Use of influenza vaccines in children with an egg allergy

Charles PS Hui, Noni E MacDonald; Canadian Paediatric Society, Infectious Diseases and Immunization Committee

Abridged version: Paediatr Child Health 2011;16(8):491-2

Reference No. ID 2011-06

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ABSTRACT

Children are at increased risk of morbidity from influenza. Influenza vaccines are grown in eggs, leading to a minute amount of egg protein in their composition. Recent research and new practice parameters spurred by the 2009 global influenza pandemic have challenged the need to withhold influenza vaccine from patients with an egg allergy. The available data suggest that anaphylaxis from influenza vaccines is exceptionally rare, even in patients with an egg allergy. Reported allergic reactions to trivalent inactivated influenza vaccine and pH1N1 influenza vaccines have been rare; when reactions occurred, they have not caused anaphylaxis. This position statement reviews the available evidence on influenza vaccine/egg allergy-related anaphylaxis, and recommends protocols to safely administer the trivalent inactivated vaccine in lower- and higher-risk children with an egg allergy.

Key Words: Anaphylaxis, Egg allergy, Influenza vaccine

Contents

Background
Definitions
Risk of ansphylaxis with influenza vaccine
Ovalbumin content in influenza vaccines
Influenza vaccine skin testing versus egg skin testing
Seasonal influenza vaccine patients with an egg allergy
Pandemic influenza vaccine in patients with an egg allergy
Conclusions
Recommendations
Acknowledgements
References

BACKGROUND
Egg allergy affects 1% to 2% of young children, the majority of whom outgrow this condition by late childhood (1). Trivalent inactivated (killed) influenza vaccines (TIVs) are grown in embryonated hen’s eggs, leading to concern that ovalbumin (egg protein) may stimulate an allergic reaction in patients with an egg allergy. Live, attenuated influenza vaccine (LAIV, or FluMist) is also grown in eggs, but there are as yet no data on the use of this vaccine in children with an egg allergy. Given that LAIV is inhaled rather than injected, the risks of reacting are predicted to be less than with injected TIV. However, until there is more data, TIV should be the vaccine of choice for children with an egg allergy.

The previous Canadian Immunization Guide (2006) recommended that influenza vaccines not be given to individuals with an egg allergy unless the risk of infection outweighs the small risk of a systemic hypersensitivity reaction (2). The risk associated with influenza is significant, especially in young children and in children with asthma (3).

Recent research and new practice parameters spurred by the 2009 global influenza pandemic have challenged the need to withhold influenza vaccine from patients with an egg allergy.

DEFINITIONS
To optimally manage patients with an egg allergy, the diagnosis of egg allergy should be confirmed in consultation with a physician with knowledge in clinical allergy.

According to the Canadian Society of Allergy and Clinical Immunology (4), egg allergy is defined as:

Immediate symptoms within 1 to 2 h after exposure, such as urticaria and angioedema, respiratory or gastrointestinal symptoms, OR cardiovascular symptoms plus confirmatory allergy tests (skin test or egg-specific IgE [RAST testing])

Confirmed egg-allergic patients can be subdivided into two groups:

Lower-risk patients experience mild gastrointestinal or mild local skin reaction, tolerate ingestion of small amounts of egg, or have a positive skin/specific IgE test to egg without known exposure to egg.
Higher-risk patients have experienced previous respiratory or cardiovascular reaction or generalized hives with egg ingestion, or are children with an egg allergy and poorly controlled asthma.

RISK OF ANAPHYLAXIS WITH INFLUENZA VACCINE
The overall risk of anaphylaxis from influenza vaccines has not been quantified, but indirect evidence suggests that it is exceptionally small. Of the 747 million influenza vaccines given in 1990-2005 to adults in the United States, only four cases of anaphylaxis were recorded by the Vaccine Adverse Event Reporting System (5), and none of these cases were linked to egg allergy. In almost 7.7 million vaccinations given in four health maintenance organizations in 1991-1997 in the United States, the risk of anaphylaxis was 0.65 per million vaccinations given. Of the five cases of anaphylaxis, none related to influenza vaccine (6).

OVALBUMIN CONTENT IN INFLUENZA VACCINES
Historically, the ovalbumin content in influenza vaccines has been much higher than in currently produced vaccines. A multicentred study in the 1990s examined a 10%:90% split-dose protocol (giving 10% of the dose initially, followed by the other 90% in 30 min if tolerated) in 83 egg-allergic and 124 control patients (7). There were no significant reactions in patients with egg allergy. Based on this study, the level of 1.2 µg/mL egg protein (the highest concentration in vaccines used in the study) is still considered to be the upper limit for influenza vaccines.

Manufacturers now publish the ovalbumin content in their package inserts. A summary of influenza vaccine ovalbumin contents has been published (8). The contents have been independently verified in recent seasonal and pandemic influenza vaccines (9,10). The ovalbumin content of the TIV used in Canada in 2010-2011 was less than 0.2 µg/mL dose (Letter, GlaxoSmithKline, 2011).

INFLUENZA VACCINE SKIN TESTING VERSUS EGG SKIN TESTING
Reactions to influenza vaccine skin testing are common and often are false positive results (11). Studies confirm that skin prick and intradermal vaccine testing do not predict vaccine intolerance (12-15), so there is no role for such testing.

SEASONAL INFLUENZA VACCINE PATIENTS WITH AN EGG ALLERGY
A summary of studies from 1977 to 2010 on influenza vaccination in egg-allergic patients, with more than 30 patients per study, noted that of 974 patients, most of whom had had a diagnosis of egg allergy confirmed by an allergist, 60 reacted to the influenza vaccine. The majority of these reactions were minor and no cases of anaphylaxis were described (16). However, the exclusion of high-risk patients and lack of detail about the nature of their allergy in other patients in many of these studies makes generalization from their findings difficult.

PANDEMIC INFLUENZA VACCINE IN PATIENTS WITH AN EGG ALLERGY
In the Canadian study by Gagnon et al on patients with egg allergy, the pH1N1 vaccine (Arepanrix – less than 0.03µg/mL ovalbumin) was studied using two different protocols (16). Of 830 patients with a confirmed history of egg allergy, 75 (9%) had a history of severe egg allergy with respiratory or cardiovascular reactions. They were given influenza vaccine in two divided doses (10% and 90%) administered at a 30 min interval. The other 755 (91%) with less severe egg allergy by history received the usual full dose of influenza vaccine. All were observed for 60 min. None of these egg-allergic patients had an anaphylactic reaction; however 17 (2%) had an allergic reaction according to the Brighton Collaboration definition (17). In phase II a further 3640 patients with a self-reported egg allergy were vaccinated using the single-dose protocol. Two patients required epinephrine, but did not meet the definition of anaphylaxis. Sixty-nine (1.9%) had symptoms compatible with an allergic reaction.

A number of other single-centre studies have also demonstrated that the pH1N1 was well tolerated by patients with an egg allergy, although all of these studies were done utilizing a two-dose protocol (12,13,18).

Many organizations are now making recommendations on the safe administration of influenza vaccine to patients with an egg allergy (19-21).

North American practice parameters for influenza vaccination patients with egg allergy

Organization (year published)	Recommendation for vaccine skin testing	Vaccine recommendations for patients with a higher-risk egg allergy	Vaccine recommendations for patients with a lower-risk egg allergy	Who vaccinates
American Academy of Pediatrics (22) (2010)	Discuss with allergist	Contraindicated in anaphylactic reactions to chicken or egg proteins	Two strategies: Skin testing with TIV with two dose or multi-dose Two doses (10%:90%) without skin testing	Discuss with allergist
American Academy of Allergy Asthma and Immunology (8) (2011)	Not recommended	Caution is warranted, especially for patients who have experienced more severe adverse reactions. No clear-cut consensus on how to vaccinate: either two or multi-dose.	Two strategies: Single dose Two doses (10%:90%)	Clinicians experienced in recognizing and managing anaphylaxis and in a setting equipped to manage potential adverse reactions (including anaphylaxis).
Canadian Society of Allergy and Clinical Immunology (4) (2010)	At the discretion of the allergist	Includes patients whose risk level is unknown. Two doses (10%:90%)	Single dose, watch for 60 min	“Whenever possible, egg-allergic patients, particularly those with recent or severe reactions, should be referred to their local allergist for influenza vaccine testing, if indicated. The allergist will then make a decision, based on history, skin tests or specific IgE results, if the vaccine should be given as a single or multiple stage injection.”
National Advisory Committee on Immunization (23) (2011)	Not routinely recommended. May be appropriate in special cases as a precautionary measure, ie, documented allergic reaction to the influenza vaccine.	Two doses (10%:90%) Where there is concern around vaccine tolerance, an evaluation by an allergist is warranted. If this is not possible, the risk of an allergic reaction must be weighed against the risk of influenza disease	Two strategies: Single dose Two doses (10%:90%)	Strongly recommended that any provider administering vaccinations to egg-allergic individuals has appropriate emergency treatment and resuscitative equipment immediately available to manage potential severe reactions or anaphylaxis.

CONCLUSIONS
Egg allergy in children is common but decreases with age. Influenza causes significant morbidity in children. Anaphylaxis caused by influenza vaccines is exceptionally rare, even in patients with egg allergy. The vaccine skin test is not a reliable way to predict vaccine intolerance. Reported allergic reactions to TIVs and pH1N1 influenza vaccines are rare and when they occurred, have not caused anaphylaxis. However, given the selection bias and the small numbers of patients studied to date with higher-risk egg allergy, caution must still be exercised when giving killed TIVs grown in hen’s eggs to higher-risk patients with egg allergy.

RECOMMENDATIONS

The diagnosis of egg allergy should be made in consultation with a clinician with knowledge in clinical allergy.
Influenza vaccine skin testing is NOT routinely recommended because it is not predictive of vaccine tolerance.
After obtaining informed consent of the risks/benefits of the influenza vaccine, patients with an egg allergy who are at HIGHER RISK should:

Be given influenza vaccine in a setting where there is the equipment and ability to emergently manage a patient with anaphylaxis or a severe reaction.
Be given trivalent inactivated influenza vaccine (TIV), grown in hen’s eggs but having the lowest possible ovalbumin content. This content should be less than 1.2 µg/mL.
TIV should be given in a two-dose 10%:90% protocol:
1. 10% of the total dose should be given, followed by an observation period of 30 min.
2. If the patient tolerated the 10% dose, then the remaining 90% of the TIV vaccine should be given, followed by an observation period of 60 min.
Children who tolerate the split dose and who require a second dose that season (first time receiving influenza vaccine) can receive the next dose in one injection.
Given the potential variability of ovalbumin content in the influenza vaccine from year to year, until there are further data on the risk of anaphylaxis from the subsequent season’s influenza vaccine, children with egg allergies who are at HIGHER RISK, but who tolerated the split dose, should receive the next year’s influenza vaccine in the same split dose (10%:90%).

After informed consent of the risks/benefits of the influenza vaccine has been obtained, patients with an egg allergy who are at LOWER RISK should:
- Be given influenza vaccine in a setting equipped to manage anaphylaxis as per the Canadian Immunization Guide.
- Be given TIV in a one-dose protocol, followed by an observation period of 60 min.
If a child has had a SERIOUS reaction to an influenza vaccine in the past, the decision to immunize with influenza vaccines should be made in consultation with a clinician with knowledge in clinical allergy.

ACKNOWLEDGEMENTS: This position statement has been reviewed by Jan Roberts MD and Nestor Cisneros MD of the Allergy Section of the CPS.

FOR MORE INFORMATION:

Statement on Seasonal Influenza Vaccine for 2011–2012, National Advisory Committee on Immunization

REFERENCES

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INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE
Members: Jane C Finlay, MD; Susanna Martin, MD (Board Representative); Jane C McDonald, MD; Heather Onyett, MD; Joan L Robinson, MD (Chair)
Liaisons: Upton D Allen, MD, Canadian Pediatrics AIDS Research Group; Janet Dollin, MD, The College of Family Physicians of Canada; Charles PS Hui, MD, Health Canada, Committee to Advise on Tropical Medicine and Travel; Nicole Le Saux, MD, Canadian Immunization Monitoring Program ACTive; Larry Pickering, MD, American Academy of Pediatrics, Committee on Infectious Diseases; Marina I Salvadori, MD, National Advisory Committee on Immunization; John S Spika, MD, Public Health Agency of Canada
Consultants: Robert Bortolussi, MD; Noni E MacDonald, MD; Dorothy L Moore, MD
Principal authors: Charles PS Hui, MD; Noni E MacDonald, MD

Posted: October 2011

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.