 

medical-surgical-dental procedures performed in 

a latex-safe environment and as the first case of the 

day. D 

24. A latex-free environment is an environment in which 

no latex gloves are used in the room or surgical suite 

and no latex accessories (catheters, adhesives, tourniquets, 

and anesthesia equipment) come into contact 

with the patient. D 

25. In health care settings general use of latex gloves 

with negligible allergen content, powder-free latex 

gloves, and nonlatex gloves and medical articles 

should be considered in an effort to minimize 

exposure to latex allergen. Such a combined approach 

might minimize latex allergen. Such a combined 

approach might minimize latex sensitization of 

health care workers and patients and should reduce 

the risk of inadvertent reactions to latex in previously 

sensitized individuals. C 

Latex sensitization caused by IgE mast cell–mediated 

reactivity to any or a number of antigens from Hevea 

brasiliensis, the source of latex, occurs in a significant 

percentage of the health care worker population, 117 up to 

75% of the spina bifida population, 118,119 and in the population 

undergoing multiple surgical procedures. Sporadic 

cases of latex-induced anaphylaxis have been reported 

because of hair glue and plastic balls with latex pits. 120,121 

An incidence of up to 6.5% of the general population has 

been noted to have detectable IgE to latex. 122 Atopic and 

latex-exposed individuals are also at higher risk of latex 

sensitization. Individuals might be sensitized to minor or 

major antigens. No more than 240 separate polypeptides 

can be discerned by means of 2-dimensional electrophoresis 

of latex cap. Less than 25% of these react with IgE 

from patients with latex allergy. These tend to cluster into 

groups of 11 proteins. 123 With exposure, sensitized 

individuals might experience urticaria, angioedema, rhinitis, 

bronchospasm, and anaphylaxis. 

Incidence 

Latex-induced anaphylaxis can present in the operating 

room in patients, surgeons, nurses, or anesthesiologists. 

Latex has been reported to account for up to 17% of cases 

of intraoperative anaphylaxis. 123 

Clinical findings 

The features of intraoperative anaphylaxis from latex 

might differ considerably from latex-induced anaphylaxis 

not associated with surgical procedures. Although cutaneous, 

hypotensive, and respiratory events occur in both, 

hypotensive cardiovascular collapse is a feature of 

surgical reactions, and dizziness or syncope might be 

found largely in anaphylaxis induced by nonsurgical 

procedures. 124 In some situations anaphylaxis might not 

be IgE mediated, such as those caused by radiocontrast 

media, but it has become clear that latex-induced anaphylaxis 

is due to IgE mast cell–mediated mechanisms. Thus 

after a careful history and physical examination, detection 

of IgE to latex is quite helpful in the diagnosis. 

Unfortunately, no commercially available skin test reagent 

is available in the United States. For this reason, other 

materials, such as latex glove extracts, are often used. It 

should be noted that such extracts are not standardized, 

and the amount of latex allergen within these extracts is 

highly variable. Latex ELISA or CAP are also available, 

but because of the variability in the antigen response, the 

in vitro tests have highly variable sensitivity and specificity 

characteristics. The sensitivity has been found to be as 

low as 50% to as high as 100%. 125,126 

Latex-induced anaphylaxis might occur in a variety of 

situations, all involving direct contact with latex devices, 

usually gloves, or instruments or with aerosolization of 

latex antigen adhered to the cornstarch donning powder of 

latex gloves. Thus latex-induced reactions can occur with 

operative procedures when gloves are donned. Latexinduced 

reactions might occur immediately with latex 

contact or might be delayed from 30 to 60 minutes. 

Intraoperative latex-induced anaphylaxis might be related 

to the administration of drug through a latex port before 

surgery or during the surgical procedure itself. Latexinduced 

reactions have also been reported to occur during 

dental procedures from latex glove or dams, during obstetric 

or gynecologic examinations, during latex condom 

use, and from blowing into rubber balloons. Patients 

with spina bifida are potentially at risk at each surgical 

procedure because of the numbers of procedures they 

undergo.




Treatment 

Latex-induced anaphylaxis is an IgE mast cell– 

mediated reaction and should be treated as any other 

case of anaphylaxis (see section on management of 

anaphylaxis, beginning on page S500). 

Prevention 

As aerosolization, inhalation, or direct contact with 

latex devices or latex antigen is the event resulting in the 

allergic response, and avoidance is clearly the prime mode 

of therapy. For the sensitive health care worker, latex 

gloves should not be worn, and the worker’s colleagues 

should wear nonpowdered latex or nonlatex gloves. The 

workplace should be latex safe, with all nonglove latex 

devices replaced by nonlatex devices. A latex-free emergency 

cart (Table V) should be available to treat reactions. 

Although it is unclear whether rubber stopper vials can 

cause anaphylaxis, they should be avoided. 

Latex precautions should be instituted when a latexsensitive 

patient undergoes a surgical procedure, an obstetric 

or gynecologic examination, or dental care. The 

surgical room, dental area, or examination area should be 

free of latex devices. No latex gloves should be used, and 

the patient should be the first case of the day. Appropriate 

emergency medications must be available for treatment 

should a reaction occur. With these measures, latexinduced 

anaphylaxis should be markedly reduced. 

It is important to recognize that cross-reactivity between 

latex and foods can occur. The commonly reported 

cross-reactive foods include banana, avocado, kiwi, and 

chestnut (see ‘‘Food allergy: a practice parameter’’). 

ANAPHYLAXIS DURING GENERAL 

ANESTHESIA, THE INTRAOPERATIVE 

PERIOD, AND THE POSTOPERATIVE PERIOD 


26. The incidence of anaphylaxis during anesthesia has 

been reported to range from 1 in 4000 to 1 in 25,000. 

Anaphylaxis during anesthesia can present as cardiovascular 

collapse, airway obstruction, flushing, 

and/or edema of the skin. C 

27. It might be difficult to differentiate between immune 

and nonimmune mast cell–mediated reactions and 

pharmacologic effects from the variety of medications 

administered during general anesthesia. B 

28. Thiopental allergy has been documented with skin 

tests. B 

29. Neuromuscular blocking agents, such as succinylcholine, 

can cause nonimmunologic histamine release, 

but there have been reports of IgE-mediated 

mechanisms in some cases. B 

30. Reactions to opioid analgesics are usually caused 

by direct mast cell–mediator release rather than 

IgE-dependent mechanisms. B 

31. Antibiotics that are administered perioperatively can 

cause immunologic or nonimmunologic generalized 

reactions. B 

TABLE V. Example of contents of latex-free cart 

I. Glass syringes 

II. Ampules 

III. Tubing without ports (taped ports) 

IV. Stopcocks 

V. Nonlatex stethoscope 

VI. Nonlatex gloves 

VII. Nonlatex breathing system 

Neoprene bags 

Plastic masks 

Nonlatex Ambu 

Uncuffed polyvinyl chloride endotracheal tube 

VIII. Dermicel 

IX. Disposable nonlatex blood pressure cuffs 

Webril tourniquets 

32. Protamine can also cause severe systemic reactions 

through IgE-mediated or nonimmunologic mechanisms. 

B 

33. Latex is a potent allergen, and IgE-mediated reactions 

to latex during anesthesia have been clearly 

documented. Patients with multiple surgical procedures 

(eg, patients with spina bifida) and health care 

workers are at greater risk of latex sensitization. 

Precautions for latex-sensitive patients include 

avoiding the use of latex gloves and latex blood 

pressure cuffs, as well as latex intravenous tubing 

ports and rubber stoppers from medication vials. B 

34. Blood transfusions can elicit a variety of systemic 

reactions, some of which might be IgE mediated or 

mediated through other immunologic mechanisms. B 

35. Methylmethacrylate (bone cement) has been associated 

with hypotension and various systemic reactions, 

although no IgE mechanism has yet been 

documented. C 

36. The evaluation of IgE-mediated reactions to medications 

used during anesthesia can include skin 

testing to a variety of anesthetic agents. B 

37. The management of anaphylactic or anaphylactoid 

reactions that occur during general anesthesia is 

similar to the management of anaphylaxis in other 

situations. B 

Anaphylaxis or anaphylactoid reactions occur in 

1:5000 to 1:25,000 general anesthetic administrations. 1 

The mortality from anaphylaxis related to anesthesia is 

estimated to be as high as 6%. The multiple physiologic 

changes occurring before and during general anesthesia 

might limit or delay recognition of anaphylaxis. Signs of 

anaphylaxis include flushing or urticaria, hypotension, 

difficulty with intubation caused by laryngeal edema or 

increased ventilatory pressure, or inability to ventilate 

because of bronchospasm. Serum tryptase quantification 

during or immediately after a presumed anaphylactic or 

anaphylactoid event might be helpful in confirming 

clinical suspicion, particularly if a postevent sample 

demonstrates a decrease to normal value after the 

event. 1



MARCH 2005 

The causes of anaphylaxis or anaphylactoid reactions 

related to anesthesia are listed in order of approximate 

frequency of occurrence. 127-129 

d Muscle relaxants 

d Latex 

d Antibiotics, particularly b-lactam antibiotics 

d Induction agents or hypnotics 

d Opioids 

d Colloids, particularly dextran, mannitol, or hydroxyethyl 

starch 

d Blood products 

d Others, including protamine, isosulfan blue dye for 

lymph node dissection, gelatin solution used for 

hemostasis, chlorhexidine, ethylene oxide, radiocontrast 

media, streptokinase, methylmethacrylate, chymopapain 

130-133 

The rank order of occurrence is based on reviews for 

anesthesia during general surgery, but specific surgical 

procedures might differ with respect to likely cause. 127,128 

For example, in cardiovascular surgery anesthesiainduced 

anaphylaxis is more likely caused by cephalosporins, 

gelatin solution, or protamine allergy rather than 

muscle relaxants. 

Muscle relaxants are responsible for more than 60% 

of reactions during general anesthesia. 127,128,134,135 Most 

reactions occur because of direct mast cell activation, but 

life-threatening reactions are usually caused by specific 

IgE. 127,128 The shared tertiary or quaternary ammonium 

group results in cross-reactions among the muscle relaxants. 

127,129 Succinylcholine might be more likely to cause 

reactions caused by flexibility of the molecule facilitating 

the cross-linking of specific IgE on mast cell or basophil 

membranes. Skin testing to specific dilutions of muscle 

relaxants has been useful in determining the safest agent 

after a suspected reaction. 136 

Natural rubber latex sensitivity is the second most 

common cause of perioperative anaphylaxis in some 

series. The incidence might be decreasing with time. 

Anaphylaxis caused by latex is more likely to be delayed 

or occur later during the procedure compared with that 

caused by muscle relaxants or induction agents. Multiple 

prior surgical procedures are a risk factor. A US Food and 

Drug Administration–approved in vitro test for latexspecific 

IgE is available, although false-negative results 

occur. A standardized skin-testing reagent is not available 

in the United States but is in Canada. Latex precautions are 

indicated if latex sensitivity is confirmed or highly 

suspected. Ideally, latex-safe operative suites should be 

available. If this is not an option, scheduling the anesthesia 

and procedure as the first case of the day and avoiding the 

use of latex products is suggested. Premedication regimens, 

usually including corticosteroids and combinations 

of antihistamines, might lessen the severity but have not 

been shown to prevent anaphylactic reactions. 

Hypnotic induction agents are the third most likely 

cause of anesthesia anaphylaxis. Intravenous barbiturates 

have most commonly been responsible, but the reaction 

rate is probably less than 1:25,000, with the reported 

occurrence reflecting the common use of barbiturates. 

Mixing intravenous barbiturates with neuromuscular 

blocking agents in the same intravenous line might 

increase the likelihood of reactions. Skin testing has 

been reported with thioamyl and thiopental at 0.01 and 

0.2 mg/mL, respectively. 137 Propofol is a nonbarbiturate 

induction agent and is useful if sensitivity to barbiturates is 

suspected. Specific IgE to propofol occurs, but most 

propofol reactions are due to direct mast cell activation. 138 

Narcotics used in anesthesia commonly cause flushing 

and urticaria after intravenous administration. The risk of 

anaphylaxis or anaphylactoid reactions, in contrast, is very 

rare. 139 Reducing the rate of opioid administration usually 

limits the severity of these reactions. Fentanyl does not 

directly stimulate histamine release through the mast cell 

opioid receptor. 

Antibiotics are frequently administered before, during, 

or immediately after anesthesia and surgery. The most 

commonly implicated antibiotics resulting in reactions are 

b-lactams or vancomycin. IgE-mediated reactions occur 

in 0.04% to 0.015% of penicillin-treated subjects, and 

anaphylaxis occurs in approximately 0.001%. Intravenous 

administration of penicillin results in the most severe 

forms of anaphylaxis. Penicillin skin testing is useful to 

identify specific IgE. The sensitivity of penicillin skin 

testing is approximately 97% if aqueous penicillin and 

penicillin major determinant (Pre-pen) are used. The lack 

of a commercially available minor determinant, sensitivity 

to which can be associated with severe reactions, is an 

impediment. Percutaneous, followed by intracutaneous, 

testing with concentrations of up to 3 mg/mL for aqueous 

penicillin and 6 3 10 25 molar for major determinant are 

recommended to exclude penicillin allergy. In vitro testing 

for the major determinant is also available, but its negative 

predictive value is less well established and is less 

compared with immediate hypersensitivity testing. 140 

Skin testing with penicillin derivatives or cephalosporins 

is not as well studied. Maximum testing concentrations 

of 1 to 3 mg/mL have been suggested for these other 

b-lactams. Carbapenems do not cross-react immunologically 

with penicillin. Desensitization schedules are available 

to facilitate use of b-lactam antibiotics, if absolutely 

necessary, in subjects with documented or suspected 

allergy. Vancomycin is a glycopeptide antibiotic selectively 

used for treatment of resistant organisms and for 

individuals with penicillin allergy. Administration, particularly 

rapid administration, might result in life-threatening 

anaphylactoid reactions. Evidence for both direct 

histamine release and direct myocardial depression partially 

explains this phenomenon. These nonimmunologic 

reactions to vancomycin can be reduced or eliminated by 

administration of a dilute solution, dissolved in at least 

200 mL, that is slowly infused. Anaphylactic reactions to 

vancomycin occur but are much less common than 

anaphylactoid reactions. Skin testing with a concentration 

of up to 0.15 mg/mL has been reported, but the reliability 

of this testing is less secure than with penicillin. Skin 

testing might be of some value in distinguishing raterelated 

anaphylactoid reactions from anaphylaxis.




Intravenous protamine used to reverse heparin anticoagulation 

might cause anaphylactic or anaphylactoid 

reactions. The latter reactions are characterized by an 

increase in pulmonary blood pressure. Proposed causes 

include both immunologic and nonimmunologic mechanisms. 

A case-control study showed that prior neutral 

protamine Hagedorn insulin use (odds ratio, 8.18 

[2.08,32.2]), fish allergy (odds ratio, 24.5 [1.24,482.3]), 

and other medication allergy (odds ratio, 2.97 [1.25,7.07]) 

are independent risk factors. 141 Estimates are that up to 

39% of patients undergoing cardiopulmonary bypass have 

one or more of these risk factors. Alternative agents might 

be used for heparin reversal, but these are not readily 

available. Pretreatment regimens with corticosteroids and 

antihistamines have been recommended, but no studies 

confirm efficacy. 

Dextran and hydroxyethel starch (HES), largemolecular-weight 

polysaccharides, might be used as 

a nonblood product and for high oncotic fluid replacement 

during surgery. These agents are rarely associated with 

adverse reactions, probably anaphylactoid, because of 

complement activation. Estimates of reaction rates are 

0.008% to 0.08% for dextran and 0.08% for HES. Specific 

antibodies can be detected for dextran and HES, but the 

clinical significance of these is unknown. Confirmation of 

dextran or HES as the cause of an adverse reaction is 

limited by the absence of accurate serologic or skin tests. 

Skin test reactivity to undiluted solutions has been 

described but again is of unknown significance. 142 

Case reports are also in the literature describing 

systemic reactions to albumin. Details are not available 

as to the mechanism of the adverse effects. 

The ideal of preventing perianesthetic reactions is 

elusive because of the rare occurrence of reactions; the 

multiple pathophysiologic mechanisms, many of which 

are undefined; and the limited ability to test for risk or 

sensitization. 143 A careful medical history focusing on 

prior adverse reactions is most important. Any prior 

medication reactions nonspecifically increase the possibility 

of adverse reactions, and multiple previous medication 

reactions are a greater risk. Atopic subjects might be at 

heightened risk, either because of increased occurrence of 

reactions or, more often, increased severity of reactions. 

Asthma should be stabilized with lung function maximized 

and bronchial hyperreactivity minimized, if possible. 

b-Blocker therapy is a risk factor that ideally should 

be avoided. Previous anesthetic associated reactions 

should be evaluated thoroughly with specific testing if 

indicated. IgA-deficient subjects should receive washed 

red blood cells and no whole blood to avoid exposure to 

exogenous IgA. Intraoperative antibiotic administration 

should be at a slow rate with careful hemodynamic 

monitoring. Drugs with histamine-releasing properties, 

for example morphine, d-tubocurarine, vancomycin, or 

quaternary muscle relaxants, should be administered as 

slowly as possible, particularly in subjects with asthma or 

cardiopulmonary disease. Risk factors for latex hypersensitivity 

should be reviewed and consideration given to 

testing for specific IgE if any risk factors are identified. 

Pretreatment regimens, as used for radiocontrast anaphylactoid 

reactions, have not been proved to prevent 

perianesthetic reactions but might reduce the severity of 

such reactions. 

Local anesthetics 

Adverse effects from local anesthetics are not uncommon, 

but immunologic mediated reactions after 

parenteral administration are very unusual. The usual 

cause of a local anesthetic reaction is a vasovagal response, 

anxiety, toxic complications, or an idiosyncratic 

reaction. Toxic effects usually result from inadvertent, 

systemic, high-dose administration. Systemic toxicity 

includes central nervous system stimulation or suppression 

and cardiac suppression with peripheral vasodilation. 

Epinephrine mixed with local anesthetics might contribute 

to the sensation of anxiety if systemic absorption occurs. 

IgE-mediated reactions to local anesthetics are exceedingly 

rare. 144 

SEMINAL FLUID–INDUCED ANAPHYLAXIS 


38. Anaphylaxis caused by human seminal fluid has 

been shown to be due to IgE-mediated sensitization 

by proteins of varying molecular weight. B 

39. Localized seminal plasma hypersensitivity has been 

well described and is likely IgE mediated on the 

basis of successful response to rapid seminal plasma 

desensitization. C 

40. History of atopic disease is the most consistent risk 

factor. However, anecdotal case reports have been 

associated with gynecologic surgery, injection of anti- 

RH immunoglobulin, and the postpartum state. C 

41. The diagnosis is confirmed by means of skin and/or 

in vitro tests for serum-specific IgE by using proper 

reagents obtained from fractionation of seminal fluid 

components. C 

42. Prevention of reactions to seminal fluid can be 

accomplished by barrier use of condoms. C 

43. Immunotherapy to properly fractionated seminal 

fluid proteins has been universally successful in 

preventing anaphylaxis to seminal fluid, provided 

the sensitizing seminal fluid fractions are used as 

immunogens. Successful intravaginal graded challenge 

with unfractionated seminal fluid has been 

reported in a few cases, but the duration of protection 

is unknown. C 

44. Localized and/or systemic seminal plasma hypersensitivity 

is not associated with infertility. D 

Diagnosis 

Anaphylaxis caused by coital exposure to human 

seminal fluid is a rare occurrence. Since the initial report 

in 1958, approximately 30 cases of seminal fluid–induced 

anaphylaxis have been described. 145-147 All reactions have 

occurred in female patients during or after sexual intercourse. 

The vast majority of such reactions are caused



MARCH 2005 

by IgE-mediated sensitization to human seminal plasma 

proteins with molecular weights ranging from 12 to 

75 kd. 148-150 In rare cases spermatozoa have been identified 

as the source of allergens inducing a cell-mediated 

reaction. 151 Coital anaphylaxis has also been attributed to 

exposure to exogenous allergens transferred through 

semen during sexual intercourse. Such unusual reactions 

occur when a male partner ingests a food (eg, walnuts) or 

drug (eg, penicillin) to which there is established sensitization 

in the female partner. 152,153 Human anaphylaxis has 

also been described after repetitive coital exposure to 

canine seminal plasma. 154 

Seminal plasma hypersensitivity is essentially a diagnosis 

by exclusion. A detailed history is essential to rule 

out underlying causes, such as sexually transmitted 

diseases, latex sensitivity, or transfer of food or drug 

proteins from the male sexual partner to the female who 

might be sensitized to these agents or other contactants, 

such as fragrant sanitary napkins. Seminal plasma protein 

anaphylaxis begins within seconds to minutes after 

ejaculation and presents with a range of symptoms, 

including the following: diffuse pruritus and urticaria; 

pelvic pain associated with uterine contractions; nasal 

symptoms, including rhinorrhea and sneezing; wheezing, 

dyspnea, and/or laryngeal edema; and, rarely, hypotension 

and syncope. The effective prevention of reactions by 

correct use of condoms is a common feature. 155 Failure of 

condoms to prevent anaphylaxis suggests either incorrect 

condom technique or concurrent sensitization to latex. 156 

Localized vulvar and vaginal burning might occur as 

isolated symptoms or in conjunction with itching and 

swelling after ejaculation. There is no evidence to support 

the contention that localized vaginal seminal plasma 

hypersensitivity increases susceptibility of the individual 

to have future systemic anaphylactic symptoms. 

The most significant risk for seminal plasma protein 

anaphylaxis is in patients with a history of allergic asthma 

or atopic dermatitis. 146,150,157,158 However, anecdotal case 

reports of seminal fluid–induced anaphylaxis have occurred 

postpartum, after gynecologic surgery, and after 

injection of anti-Rh immune globulin. 146 It has not been 

established whether such events are coincidental or could 

somehow modulate immune tolerance, resulting in sensitization 

to seminal fluid proteins. Reactions have also been 

observed in women whose male partners have recently 

undergone prostatectomy or vasectomy. 159 Anaphylactic 

events have been reported in women with multiple previous 

sexual encounters or in others after the first coital 

act. 146 Postcoital allergic reactions are not specific to one 

partner and almost always recur with different male 

partners. Surveys have indicated that most subjects with 

seminal plasma hypersensitivity are not generally promiscuous 

in that they typically have reported a history of 

less than 2 sexual partners. 146 

The diagnosis must be confirmed by means of demonstration 

of sensitization to seminal fluid proteins through 

in vivo and/or in vitro immunologic methods. Demonstration 

of increased serum specific IgE assays with both 

positive and negative control sera confirms sensitization. 

149 On the basis of available data, in vitro tests (eg, 

RAST and ELISA) of serum specific IgE appear to be less 

sensitive than skin testing and could be due to the lack of 

reliable test allergens. 146 Thus a negative serologic test 

result for seminal plasma specific IgE does not exclude 

sensitization. 

Because sensitive specific IgE assays are not readily 

available, skin prick testing with whole human seminal 

plasma from the male partner is recommended for initial 

screening of suspect cases. Before skin testing, the male 

donor must be screened for viral hepatitis, syphilis, and 

HIV infection, and if there is evidence of infection, in vivo 

procedures should not be performed. Whole seminal 

plasma is prepared from a fresh specimen of ejaculate. 

Semen is allowed to liquefy at room temperature and 

centrifuged at 4°C to separate seminal plasma containing 

supernatant from spermatozoa, which is then filter sterilized. 

149-151 The male donor is also tested to control for 

irritant responses. A positive response is defined as a wheal 

of 3 mm greater than or equal to that produced with saline 

with a flare and a concomitant negative response in 

the male donor. Typically, intracutaneous skin testing to 

whole seminal plasma has not been performed as a screening 

test in that it has been previously demonstrated to 

result in a nonspecific irritant response. Therefore screening 

for seminal plasma hypersensitivity should be limited 

to skin prick testing to whole seminal fluid. It should be 

emphasized that protein allergens contained in whole 

seminal plasma might not be present in sufficient concentrations 

to elicit a positive response. Thus a negative skin 

prick test response to whole seminal plasma does not 

exclude allergic sensitization. In this case skin test reagents 

with high diagnostic sensitivity should be obtained 

by means of gel filtration (Sephadex G-100) of whole 

seminal plasma to isolate allergen-rich fractions. 149-151 

Percutaneous or intracutaneous responses to relevant 

seminal plasma protein fractions have been detected in all 

reported cases of anaphylaxis. The presence of positive 

serologic specific IgE antibodies to these fractions and 

specific skin tests to the same fractions is highly predictive 

of a successful treatment outcome with seminal plasma 

protein desensitization. 160 

Treatment 

Consideration must be given to the psychological effect 

of this condition on the patient, her spouse, and the future 

of their marital relationship. Couples should be informed 

that successful pregnancies have been achieved after 

artificial insemination with sperm washed free of seminal 

plasma. 159 Once the diagnosis is suspected, the patient 

must be advised to avoid coital exposure to seminal fluid. 

This can be achieved by means of either temporary 

cessation of intercourse or with the correct use of latex 

condoms. Coitus interruptus is often not successful 

because of potential leakage of seminal fluid during 

intercourse, which can result in a reaction and is therefore 

discouraged. Condoms made from lambskin or a plastic 

polymer can be substituted in the latex-sensitive patient. If 

anaphylaxis is caused by seminal transfer of exogenous




allergens, the male partner should avoid the causative food 

or drug before engaging in sexual intercourse. 151,152 It is 

essential that patients and spouses be trained in the 

emergency use of subcutaneous epinephrine. Although 

there are reports of successful use of precoital treatment 

with antihistamines or intravaginal cromolyn sodium, 

these options have generally been ineffective in the 

prevention of severe anaphylaxis. 160 

There are couples for whom abstinence, regular use of 

condoms, or artificial insemination to achieve pregnancy 

are unacceptable options. In such situations immunotherapy 

with seminal plasma fractions of the male partner 

should be considered. This procedure should only be 

performed in specialized centers and under the supervision 

of experienced physicians. Several (usually 4-7) fraction 

pools that correspond to different absorption peaks are 

collected by means of elution of whole seminal plasma 

over a Sephadex G-100 column. 148-151,161 Fraction pools 

are concentrated, quantitated for protein, and filter sterilized. 

In vivo allergenicity is evaluated by means of end 

point intracutaneous threshold testing. Because of its 

known immunosuppressive properties, the first fraction 

pool representing the initial absorption peak and containing 

high-molecular-weight proteins should not be used. 151 

After obtaining informed consent, subcutaneous injections 

of allergenic fractions are administered by using 

a rapid immunotherapy program beginning with a concentration 

that is at least 2 log dilutions higher than the end 

point threshold concentration. Because systemic reactions 

can occur during immunotherapy, emergency equipment 

necessary for treating anaphylaxis must be available. 

Injections are continued every 15 to 20 minutes until the 

highest available protein concentration is achieved for 

each allergenic fraction. Decreased or absent skin reactivity 

to treatment fractions and disappearance of serum 

specific IgE observed after immunotherapy has indicated 

that desensitization can be accomplished at the conclusion 

of the immunotherapy protocol. In highly sensitive 

patients injections might only be advanced over a period 

of weeks to months. An intravaginal instillation of fresh 

ejaculate should be used to confirm the efficacy of 

treatment. If a challenge is well tolerated, unprotected 

coitus can then be safely initiated. Intercourse must be 

continued on a regular schedule (2-3 times per week). 

Prolonged abstinence has resulted in loss of tolerance and 

recurrence of anaphylactic episodes. 149,151,155,161 If abstinence 

periods can be predicted, subcutaneous injections of 

relevant allergens might be resumed to prevent loss of 

tolerance. 

Successful intravaginal graded challenges have been 

reported in women given diagnoses of human seminal 

plasma–induced anaphylaxis confirmed by means of skin 

prick test reactivity to whole seminal plasma. 162-167 

Increasing 10-fold concentrations (1;10,000 to neat) of 

whole seminal plasma are deposited intravaginally at 

20-minute intervals and followed by a frequent schedule 

of unprotected sexual intercourse. No procedure-related 

systemic reactions have been reported to date. This 

approach has been successful in preventing subsequent 

anaphylactic episodes. As with parenteral desensitization 

protocols, frequent intercourse (2-3 times per week) is 

required to maintain the desensitized state. One case 

reported that abstinence for as short as 5 days resulted in 

recurrence of a postcoital reaction. The efficacy of intravaginal 

graded challenge is based entirely on single 

anecdotal reports. Because decreased percutaneous reactivity 

to seminal plasma has not been demonstrated, it is 

unknown whether the intravaginal approach represents 

true desensitization. Moreover, the duration of the protective 

effect is unknown. Graded intravaginal challenges 

have been less effective in women with localized seminal 

plasma–induced hypersensitivity reactions. 168 

Finally, it is very important to inform women with this 

problem that although seminal plasma hypersensitivity 

can cause significant stress on interpersonal relationships, 

it has no effect on their ability to get pregnant because it 

has not been associated with infertility. 166,168 

EXERCISE-INDUCED ANAPHYLAXIS 


45. Exercise-induced anaphylaxis is a form of physical 

allergy. Premonitory symptoms can include diffuse 

warmth, itching, and erythema. Urticaria generally 

ensues, with progression to confluence and often 

angioedema. Episodes can progress to include 

gastrointestinal symptoms, laryngeal edema, and/or 

vascular collapse. B 

46. Factors that have been associated with exerciseinduced 

anaphylaxis include medications (eg, aspirin 

or other nonsteroidal anti-inflammatory drugs) or 

food ingestion before and after exercise. C 

47. Patients with exercise-induced anaphylaxis might 

have a higher incidence of personal and/or family 

history of atopy. C 

48. Medications used prophylactically are not useful in 

preventing exercise-induced anaphylaxis. C 

49. If exercise-induced anaphylactic episodes have been 

associated with the ingestion of food, exercise 

should be avoided in the immediate postprandial 

period. C 

50. Patients with exercise-induced anaphylaxis should 

carry epinephrine and should wear and/or carry 

Medic Alert identification denoting their condition. 

They should have a companion with them when 

exercising. This companion should be versed in the 

use of an EpiPen. D 

Exercise-induced anaphylaxis is a form of physical 

allergy. Initial symptoms typically include diffuse 

warmth, pruritus, erythema, and urticaria, with progression 

to angioedema, gastrointestinal symptoms, fatigue, 

laryngeal edema, and/or vascular collapse. 169 Symptoms 

can persist for 30 minutes to hours. Transient loss of 

consciousness occurs in about a third of patients because 

of vascular collapse, whereas symptoms of upper respiratory 

tract obstruction occur in almost two thirds of 

patients.



MARCH 2005 

Jogging is a common activity precipitating attacks, but 

brisk walking, bicycling, racquet sports, skiing, and 

aerobic exercise might also be associated with such 

anaphylactic reactions. 170-172 In some patients exerciseinduced 

anaphylaxis will only occur after ingestion of 

a specific food or medication, such as aspirin or other 

nonsteroidal anti-inflammatory agents. Ingestion of these 

medications before exercise has been reported by 13% of 

affected individuals, 173 and their elimination might enable 

the patient to tolerate exercise. Exercise-induced anaphylaxis 

in the postprandial state, without identification of 

a specific food, occurred in 54% of the respondents in 

the same survey. Exercise-induced anaphylaxis has also 

been reported when a certain food is ingested after, as 

well as before, exercise (see food allergy parameter). In 

some patients specific foods have been shown to trigger 

these reactions. Elimination of these foods might allow 

the patient to exercise without anaphylaxis development. 

113,173-176 These patients might ingest these foods 

without anaphylaxis development if they do not exercise 

for 4 to 6 hours after eating them. Provocation of exerciseinduced 

anaphylaxis with a latency period after food 

consumption of 24 hours has been reported. 113 For this 

reason, it is prudent to individualize this management 

recommendation, particularly for individuals with postparandial 

(nonfood specific) exercise-induced anaphylaxis. 

It should also be clear that these foods might be 

ingested in the absence of exercise without difficulty. Thus 

both exercise and food ingestion are necessary to produce 

the reaction. Individuals who have exercise-induced 

anaphylaxis might have a higher incidence of a personal 

and/or family history of atopy. 170 

Exercise-induced anaphylaxis should be distinguished 

from other exercise-associated medical conditions. 

Arrhythmias or other isolated cardiovascular events related 

to exercise can be first seen with vascular collapse 

but are not associated with pruritus, erythema, urticariaangioedema, 

or upper respiratory obstruction. Patients 

who have exercise-induced anaphylaxis usually have 

wheezing in association with other symptoms of anaphylaxis, 

whereas patients who have exercise-induced bronchospasm 

have symptoms referable only to the lower 

respiratory tract. 

Cholinergic urticaria is a physical allergy characterized 

by the development of punctate (1-3 mm diameter), 

intensely pruritic wheals with erythematous flaring after 

an increase in core body temperature or stress. A minority 

of individuals with exercise-induced anaphylaxis have 

cutaneous lesions consistent with cholinergic urticaria. 

Classic cholinergic urticaria elicited by means of 

exercise, as noted above, is characteristically associated 

with an increase in the core body temperature without 

vascular collapse. However, in 2 of 16 patients who did 

not have punctate urticaria with increase of core body 

temperature, a syndrome resembling exercise-induced 

anaphylaxis was seen with punctate urticaria progressing 

to collapse. 171 Unlike cholinergic urticaria, simply 

increasing the core body temperature does not necessarily 

produce symptoms of exercise-induced anaphylaxis. 

In addition, these syndromes might rarely appear 

concurrently. 

A detailed history of symptoms associated with the first 

episode, as well as previous attacks, should be obtained. 

The history should include details concerning activities 

and ingestants that might precipitate an episode of 

anaphylaxis. Particular attention should be given to the 

antecedent use of aspirin or other nonsteroidal antiinflammatory 

agents, as well as any seasonality to the 

attacks. 

Prophylactic use of H 1 and H 2 antihistamines has 

generally not been effective in preventing exercise-induced 

anaphylaxis. 172 This is not without controversy, 

however, because reports have demonstrated in selected 

patients that antihistamine prophylaxis might help reduce 

the frequency and/or intensity of attacks. 177,178 

Early recognition of the prodromal manifestations of 

exercise-induced anaphylaxis is extremely important, with 

discontinuation of exercise at the earliest symptom. 

Modification of the exercise program by means of reduction 

in intensity or duration might be helpful in 

reducing episodes of exercise-induced anaphylaxis. 

Avoidance of exercise for 4 to 6 hours after eating is 

important in those individuals with documented exerciseinduced 

anaphylaxis after food ingestion. 

The emergency management of exercise-induced anaphylaxis 

is the same as that of anaphylaxis of other causes. 

The early administration of epinephrine is essential. 

Intravenous volume replacement, adequate oxygenation, 

and vigilance for upper airway compromise, with possible 

endotracheal intubation or tracheostomy, might also be 

required. H 1 blocking agents might be helpful but should 

not be relied on to abort the attack. 

Affected individuals should discontinue exercise at 

the earliest symptom consistent with exercise-induced 

anaphylaxis, usually pruritus and cutaneous warmth or 

erythema (flushing). Such individuals should be accompanied 

during exercise by a companion aware of their 

condition and capable of providing emergency assistance. 

Patients with exercise-induced anaphylaxis should 

have injectable epinephrine available at all times of 

exercise for self-administration in the event of symptoms. 

Any patient who has a history consistent with 

food-dependent exercise-induced anaphylaxis should be 

told not to exercise for 4 to 6 hours after eating. There is 

controversy as to whether all patients should similarly 

be told not to exercise postprandially, and the decision 

to do so in such instances remains a clinical decision for 

the physician. 

IDIOPATHIC ANAPHYLAXIS 


51. The symptoms of idiopathic anaphylaxis are identical 

to those of episodes related to known causes. C 

52. Patients with idiopathic anaphylaxis should receive 

an intensive evaluation, including a meticulous 

history to rule out a definite cause of the events. C




53. There might be a need for specific laboratory studies 

to exclude systemic disorders, such as systemic 

mastocytosis. This might include a serum tryptase 

measurement when the patient is asymptomatic, 

measurement of the ratio of b-tryptase to total 

tryptase during an event, and selective allergy skin 

testing. C 

In spite of efforts to define the pathogenesis of 

idiopathic anaphylaxis, we still do not know why patients 

experience these attacks. However, it is known that some 

might exhibit activated T cells shortly after episodes. 179 

The diagnosis of idiopathic anaphylaxis must be 

considered in those cases of anaphylaxis for which neither 

a causative allergen nor an inciting physical factor can be 

identified. Episodes can occur in both adults and children. 

180-184 

The presenting manifestations of idiopathic anaphylaxis 

are identical to those of any form of anaphylaxis. 2 

The vast majority of cases occur in adults, but there have 

been reports of episodes in children as well. Fatalities are 

rare but have occurred. 185 

The diagnosis of idiopathic anaphylaxis is a diagnosis of 

exclusion. Patients with idiopathic anaphylaxis should 

receive intensive evaluation, including a careful history 

with analysis of the events surrounding the development of 

the episodes. Clinical evaluation might indicate the need 

for specific laboratory studies, which might help to exclude 

an underlying systemic disorder, such as systemic mastocytosis. 

In addition, selective skin testing to foods (and if 

indicated to fresh food extracts) might be helpful. 103 

Because systemic mastocytosis can present as anaphylaxis 

of unknown cause, it is important to rule out this 

condition. The definitive test in this condition is a bone 

marrow biopsy, but serum tryptase levels can be helpful. 

In systemic mastocytosis, the baseline level (level obtained 

during an asymptomatic period) of total tryptase 

can be increased, whereas this is not the case in idiopathic 

anaphylaxis. In addition, the total b-tryptase to total 

tryptase ratio in systemic mastocytosis is usually greater 

than 20, whereas it is 10 or less in idiopathic anaphylaxis. 

186 

The treatment of the acute episode is the same as the 

treatment for any other form of anaphylaxis. Various 

protocols have been published to prevent recurrent 

episodes. These protocols have recommended the administration 

of H 1 and H 2 antagonists, b-agonists, antileukotrienes, 

and corticosteroids. All of these have proved 

successful in individual cases. The decision to institute 

preventive therapy is under the aegis of the treating 

physician, and the decision to use a preventive protocol 

and the medications used should be based on the 

frequency and severity of recurrent episodes. Patients 

should of course be supplied a kit for the self-injection of 

epinephrine and should be instructed in its use. They 

should also have Medic Alert identification because 

syncope can occur during these events. Fortunately, the 

symptoms of most patients improve with time, and many 

undergo complete remission. 59,187,188 

ANAPHYLAXIS AND ALLERGEN 

IMMUNOTHERAPY VACCINES 


54. There is a small risk of near-fatal and fatal anaphylactic 

reactions to allergen immunotherapy injections. 

C 

The rate of fatal anaphylaxis to allergen immunotherapy 

injections is approximately 1 in 2.5 million 

injections. 66,189-191 The rate of systemic reactions to 

allergen immunotherapy injections is approximately 

0.5%. 192 Thus although severe systemic reactions to 

allergen immunotherapy are uncommon, physicians 

and patients should be prepared for possible systemic 

reactions after immunotherapy. 

55. Patients with asthma, particularly poorly controlled 

asthma, are at higher risk for serious systemic 

reactions to allergen immunotherapy injections (C). 

Patients taking b adrenergic blocking agents are at 

higher risk for serious systemic reactions to allergen 

immunotherapy injections (B). 

Numerous studies suggest that patients with 

asthma, particularly poorly controlled asthma, are 

at higher risk for serious systemic reactions to 

allergen immunotherapy injections. 66,189,190,192-195 

However, allergic asthma is an important clinical 

indication for allergen immunotherapy. Caution is 

advised when administering allergen immunotherapy 

vaccine if asthma is severe or poorly controlled. 

Many practitioners measure the peak expiratory flow 

rate before administering the allergen vaccine. 

Patients receiving b-adrenergic blocking agents 

are at increased risk for more serious anaphylaxis. 

66,196 Thus b-adrenergic blockade is a relative 

contraindication for allergen immunotherapy. The 

benefits of allergen immunotherapy might outweigh 

the risk of anaphylaxis to the allergen vaccine for 

patients with hypersensitivity to stinging insects. 

56. Allergen immunotherapy vaccines should be administered 

only by health care professionals trained in 

the recognition and treatment of anaphylaxis, only in 

health care facilities with the proper equipment for 

the treatment of anaphylaxis, and in clinics with 

policies and procedures that minimize the risk of 

anaphylaxis. D 

Allergen immunotherapy vaccines should be administered 

only by health care professionals trained 

in the recognition and treatment of anaphylaxis. 

Allergen immunotherapy should be administered 

only in health care facilities with the proper equipment 

for the treatment of anaphylaxis. Such equipment 

includes epinephrine, oxygen, antihistamines, 

corticosteroids, vasopressors, oral airway, and equipment 

for the administration of intravenous fluids and 

medications. 

Allergen immunotherapy should be administered 

in clinics with policies and procedures that minimize 

the risk of anaphylaxis. These policies and procedures 

should reduce the risk of error, ensure proper



MARCH 2005 

training of personnel, and facilitate treatment of 

anaphylaxis (practice parameters). 

Most systemic reactions occur within 20 or 30 

minutes after allergen vaccine administration, although 

late reactions do occur. 193,197 To better 

recognize and treat anaphylactic reactions, patients 

should wait in clinic for 20 or 30 minutes after 

receiving an allergen immunotherapy injection. In 

addition, patients who are at increased risk of 

systemic reactions, particularly if they previously 

have had a systemic reaction more than 30 minutes 

after an injection, might need to carry injectable 

epinephrine. 198 These patients should be instructed 

in the use of epinephrine to treat a systemic reaction 

that occurs after they have left the physician’s office 

or other location where the injection was given. Such 

patients might also need to remain in the physician’s 

office more than 30 minutes after an injection. 

ANAPHYLAXIS TO DRUGS 


57. In most cases low-molecular-weight medications 

induce an IgE-mediated reaction only after combining 

with a carrier protein to produce a complete 

multivalent antigen. B A few drugs might elicit IgEmediated 

reactions without first combining with 

a carrier protein. 

58. Penicillin is the most common cause of drug-induced 


59. Penicillin spontaneously degrades to major and 

minor antigenic determinants, and skin testing with 

reagents on the basis of these determinants yields 

negative results in about 90% of patients with 

a history of penicillin allergy. B 

60. The negative predictive value of penicillin skin 

testing (for immediate-type reactions) is between 

97% and 99% (depending on the reagents used), and 

the positive predictive value is at least 50%. B 

61. The extent of allergic cross-reactivity between 

penicillin and cephalosporins is unknown but appears 

to be low. A small percentage of patients 

proved to have penicillin allergy through penicillin 

skin testing react to cephalosporin challenges. C 


negative penicillin skin test responses might safely 

receive cephalosporins. B 

63. Patients with a history of penicillin allergy who 

have positive penicillin skin test responses might 

(1) receive an alternate (non–b-lactam) antibiotic, 

(2) receive a cephalosporin through graded challenge, 

or (3) receive a cephalosporin through rapid 

desensitization. F 

64. Aztreonam does not cross-react with other b-lactams 

except ceftazidime, with which it shares a common 

R-group side chain. B 

65. Carbapenems should be considered cross-reactive 

with penicillin. C 

66. Diagnosis of IgE-mediated reactions to non–blactam 

antibiotics is limited by a lack of knowledge 

of the relevant allergenic determinants and/or metabolites. 

C 

67. Aspirin and nonsteroidal anti-inflammatory drugs are 

the second most common cause of drug-induced 

anaphylactic reactions. C 





drugs. D 





drugs. D 

Introduction 

Medications are a common cause of anaphylaxis. 

Drug-induced anaphylactic reactions are due to the 

development of drug-specific IgE antibodies during 

a preceding period of sensitization, typically during 

a previous course with the same or cross-reacting 

compound. The relatively low molecular weight of 

most drugs prevents them acting as complete antigens 

and inducing an immune response. In most cases 

medications must first combine with larger carrier 

molecules (eg, normal tissue or serum proteins) to 

form an immunogenic multivalent antigen. A few drugs 

might elicit IgE-mediated reactions without first combining 

with a carrier protein. Furthermore, most drugs 

are not chemically reactive in their native state. They 

need to undergo degradation or metabolism to produce 

reactive intermediates, which then covalently bind to 

host proteins and might lead to an allergenic response 

with the production of IgE antibodies. In some cases the 

allergenic determinants against which specific IgE is 

directed are known, such as with penicillin, and 

immediate type skin testing can be performed to aid 

in diagnosis. In most situations the allergenic determinants 

are unknown, and the diagnosis can only be made 

clinically. 

Some drugs are also capable of causing anaphylactoid 

reactions, which are due to direct nonimmunologic mast 

cell degranulation and do not require a preceding sensitizing 

period. Anaphylactoid reactions typically occur 

on initial exposure to a given drug and do not require 

a period of sensitization. Some medications are capable of 

causing both anaphylactic and anaphylactoid reactions, 

and because of this, it might be difficult to determine the 

cause of a given reaction. 

Antibiotics 

Penicillins. Penicillin is the most common cause of 

drug-induced anaphylaxis. 199 Under physiologic conditions, 

penicillin spontaneously degrades to reactive intermediates, 

which are broadly categorized into major and 

minor antigenic determinants. Because the immunochem-




istry of penicillin is well characterized, validated skin 

testing reagents representing the various allergenic determinants 

have been developed. In large-scale studies about 

90% of patients with a history of penicillin allergy have 

negative penicillin skin test responses. 200,201 

The positive predictive value of penicillin skin testing 

is 50% or greater. 201,202 Patients with positive penicillin 

skin test responses should receive an alternate antibiotic 

or undergo rapid desensitization if administration of 

penicillin is mandated. The negative predictive value of 

penicillin skin testing (for immediate-type reactions) is 

between 97% and 99%, depending on the skin test 

reagents used. 200,201,203 Patients with negative penicillin 

skin test responses might be safely treated with penicillin, 

and depending on the reagents used for skin 

testing, the therapeutic dose might be preceded by a test 

dose. 

Penicillin skin testing is safe in that the risk of inducing 

serious reactions during properly performed penicillin 

skin testing is comparable with the risk of other types of 

skin testing. 204 Penicillin skin testing itself might sensitize 

a very small proportion of patients. 205 Skin testing with 

semisynthetic penicillins, such as ampicillin or amoxicillin, 

is not standardized, and its predictive value is 

unknown. Penicillin skin testing should not be performed 

on patients with histories of severe non–IgE-mediated 

allergic reactions to penicillin, such as Stevens-Johnson 

syndrome or toxic epidermal necrolysis. 

Cephalosporins. Penicillins and cephalosporins share 

a common b-lactam ring, but the extent of allergic crossreactivity 

between the 2 families appears to be relatively 

low. Recent studies demonstrated no serious allergic 

reactions in large groups of patients with a history of 

penicillin allergy who were treated with cephalosporins. 

206,207 Patients in these retrospective studies, however, 

were given diagnoses of penicillin allergy on the basis of 

self-report. Patient history is known to be poor predictor of 

true penicillin allergy in that about 90% of patients with 

such a history turn out to have negative penicillin skin test 

responses and are able to tolerate penicillin. 200,201 A 

review of the published literature showed that among 

patients with a history of penicillin allergy who were 

proved to have positive penicillin skin test responses, only 

a small percentage of patients experienced an allergic 

reaction on being challenged with cephalosporins. 208 

However, fatalities have occurred when patients are not 

skin tested for penicillin and given cephalosporins. 209 

There are distant case reports of cephalosporin-induced 

anaphylactic reactions in patients with a history of 

penicillin allergy, 210,211 but these patients did not undergo 

penicillin skin testing, and early cephalosporins were also 

known to contain trace amounts of penicillin. 

Patients with a history of penicillin allergy who have 

negative penicillin skin test responses might receive 

cephalosporins because they are at no higher risk of 

experiencing allergic reactions. 212 In patients with a history 

of penicillin allergy who have positive penicillin skin 

test responses, the physician has 3 options: (1) administration 

of an alternate non–b-lactam antibiotic; (2) administration 

of a cephalosporin through graded challenge; or 

(3) desensitization to the cephalosporin. 212 

Other b-lactam antibiotics. Monobactams (aztreonam) 

do not-cross react with penicillin or other b-lactams, aside 

from ceftazadime, with which it shares an identical R- 

group side chain. 213 Therefore patients allergic to penicillin 

and other b-lactams (except for ceftazidime) might 

safely receive aztreonam. Similarly, patients allergic to 

aztreonam might safely receive other b-lactams, except 

for ceftazidime. 

Skin test studies indicate allergic cross-reactivity 

between carbapenems and penicillin. 214 Although clinical 

challenge studies in patients with penicillin allergy are 

lacking, carbapenems should be considered cross-reactive 

with penicillin. 

Non–b-lactam antibiotics. Non–b-lactam antibiotics 

appear to be uncommon causes of anaphylactic reactions. 

Diagnosis of IgE-mediated allergy to these drugs is more 

difficult because of lack of knowledge (in most cases) of 

the relevant metabolites and allergenic determinants. Skin 

testing with the native antibiotic can yield some useful 

information because if a nonirritating concentration is 

used, a positive result suggests the presence of drugspecific 

IgE antibodies. 215 However, the positive predictive 

value of such testing is unknown, and the negative 

predictive value is even less certain. Therefore diagnosis 

of anaphylactic reactions to non–b-lactam antibiotics is 

primarily based on the patient’s history. 

Aspirin and nonsteroidal anti-inflammatory drugs. 

Aspirin and nonsteroidal anti-inflammatory drugs 

(NSAIDs), including COX-2–specific inhibitors, have 

all been described to cause anaphylactic reactions. 

Aspirin and NSAIDs appear to be the second most 

common cause of drug-induced anaphylaxis (after penicillin). 

2,216 Anaphylactic reactions are unrelated to other 

reactions caused by these drugs, such as respiratory 

reactions and exacerbations of chronic idiopathic urticaria. 

217 Although the reactions are referred to as anaphylactic, 

in most cases efforts to detect drug-specific IgE 

antibodies (through skin testing or in vitro testing) have 

been unsuccessful. The reactions are assumed to be 

anaphylactic because generally patients are able to tolerate 

the drug for a period of time before a reaction ensues. 

Anaphylactic reactions to aspirin and NSAIDs appear to 

be medication specific in that allergic patients are able to 

tolerate other NSAIDs, but this is largely based on clinical 

experience rather than large-scale challenge studies. 217 

Cancer chemotherapeutic agents. Anaphylaxis to 

anticancer chemotherapy drugs is being encountered 

more frequently because use of these drugs has increased, 

218 particularly the platinum-containing drugs, 

such as cisplatinum and carboplatinum. In some instances 

the solvent in which these drugs are formulated 

(Cremophor-L) might cause an anaphylactoid reaction. 219 

Such anaphylactoid reactions to the drug product must be 

distinguished from anaphylaxis because of the drug. Skin 

testing to these agents is helpful in determining whether 

sensitivity exists and at what dose to proceed with 

sensitization if this is necessary. 220



MARCH 2005 

PREVENTION OF ANAPHYLAXIS 


70. Major risk factors related to anaphylaxis include, but 

are not limited to, prior history of such reactions, b- 

adrenergic blocker exposure, or atopic background. 

Atopic background might be a risk factor for venomand 

latex-induced anaphylaxis and possibly anaphylactoid 

reactions to radiographic contrast material 

but not for anaphylactic reactions to medications. 

71. Avoidance measures are successful if future exposure 

to drugs, foods, additives, or occupational 

allergens can be prevented. Avoidance of stinging 

and biting insects is also possible in many cases. 

Prevention of systemic reactions during allergen 

immunotherapy are dependent on the specific circumstances 

involved. 

72. Avoidance management should be individualized, 

taking into consideration factors such as age, 

activity, occupation, hobbies, residential conditions, 

access to medical care, and the patients’ level of 

personal anxiety. 

73. Pharmacologic prophylaxis should be used to prevent 

recurrent anaphylactoid reactions to radiographic 

contrast material, fluorescein, as well as to 

prevent idiopathic anaphylaxis. Prophylaxis with 

glucocorticosteroids and antihistamines markedly 

reduces the occurrence of subsequent reactions. 

74. Allergen immunotherapy with the appropriate stinging 

insect venom should be recommended for 

patients with systemic sensitivity to stinging insects 

because this treatment is highly (90% to 98%) 

effective. 

75. Desensitization to medications that are known to 

have caused anaphylaxis can be effective. In most 

cases the effect of desensitization is temporary, and 

if the medication is required some time in the future, 

the desensitization process must be repeated. 

76. Patient education might be the most important 

preventive strategy. Patients should be carefully 

instructed about hidden allergens, cross-reactions to 

various allergens, unforeseen risks during medical 

procedures, and when and how to use self-administered 

epinephrine. Physicians should educate patients 

about the risks of future anaphylaxis, as well as 

the benefits of avoidance measures. 

Radiographic contrast material (RCM) is used in more 

than 10 million radiologic examinations annually in the 

United States. The overall frequency of adverse reactions 

(including anaphylactoid and nonanaphylactoid reactions) 

is 5% to 8%, and life-threatening reactions occur with 

a frequency of less than 0.1% with conventional highosmolality 

RCM. 221 Among the 5% to 8% of patients who 

experience an adverse reaction to conventional RCM, 

most have minor reactions that require no specific 

treatment. 222 Moderate reactions, such as severe vomiting, 

diffuse urticaria, or angioedema, that require therapy 

occur in about 1% of patients who receive RCM. 

Although studies quote a wide spectrum of mortality, 

a reasonable estimate is one in every 75,000 patients who 

receive RCM. 223 With the recent development of lowerosmolality 

RCM, it appears that the overall risk of 

anaphylactoid reactions is decreased to about one fifth 

that of conventional RCM. 224 

The prevalence of adverse reactions to RCM appears to 

be greatest in patients 20 to 50 years of age. When adverse 

reactions occur, however, they are usually most severe in 

elderly patients. 

Patients who are at greatest risk for an anaphylactoid 

reaction to RCM are those who have experienced a previous 

anaphylactoid reaction to RCM. This risk can range 

from as low as 16% to as high as 44%. 225,226 Other 

patients at increased risk are asthmatic and atopic patients, 

as well as those receiving b-adrenergic blocking agents 

and patients with cardiovascular disease. 227-229 Anaphylactoid 

reactions have occurred when RCM is used 

for hysterosalpingograms, myelograms, and retrograde 

pyelograms. 225 With pretreatment and the use of lowerosmolarity 

agents, the risk can be reduced to approximately 

1%. 230 

Anaphylactoid reactions to RCM are independent of 

the dosage or concentration of RCM. Clinically, these 

reactions are identical to immediate hypersensitivity IgEmediated 

reactions (anaphylaxis) but do not appear to 

involve IgE or any other immunologic mechanism. 228 

In almost all instances, the infusion of RCM should be 

discontinued if symptoms begin. The treatment of anaphylactoid 

reactions to RCM is not different than the 

treatment of anaphylactic-anaphylactoid reactions in other 

settings. 

If the patient has a history of a prior anaphylactoid 

reaction to RCM, pretreatment regimens for prevention of 

repeat anaphylactoid reactions have consisted of oral 

glucocorticosteroids, H 1 and H 2 antihistamines, and other 

medications, such as ephedrine. A regimen that has been 

commonly recommended in the past has been 50 mg of 

prednisone given orally 13, 7, and 1 hours before 

administration of RCM; 50 mg of diphenhydramine given 

orally or intramuscularly 1 hour before the administration 

of RCM; and 25 mg of ephedrine given orally 1 hour 

before RCM administration. However, modifications to 

this regimen have included lower doses of glucocorticosteroids, 

oral rather than intramuscular diphenhydramine 

or other H 1 antihistamines, additional use of H 2 antihistamines, 

and/or exclusion of ephedrine. If the patient has to 

undergo an emergency radiographic procedure, an emergency 

pretreatment protocol that has been used successfully 

consists of 200 mg of hydrocortisone administered 

intravenously immediately and every 4 hours until the 

RCM is administered, and 50 mg of diphenhydramine 

administered intramuscularly 1 hour before RCM. 229 

In a setting in which RCM is being administered, 

a differential diagnosis might include adult respiratory 

distress syndrome or noncardiogenic pulmonary edema. 

In at least 2 reports of failure of standard pretreatment 

regimens to prevent anaphylactoid reactions, the initial 

reactions were apparently caused by noncardiogenic




pulmonary edema rather than anaphylactoid reactions. 

231,232 In addition, RCM can cause intravascular 

volume expansion and precipitate cardiogenic pulmonary 

edema in patients with ischemic cardiac disease. 

Anaphylactoid reactions in patients receiving b-adrenergic 

blocking agents might require more intensive and 

prolonged treatment. Therefore a careful benefit-risk 

assessment should be made in patients receiving b- 

adrenergic blocking agents if there is a pre-existing 

increased risk of having an anaphylactoid reaction to 

RCM. There is no evidence that the inorganic iodine levels 

present in seafood are related to adverse events from RCM. 

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reference article





reference article

Date _______________ 

______________ CLINIC 

Standard Operating Procedures 

IMMUNOTHERAPY 

1. Purpose: This operating instruction provides procedures to follow when administering 

immunotherapy. 

2. Responsibility: All assigned Clinic personnel. 

3. References: 

a. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol. 2003 

Jan;90(1 Suppl 1):1-40. 

b. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy 

Clin Immunol. 2005 Mar;115(3 Suppl 2):S483-523 

4. General: 

a. Immunotherapy (AIT) is initiated by the prescribing Allergist whose name and contact 

information will be readily available to all clinic staff. By design, the patient will arrive at the 

clinic with an allergen extract kit (allergy shot vials) that has originated from another 

facility/provider. The vials and accompanying documentation will be reviewed by the ____ 

Clinic’s Physician-In-Charge assuring adherence to established standards to ensure 

appropriateness and safety before the patient receives his/her AIT. The prescribing Allergist is 

responsible for providing AIT extracts labled IAW Ref. (a), protocols for AIT administration and 

alteration in dosing in the event of an adverse reaction or missed doses, and for providing point 

of contact information. Allergen immunotherapy can be temporarily withheld without placing 

the patient at undue risk. 

b. An Allergy Treatment Record will be maintained on all patients receiving AIT in the 

Clinic. All AIT injections, reactions (immediate and delayed), and alterations in dosing will be 

recorded in this record. This record will contain the signed informed consent, Problem Summary 

List, AIT prescription, AIT administration instructions, AIT Adjustment protocol, name and 

contact information of the prescribing Allergist. 

c. Prior to beginning AIT, all patients or, in the case of a minor, the parent or legal guardian, 

will review/complete and sign all required forms including the informed consent, patient 

instruction sheet, and the problem list. In general, allergy shots will not be administered to 

patients on Beta blockers. Any patient on Beta blockers will have their shots withheld and will 

be referred to the Physician-In-Charge for further consultation with the prescribing Allergist. 

d. All persons under 18 years of age must be accompanied by a parent/legal guardian. 

5. Patient Instructions: 

a. The Clinic’s nurse/technician will instruct the patient about what is expected when AIT is 

begun. 

b. The patient will be informed that the allergen extract(s) will be maintained at the ________ 

Clinic. Patients will not be allowed to maintain their allergy extracts in their home.

c. The patient will be counseled concerning the possibility for adverse reactions and of the 

signs and symptoms preceding possible adverse reactions they may have after receiving their 

immunotherapy. The patient/guardian will sign the informed consent. 

d. The dosage schedule in the patient's prescribed course of AIT will be discussed. 

e. The nurse/technician must physically examine the injection site prior to the patient 

departing the clinic. The allotted time period for waiting after injection is a minimum of thirty 

minutes. If the use of the toilet is necessary before the end of the 30 minute wait, the 

nurse/technician must be informed, and only the handicapped (distress alarmed) toilet is to be 

used. Failure to remain in the patient waiting area for the prescribed time after injection may 

result in the termination of immunotherapy. 

6. Immunotherapy Procedures: 

a. Retrieve the patient's allergy record. 

b. Retrieve the patient's extract from the refrigerated storage. Ensure that the extract pulled is 

for the right patient, that the vial content agrees with what is ordered on the Allergen Extract 

Prescription and is listed on the injection record. 

c. Question the patient about any delayed local reaction or systemic symptoms. Make the 

appropriate adjustment in the dosage according to the provided protocol for that patient. If the 

patient states (s)he had a delayed systemic reaction, record this on the Immunotherapy 

Administration Form. An appointment with the Physician-In-Charge is necessary before 

proceeding with immunotherapy. 

d. Check dosage advancement schedule for the amount of extract to be given. Document the 

dosage in the appropriate column on the Immunotherapy Administration Form. The 

nurse/technician administering the AIT will annotate the date and time of administration, the 

injection site (R or L), and initial the form. 

e. Gently shake the vial before using. Draw up the dosage required using a tuberculin/1cc 

syringe and a 26 - 27 gage needle. Ensure that the pertinent information is checked; confirm this 

information with the patient. 

(1) Right patient 

(2) Right extract 

(3) Right interval 

(4) Right dosage 

(5) Right method, route, and technique 

f. Administer the allergy injection. Give the injection subcutaneously into the posterolateral 

surface of the middle third of the upper arm. Always pull back on the plunger before the allergy 

extract is administered; if blood returns, withdraw the needle and use the other arm. Avoid 

massaging the injection site to lessen unduly rapid absorption of the allergen. 

g. Instruct the patient to wait 30 minutes in the clinic patient waiting area and to report any 

problems immediately. 

h. Check the injection site(s) and annotate the appearance of the injection site(s) prior to the 

patient leaving the clinic. 

i. Document all reactions in the patient's allergy record. Notify the Physician-In-Charge if 

there are recurrent local reactions preventing advancement of the patient’s AIT, any systemic 

reactions, or other problems affecting administration of immunotherapy. 

j. Unless reactions dictate a change in dosage and/or the Physician-In-Charge (in consultation 

with the prescribing Allergist) annotates otherwise, the nurse/technician will always follow the

prescribed schedule on the Allergen Extract Prescription. Any questions will be directed to the 

Physician-In-Charge before administering the shot. 

k. No patient will be permitted to administer their own injections. 

7. Anaphylaxis Guidelines 

a. In the event of signs or symptoms of anaphylaxis in a patient receiving AIT, the following 

guidelines will be initiated: 

(1) Administer 0.3 cc of 1:1,000 Epinephrine IM (lateral thigh) if the patient 

complains of spreading hives, throat or chest tightness, cough, wheeze, vomiting, 

abdominal cramping, or lightheadedness (hypotension). 

(2) Alert the medical provider (physician). 

(3) Establish/maintain the airway. 

(4) If difficulty in breathing occurs, administer oxygen 6-8 liters/min. via face mask. 

(5) Monitor blood pressure, heart rate, O2 saturation (Pulse Oxymetry), and level of 

consciousness every 5 minutes until stable. 

(6) If cardiopulmonary comprominse persists after 10-15 minutes have elaspsed since 

epinephrine was given, repeat 0.3 cc of 1:1,000 epinephrine (IM). Epinephrine may 

be repeated every 10-15 minutes if symptoms do not diminish or cease. 

(7) If a second dose of epinephrine is required, notify the next echelon of care/EMS 

and expidite the transfer of the patient to a higher level of care. 

b. This guideline is based upon the recognition of, but not limited to the following signs 

and/or symptoms: 

(1) Generalized hives. 

(2) Wheezing or chest tightness. 

(3) Stridor. 

(4) Erythema (redness of the face, trunk, and/or extremities). 

(5) Edema (swelling of the face, tongue, and/or throat). 

(6) Apprehension, weakness, or syncope (fainting). 

(7) Nausea, vomiting, or abdominal cramping. 

c. Any systemic reaction to AIT will be annotated in the patient’s record. The patient will 

undergo re-assessment by an Allergist before AIT is resumed. 

8. Training/Certification: 

Those providing allergen immunotherapy in the _____ Clinic will be trained personnel. It is 

highly desirable that physicians, nurses, and technicians be certified by either the US Air Force’s 

Introduction to Allergy/Allergy Extender Program or through the US Army’s Walter Reed 

Immunization Technicians’ Course. If this is not operationally feasible, then for the purpose of 

providing allergen immunotherapy only, the Navy’s “Remote Site Allergen Immunotherapy 

Administration Course” (via electronic media) coupled with diligent oversight by the Clinic’s 

Physician-In-Charge must suffice. 

All personnel involved in the administration of allergen immunotherapy will be expected to 

participate in annual refresher training. Documentation of annual competency assessment and 

quarterly allergy treatment record review is mandatory.





reference article


JENNIFER L. HUGGINS, M.D., and R. JOHN LOONEY, M.D. 

University of Rochester School of Medicine and Dentistry, Rochester, New York 

Allergen immunotherapy (also called allergy vaccine therapy) involves 

the administration of gradually increasing quantities of specific allergens 

to patients with IgE-mediated conditions until a dose is reached 

that is effective in reducing disease severity from natural exposure. 

The major objectives of allergen immunotherapy are to reduce 

responses to allergic triggers that precipitate symptoms in the short 

term and to decrease inflammatory response and prevent development 

of persistent disease in the long term. Allergen immunotherapy 

is safe and has been shown to be effective in the treatment of stinginginsect 

hypersensitivity, allergic rhinitis or conjunctivitis, and allergic 

asthma. Allergen immunotherapy is not effective in the treatment of 

atopic dermatitis, urticaria, or headaches and is potentially dangerous 

if used for food or antibiotic allergies. Safe administration of allergen 

immunotherapy requires the immediate availability of a health care 

professional capable of recognizing and treating anaphylaxis. An 

observation period of 20 to 30 minutes after injection is mandatory. 

Patients should not be taking beta-adrenergic blocking agents when 

receiving immunotherapy because these drugs may mask early signs 

and symptoms of anaphylaxis and make the treatment of anaphylaxis 

more difficult. Unlike antiallergic medication, allergen immunotherapy 

has the potential of altering the allergic disease course after three 

to five years of therapy. (Am Fam Physician 2004;70:689-96,703-4. 

Copyright© 2004 American Academy of Family Physicians.) 

Allergen immunotherapy involves 

subcutaneous injections of gradually 

increasing quantities of specific 

allergens to an allergic patient 

until a dose is reached that will raise the 

patient’s tolerance to the allergen over time, 

thereby minimizing symptomatic expression 

of the disease. Because the proteins and glycoproteins 

used in allergen immunotherapy 

are extracted from materials such as pollens, 

molds, pelt, and insect venoms, they were 

originally called allergen extracts. In 1998, 

the World Health Organization (WHO) proposed 

the term “allergen vaccine” to replace 

“allergen extract,” because allergen immunotherapy 

is an immune modifier just as 

vaccines are. 1 

The efficacy of allergen immunotherapy has 

been known since 1911, when Noon injected 

an extract of grass pollen into a person in 

England whose allergic symptoms coincided 

with the pollination of grass. 2 Since then, 

controlled studies have shown that allergen 

immunotherapy is effective in patients with 

allergic rhinitis, allergic conjunctivitis, allergic 

asthma, and allergic reactions to Hymenoptera 

venom. 3-6 Patients with one or more 

of these diagnoses are considered for immunotherapy 

if they have well-defined, clinically 

relevant allergic triggers that markedly 

affect their quality of life or daily function, 

and if they do not attain adequate symptom 

relief with avoidance measures and pharmacotherapy. 

Despite proven efficacy, the 

exact mechanism of allergen immunotherapy 

remains unknown. 

Selection of Patients 

To make a definitive diagnosis of allergy, IgEmediated, 

type I, immediate-hypersensitivity 

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use of one individual user of the Web site. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

skin testing typically is performed by scratching 

diluted allergen into the skin surface or 

by injecting it intradermally. A positive skin 

test reaction reflects the presence of specific 

IgE antibodies to the tested allergen, and a 

correlation of the specific IgE 

antibodies with the patient’s 

Type 1 immediate-hypersensitivity 

skin testing with 

symptoms, suspected triggers, 

and allergen exposure is definitive. 

In vitro, allergen-specific 

clinical correlation is used 

to diagnose a specific IgEmediated 

allergy. 

immunoassays to detect serum 

IgE antibodies are less sensitive 

than skin testing but may be 

used in patients with skin diseases that would 

obscure skin testing results or in those who 

cannot stop taking medications that suppress 

the skin test response. The circumstances in 

which allergen immunotherapy is particularly 

useful are summarized in Table 1. The 

allergens for which immunotherapy is known 

to be effective are Hymenoptera venom, 5 pollens, 

5,6 cat dander, 7 dust mites, 8 cockroaches, 9 

and fungi. 10 Allergy immunotherapy is not 

efficacious for atopic dermatitis, urticaria, 

or headaches, and cannot be used for food 

allergies because the risk of anaphylaxis is 

too great. 

The Authors 

Benefits 

Durham and colleagues 11 conducted a randomized, 

double-blind, placebo-controlled 

trial to look at effects in patients who had 

JENNIFER L. HUGGINS, M.D., is a fellow in allergy/immunology and rheumatology 

at the University of Rochester School of Medicine and Dentistry, Rochester, 

N.Y. She received her medical degree from the University of Kansas School 

of Medicine, Kansas City, Kan. Dr. Huggins completed postdoctoral training 

in pediatrics at Baylor University in Houston, and in internal medicine at the 

University of Rochester School of Medicine and Dentistry. She is board-certified 

in internal medicine and pediatrics. 

R. JOHN LOONEY, M.D., is associate professor of medicine and director of the 

Allergy and Immunology training program at the University of Rochester School 

of Medicine and Dentistry, where he also received his medical degree and 

completed postdoctoral training in internal medicine, infectious diseases, and 

immunology. He is board certified in infectious diseases, allergy and immunology, 

and rheumatology. 

Address correspondence to Jennifer L. Huggins, M.D., University of Rochester, 

Allergy/Immunology/Rheumatology Fellow, 601 Elmwood Ave., Box #695, 

Rochester, NY 14642 (e-mail: Jennifer_Huggins@urmc.rochester.edu) Reprints 

are not available from the authors. 

TABLE 1 

Best Indications for Immunotherapy 

Allergic rhinitis, conjunctivitis, or allergic 

asthma 

History of a systemic reaction to Hymenoptera 

and specific IgE antibodies to Hymenoptera 

venom 

Patient wishes to avoid the long-term use or 

potential adverse effects of medications 

Symptoms are not adequately controlled by 

avoidance measures or medications 

Cost of immunotherapy will be less than cost 

of long-term medications 

received three to four years of immunotherapy. 

They were able to demonstrate a 

marked reduction in allergy symptom scores 

and antiallergic medication usage, as well 

as an alteration in the natural course of 

allergic disease. Preliminary reports suggest 

that immunotherapy for allergic rhinitis 

may reduce the risk for later development 

of asthma in children. 12,13 In addition, early 

treatment with allergen immunotherapy in 

children who were sensitive only to house 

dust mites reduced development of sensitivity 

to other allergens. 14 In contrast to 

the use of antiallergic medication, allergen 

immunotherapy has the potential to alter 

the natural course of allergic disease and 

prevent progression or development of multiple 

allergies. Consequently, many allergists 

have suggested its use earlier in the course of 

allergic disease. 

In 2000, the Immunotherapy Committee 

of the American Academy of Allergy, 

Asthma, and Immunology (AAAAI) provided 

a five-year cost comparison of medication 

usage and single-injection allergen 

immunotherapy for allergic rhinitis. The 

cost of medications is much greater than that 

of single-injection immunotherapy. Longterm 

costs deriving from the morbidity and 

complications of allergic diseases are not 

established, but allergies usually begin early 

in life and persist if not treated with allergen 

immunotherapy. A reasonable assumption is 

that allergen immunotherapy dramatically 

lowers the cost of treating allergic diseases. 

690 American Family Physician www.aafp.org/afp Volume 70, Number 4 August 15, 2004


Standardization, Storage, and 

Mixing of Allergen Vaccines 

Ideally, vaccines should be standardized 

with a defined potency and labeled with 

a common unit. 15 Such standardization 

would eliminate the variability in vaccines 

and allow for safer and more effective dosing. 

The Bioequivalent Allergy Unit (BAU), 

which is assigned by the U.S. Food and Drug 

Administration based on quantitative skin 

testing performed on a reference population 

of allergic patients known to be highly skintest–reactive 

to that allergen, reflects clinical 

potency and is currently used for standardization 

of vaccines. 

Standardized allergens available in the 

United States include cat dander, grass pollens, 

dust mites, and short ragweed pollen. 

Unstandardized vaccines may vary widely 

in biologic activity based on manufacturer 

and by lot, depending on the allergen 

content of the raw material and the conditions 

of extraction. Furthermore, the labeling 

conventions of Protein Nitrogen Units 

(PNUs) or weight by volume (wt/V) reflect 

protein content but not allergenic potency. 

Research is underway on new technologies 

for DNA and protein analysis that would 

allow an allergen vaccine to be characterized 

by the content of the major allergen 

and the consistency of each lot to be monitored 

accurately. 

Vaccine strength is maintained by a number 

of procedures, including lyophilization 

and reconstitution with a stabilizer that 

TABLE 2 

Factors Affecting Allergen 

Vaccine Potency 

Time (always check the expiration date) 

Storage temperature 

Concentration 

Volume of the vial 

Type and number of allergens in the vial 

Diluent used 

Preservatives added 

Information from references 16 and 17. 

contains an antimicrobial agent. A volume 

effect can occur as a result of adherence of 

the allergen to the vial surface; the larger 

the surface area of the vial, the more allergen 

is lost. Glycerol and human serum albumin 

(0.03 percent) are used to 

mitigate the volume effect. Glycerol 

has the added advantage of 

The maintenance concentrate 

is the dose of 

being an antimicrobial agent. At 

vaccine considered to be 

a concentration of 50 percent, 

therapeutically effective 

glycerol inhibits enzymatic degradation 

of the allergens, but 

for each of its constituent 

components. 

it may be irritating at this concentration. 

The combination of 

human serum albumin as a stabilizer and 

phenol as an antimicrobial additive often is 

used. However, human serum albumin typically 

is refused by patients who are Jehovah’s 

Witnesses. 

Vaccines must be stored properly to preserve 

biologic activity (Table 2). 16,17 Vaccines 

should be refrigerated at 4°C (39.2°F) because 

storage at ambient room temperature results 

in loss of potency within weeks, with degradation 

occurring within days at higher 

temperatures. Critical to vaccine potency is 

the dilution effect: highly concentrated vaccines 

are more stable than dilute vaccines. 18 

The vaccine label should always be checked 

for the expiration date. 

For immunotherapy to be effective, an 

optimal dose of each allergen must be 

determined. When a patient has multiple 

sensitivities caused by related and unrelated 

allergens, vaccines containing mixtures 

of these allergens may be prescribed. 

As multiple vaccines are mixed, not only 

will the concentration of each allergen be 

decreased, but certain allergens will interact. 

For example, fungi, dust mites, insect 

venoms, and cockroach have high proteolytic 

enzyme activity and may be combined 

with each other but should not be mixed 

with other allergens. Insect venoms usually 

are given alone. 

Vaccine Administration 

The maintenance concentrate is the dose of 

vaccine that is considered to be therapeutically 

effective for each of its constituent 

components. The maintenance concentrate 

August 15, 2004 Volume 70, Number 4 www.aafp.org/afp American Family Physician 691

TABLE 3 

Required Information on Vaccine Vials 

Patient’s name, date of birth, and patient number 

Generalized content of the vaccine* 

Expiration date 

Dilution from maintenance concentrate in volume per volume (v/v) 

Number identifier† 

Appropriate colored caps‡ 

*—Specific contents of each vaccine should be written on a standardized form similar to 

the “Immunotherapy Mix Components” form found online at: http://www.aaaai.org. 

†—In the numbering system, the maintenance concentrate should always be number 1; 

subsequent dilutions should be numbered from the maintenance concentrate. 

‡—The color-coding system should always start with red for the maintenance concentrate 

followed by yellow, blue, green, and silver, in that order. 

Information from reference 18. 

should be determined by a prescribing allergist 

and clearly written on a standardized 

Maintenance Concentrate Prescription Form 

(available online at http://www.aaaai.org). An 

optimal maintenance dose in the range of 5 to 

20 mcg of major allergen per injection correlates 

with efficacy. Maintenance concentration 

is usually achieved by administering 

between 18 and 27 serial dose increments 

at weekly intervals (a build-up schedule 

written by the allergist) until the maintenance 

concentrate is achieved. In a typical 

build-up schedule, the patient will reach 

the maintenance concentrate in six months, 

but patients with a higher degree of allergen 

sensitivity may require a longer build-up 

TABLE 4 

Sample Adjustment to Immunotherapy Following 

Interruption of Dosage Schedule 

Weeks from last injection 

Dosage adjustment* 

6 Repeat previous dose. 

7 Drop back two increments. 

8 Drop back three increments. 

9 Check with allergist. 

NOTE: Patients on maintenance therapy (injections every three to four weeks). 

Increments are provided by the allergist. 

*—Patients must return weekly until they reach the maintenance concentrate again. 

phase. The maintenance dose usually is 

administered every three to four weeks, and 

maximum benefit typically is achieved in 

four to five years. Some patients will note 

early improvement in their symptoms, but 

long-term benefit seems to be related to the 

cumulative dose of vaccine given over time. 

To reduce administration errors, the 

AAAAI recommends a universal, consistent, 

and redundant labeling system for every vial 

(Table 3). 18 

Some circumstances warrant adjustments 

in the dosage schedule. In these situations, 

communication between the family physician 

and the prescribing allergist is encouraged 

to increase safety and avoid unexpected 

reactions. If the interval between injections is 

prolonged (Table 4), the dose of vaccine must 

be reduced; when a new maintenance vial 

is obtained from the manufacturer, a dose 

reduction of 50 percent is recommended. 

For example, 0.5 mL of 1:500 V/V dilution 

should be reduced to 0.25 mL of 1:500 V/V 

dilution. The dose is increased every seven to 

14 days until the maintenance dose is reached 

again. No evidence-based guidelines for dose 

adjustments following local, systemic, or 

delayed reactions are available, and the allergist 

should provide treatment suggestions for 

each of these reactions (Table 5). 

Listed in Table 6 are items that should be 

reviewed before injecting the patient. The 

desired injection site is the outer aspect of 

the upper arm, midway between the shoulder 

and the elbow in the groove between the 

deltoid and triceps muscles. The injection 

is given subcutaneously, preferably with a 

26- or 27-gauge needle; if blood is aspirated 

initially, the vaccine should not be 

injected. The plunger on the syringe should 

be depressed at a rate that does not result 

in wheal formation or excessive pain. Mild 

pressure should be applied to the injection 

site for about one minute, and a bandage may 

be placed if needed. Rubbing the injected 

area causes rapid absorption and should be 

avoided. 

Safety Issues 

Allergen immunotherapy is safe, but the 

potential for an adverse reaction is always 



present. Although these reactions are rare, 

they can be life-threatening. In 1924, Lamson 

reported the first case of death following 

immunotherapy. 19 A statistical review of 

the literature about systemic reactions following 

allergen immunotherapy by Lockey 

and colleagues 20 found that severe systemic 

reactions occurred in less than 1 percent of 

the patients receiving conventional immunotherapy 

in the United States. From 1985 

to 1993 in the United States, 52.3 million 

administrations of immunotherapy 

resulted in 35 deaths. These numbers equate 

to a mortality incidence of less than one per 

1 million. 21 

Patients with medical conditions that 

reduce their ability to survive systemic allergic 

reactions are not candidates for allergen 

immunotherapy. Examples of such conditions 

include chronic lung disease with a 

forced expiratory volume in one second 

(FEV 1 ) of less than 50 percent, beta-blocker 

or angiotensin-converting enzyme (ACE) 

inhibitor therapy, unstable angina or myocardial 

infarction, uncontrolled hypertension, 

and major organ failure. Allergen immunotherapy 

also cannot be used in patients who 

would have difficulty reporting signs and 

symptoms of a systemic reaction, such as 

children younger than three or four years. 

In addition, beta-blocker or ACE-inhibitor 

therapy may mask early signs of anaphylaxis. 

Patients who have not been compliant 

with other forms of therapy are not likely 

to be compliant with immunotherapy, thus 

necessitating frequent alteration in dosage 

schedules and increasing the chance for 

errors. Patients should be assessed with each 

injection for newly acquired risks that may 

not have been present at the beginning of 

allergen immunotherapy. 

Patients with severe, poorly controlled 

asthma are at higher risk for systemic reactions 

to immunotherapy injections than patients 

with stable, well-controlled asthma. 20 Some 

physicians measure peak expiratory flow 

readings in all patients with asthma before 

administering allergen immunotherapy and 

withhold injections if the reading is less than 

70 percent of predicted. Other measures that 

should be performed to minimize the risk of 

adverse reactions to allergen immunotherapy 

are listed in Table 6. 

Because a systemic reaction occurring 

during pregnancy may produce severe fetal 

hypoxia or precipitate premature uterine 

contractions, immunotherapy should not 

be initiated during pregnancy. 18 However, 

immunotherapy can be maintained during 

pregnancy provided the patient is tolerating 

and benefiting from the injections. 

TABLE 5 

Potential Adverse Reactions to Allergy Vaccines 

and Suggested Treatment 

Adverse reaction 

Local reaction 

Common, occurs at 

the injection site, IgEmediated, 

manifested 

primarily by wheal and 

flare with pruritus, 

usually begins 20 to 30 

minutes after injection 

Large local induration 

Occurs at injection site, 

IgG complex (Arthrus) 

reaction, manifested by 

pain, tenderness, and 

hard swelling 

Systemic reactions 

Low incidence (< 0.05 

to 3.5 percent), 

manifestations can 

include: urticaria, 

angioedema, increased 

respiratory symptoms 

(nasal or pulmonary), 

increased ocular 

symptoms, and 

hypotension. 

Delayed reaction 

May be local or systemic 

IM = intramuscular; IV = intravenous. 

Suggested treatments 

Local cold pack; oral antihistamine; topical 

steroid; if reaction recurs, consider 

premedication with an antihistamine; rinse 

the syringe with diphenhydramine (Benadryl) 

or epinephrine before vaccine; consult 

allergist for dose adjustment 

Oral steroids, nonsteroidal anti-inflammatory 

drug, oral antihistamine 

Tourniquet above injection site; aqueous 

epinephrine 1:1,000 IM: (adults, 0.3 mL; 

children, 0.01 mL per kg; readminister every 

10 minutes if systemic symptoms persist, up 

to three times); diphenhydramine, IM or IV 

(adults, 25 to 50 mg; children, 1 to 2 mg 

per kg); histamine H 2 receptor blockers IV or 

orally for epinephrine-resistant hypotension; 

IV fluids or vasopressors, as needed; 

consider glucagon if patient is taking a 

beta blocker; consult allergist before any 

additional doses. 

Oral antihistamine (liquid is preferred); 

prednisone, 5 to 20 mg orally every 12 hours 

for two doses (depending on the patient’s 

weight); epinephrine is not helpful; consult 

allergist for dose adjustment. 


TABLE 6 

Checklist for Safe Vaccine Administration 

Identify the patient. 

Analyze the health status of the patient before every injection. The risk of 

anaphylaxis is increased if the patient: 

Has a fever, is acutely ill, or has a newly reported illness. 

Is having an exacerbation of asthma or respiratory difficulties. 

Is having an exacerbation of allergy symptoms. 

Is taking new medications, namely beta blockers and angiotensinconverting 

enzyme inhibitors. 

Inquire about any reactions occurring with the previous injection and 

consult with the allergist about appropriate adjustments to therapy. 

Institute a checklist to reduce clerical and nursing errors: 

Identify the patient’s record by name and, preferably, photograph. 

Check the identity, expiration date, concentration, and cap color of the 

vaccine vial. 

Record the proper dose of vaccine on the immunotherapy record and 

the arm used to administer the vaccine. Alternate arms. 

Draw the proper dose. 

Administer the vaccine only after the patient’s identity has been 

rechecked by comparing the patient’s name with the name on the vial 

from which the vaccine is taken. 

Remind the patient to remain in the office for 30 minutes following the 

injection. Check the injection site before the patient leaves. 

Strenuous exercise one hour before and two hours after the injection 

increases the chance of anaphylaxis and should be avoided. 

Document any adverse reactions. 

TABLE 7 

Equipment and Medications 

Needed to Treat Anaphylaxis 

Stethoscope 

Tourniquet 

Equipment for monitoring blood pressure 

Large-bore (14-gauge) IV catheter 

Epinephrine, 1:1,000 for IM injection 

Oxygen 

Oral airway 

Equipment for administering IV fluids 

H 1 and H 2 antihistamines for injection 

Corticosteroid for IV injection 

Vasopressor 

Glucagon for use in patients receiving betaadrenergic 

blocking agents 

IV = intravenous; IM = intramuscular. 

The immunotherapy dose should not be 

increased in a pregnant patient until after 

delivery. 

Anaphylaxis is the most serious risk 

related to allergen immunotherapy. The vaccines 

must be administered in a setting with 

trained professionals who are equipped to 

recognize and treat anaphylaxis 22 (Table 7). 

A retrospective study found that most systemic 

reactions occurred within 30 minutes 

of injection. 23 Hence, the current recommendation 

is to allow at least 20 to 30 minutes of 

observation following an injection. Patients 

who have had a systemic reaction after 

more than 30 minutes following an injection 

require longer observation; in addition, they 

should be given injectable epinephrine to 

carry and instructions about how to use it. 

Nonetheless, reactions may occur without 

warning signs or symptoms, and documentation 

of informed consent must be obtained 

from the patient (Figure 1). 

Assessment of Immunotherapy Efficacy 

After one year on a maintenance dose, clinical 

improvement should be apparent. 24 The 

therapy often may be discontinued after three 

to five years because by then the disease course 

has been altered. 11 Evaluation by an allergist, 

at least annually, should include monitoring of 

adverse reactions, assessment of efficacy, reinforcement 

of compliance and safe administration 

of immunotherapy, and determination of 

whether adjustments in the dosing schedule or 

allergen content are necessary. 

The authors indicate that they do not have any conflicts 

of interest. Sources of funding: none reported. 

The authors thank Barbara J. Kuyper, Ph.D., and David M. 

Siegel, M.D., for assistance with the manuscript. 

REFERENCES 

1. Allergen immunotherapy: therapeutic vaccines for allergic 

diseases. Geneva: January 27-29, 1997. Allergy 

1998;53(44 suppl):1-42. 

2. Noon L, Cantab BC. Prophylactic inoculation against 

hay fever. Lancet 1911;1:1572-4. 

3. Pichler CE, Helbling A, Pichler WJ. Three years of specific 

immunotherapy with house-dust-mite extracts in 

patients with rhinitis and asthma: significant improvement 

of allergen-specific parameters and of nonspecific 

bronchial hyperreactivity. Allergy 2001;56:301-6. 



Informed Consent 

Date: 

Patient name: 

Date of birth: 

I have been made aware by __________________________________________________ of the 

following: 

During the build-up phase of my allergen immunotherapy (allergy injections), I agree to come 

every seven to 10 days to safely increase my vaccines at every visit. If more than 10 days have 

passed since my last visit, my dose will be adjusted as necessary. 

Local reactions are not uncommon. I will monitor the size of the reactions and the length of 

time they last and inform the medical staff. 

Generalized reactions occur less commonly and may include symptoms of itching of the skin; 

sudden itching of the nose, mouth, ears, and throat; hives, wheezing, coughing, tightness of 

the chest, plugging of the nose, or sneezing. Although rare, serious reactions may result in 

significant respiratory reactions or anaphylactic shock, which may be life-threatening. A serious 

reaction usually occurs within 30 minutes after an injection. 

I agree to remain in the medical facility for 30 minutes after my injections and to immediately 

report any symptoms to the medical staff. 

I have had the opportunity to have all of my questions about allergen immunotherapy 

answered to my satisfaction. I have been informed of the potential risks and benefits of 

allergen immunotherapy and available alternative therapies. 

Signature of patient or guardian: _____________________________________________________ 

Date: _________________________ 

Signature of witness: _______________________________________________________________ 

Date: _________________________ 

Figure 1. Example of informed consent form for allergen immunotherapy. 


Strength of Recommendations 

Key clinical recommendation SOR labels References 

Allergen immunotherapy is effective in patients with allergic rhinitis, 

allergic conjunctivitis, allergic asthma, and allergic reactions to 

Hymenoptera venom. 

A 3, 4, 5, 6 

The allergens for which immunotherapy is known to be effective are 

Hymenoptera venom, pollens, cat dander, dust mites, cockroach, 

and fungi. 

In patients who had received three to four years of immunotherapy, 

a marked reduction in allergy symptom scores and antiallergic 

medication usage, as well as an alteration in the natural course of 

allergic disease, was demonstrated. 

Immunotherapy for allergic rhinitis may reduce the risk for later 

development of asthma in children. 

Early treatment with allergen immunotherapy in children who 

were sensitive only to house dust mites reduced development of 

sensitivity to other allergens. 

Patients with severe, poorly controlled asthma are at higher risk for 

systemic reactions to immunotherapy injections than patients with 

stable, well-controlled asthma. 

A 

B 

A 11 

5, 6, 8, 10 

7, 9 

B 12, 13 

C 14 

B 20 

4. Adkinson NF Jr, Eggleston PA, Eney D, Goldstein EO, 

Schuberth KC, Bacon JR, et al. A controlled trial of 

immunotherapy for asthma in allergic children. N Engl J 

Med 1997;336:324-31. 

5. Ross RN, Nelson HS, Finegold I. Effectiveness of specific 

immunotherapy in the treatment of asthma: a 

meta-analysis of prospective, randomized, single or 

double-blind, placebo-controlled studies. Clin Ther 

2000;22:329-41. 

6. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy 

effective in asthma? A meta-analysis of 

randomized controlled trials. Am J Respir Crit Care Med 

1995;151:969-74. 

7. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon 

G, Frew AJ. Clinical efficacy of specific immunotherapy 

to cat dander: a double-blind, placebo-controlled trial. 

Clin Exp Allergy 1997;27:860-7. 

8. Olsen OT, Larsen KR, Jacobsan L, Svendsen UG. A oneyear, 

placebo-controlled, double-blind house-dust-mite 

immunotherapy study in asthmatic adults. Allergy 

1997;52:853-9. 

9. Kang BC, Johnson J, Morgan C, Chang JL. The role 

of immunotherapy in cockroach asthma. J Asthma 

1988;25:205-18. 

10. Dreborg S, Agrell B, Foucard T, Kjellman NI, Koivikko A, 

Nilsson S. A double-blind, multicenter immunotherapy 

trial in children, using a purified and standardized 

Cladosporium herbarum preparation. I. Clinical results. 

Allergy 1986;41:131-40. 

11. Durham SR, Walker SM, Varga EM, Jacobson MR, 

O’Brien F, Noble W, et al. Long-term clinical efficacy 

of grass-pollen immunotherapy. N Engl J Med 

1999;341:468-75. 

12. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, 

Jacobsen L, et al. Pollen immunotherapy reduces the 

development of asthma in children with seasonal rhinoconjunctivitis 

(the PAT-study). J Allergy Clin Immunol 

2002;109:251-6. 

13. Grembiale RD, Camporota L, Naty S, Tranfa CM, Djukanovic 

R, Marsico SA. Effects of specific immunotherapy 

in allergic rhinitic individuals with bronchial hyperresponsiveness. 

Am J Respir Crit Care Med 

2000;162:2048-52. 

14. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures 

JP, Bousquet J. Immunotherapy with a standardized 

Dermatophagoides pteronyssinus extract. VI. Specific 

immunotherapy prevents the onset of new sensitizations 

in children. J Allergy Clin Immunol 1997;99:450-3. 

15. Nelson HS. The use of standardized extracts in allergen 

immunotherapy. J Allergy Clin Immunol 2000;106(1 pt 

1):41-5. 

16. Nelson HS. Effects of preservatives and conditions of 

storage on the potency of allergy extracts. J Allergy Clin 

Immunol 1981;67:64-9. 

17. Nelson HS, Ikle D, Buchmeier A. Studies of allergen 

extract stability: the effects of dilution and mixing. J 

Allergy Clin Immunol 1996;98:382-8. 

18. Joint Task Force on Practice Parameters. Allergen immunotherapy: 

a practice parameter. Ann Allergy Asthma 

Immunol 2003;90(1 suppl 1):1-40. 

19. Lamson RW. Sudden death associated with injection of 

foreign substances. JAMA 1924;82:1090. 

20. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, 

Bukantz SC. Systemic reactions and fatalities associated 

with allergen immunotherapy. Ann Allergy Asthma 

Immunol 2001;87(1 suppl 1):47-55. 

21. Turkeltaub P. Deaths associated with allergenic extracts. 

FDA Medical Bulletin 24, May 1994. 

22. Pumphrey RS. Lessons for management of anaphylaxis 

from a study of fatal reactions. Clin Exp Allergy 

2000;30:1144-50. 

23. Greenberg MA, Kaufman CR, Gonzalez GE, Rosenblatt 

CD, Smith LJ, Summers RJ. Late and immediate systemic-allergic 

reactions to inhalant allergen immunotherapy. 


24. McHugh SM, Lavelle B, Kemeny DM, Patel S, Ewan PW. 

A placebo-controlled trial of immunotherapy with two 

extracts of Dermatophagoides pteronyssinus in allergic 

rhinitis, comparing clinical outcome with changes in 

antigen-specific IgE, IgG, and IgG subclasses. J Allergy 

Clin Immunol 1990;86(4 pt 1):521-31. 






reference article

Original articles 

Evaluation of near-fatal reactions to 

allergen immunotherapy injections 

Hetal S. Amin, MD, a Gary M. Liss, MD, b and David I. Bernstein, MD a 

Cincinnati, Ohio, and Toronto, Ontario, Canada 

Background: The overall incidence of near-fatal reactions 

(NFRs) after immunotherapy injections is unknown. 

Investigation of NFRs might identify preventive strategies 

that could avert fatal immunotherapy reactions. 

Objective: We sought to determine the incidence and 

characteristics of NFRs to allergen immunotherapy. 

Methods: In a brief survey of fatal reactions (FRs) and NFRs 

administered to practicing allergists, 273 of 646 respondents 

reported NFRs after immunotherapy injections; a NFR was 

defined as respiratory compromise, hypotension, or both 

requiring emergency epinephrine. Respondents were mailed 

a 105-item questionnaire regarding the details of NFRs and 

circumstances of these events. 

Results: During the period from 1990 through 2001, the 

incidence of unconfirmed NFRs was estimated at 23 per year 

(5.4 events per million injections). There were 68 confirmed 

NFRs on the basis of responses to the long survey, with a mean 

case incidence of 4.7 per year or 1 NFR per million injections. 

Asthma was present in 46% of near-fatal reactors and in 88% 

of fatal reactors identified in this study. Hypotension was 

reported in 80% and respiratory failure occurred in 10% of 

NFRs and exclusively in asthmatic subjects. Epinephrine was 

delayed or not administered in 6% of NFRs versus 30% of 

reported FRs (OR, 7.3; 95% CI, 1.4-39.8; P 5 .01). 

Conclusions: Confirmed NFRs were 2.5 times more frequent 

than FRs. Favorable outcomes of NFRs when compared with 

FRs could be related to lower asthma prevalence and 

appropriate management of life-threatening anaphylaxis. 

(J Allergy Clin Immunol 2006;117:169-75.) 

Key words: Immunotherapy, anaphylaxis, near-fatal reactions, 

asthma, epinephrine 

Immunotherapy with subcutaneous injections of 

aeroallergen extracts has proved beneficial in reducing 

symptoms of allergic rhinitis and asthma. 1 However, 

injection-related systemic reactions reportedly occur in 

From a the Department of Internal Medicine, Division of Immunology and 

Allergy, University of Cincinnati; and b Gage Occupational and 

Environmental Health Unit, Department of Public Health Sciences, 

University of Toronto. 

Supported by the Immunotherapy Committee of the American Academy of 

Allergy and Clinical Immunology (AAAAI). 

Received for publication July 8, 2005; revised October 9, 2005; accepted 

for publication October 12, 2005. 

Reprint requests: David I. Bernstein, MD, University of Cincinnati, PO Box 

670563, Cincinnati, OH 45267-0563. E-mail: bernstdd@ucmail.uc.edu. 

0091-6749/$32.00 

Ó 2006 American Academy of Allergy, Asthma and Immunology 

doi:10.1016/j.jaci.2005.10.010 

Abbreviations used 

AAAAI: American Academy of Allergy, Asthma and 

Immunology 

FR: Fatal reaction 

NFR: Near-fatal reaction 

OR: Odds ratio 

5% to 7% of patients receiving build-up and maintenance 

injections of allergen immunotherapy in North America. 2-4 

In these surveys there were few if any descriptions of 

serious near-fatal systemic reactions. 3,4 In North America 

several studies have been conducted over the past 20 years 

with the purpose of characterizing and estimating the 

incidence of fatal reactions (FRs) to immunotherapy. 5,6 

In the first of these surveys, Lockey et al 5 reported 24 FRs 

that occurred between 1973 and 1984 and estimated 

that 1 FR occurred in every 2.8 million injections. Subsequently, 

Reid et al 6 described 15 immunotherapy-related 

fatalities that transpired between 1985 and 1989 and estimated 

1 fatality in every 2.0 million injections. Recently, 

we reported the results of an immunotherapy fatality survey 

that documented 41 FRs between 1990 and 2001, 

and from these data, we estimated 1 FR in every 2.5 

million injections. 7 

Despite characterization of susceptibility factors for 

immunotherapy fatalities, dissemination of earlier survey 

findings, and publication of immunotherapy practice parameters, 

the apparent incidence rate of immunotherapyrelated 

deaths has not changed in the past 40 years. 8 

Although characteristics of immunotherapy-related 

fatalities have been well defined, there are no data that 

define factors that contribute to serious near-fatal reactions 

(NFRs). Characterization of NFRs and effective interventions 

that prevent fatal outcomes could be useful in formulating 

guidelines aimed at reducing future fatal events. We 

conducted a retrospective cross-sectional national survey 

of immunotherapy-induced NFRs; the objectives were to 

estimate the incidence of NFRs, define characteristics 

and treatment of NFRs, and compare characteristics of 

NFRs with those of FRs. 

METHODS 

The first phase of the study was initiated with a brief 6-question 

survey distributed to all physician members of the American 

Academy of Allergy, Asthma and Immunology (AAAAI) by fax, 

169 

Food allergy, dermatologic 

diseases, and anaphylaxis

170 Amin, Liss, and Bernstein 


JANUARY 2006 


diseases, and anaphylaxis 

e-mail, and the organizational newsletter between 2000 and 2001. 

The short survey (available in the Online Repository of this article at 

www.jacionline.org) queried about both FRs and NFRs associated 

with immunotherapy injections, and results of fatal events have 

already been published. 7 Individuals who did not respond initially 

were resent the form at least twice; one completed survey response 

was requested from each allergy practice. In the survey a NFR was 

defined as severe respiratory compromise, hypotension, or both requiring 

emergency treatment with epinephrine. On the basis of billing 

codes, respondents were asked to provide the total number of immunotherapy 

injections administered in their respective clinics during 

the previous 1 and 3 years. 

Physicians who reported FRs to immunotherapy or skin testing in 

the short survey were subsequently sent an 87-item questionnaire 

(available in the Online Repository of this article at www.jacionline. 

org), which they were asked to complete. Results of the latter survey 

of FRs have been published. 7 In this final phase of the study, conducted 

during 2003 and 2004, detailed 105-item questionnaires 

were sent to 273 physicians who had reported NFRs on the initial short 

survey. Key elements captured in the latter questionnaire included (1) 

demographics; (2) clinical indications for starting immunotherapy; (3) 

classification of asthma severity, asthma exacerbations, emergency 

department and hospital visits for acute asthma, and oral steroid requirements; 

(4) clinical setting where events occurred (allergist vs primary 

care office); (5) dosing errors, allergen extract concentration, 

and schedule for immunotherapy administration; (6) timing of immunotherapy 

injections relative to patient’s pollen season; (7) prior local, 

systemic, or both injection-related reactions; (8) observance by patients 

of postinjection waiting periods; (9) time of onset of reactions; 

(10) clinical manifestations of NFRs; (11) treatment of NFRs, including 

details of epinephrine administration; and (12) physicians’ assessments 

of key factors leading to NFRs. 

As described in our previous article on FRs, estimates of incidence 

rates of NFRs per million injections were based on assumptions that 

injection data of 646 respondents were representative of 2404 

AAAAI member physicians. Analysis of the data was performed 

with SAS (version 8.1; SAS Institute, Cary, NC) and Epistat (Epistat 

Services, Richardson, Tex). Because the number of injections was not 

normally distributed, geometric mean data are presented and used in 

the calculation of incidence rates. Confirmed NFRs refers to the 68 

cases reported in both the short and long surveys, whereas unconfirmed 

NFRs are those that were only reported on the initial short 

survey. 

RESULTS 

The sample represented 646 (27%) of 2404 clinical 

practices affiliated with the AAAAI who responded to the 

short survey. All were located in the United States and 

Canada. Physicians in 273 practices identified a NFR. Of 

these, 70 respondents completed the 105-item questionnaire 

after repeated requests were made through e-mail, 

fax, and personal communication through the AAAAI. No 

NFRs to skin testing were reported. There was one report 

of a vasovagal response after an immunotherapy injection 

and a second patient who experienced a mild systemic 

urticarial reaction. The results of 68 reported events 

meeting the NFR definition are presented below. 

Incidence of NFRs 

Data from the initial short survey used to estimate the 

mean annual number of injections administered in allergy 

practices reporting no systemic reactions, NFRs, and FRs 

have already been published. 7 As reported in the latter 

article, the geometric mean number of injections administered 

over 3 years was highest in the practices reporting 

FRs (mean number, 27,447 injections), followed by those 

experiencing NFRs (mean number, 23,860 injections). 

The clinic groups that reported no life-threatening reactions 

administered a significantly lower geometric mean 

number of immunotherapy injections (15,835) compared 

with the groups reporting FRs and NFRs (P 5 .016, 

ANOVA). Pairwise comparison indicated that the mean 

number of injections was significantly greater in the 

near-fatal reactor group versus the nonreactor group 

(P



Amin, Liss, and Bernstein 171 

having mild intermittent or mild persistent asthma, 11 

(35%) as having moderate persistent asthma, and 3 

(10%) as having severe persistent asthma. Although 

only 20 respondents reported FEV 1 values, 8 (40%) individuals 

had baseline (before initiation of immunotherapy 

injections) FEV 1 of less than 70% of predicted values; 4 

(50%) experienced respiratory failure requiring intubation 

during their NFRs versus 2 (17%) of 12 with FEV 1 values 

of greater than 70%. There were 7 (23%) asthmatic subjects 

treated with oral corticosteroids within the 6 months 

before the NFR. Nearly all asthmatic subjects (85%) were 

receiving inhaled corticosteroids; 5 (16%) were also receiving 

a concomitant long-acting b-agonist, and 4 

(13%) were using leukotriene antagonists exclusively for 

asthma management. Two (7%) asthmatic subjects were 

taking oral corticosteroids at the time of the NFR, and physicians 

reported that 23 (74%) of 31 asthmatic subjects 

were compliant with recommended inhaled corticosteroids 

before the NFR. Furthermore, 9% had had emergency 

department visits for asthma in the past, and 4% 

had been hospitalized. 

Prior reactions to allergen injections. During the 6 

months preceding NFRs, local and systemic reactions were 

reported in 13 (19%) and 6 (9%) respondents, respectively. 

Prior systemic reactions in 6 patients were manifested as 

acute bronchospasm in 2 patients, upper airway obstruction 

in 1 patient, hypotension in 1 patient, and pruritus and hives 

in 2 patients. Epinephrine was not administered, suggesting 

that these systemic reactions were not perceived as serious. 

The next immunotherapy doses were reduced in 1 patient; 

the remaining 5 patients remained at the same dose that 

elicited the systemic reaction. 

Details of immunotherapy administration 

In 67 (99%) of 68 NFRs, allergen extracts were 

prescribed by board-certified allergists. The near-fatal 

injections were administered subcutaneously in all but 

3 (4%) individuals who received intramuscular injections, 

which physician respondents attributed to administration 

errors. Sixty-three (93%) near-fatal events occurred in 

clinics of board-certified allergists who were present 

during the reaction; the remaining 5 (7%) NFRs occurred 

in primary care settings. There were no reports of NFRs in 

unsupervised clinics or after self-administration. Thirtyeight 

(58%) received near-fatal injections from maintenance 

extracts, and the remainder were from build-up 

vials. Twelve (18%) NFRs followed an initial injection 

from a new nonmaintenance vial, and only 2 of 68 

respondents noted a recent change in allergen extract 

manufacturer. Nearly all (98%) of the near-fatal injections 

were administered from vials that were 6 months old or 

less. NFRs reportedly occurred during the patients’ allergy 

season in 38 (56%) subjects, and dosing errors were 

reported in 15 (25%) of the near-fatal events. 

Clinical manifestations of NFRs 

Time of onset. Initial manifestations of NFRs began 

30 minutes or less after immunotherapy injection in 65 

(96%) of 68 patients, and late-onset reactions occurred in 3 

individuals more than 30 minutes after immunotherapy 

administration. Two of the 3 latter individuals returned to 

the clinic 45 minutes after receiving the injection, and 

both experienced pruritus, hives, and bronchospasm. 

Epinephrine was delayed (>30 minutes) but administered 

in both individuals. The third patient experienced pruritus 

and severe hypotension 60 minutes after the injection was 

administered by a primary care physician; epinephrine 

was administered immediately on arrival. 

Clinical features. Fig 1 shows the clinical manifestations 

of NFRs, as well as previously reported FRs from 

this survey. 7 Nearly all near-fatal reactors experienced 

hypotension (88%), but fewer had respiratory features 

of upper airway obstruction (41%) or bronchospasm 

(51%). There were 20 (30%) patients who experienced 

no cutaneous manifestations during NFRs (ie, urticaria, 

angioedema, and/or pruritus). Three (4%) individuals 

had late-onset reactions (occurring >30 minutes after 

immunotherapy administration), and 30 (44%) of 68 

near-fatal reactors experienced loss of consciousness. 

Respiratory failure occurred in 7 (10%) of 68 near-fatal 

reactors, all of whom had moderate or severe asthma; 

4 (57%) of 7 requiring intubation had pretreatment FEV 1 

values of less than 70% of predicted value. Four of 5 

near-fatal reactors who had cardiopulmonary arrest were 

asthmatic subjects. 

Circumstances contributing to 

near-fatal outcomes 

Respondents were queried about factors that significantly 

contributed to NFRs. Important contributing factors 

included administration of injections during the height of 

the allergy season (46% of respondents), allergen vaccine 

dosing errors (25%), less than optimal asthma control at 

the time of the NFR (10%), history of previous systemic 

reactions to allergen injections (9%), concomitant medication 

(eg, b-blockers; 3%), and premature clinic departure 

before the end of the required waiting period (3%). 

Management of NFRs 

One patient who experienced a NFR in a primary care 

clinic did not receive epinephrine and was managed with 

intravenous fluids and antihistamines. Eighty-two percent 

(56/68) of NFRs were treated within 3 minutes of onset of 

NFRs, and 94% received epinephrine within 20 minutes. 

The initial epinephrine dose was 0.3 to 0.5 mg in 58 (85%) 

patients, whereas 7 patients received less than 0.2 mg 

and 2 patients received more than 0.5 mg. Epinephrine 

was administered subcutaneously in 45 (66%) patients by 

the intramuscular route in 18 (27%) patients and by 

both routes in 4 (6%) patients. There was no significant 

difference in mean total epinephrine dose between patients 

receiving subcutaneous (0.6-1.0 mg) versus those receiving 

intramuscular (0.3-0.6 mg) dosing. Four received both 

subcutaneous and subsequently intramuscular epinephrine 

for persistent hypotension and respiratory symptoms. Three 

patients received intravenous epinephrine (1:10,000). 

Of 67 patients given epinephrine, 53 (78%) also received 

systemic corticosteroids, 51 (75%) received H 1 





JANUARY 2006 

FIG 1. Comparison of clinical features during FRs and NFRs. Any cutaneous signs refers to hives, angioedema, 

and/or pruritus. Hypotension refers to either transient or sustained decrease in blood pressure, and shock 

refers to cardiovascular collapse. 


diseases, and anaphylaxis 

antihistamines, 47 (69%) were given oxygen, and 28 

(41%) were given intravenous fluids, and vasopressors 

were begun in 3 (4%) near-fatal reactors. Antihistamines 

and systemic corticosteroids were administered along 

with epinephrine in 43 (63%) NFRs. 

Comparisons of near-fatal and fatal reactors 

Characteristics and management of 68 patients with 

NFRs were compared with previously reported characteristics 

of 17 patients with fatal events in this survey. 7 

Common items used in both fatal and near-fatal surveys 

facilitated these comparisons. It was noteworthy that 15 

(88%) of 17 fatal reactors had been given diagnoses of 

asthma compared with 46% in the larger NFR group. As 

shown in Fig 1, a similar proportion of patients with 

FRs (81%) and NFRs (88%) experienced hypotension or 

shock. Severe airway obstruction leading to respiratory 

failure was far less common with NFRs. Near-fatal reactors 

experienced cutaneous symptoms (ie, urticaria and 

angioedema) more often than fatal reactors. 

As shown in Fig 2, there was a higher frequency of responses 

for all questionnaire items reflecting poorly controlled 

asthma in fatal reactors. Fatal reactors were much 

more likely to have had a prior emergency department visit 

(54% vs 9%; odds ratio [OR], 12.1; 95% CI, 2.6-61.1; P< 

.001) and to have been hospitalized for asthma (61.5% vs 

4%; OR, 34.7; 95% CI, 5.7-251; P




FIG 2. Comparison of asthma severity in fatal and near-fatal reactors. *OR, 12.1 (95% CI, 2.6-61.0; P < .001); 

**OR, 34.7 (95% CI, 5.7-251.1; P < .001). ER, Emergency department. 

attributed to injections with maintenance doses of mold 

extract in 106 asthmatic children. More recent prospective 

studies of asthmatic children reported no serious systemic 

reactions to pollen, dust mite extracts, or both. 11,12 Clearly 

our survey indicates that NFRs and FRs occur among children 

and primarily in asthmatic subjects. However, there 

are insufficient data to estimate the risk relative to that 

seen in adult patients. 

We estimated that one confirmed NFR occurred with 

every 1 million injections and at a rate that was 2.5 times 

greater than that found for confirmed FRs. 7 This translated 

into nearly 5 NFRs per year in North America. However, 

because unconfirmed NFRs based on responses to the brief 

survey alone yielded more than 5 times more cases, it is 

likely that analyzing ‘‘confirmed’’ NFRs (ie, long NFR survey 

responders) greatly underestimated the true incidence 

rates of NFRs. As noted in our previous report of FRs, the 

number of injections administered in clinics reporting 

NFRs was significantly greater than that in clinics reporting 

no serious or life-threatening immunotherapy reactions. 7 

This interesting observation could be attributable to reduced 

probability of NFRs because of fewer overall injections or 

to the fact that physicians who administer fewer injections 

are more selective in excluding high-risk patients. 

As in fatal surveys, we examined putative contributing 

factors. Only one of the near-fatal reactors was receiving 

a b-blocking agent. Interestingly, this therapy did not 

appear to inhibit treatment responses to epinephrine, nor 

was glucagon required. The infrequent use of b-blockers 

in this study likely reflects adherence to published immunotherapy 

guidelines recommending avoidance of these 

drugs. 8,13 Hepner et al 14 conducted a prospective study of 

b-blocker use in more than 3100 patients receiving immunotherapy, 

including 68 patients receiving b-blockers. 

They concluded that the risk of injection-related systemic 

reactions was not increased but cautioned that b-blockade 

might increase severity of reactions as they occur. 

However, current guidelines advise avoidance of immunotherapy 

in patients requiring b-blockers. 8 Because 

no patients in this study were receiving angiotensinconverting 

enzyme inhibitors, the effects of these agents 

in NFRs could not be assessed. 

It was not surprising that the majority (54%) of NFRs 

were reported in nonasthmatic subjects, which contrasted 

sharply with reports of fatal reactors, most of whom had 

asthma that was often suboptimally controlled. 5-7,15 In our 

study the most severe reactions manifested by acute respiratory 

failure occurred in 7 patients with asthma, 4 (57%) 

of whom had reported baseline FEV 1 values below 70% of 

predicted value. Bousquet and Michel 16 have recommended 

that immunotherapy with aqueous extracts be withheld 

from such patients in light of data indicating that 

asthmatic subjects with FEV 1 value of less than 70% of 

predicted value are at greater risk for systemic reactions. 

This report of NFRs further demonstrates the heightened 

risk of life-threatening reactions in patients with asthma 

with moderate and severe airway obstruction. 

Physician respondents identified immunotherapy administration 

during peak allergy seasons (46% of respondents) 

and dosing errors (25% of respondents) as the 2 

most important factors contributing to NFRs. In a large 

physician survey, dosing errors were reported by most 

respondents and were most often attributed to misidentification 

of patients and injection of incorrect doses. 17 Our 

data suggest that dosing mistakes can have serious consequences. 

As with FR reports, NFRs were more common 

after injections from maintenance rather than build-up 

vials. 2,7,10 It is possible that reactions to maintenance 

injections might have been related to priming by natural 

allergen exposure, which could have enhanced sensitivity 

to doses of previously well-tolerated allergens. Furthermore, 

intramuscular administration of immunotherapy in 

a few responders was attributed to error in administration 

of immunotherapy injection. Although this is definitely in 





JANUARY 2006 

TABLE I. Summary of key findings from the Near Fatal Reaction Survey and proposed recommendations aimed at 

preventing life-threatening reactions after immunotherapy injections 

Study findings 

Patients with reduced FEV 1 (




should include treatment with epinephrine, diphenhydramine, 

and corticosteroids. 

The major findings of this survey and the proposed 

recommendations aimed at preventing life-threatening reactions 

after immunotherapy injections are listed in Table I. 

These recommendations address measures aimed at preventing 

severe reactions associated with moderate to severe 

airway obstruction, prior systemic reactions, reactions during 

the height of an allergy season, and dosing errors. 

In conclusion, NFRs are not uncommon, and the incidence 

of fatal immunotherapy reactions has not changed 

in the past 40 years. More effort is needed to identify and 

develop methods to control risks associated with NFRs. 7 

NFRs occur more frequently than FRs. Near-fatal events 

were managed successfully with prompt administration 

of epinephrine in physician-supervised clinic settings, affirming 

recent recommendations of the Joint Task Force 

Allergen immunotherapy practice parameters that immunotherapy 

be given in a setting where procedures that 

can reduce the risk of anaphylaxis are in place and where 

the prompt recognition and treatment of anaphylaxis are 

assured. 8 Patients with asthma and reduced lung function 

(





reference article

Allergy Treatment Record Review 

Chart ID: _________________ Reviewer: _________________ Date: _______________ 

1. All necessary forms present: 

a. Intake questionnaire 

b. Signed informed consent form 

c. Current allergen extract prescription 

d. Pre-shot questionnaire 

e. Treatment form 

f. Missed-dose/reaction AIT dose adjustment instruction 

2. Patient identification on all forms. Name alert on chart cover. 

3. Treatment form: 

a. Legible 

b. Drug/latex allergies documented 

c. Current prescription number & therapy start date 

d. Shot dates entered 

e. Concentration (cap color/dilution) entered 

f. Delayed reaction noted prior to administering shot 

g. Document dose verified by patient/guardian 

h. Dosages are correct per schedule with appropriate 

adjustments as indicated 

i. Arm(s) used noted 

j. Immediate reaction noted prior to departing clinic 

k. Entry initialed and initials correspond to signature 

4. Asthma patient: 

a. Chart flagged and minimum PF or FEV1 present 

b. PF or FEV1 recorded prior to shot 

c. No shot given and physician’s note if PF/FEV1 below 

minimum (< 80% predicted or > 15% below baseline) 

5. Nursing notes: 

a. Dose changes documented on treatment form 

b. Systemic reactions documented: 

i. Vital signs recorded 

ii. Treatment documented 

iii. Physician note included 

iv. Patient disposition documented 

Yes No* N/A 

Comments (note praise-worthy findings and explain all items answered No above): 

________________________________________________________________________ 

________________________________________________________________________ 

________________________________________________________________________ 

Reviewer’s signature ________________________





reference article

References 

Acknowledgment: 

Linda Cox, MD FAAAAI, David R. Weldon, MD FAAAAI, David I. Bernstein, MD FAAAAI, Arline 

M. Gerard, RN, and Harold S. Nelson, MD FAAAAI and the American Academy of Allergy, 

Asthma, and Immunology’s Immunotherapy & Diagnostics Committee for laying the groundwork 

for this training material through their CME course: “Optimizing the Safety of Immunotherapy 

Administration Outside of the Prescribing Allergist's Office” January 2006 

(http://www.aaaai.org/members/cme_ce/immunotherapy/) 

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