influenza vaccination in individuals with egg allergy

Influenza vaccination in Influenza vaccination in individuals with egg allergyindividuals with egg allergy

AuthorsJohn M Kelso, MDJulie Wang, MDSection Editor

Scott H Sicherer, MD, FAAAAIDeputy Editor

Elizabeth TePas, MD, MSLast literature review version 19.1: January 2011 | This topic last Last literature review version 19.1: January 2011 | This topic last

updated: February 9, 2011 (More) updated: February 9, 2011 (More)

INTRODUCTION INTRODUCTION Both the intramuscular inactivated Both the intramuscular inactivated and intranasal live-attenuated and intranasal live-attenuated influenza vaccines are cultured on influenza vaccines are cultured on fluid from chicken embryos. As a fluid from chicken embryos. As a result, there is a small amount of egg result, there is a small amount of egg protein in these vaccines. Thus, there protein in these vaccines. Thus, there is a potential risk of inducing an is a potential risk of inducing an allergic reactionallergic reaction when administering when administering the influenza vaccine to an individual the influenza vaccine to an individual with egg allergy. with egg allergy.

INTRODUCTION INTRODUCTION

However, many of these same However, many of these same patients are also at patients are also at higher risk of an higher risk of an adverse outcomeadverse outcome due to influenza due to influenza infection (eg, age <2 years, history infection (eg, age <2 years, history of asthma) and would therefore of asthma) and would therefore benefit from vaccination.benefit from vaccination.

INTRODUCTION INTRODUCTION

This topic reviews the This topic reviews the risks and risks and benefitsbenefits of administration of the of administration of the influenza vaccine in patients with influenza vaccine in patients with egg allergy and discusses several egg allergy and discusses several possible approachespossible approaches. .

The measles, mumps, and rubella The measles, mumps, and rubella (MMR) vaccine is not contraindicated (MMR) vaccine is not contraindicated in egg allergic patients. in egg allergic patients.

RISKS ASSOCIATED WITH RISKS ASSOCIATED WITH INFLUENZA INFECTIONINFLUENZA INFECTION

Both seasonal and pandemic Both seasonal and pandemic influenza infection can lead to influenza infection can lead to severe severe infection and deathinfection and death, particularly in , particularly in certain high risk groups. Seasonal certain high risk groups. Seasonal influenza results in higher mortality influenza results in higher mortality rates among patients with certain rates among patients with certain chronic medical conditions (eg, chronic medical conditions (eg, asthma), pregnant women, and those asthma), pregnant women, and those at the extremes of age. at the extremes of age.

RISKS ASSOCIATED WITH RISKS ASSOCIATED WITH INFLUENZA INFECTIONINFLUENZA INFECTION

The 2009 H1N1 influenza pandemic also The 2009 H1N1 influenza pandemic also led to higher rates of led to higher rates of severe infectionsevere infection and/or and/or deathdeath among patients with among patients with underlying conditionsunderlying conditions and and pregnantpregnant womenwomen, - but , - but elderly individualselderly individuals had a had a lower rate of infection and death, and lower rate of infection and death, and younger individuals a higher rate, younger individuals a higher rate, compared with what has been observed compared with what has been observed during seasonal influenza epidemics.during seasonal influenza epidemics.Both seasonal influenza and pandemic Both seasonal influenza and pandemic H1N1 influenza result in high rates of H1N1 influenza result in high rates of infection in infection in childrenchildren. .

Influenza vaccination is Influenza vaccination is recommended for all recommended for all individuals six months of age individuals six months of age and older and is particularly and older and is particularly important in those at important in those at increased risk of increased risk of complications.complications.

RISK OF ANAPHYLAXIS TO RISK OF ANAPHYLAXIS TO VACCINEVACCINE

Allergic reactions to a vaccine may be Allergic reactions to a vaccine may be caused by the caused by the immunizing agent itselfimmunizing agent itself or or to other to other proteins/haptensproteins/haptens that are that are introduced into the vaccine during the introduced into the vaccine during the production process. production process. These may include residual animal These may include residual animal proteins, antibiotics, preservatives, proteins, antibiotics, preservatives, stabilizers, virus-inactivating compounds, stabilizers, virus-inactivating compounds, and latex . and latex . Thus, not all episodes of anaphylaxis Thus, not all episodes of anaphylaxis caused by the influenza vaccine are due to caused by the influenza vaccine are due to egg allergyegg allergy. .

RISK OF ANAPHYLAXIS TO RISK OF ANAPHYLAXIS TO VACCINE VACCINE

Overall, anaphylaxis induced by influenza Overall, anaphylaxis induced by influenza vaccine is vaccine is a rare eventa rare event. However, it is . However, it is possible that anaphylaxis to influenza possible that anaphylaxis to influenza vaccine is a rare event in patients with egg vaccine is a rare event in patients with egg allergy because many of these patients do allergy because many of these patients do not receive the vaccinenot receive the vaccine. In addition, rates . In addition, rates may be lower now than in years past may be lower now than in years past because overall the vaccines contain because overall the vaccines contain lower lower amounts of egg proteinamounts of egg protein..


A nationwide surveillance of A nationwide surveillance of reactions to the influenza vaccine in reactions to the influenza vaccine in the United States during the 1976-77 the United States during the 1976-77 epidemic found only epidemic found only 11 cases11 cases of of anaphylaxis out of anaphylaxis out of 48,161,01948,161,019 persons immunized. A known history persons immunized. A known history of egg allergy was not reported in of egg allergy was not reported in any of these cases.any of these cases.


A survey of children and adolescents A survey of children and adolescents enrolled at four health maintenance enrolled at four health maintenance organizations from 1991-97 revealed organizations from 1991-97 revealed no episodes of anaphylaxisno episodes of anaphylaxis to to influenza vaccine out of influenza vaccine out of 197,964 197,964 dosesdoses administered during this time administered during this time period period


Several cases of anaphylaxisSeveral cases of anaphylaxis to the to the intranasal influenza vaccine have been intranasal influenza vaccine have been reported, although these cases were reported, although these cases were not not directly linked to egg allergydirectly linked to egg allergy..

No studies have directly compared the No studies have directly compared the rate of anaphylactic reactions between the rate of anaphylactic reactions between the intranasal live-attenuated vaccine and the intranasal live-attenuated vaccine and the injectable trivalent inactivated vaccine. injectable trivalent inactivated vaccine.

Fatal anaphylaxisFatal anaphylaxis

There is a There is a single anecdotal reportsingle anecdotal report from 1969 of fatal anaphylaxis after from 1969 of fatal anaphylaxis after administration of influenza vaccine to administration of influenza vaccine to a child with egg allergy a child with egg allergy

Fatal anaphylaxisFatal anaphylaxis A review of reports to the Vaccine Adverse A review of reports to the Vaccine Adverse Event Reporting System over a 15-year Event Reporting System over a 15-year period from 1990 to 2005, during which period from 1990 to 2005, during which 747 million747 million doses of influenza vaccine doses of influenza vaccine were administered in the United States, were administered in the United States, revealed revealed four reports of deathfour reports of death shortly after shortly after influenza vaccination that identified influenza vaccination that identified anaphylaxis as the cause . No information anaphylaxis as the cause . No information on egg allergy was provided nor was any on egg allergy was provided nor was any evaluation performed to determine evaluation performed to determine whether these were allergic reactions. whether these were allergic reactions.

VACCINE EGG PROTEIN CONTENTVACCINE EGG PROTEIN CONTENT

In the past, influenza vaccine In the past, influenza vaccine manufacturers did not state the egg manufacturers did not state the egg protein content of the vaccines.protein content of the vaccines.Independent research laboratories Independent research laboratories found that the levels of ovalbumin found that the levels of ovalbumin were as high as 42 mcg/mL. were as high as 42 mcg/mL. Now most manufacturers of these Now most manufacturers of these vaccines provide this information in vaccines provide this information in the package inserts. the package inserts.

The vaccine ovalbumin content is The vaccine ovalbumin content is typically expressed in typically expressed in micrograms micrograms per doseper dose . .

The 2010-2011 seasonal trivalent The 2010-2011 seasonal trivalent influenza vaccines all contain the influenza vaccines all contain the H1N1 strain used in the 2009-2010 H1N1 strain used in the 2009-2010 monovalent pandemic vaccine. monovalent pandemic vaccine.



Those manufactured by CSL Biotherapies, Those manufactured by CSL Biotherapies, Inc (King of Prussia, PA), GlaxoSmithKline Inc (King of Prussia, PA), GlaxoSmithKline (Research Triangle Park, NC), MedImmune, (Research Triangle Park, NC), MedImmune, LLC (Gaithersburg, MD), and Novartis LLC (Gaithersburg, MD), and Novartis Vaccines and Diagnostics, Inc (Cambridge, Vaccines and Diagnostics, Inc (Cambridge, MA) all are reported to contain MA) all are reported to contain ≤1 mcg per ≤1 mcg per dosedose. . The influenza vaccines manufactured by The influenza vaccines manufactured by Sanofi Pasteur, Inc (Swiftwater, PA) are Sanofi Pasteur, Inc (Swiftwater, PA) are reported by personal communication to reported by personal communication to contain contain ≤5 mcg per dose≤5 mcg per dose . .


Independent investigators assayed Independent investigators assayed several brands and lots of the 2009-several brands and lots of the 2009-2010 seasonal and H1N1 influenza 2010 seasonal and H1N1 influenza vaccines and found that the actual vaccines and found that the actual ovalbumin content of the vaccines ovalbumin content of the vaccines was one or two orders of magnitude was one or two orders of magnitude lower than the manufacturers' lower than the manufacturers' claimed maximum levels.claimed maximum levels.

Safety of low egg protein vaccines Safety of low egg protein vaccines in patients with egg allergy in patients with egg allergy

The lowest observed adverse-effect The lowest observed adverse-effect level (level (LOAELLOAEL, the lowest dose , the lowest dose reported to cause harmful effects) for reported to cause harmful effects) for egg white triggering a reaction upon egg white triggering a reaction upon ingestion was estimated to be ingestion was estimated to be around around 130 mcg130 mcg for egg-white for egg-white proteins and 2 mg for raw egg white proteins and 2 mg for raw egg white (equivalent to 200 mcg of proteins). (equivalent to 200 mcg of proteins).


The no observed adverse-effect level The no observed adverse-effect level ((NOAELNOAEL, the greatest level of , the greatest level of exposure that causes no detectable exposure that causes no detectable adverse effects) is not known. adverse effects) is not known.

The LOAEL and NOAEL for egg in a The LOAEL and NOAEL for egg in a product given by injection or product given by injection or intranasally are not clearly defined.intranasally are not clearly defined.


Safe administration of injectable Safe administration of injectable influenza vaccine containing up to influenza vaccine containing up to 1.2 mcg1.2 mcg egg protein/mL to egg- egg protein/mL to egg-allergic recipients was reported in a allergic recipients was reported in a multicenter trial that evaluated the multicenter trial that evaluated the administration of influenza vaccine to administration of influenza vaccine to

83 people83 people with histories of allergic with histories of allergic reactions to egg reactions to egg


including 27 patients with a history of including 27 patients with a history of anaphylaxis to egg, in whom skin testing or oral anaphylaxis to egg, in whom skin testing or oral challenge with egg was positive, challenge with egg was positive, and to 124 control patients. and to 124 control patients. Skin prick test with the vaccine was positive in Skin prick test with the vaccine was positive in four egg-allergic patients and one control patient. four egg-allergic patients and one control patient. All egg-allergic patients were given the influenza All egg-allergic patients were given the influenza vaccine in two doses, 30 minutes apart. The first vaccine in two doses, 30 minutes apart. The first dose was one-tenth, and the second dose was dose was one-tenth, and the second dose was nine-tenths of the total volume. nine-tenths of the total volume. There were no There were no allergic reactions in any of the 83 egg-allergic allergic reactions in any of the 83 egg-allergic subjects.subjects.


No casesNo cases of anaphylaxis were of anaphylaxis were reported in a series of reported in a series of 830 children830 children with confirmed egg allergy who were with confirmed egg allergy who were given an adjuvanted pandemic H1N1 given an adjuvanted pandemic H1N1 vaccine that contained <0.015 vaccine that contained <0.015 mcg/mL of ovalbumin [15]. mcg/mL of ovalbumin [15].

Safety of higher egg protein vaccines in Safety of higher egg protein vaccines in patients with egg allergypatients with egg allergy

The current higher egg protein The current higher egg protein vaccines still have vaccines still have significantly lower significantly lower levels than in the pastlevels than in the past. However, the . However, the ovalbumin content may be 5- to 100-ovalbumin content may be 5- to 100-fold higher (per stated content) in fold higher (per stated content) in these vaccine compared with the low these vaccine compared with the low egg protein vaccine. egg protein vaccine.


In a retrospective series, In a retrospective series, none of the none of the 64 patient64 patient with egg allergy (positive with egg allergy (positive skin or blood test results and a skin or blood test results and a clinical history of a reaction or no clinical history of a reaction or no history of egg consumption) who history of egg consumption) who were vaccinated with higher were vaccinated with higher ovalbumin content seasonal and ovalbumin content seasonal and H1N1 vaccines during the 2009 to H1N1 vaccines during the 2009 to 2010 season had 2010 season had anaphylaxis anaphylaxis


Three patients had mild cutaneous Three patients had mild cutaneous symptoms (urticaria or erythema) symptoms (urticaria or erythema) with the 1/10 dose, and one patient with the 1/10 dose, and one patient reacted with the 9/10 dose. Three of reacted with the 9/10 dose. Three of the four patients who had these mild the four patients who had these mild reaction tolerated egg in baked reaction tolerated egg in baked goods.goods.

ALTERNATIVE TO ALTERNATIVE TO VACCINATION VACCINATION

An alternative to vaccination is An alternative to vaccination is chemoprophylaxischemoprophylaxis after exposure to after exposure to the influenza virus. However, there is the influenza virus. However, there is increasing emergence of resistance increasing emergence of resistance of the influenza virus to the available of the influenza virus to the available antiviral agents. antiviral agents.

ALTERNATIVE METHODS OF ALTERNATIVE METHODS OF VACCINE PRODUCTION VACCINE PRODUCTION

The influenza vaccine is produced in The influenza vaccine is produced in fluid from embryonated eggs. fluid from embryonated eggs. Alternative methods of influenza Alternative methods of influenza virus propagation are under virus propagation are under investigation. These methods do not investigation. These methods do not use embryonated hen's eggs, and use embryonated hen's eggs, and therefore would not be therefore would not be contraindicated in patients with egg contraindicated in patients with egg allergy. allergy.

OPTIONS FOR TESTING AND OPTIONS FOR TESTING AND ADMINISTRATIONADMINISTRATION

A history of allergy to the ingestion of egg, A history of allergy to the ingestion of egg, raw or cooked, should be sought prior to raw or cooked, should be sought prior to the administration of any egg-containing the administration of any egg-containing vaccine. People who react to raw egg, but vaccine. People who react to raw egg, but tolerate cooked egg, may still experience tolerate cooked egg, may still experience allergic reactions to egg-containing allergic reactions to egg-containing vaccines [23]. Such patients may not be vaccines [23]. Such patients may not be easily detected, since they may not think easily detected, since they may not think of themselves as "egg-allergic."of themselves as "egg-allergic."


In a prospective series, 2 percent (2/105) of those In a prospective series, 2 percent (2/105) of those with egg allergy and 5 percent (1/19) without egg with egg allergy and 5 percent (1/19) without egg allergy reacted to the H1N1 vaccine on skin prick allergy reacted to the H1N1 vaccine on skin prick testing and 39 percent (40/105) with egg allergy testing and 39 percent (40/105) with egg allergy and 5 percent (1/19) without egg allergy reacted and 5 percent (1/19) without egg allergy reacted to intradermal testing. All patients, including 25 to intradermal testing. All patients, including 25 with a history of egg anaphylaxis, received the with a history of egg anaphylaxis, received the H1N1 vaccine without significant allergic H1N1 vaccine without significant allergic reactions (those with “positive” skin tests reactions (those with “positive” skin tests received the vaccine via a two-step protocol and received the vaccine via a two-step protocol and those with negative skin tests received the those with negative skin tests received the vaccine in a single dose; all booster doses were vaccine in a single dose; all booster doses were given as a single dose).given as a single dose).


In another prospective series of children with egg In another prospective series of children with egg allergy (but no history of reaction to vaccines), allergy (but no history of reaction to vaccines), some with positive prick skin tests to influenza some with positive prick skin tests to influenza vaccine were given the vaccine uneventfully with vaccine were given the vaccine uneventfully with a two-dose protocol [14].a two-dose protocol [14].Five out of six children with chronic severe Five out of six children with chronic severe asthma, egg allergy, and negative prick skin asthma, egg allergy, and negative prick skin tests, but positive intradermal tests to influenza tests, but positive intradermal tests to influenza vaccine, tolerated immunization by a multidose vaccine, tolerated immunization by a multidose protocol [25]. One child developed mild wheezing protocol [25]. One child developed mild wheezing after the first dose of influenza vaccine, but did after the first dose of influenza vaccine, but did not react four weeks later to the second dose.not react four weeks later to the second dose.


Likewise, some healthy adults with Likewise, some healthy adults with positive intradermal skin tests to influenza positive intradermal skin tests to influenza vaccine diluted 1:100 have been given the vaccine diluted 1:100 have been given the vaccine uneventfully [26].vaccine uneventfully [26].

The rate of serious adverse reactions to The rate of serious adverse reactions to the vaccine was the same whether vaccine the vaccine was the same whether vaccine skin testing was performed prior to a two-skin testing was performed prior to a two-step administration protocol or not (5 step administration protocol or not (5 versus 3 percent, respectively) [27].versus 3 percent, respectively) [27].


Prick and intradermal skin Prick and intradermal skin testing — Clinically irrelevant testing — Clinically irrelevant positive skin tests are possible, as positive skin tests are possible, as with skin testing to any allergen.with skin testing to any allergen.=>=>Thus, the presence of a positive skin Thus, the presence of a positive skin test to influenza vaccine is not test to influenza vaccine is not necessarily predictive of a necessarily predictive of a subsequent reaction.subsequent reaction.

Irritant reactionsIrritant reactionsFalse positive irritant skin test reactions are also False positive irritant skin test reactions are also

possible, particularly with intradermal testing at possible, particularly with intradermal testing at concentrations of 1:10 or undiluted. One study of concentrations of 1:10 or undiluted. One study of 20 healthy adult volunteers without histories of 20 healthy adult volunteers without histories of vaccine reactions evaluated rates of false positive vaccine reactions evaluated rates of false positive results in response to prick and intradermal skin results in response to prick and intradermal skin testing with 10 common vaccines [28]. False testing with 10 common vaccines [28]. False positives were not seen with prick testing, but positives were not seen with prick testing, but false positive rates of 15, 55, and 65 percent false positive rates of 15, 55, and 65 percent were seen on intradermal testing with 1:100, were seen on intradermal testing with 1:100, 1:10, and undiluted concentrations of influenza 1:10, and undiluted concentrations of influenza vaccine, respectively.vaccine, respectively.

Administration protocolsAdministration protocols

The administration of influenza The administration of influenza vaccine to an egg-allergic patient is a vaccine to an egg-allergic patient is a relatively common clinical dilemma. relatively common clinical dilemma. The risk of a serious allergic reaction The risk of a serious allergic reaction to the vaccine needs to be weighed to the vaccine needs to be weighed against the risks of severe illness and against the risks of severe illness and death due to influenza infection and death due to influenza infection and secondary complications. secondary complications.

Administration protocolsAdministration protocols

The American Academy of Pediatrics The American Academy of Pediatrics (AAP), the United States Centers for (AAP), the United States Centers for Disease Control and Prevention, and the Disease Control and Prevention, and the National Institute of Allergy and Infectious National Institute of Allergy and Infectious Diseases (NIAID) in the United States note Diseases (NIAID) in the United States note the relative contraindication to the relative contraindication to administration of the influenza vaccine in administration of the influenza vaccine in patients with severe egg allergy or patients with severe egg allergy or anaphylaxis, but acknowledge that anaphylaxis, but acknowledge that vaccination may be indicated in certain vaccination may be indicated in certain individuals in whom the benefits outweigh individuals in whom the benefits outweigh the risks the risks

Two-step protocolTwo-step protocol

The two-step protocol is considered a The two-step protocol is considered a graded challenge. This procedure should graded challenge. This procedure should be administered only under close be administered only under close observation by personnel prepared to observation by personnel prepared to recognize and treat anaphylaxis.recognize and treat anaphylaxis.Administer one-tenth of the inactivated Administer one-tenth of the inactivated vaccine dose intramuscularly followed by a vaccine dose intramuscularly followed by a 30 minute observation period.30 minute observation period.If no reaction is noted, then administer the If no reaction is noted, then administer the remaining nine-tenths dose remaining nine-tenths dose intramuscularly followed by an observation intramuscularly followed by an observation period of at least 30 minutes.period of at least 30 minutes.

SUMMARY AND SUMMARY AND RECOMMENDATIONSRECOMMENDATIONS

The large majority of patients with The large majority of patients with egg allergy are young children, egg allergy are young children, although this allergy can persist into although this allergy can persist into adulthood. Many patients with egg adulthood. Many patients with egg allergy are at increased risk of allergy are at increased risk of influenza complications, including influenza complications, including young children and those with a young children and those with a history of asthma or wheezing. history of asthma or wheezing.


Both the intramuscular inactivated Both the intramuscular inactivated and intranasal live-attenuated and intranasal live-attenuated influenza vaccines contain a small influenza vaccines contain a small amount of egg protein. Safe amount of egg protein. Safe administration of injectable influenza administration of injectable influenza vaccine containing ≤1.2 mcg vaccine containing ≤1.2 mcg ovalbumin/mL to egg-allergic ovalbumin/mL to egg-allergic recipients has been reported.recipients has been reported.


The risk of a serious allergic reaction The risk of a serious allergic reaction to the vaccine needs to be weighed to the vaccine needs to be weighed against the risks of severe illness and against the risks of severe illness and death due to influenza infection and death due to influenza infection and secondary complications. secondary complications.


For the patient who is six months of For the patient who is six months of age or older and has known egg age or older and has known egg allergy of any severity, we suggest allergy of any severity, we suggest administration of an age-appropriate, administration of an age-appropriate, approved vaccine that contains the approved vaccine that contains the lowest ovalbumin per dose without lowest ovalbumin per dose without prior vaccine skin testing, followed prior vaccine skin testing, followed by a 30 minute observation period in by a 30 minute observation period in a facility prepared to recognize and a facility prepared to recognize and treat anaphylaxis (Grade 2C) treat anaphylaxis (Grade 2C)


Vaccine options are shown in the Vaccine options are shown in the table (table 3). For most patients, we table (table 3). For most patients, we suggest administration of the vaccine suggest administration of the vaccine as a single dose (Grade 2C). as a single dose (Grade 2C). However, a two-step protocol is a However, a two-step protocol is a reasonable alternative, especially for reasonable alternative, especially for patients with a history of anaphylaxis patients with a history of anaphylaxis to egg or when a low ovalbumin to egg or when a low ovalbumin vaccine is not available.vaccine is not available.

Xin chân thành cảm ơnXin chân thành cảm ơn

influenza vaccination in individuals with egg allergy

Documents