When educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and 2) coincidental respiratory disease unrelated to influenza vaccine can occur after vaccination.¹

Local Reactions

In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts < 2 days, local pain and swelling. These local reactions typically are mild and rarely interfere with the person's ability to conduct usual daily activities.¹

Systemic Reactions

Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no prior exposure to the influenza virus antigens in the vaccine (eg, young children). ^{1, 23} These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (eg, fever, malaise, myalgia, and headache) when compared with placebo injections.¹

Immediate - presumably allergic - reactions (eg, hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies.^1,24

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré Syndrome (GBS).^1,25 Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear.¹ Obtaining strong epidemiologic evidence for such a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10-20 cases/1 million adults,¹ and stretches the limits of epidemiologic investigation.

During three of four influenza seasons studied from 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies. However, in a study of the 1992-1993 and 1993-1994 seasons, the overall relative risk for GBS was 1.7 (95% confidence interval = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The combined number of GBS cases peaked two weeks after vaccination. Thus, investigations to date indicate that there is no substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine does pose a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated.¹

Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately 1 additional case/1,000,000 persons vaccinated is substantially less than the risk for severe influenza, which could be prevented by vaccination among all age groups, especially persons aged ≥ 65 years and those who have medical indications for influenza vaccination.¹

The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for developing vaccine-associated GBS. The average case-fatality ratio for GBS is 6% and increases with age. No evidence indicates that the case-fatality ratio for GBS differs among vaccinated persons and those not vaccinated.¹

The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history. Thus, the likelihood of coincidently experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown.¹

Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy,^26,27 partial facial paralysis, and brachial plexus neuropathy have been reported. However, no cause and effect has been established.^21,28 Almost all persons affected were adults, and the described clinical reactions began as soon as a few hours and as late as 2 weeks after vaccination. Full recovery was almost always reported.^25,29,30

Microscopic polyangitis (vasculitis) has been reported temporally associated with influenza vaccination.³¹

Reporting Of Adverse Events

Reporting by patients, parents, or guardians of all adverse events after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by healthcare providers to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967. ³²

The health-care providers also should report these events to the Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463.

Although influenza vaccination can inhibit the clearance of warfarin, theophylline, phenytoin, and aminopyrine therapy, studies have failed to show any adverse clinical effects attributable to these drugs in patients receiving influenza vaccine.^12-18

If Fluzone vaccine is administered to immunosuppressed persons or persons receiving immunosuppressive therapy, the expected antibody response may not be obtained. This includes patients with asymptomatic HIV infection, AIDS or AIDS-Related Complex, severe combined immunodeficiency, hypogammaglobulinemia, or aggammaglobulinemia; altered immune states due to diseases such as leukemia, lymphoma, or generalized malignancy; or an immune system compromised by treatment with corticosteroids, alkylating drugs, antimetabolites or radiation. ¹⁹

REFERENCES

1. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2004;53: 1-40.

12. Renton KW, et al. Can Med Assoc J 123: 288-290, 1980.

13. Fischer RG, et al. Can Med Assoc J 126: 1312-1313, 1982.

14. Lipsky BA, et al. Ann Intern Med 100: 6: 835-837, 1984.

15. Kramer P, et al. Clin Pharmacol Ther Vol 35, #3: 416-418, 1984.

16. Patriarca PA, et al. New Engl J Med 308: 1601-1602, 1983.

17. Levine M, et al. Clin Pharm 3: 505-509, 1984.

18. Kilbourne ED. Vaccines (Plotkin and Mortimer eds.) Saunders Company: 429, 1988.

19. ACIP. MMWR 35: 595-606, 1986.

21. Sanofi Pasteur Inc., Data on File. MKT5720, 1994.

23. Barry DW, et al. Am J Epidemiol 104: 47-59, 1976.

24. Murphy KR, et al. J Pediatr 106: 931-933, 1985.

25. Schonberger LB, et al. Am J Epidemiol 110: 105-123, 1979.

26. Hull TP, et al. Am J Opthalmol 703-704, 1997.

27. Kawasaki A, et al. J Neuro-Opthalmol: 18 (1), 56-59, 1998.

28. CDC. Surveillance Report No. 3, 1985-1986, Issued February 1989.

29. Retaillaiu HF, et al. Am J Epid III (3): 270-278, 1980.

30. Guerrero IC, et al. N Engl J Med 300 (10): 565, 1979.

31. Kelsall JT, et al. J Rheumatol 1198-1202, 1997.

32. CDC. MMWR 39: 730-733, 1990.

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