When educating patients regarding potential side-effects, clinicians should emphasize that a) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and b) coincidental respiratory disease unrelated to influenza vaccination 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. These local reactions typically are mild and rarely interfere with the person's ability to conduct usual daily activities.¹ One blinded, randomized, cross-over study among 1,952 adults and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%).1 One study1 reported 20%-28% of children with asthma aged 9 months-18 years with local pain and swelling and another study1 reported 23% of children aged 6 months – 4 years with chronic heart or lung disease had local reactions. A different study1 reported no difference in local reactions among 53 children aged 6 months-6 years with high risk medical conditions or among 305 healthy children aged 3-12 years in a placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5-32 months, no substantial local or systemic reactions were noted.¹

Systemic reactions

Fever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no prior exposure to the influenza virus antigens in the vaccine (e.g., young children). 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 (e.g., fever, malaise, myalgia and headache) when compared with placebo injections.¹

Less information from published studies is available for children, compared with adults. However, in a randomized cross-over study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group. An analysis of 215,600 children aged < 18 years and 8,476 children aged 6-23 months enrolled in one of five health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3-4 weeks before and after vaccination.¹

In a study of 791 healthy children¹, post vaccination fever was noted among 11.5% of children aged 1-5 years, 4.6% among children aged 6-10 years, and 5.1% among children aged 11-15 years. Among children with high risk medical conditions, one study of 52 children aged 6 months-4 years reported fever among 27% and irritability and insomnia among 25%¹; a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination.¹ No placebo comparison was made in these studies. However, in pediatric trials of A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection, although the vaccine was associated with mild local tenderness or erythema.¹ Limited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). During January1, 1991- January 23, 2003, VAERS received 1,072 reports of adverse events among children aged < 18 years, including 174 reports of adverse events among children aged 6-23 months. The number of influenza vaccine doses received by children during this time period is unknown. The most frequently reported events among children were fever, injection-site reactions, and rash (unpublished data, CDC, 2003).¹ Because of the limitations of spontaneous reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible by using VAERS data alone.¹

Health-care professionals should promptly report all clinically significant adverse events after influenza vaccination of children to VAERS even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré [GBS] syndrome), although no evidence exists of a causal relationship between influenza vaccine and neurologic disorders in children.¹

Immediate - presumably allergic - reactions (e.g., 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 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 who 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 - might also 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

Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions.¹

Guillain-Barré Syndrome

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS). Among persons who received the swine influenza vaccine in 1976, the rate of GBS was < 10 cases/1 million persons vaccinated. The risk for influenza vaccine-associated GBS is higher among persons aged =25 years than persons < 25 years. Evidence for a causal relationship of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10-20 cases per million adults. More definitive data probably will require the use of other methodologies (e.g., laboratory studies of the pathophysiology of GBS).¹

During three of four influenza seasons studied during 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 one additional case of GBS per million persons vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination. Thus, investigations to date indicate 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 one additional case per million persons vaccinated. Cases of GBS after influenza infection have been reported, but no epidemiologic studies have documented such an association.

Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections in general, are associated with GBS.¹

Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately one additional case per million 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. The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing 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 in 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 coincidentally 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; therefore, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within six weeks after a previous influenza vaccination is prudent. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination.¹

Other neurological disorders, including encephalopathies not defined as GBS, have been temporally associated with influenza immunization, but no causal link has been established.

Although influenza immunization can inhibit the clearance of warfarin and theophylline, studies have not established any adverse clinical effects attributable to these drugs in patients receiving influenza vaccine.

REFERENCES

1. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2004;53 (Early Release):[1-40].

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