Egg-allergic patients can be safely vaccinated against influenza
Authors: Anne Des Roches, Louis Paradis, Remi Gagnon, Chantal Lemire, Philippe Bégin, Stuart Carr, Edmond S. Chan, Jean Paradis, Lyne Frenette, Manale Ouakki, Mélanie Benoît, Gaston De Serres
Journal: Journal of Allergy and Clinical Immunology (2012)

As the influenza vaccine contains residual egg protein, its administration to egg-allergic patients had always raised theoretical concerns about anaphylaxis.1Centers for Disease Control and Prevention Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.MMWR Morb Mortal Wkly Rep. 2011; 60: 1128-1132PubMed Google Scholar We report our experience with the vaccination of egg-allergic patients with a trivalent inactivated seasonal influenza vaccine administered during 5 seasons (2007-2011) and summarize the current published clinical experience with these patients. We conducted a prospective cohort study recruiting and vaccinating egg-allergic patients in 2010-2011 and 2011-2012 in 5 Canadian hospitals (Montreal, Quebec City, Sherbrooke, Edmonton, and Vancouver). Egg allergy was defined as a history of at least 1 sign or symptom of allergy (cutaneous, ocular, respiratory, gastrointestinal, or cardiovascular symptoms) occurring within 60 minutes of egg ingestion, and the confirmation of persistent sensitization to egg (within 6 months of vaccination) shown by a skin prick test response to egg at least 3 mm larger than that of the saline control within 10 to 15 minutes, or an egg-specific IgE level of 0.35 kU/L or more (UniCAP, Pharmacia). In 2010-2011, we recruited all patients with allergy to egg, whereas in 2011-2012, the recruitment focused on patients with severe allergic reaction defined as the occurrence of anaphylaxis or cardiorespiratory symptoms upon egg ingestion. In both years, patients (or their parents/legal guardian if minor patients) had to provide written consent for the collection of data on adverse events occurring within 24 hours following vaccination. We also performed a retrospective cohort study of all egg-allergic patients referred for administration of seasonal influenza at the Sainte-Justine Hospital in Montreal, during the 2007-2008, 2008-2009, and 2009-2010 vaccination seasons. The definition of egg allergy and the threshold for skin prick test were the same as previously described, but the method of detection of specific IgE was the Immulite immunoassay system (Siemens, Muenchen, Germany). For both cohorts, patients were examined immediately before vaccination, remained under observation for 60 minutes postvaccination, and were then reexamined for any sign of allergic reaction. The vaccine used during all 5 seasons was the split-virion trivalent inactivated influenza vaccine Fluviral manufactured by GSK (Quebec City, Quebec, Canada). The ovalbumin content for the lots used was provided by the manufacturer: 0.09 μg/mL in 2007-2008, 0.03 μg/mL in 2008-2009, 0.31 μg/mL in 2009-2010, up to 0.2 μg/mL in 2010-2011, and up to 0.06 μg/mL for 2011-2012. The primary outcome was the occurrence of anaphylaxis according to the Brighton Collaboration definition.2Ruggeberg J.U. Gold M.S. Bayas J.M. Blum M.D. Bonhoeffer J. Friedlander S. et al.Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data.Vaccine. 2007; 25: 5675-5684Crossref PubMed Scopus (265) Google Scholar The study was approved by the ethics boards of all participating hospitals. Over 5 influenza seasons, 457 doses of trivalent inactivated seasonal influenza vaccines were administered to 367 patients among whom 132 (153 doses) had a history of severe allergy to egg (see Table E1 in this article's Online Repository at www.jacionline.org). Four patients reported mild allergic-like symptoms after previous influenza vaccination (1 urticaria, 2 vomiting, and 1 eczema), but none experienced an adverse event when given the current vaccine. While 13 patients developed mild allergic-like symptoms in the 24 hours following vaccination, none of the 367 patients developed anaphylaxis. We then did a literature review and retrieved articles in English or French in which at least 25 egg-allergic patients had been vaccinated. PubMed was searched with the following MESH: (influenza AND (vaccination or vaccine)) AND (egg AND (allergy OR allergic)). Further studies or conference abstracts were identified by citations in retrieved articles and by consultation with experts. Among the 87 articles retrieved from PubMed, 16 were studies including the vaccination of 25 or more egg-allergic patients. We additionally found 10 conference abstracts of studies with the same minimal number of patients. Together, these 26 studies and the current study have enrolled 4172 patients including 513 who were identified as patients with a history of severe reactions (Table I). These patients received a total of 4729 doses, and none developed anaphylaxis. With no anaphylaxis after 4729 doses of vaccine, the 95% Clopper-Pearson exact CI of the risk of anaphylaxis ranges from 0% to 0.08% (or 0 to 1 of 1250 doses).3Clopper C.J. Pearson E.S. The use of confidence or fiducial limits illustrated in the case of the binomial.Biometrika. 1934; 26: 404-413Crossref Google Scholar For the 597 doses administered to the 513 patients with a history of severe allergic reaction to egg, the exact 95% CI of the risk of anaphylaxis ranges from 0% to 0.62% (or 0 to 1 of 161 doses). Their risk of anaphylaxis is in fact smaller as many studies in Table I had patients with severe allergy but simply did not report the information regarding their number.Table IPublished studies with 25 or more egg-allergic patients vaccinated against influenzaReferenceNo. of patientsNo. of dosesAllSevere allergyAllSevere allergyBierman CW, Shapiro GG, Pierson WE, Taylor JW, Foy HM, Fox JP, et al. Safety of influenza vaccination in allergic children. J Infect Dis 1977;136:S652-55.281281James JM, Zeiger RS, Lester MR, Fasano MB, Gern JE, Mansfield LE, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatr 1998;133:624-8.83278327Zeiger RS. Current issues with influenza vaccination in egg allergy. J Allerg Clin Immunol 2002;110:834-40.28NR28Dorsey MJ, Song L, Geha T, Timmons A, Oettgen H, Schneider L. Influenza vaccine in 55 patients with egg allergy. J Allergy Clin Immunol 2005;115:S250.37NR37Hotte SL, Lejtenyi C, Primeau MN. A 6 years experience with influenza vaccination in egg allergic patients. J Allergy Clin Immunol 2008;121:S239.115NR173Esposito S, Gasparini C, Martelli A, Zenga A, Tremolati E, Varin E, et al. Safe administration of an inactivated virosomal adjuvanted influenza vaccine in asthmatic children with egg allergy. Vaccine 2008;26:4664-8.44114411Park AY, Pien GC, Stinson R, Brown-Whitehorn, Spergel JM. Administration of influenza vaccine to patients with egg allergy. J Allergy Clin Immunol 2008;121:S240.45NR45Saltzman RW, Park AY, Pien GC, Stinson R, Spergel JM. Administration of influenza vaccine to pediatric patients with egg allergy. J Allergy Clin Immunol 2009;123:S175.349NR349Thanik ES, Cox AL, Sampson HA. Administration of a low egg-containing influenza vaccine [Fluarix] in an egg-allergic pediatric population. J Allergy Clin Immunol 2010;125:AB25.214∗Number of doses, as number of patients not reported.NR214Chung EY, Huang L, Schneider L. Safety of influenza vaccine administration in egg-allergic patients. Pediatrics 2010;125:e1024-30.171NR171Gagnon R, Primeau MN, Des Roches A, Lemire C, Kagan R, Carr S, et al. Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine. J Allergy Clin Immunol 2010;126:317-23.830164830164Greenhawt MJ, Chernin AS, Howe L, Li JT, Sanders G. The safety of the H1N1 influenza A vaccine in egg allergic individuals. Ann Allergy Asthma Immunol 2010;105:387-93.1052510525Leo SH, Dean J, Chan ES. Safety of H1N1 and seasonal influenza vaccines in egg allergic patients in British Columbia. Allerg Asthma Clin Immunol 2010;6:P4.81∗Number of doses, as number of patients not reported.NR81Pien GC, LeBenger KS, Carotenuto DR, Difilippi M, Scolpino D, Simmons JM, et al. Coordination of multidisciplinary resources for vaccination of egg-allergic individuals during an H1N1 (novel) influenza pandemic. Allergy Asthma Proc 2010;31:507-10.62NR62Siret-Alatrista A, Bouali F, Demoly M, Bousquet PJ, Demoly P. The 2009-2010 H1N1 vaccination campaign for patients with egg allergy in a region of France. Allergy 2011;66:298-9.53NR53Boden SR, LaBelle VS, Sedlak DA, Kim EH, Vickery BP, Burks AW. Safe administration of flu vaccine in egg-allergic patients. J Allergy Clin Immunol 2011;127:AB114.101NR206Paschall VL, Siles RI, Bhatti H, Nolder PJ, Melton AL. Do egg-specific IgE levels predict reactions to seasonal influenza or H1N1 vaccination? J Allergy Clin Immunol 2011;127:AB182.62NR131Owens G, MacGinnitie A. Higher-ovalbumin-content influenza vaccines are well tolerated in children with egg allergy. J Allergy Clin Immunol 2011;127:264-5.64NR96Howe LE, Conlon AS, Greenhawt MJ, Sanders GM. Safe administration of seasonal influenza vaccine to children with egg allergy of all severities. Ann Allergy Asthma Immunol 2011;106:446-7.2042720427Webb L, Petersen M, Boden S, LaBelle V, Bird JA, Howell D, et al. Single-dose influenza vaccination of patients with egg allergy in a multicenter study. J Allergy Clin Immunol 2011;128:218-9.1523429234Pitt T, Kalicinsky C, Warrington R, Cisneros N. Assessment of epicutaneous testing of a monovalent influenza A (H1N1) 2009 vaccine in egg allergic patients. Allergy Asthma Clin Immunol 2011;7:3.59NR59Schuler JE, King WJ, Dayneka NL, Rastelli L, Marquis E, Chad Z, et al. Administration of the adjuvanted pH1N1 vaccine in egg-allergic children at high risk for influenza A/H1N1 disease. Can J Pub Health 2011;102:196-9.62NR62Forsdahl BA. Reactions of Norwegian children with severe egg allergy to an egg-containing influenza A (H1N1) vaccine: a retrospective audit. BMJ Open 2012;2:e000186.80198019Fung I, Spergel JM. Administration of influenza vaccine to pediatric patients with egg-induced anaphylaxis. J Allergy Clin Immunol 2012;129:1157-9.5656119119Khan FS, Virant FS, Furukawa CT, Altman LC, Williams PV, Kennedy MS, et al. Influenza vaccine administration in egg allergic children. J Allerg Clin Immunol 2012;129:AB70.643NR643Wainwaring Upton JE, Hummel DB, Kasprzak A, Atkinson AR. No systemic reactions to influenza vaccination in egg-sensitized tertiary care pediatric patients. Allerg Asthma Clin Immunol 2012;8:2.77177717Des Roches A, Paradis L, Gagnon R, Lemire C, Begin P, Carr S, et al. Egg-allergic patients can be safely vaccinated against influenza. J Allergy Clin Immunol 2012 (current study).367132457153Totals41725134729597NR, Not reported.∗ Number of doses, as number of patients not reported. Open table in a new tab NR, Not reported. The clinical experience with influenza vaccination in egg-allergic patients in our cohorts and in other studies displayed in Table I has limitations. The amount of ovalbumin varied in the different influenza vaccines used and was sometimes unknown or low. Patients rarely had a recent positive food challenge confirming the persistence of egg allergy. Some studies included young children with atopic conditions (eg, atopic dermatitis) who had never eaten eggs but had a positive skin test result and high levels of egg-specific IgE. These sensitized patients are typically managed with recommendations of food avoidance as if they were allergic, although the diagnosis of allergy for these patients may be inaccurate. Despite these limitations, the patients in Table I are representative of patients managed as egg-allergic and the large number vaccinated with no ensuing anaphylaxis constitutes a strong scientific basis for new recommendations. Egg allergy is the second most frequent food allergy and affects 1% to 2% of young children.4Eggesbo M. Botten G. Halvorsen R. Magnus P. The prevalence of allergy to egg: a population-based study in young children.Allergy. 2001; 56: 403-411Crossref PubMed Scopus (226) Google Scholar While most patients will eventually develop tolerance to eggs, it will still be present in more than 60% by 6 years of age.5Savage J.H. Matsui E.C. Skripak J.M. Wood R.A. The natural history of egg allergy.J Allergy Clin Immunol. 2007; 120: 1413-1417Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar In the United States, this grossly corresponds to 150,000 to 250,000 influenza vaccine–eligible preschoolers. Many of these patients have not benefited from the influenza vaccine in the past because of the fear of anaphylaxis or the difficulty of accessing an allergist as is often recommended.1Centers for Disease Control and Prevention Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.MMWR Morb Mortal Wkly Rep. 2011; 60: 1128-1132PubMed Google Scholar Paradoxically, given their young age and the high rate of concurrent asthma, these patients have a higher risk of complications from influenza and are among those most likely to benefit from this vaccine.6Izurieta H.S. Thompson W.W. Kramarz P. Shay D.K. Davis R.L. DeStefano F. et al.Influenza and the rates of hospitalization for respiratory disease among infants and young children.N Engl J Med. 2000; 342: 232-239Crossref PubMed Scopus (895) Google Scholar The evidence gathered over the past 15 years is overwhelmingly reassuring that this risk is minimal. The published number of egg-allergic patients safely vaccinated against influenza is nearly 4 times as large as the number that ended the precautions regarding measles, mumps and rubella (MMR) vaccine (4172 vs 1227).7James J.M. Burks A.W. Roberson P.K. Sampson H.A. Safe administration of the measles vaccine to children allergic to eggs.N Engl J Med. 1995; 332: 1262-1266Crossref PubMed Scopus (171) Google Scholar There will always be a very small risk of anaphylaxis associated with influenza or any other vaccination, but there is now robust evidence that egg-allergic patients, even those with severe allergy, can be safely vaccinated against influenza. The risk of anaphylaxis appears sufficiently low for patients with egg allergy to be vaccinated like all other individuals, without requiring administration by an allergist. We are thankful to collaborators from the different sites—Hôpital Sainte-Justine (M. Blaquière and A. Kukhta), CHUQ-CHUL (J. Hébert, P. M. Bédard, A. Lavoie, J. P. Drolet, and N. Verreault), CHUS (M. Plante, D. Leduc, A. Farrand, and C. Nault), Stollery Children's Hospital (T. Vander Leek and P. Lidman), and BC Children's Hospital (J. Dean)—and to T. Koerner from Health Canada. Table E1Characteristics of egg-allergic patients vaccinated against seasonal influenza between 2007 and 2011n (%)All patientsPatients with severe allergyRetrospectiveProspectiveTotal (N = 367)RetrospectiveProspectiveTotal (N = 132)2007-2008 to 2009-2010 (n = 137)2010-2011 (n = 187)2011-2012 (n = 43)2007-2008 to 2009-2010 (n = 31)2010-2011 (n = 58)2011-2012 (n = 43)Sex Male87 (63)98 (52)28 (65)213 (58)23 (74)29 (50)28 (65)80 (61)Age (y) <229 (21)21 (11)6 (14)56 (15)5 (16)4 (7)6 (14)15 (11) 2-453 (39)72 (39)11 (26)136 (37)14 (45)16 (28)11 (26)41 (31) 5-1151 (37)64 (34)18 (42)133 (36)11 (36)22 (38)18 (42)51 (39) >124 (3)30 (16)7 (16)41 (11)1 (3)16 (28)7 (16)24 (18)Skin prick test to egg ≥3 mm137 (100)181 (97)39 (91)357 (97)31 (100)55 (95)39 (91)125 (95) ≥10 mm71 (52)72 (39)14 (33)157 (43)22 (71)22 (38)14 (33)58 (44)Egg IgE (kUA/L)∗Measured with UniCAP for 2010-2011 and 2011-2012 and with Immulite for 2007-2010. <0.351 (1)14 (7)2 (5)17 (5)07 (12)2 (5)9 (7) 0.35-<222 (18)20 (11)2 (5)44 (12)2 (9)8 (14)2 (5)12 (9) 2-<727 (22)27 (14)7 (16)61 (17)8 (36)6 (10)7 (16)21 (16) 7-1731 (25)15 (8)1 (2)47 (13)5 (23)4 (7)1 (2)10 (8) 17.5-9943 (35)18 (10)7 (16)58 (16)7 (32)7 (12)7 (16)16 (16)Tolerate baked goods†There were 114 patients (including 36 severe cases) who had challenge with a baked good and tolerated it well. While the tolerance to baked goods in patients with severe allergy may suggest milder severity, this does not rule out the risk of severe reaction to uncooked egg proteins.49 (36)53 (28)12 (28)114 (31)6 (19)18 (31)12 (28)36 (27)Naive to flu vaccine84 (61)81 (43)11 (26)176 (48)17 (55)28 (48)11 (26)56 (42)Vaccinated Single dose227 (100)‡Some patients had more than 1 dose over several seasons. Percentage calculated on the total number of doses administered.170 (91)41 (95)438 (96)‡Some patients had more than 1 dose over several seasons. Percentage calculated on the total number of doses administered.52 (100)‡Some patients had more than 1 dose over several seasons. Percentage calculated on the total number of doses administered.45 (78)41 (95)138 (91)‡Some patients had more than 1 dose over several seasons. Percentage calculated on the total number of doses administered. 2 doses (10% + 90%)017 (9)2 (5)19 (4)013 (22)2 (5)15 (9)Allergic symptoms ≤24 h following influenza vaccination (all were mild)09 (5)4 (9)13 (6)02 (3)4 (9)6 (6)Significant differences with P values <.05 between severe and nonsevere egg-allergic patients are indicated in bold characters.∗ Measured with UniCAP for 2010-2011 and 2011-2012 and with Immulite for 2007-2010.† There were 114 patients (including 36 severe cases) who had challenge with a baked good and tolerated it well. While the tolerance to baked goods in patients with severe allergy may suggest milder severity, this does not rule out the risk of severe reaction to uncooked egg proteins.‡ Some patients had more than 1 dose over several seasons. Percentage calculated on the total number of doses administered. Open table in a new tab Significant differences with P values <.05 between severe and nonsevere egg-allergic patients are indicated in bold characters.