I have had three cases this year h/o anaphylaxis to influenza vaccine in prior years. All + ID skin tests 1:100 to all influenza vaccines tested. Any ideas for etiology? Negative tests for thimerosal, latex, gelatin, egg.


Thank you for your question.

I do not think I can provide any major insight into your clinical question. Certainly reactions occur to vaccinations, generally not anaphylaxis, but there have been reports of anaphylaxis in mass vaccination programs without a cause. The paper below from Canada identified risk factors of recent upper respiratory infection and increased occurrence in women of child bearing age. These observations would not explain your positive skin tests.

The increase in anaphylaxis from a variety of causes, particularly insect stings, in subjects with mast cell activation disorders would be another thought but also would not explain the positive skin test. It is worthy of emphasis that vaccine skin testing has not been predictive of reaction in egg allergic subjects and skin testing is not recommended in this setting. Your circumstance is different since your patients have a history of influenza vaccine anaphylaxis without egg allergy.

I have forwarded your question to Dr. John Kelso who has been actively involved in the development of vaccine recommendations from the Joint Task Force on Practice Parameters.

Risk factors associated with anaphylaxis and other allergic-like events following receipt of 2009 monovalent AS03-adjuvanted pandemic influenza vaccine in Quebec, Canada. Vaccine 2014;32:3480-87.
• Isabelle Rouleaua,
• Gaston De Serresa,
• Danuta M. Skowronskic,
• Jean Philippe Droleta,
• Chantal Lemired,
• Eveline Tothe,
• Monique Landrye
Introduction: In Quebec, Canada, receipt of the 2009 AS03-adjuvanted pandemic H1N1 vaccine was associated with increased risk of anaphylaxis and other allergic-like events (ALE), especially among women of childbearing age. In response to this safety signal, a case–control study was conducted to identify potential risk factors
Methods: A total of 435 ALE (50 anaphylaxis) occurring <24 h following pandemic vaccination were compared to 849 age-gender matched controls randomly selected from the provincial Pandemic Influenza Vaccination Registry. More than 60 potential risk factors were evaluated through phone interviews and included demographic information, medical history, medication use or acute respiratory illnesses (ARI) concurrent with vaccination and other risk factors associated with general allergy. Odds ratios (ORs) with 95% confidence intervals were estimated with unconditional logistic regression.
Results: Factors associated with increased risk of anaphylaxis included concurrent ARI (18% cases vs. 4% controls, ORadj 7.67, 95%CI: 3.04–13.37), food allergy (26% cases vs. 4% controls, ORadj 3.84, 95%CI: 1.51–9.74) and vaccination during the first four weeks of the campaign (66% cases vs. 50% controls, ORadj 2.16, 95%CI: 1.10–4.25) whereas alcohol exposure (=1 drink/week) was associated with reduced risk (29% cases vs. 42% controls, ORadj 0.26, 95%CI: 0.13–0.57). These factors were also significantly associated with any ALE but the strength of association was weaker. Allergy to components found in the vaccine (e.g., egg, thimerosal) was infrequent and did not significantly differ between cases and controls.
Conclusion: Increased anaphylaxis and other allergic-like events observed in association with AS03-adjuvanted pandemic H1N1 vaccine remain mostly unexplained despite extensive risk factor review. However, prior to mass vaccination with similar formulations this safety signal warrants further consideration and better understanding. In particular, the predominance among women of childbearing age may be a clue to underlying biological or hormonal influences on adverse immunological responses to vaccine.

Dr. Kelso replied.
A VSD report on the administration of 4,512,366 H1N1 and seasonal influenza vaccine doses during the 2009-2010 influenza season found four cases of anaphylaxis, or 0.9 per million doses [6]. The manufacturers of adjuvanted monovalent H1N1 influenza vaccines distributed in 42 countries (excluding the USA) in 2009 and 2010 reviewed a database of reactions reported by health care providers, regulatory agencies and consumers [7]. At least 30 million doses were administered. The Brighton Collaboration definitions of anaphylaxis were applied. The calculated rate of anaphylactic reactions was 1.9 per million doses. A review of VAERS reports after the distribution of 127,075,320 doses of monovalent H1N1 influenza vaccines in the USA in 2009 and 2010 using Brighton collaboration criteria found an anaphylaxis rate of 0.8 per million doses [8].
6. Lee GM, Greene SK, Weintraub ES, et al. H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project. Am J Prev Med 2011;41:121-8
7. Tavares F, Delaigle A, Slavin D, et al. Anaphylaxis following H1N1 pandemic vaccines: safety data in perspective. Vaccine 2011;29(37):6402-7
8. Halsey NA, Griffioen M, Dreskin SC, et al. Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines: reports to VAERS. Vaccine 2013;31:6107-12
Most of the rare reports of anaphylactic reactions to influenza vaccine occurred in recipients without egg allergy or whose allergy status was unknown.[2] Thus, it is possible that influenza vaccine can cause anaphylactic reactions in susceptible recipients due to IgE-mediated reactions to other vaccine constituents or through non-IgE mediated mechanisms. For this reason, it is recommended that personnel who administer vaccines (not just influenza vaccine but any vaccine) be prepared to recognize and treat anaphylactic reactions.[10] Further, the rare patients who have urticarial or anaphylactic reactions after immunization itself should be evaluated by an allergist, to include vaccine skin testing, to determine whether or not the reaction was IgE mediated and, if so, which component of the vaccine was responsible.[5]
2. Kelso JM. Administering influenza vaccine to egg-allergic persons. Expert Rev Vaccines 2014;13:1049-57.
5. Kelso JM, Greenhawt MJ, Li JT, Nicklas RA, Bernstein DI, Blessing-Moore J, et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol 2012;130:25-43.
10. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity & Mortality Weekly Report 2011;60:1-64.
Assuming that the nature and timing of the reactions were consistent with mast cell-mediated events, I believe the approach was correct, specifically skin testing with the vaccine prick full-strength and if negative ID 1:100 (which has been demonstrated to be a nonirritating concentration) and also evaluating for the known potentially allergenic components.  The fact that the skin tests were positive suggests that these were in fact an IgE mediated reactions, perhaps to the viral proteins themselves.  
For subsequent years, I would recommend repeat skin testing with that year's vaccine and, if negative, giving the vaccine in the usual manner but observing for one hour afterwards and, if positive, consideration of administration in graded doses for example:

For a vaccine where the full dose is 0.5 mL, give the following doses at 15-minute intervals as tolerated under observation prepared to treat an anaphylactic reaction should it occur:
0.05 mL 1:10 dilution
0.05 mL full-strength
0.1 mL full-strength
0.15 mL full-strength
0.2 mL full-strength
Observe for at least 30 minutes after last dose.

Kelso JM. Administering influenza vaccine to egg-allergic persons. Expert Rev Vaccines 2014; 13:1049-57.

Kelso JM. Influenza Vaccine and Egg Allergy: Nearing the End of an Evidence-based Journey J Allergy Clin Immunol Pract 2014 (in press)

All my best.
Dennis K.Ledford, M.D.,FAAAAI

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