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Committee to Review Adverse Effects of Vaccines; Institute of Medicine; Stratton K, Ford A, Rusch E, et al., editors. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2011 Aug 25.

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Adverse Effects of Vaccines: Evidence and Causality.

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6Influenza Vaccine

INTRODUCTION

Influenza viruses are 80–120 nm enveloped viruses of the family Orthomyxoviridae (Treanor, 2010). Divided into three types—A, B, and C—these viruses can infect a range of hosts from humans only (influenza B) to humans and swine (influenza C) to multiple host organisms including humans, swine, equine, avian, and marine mammals (influenza A) (Treanor, 2010). Influenza viruses are highly changeable viruses. Small antigenic changes, known as “antigenic drift,” occur regularly, usually as point mutations in the virus genome or through exchange of small gene segments with another strain of influenza virus (Han and Marasco, 2011; Treanor, 2010). Occasionally, influenza viruses undergo an abrupt and dramatic change in genome. This change, known as “antigenic shift,” results in a new virus that is so different from previous viruses that no immunity exists in the population and can lead to pandemic influenza (Treanor, 2010). Antigenic shift is usually caused by genetic recombination between two strains of influenza virus; one from a strain that can infect humans and one that, prior to the genetic exchange, could not (Han and Marasco, 2011). The impact of these changes depends on the extent of the change, but because viral epitopes from the variant strains that result from antigenic shifts and drifts may not be recognized by the immune system, vaccines must be altered regularly to combat the infection.

Influenza viruses are named based on the type of influenza, the location of initial isolation, strain designation number, and the year of isolation (e.g., A/Brisbane/59/2007). Influenza A viruses are further divided into subtypes based on the characteristics of the hemagglutinin (H or HA) and neuraminidase (N or NA) surface proteins (Treanor, 2010). This subtyping is the basis of the H#N# designations of the influenza A viruses. At least 16 distinct HA and 9 distinct NA surface proteins have been identified (Treanor, 2010). Influenza B viruses are subdivided as Yamagada or Victoria based on genetic lineage (Xu et al., 2004). Of the three distinct types of influenza viruses, influenza A viruses are the only viruses proven to cause pandemic disease and are capable of interspecies transmission, as demonstrated with the 1997 outbreak of avian (H5N1) influenza from poultry to humans (de Jong et al., 1997; Subbarao et al., 1998; Yuen et al., 1998).

Influenza viruses have caused epidemics every 1 to 3 years during the past four centuries, and four major pandemics have occurred including the great pandemic of 1918 (Treanor, 2010). These pandemics were caused by influenza A viruses H1N1 (1918 and 2009), H2N2 (1957), and H3N2 (1968) (Treanor, 2010). In any given year, two influenza A strains considered to be most likely to contribute to widespread (epidemic or pandemic) illness are included in the trivalent vaccine. Because of its ability to produce epidemic disease, an influenza B virus strain is also included in all current vaccines.

In the United States, a nearly annual influenza epidemic usually begins in late fall and peaks in mid to late winter. Influenza viruses are transmitted by contact with aerosol secretions containing the virus, and this occurs generally through coughing and sneezing (Belshe et al., 2008; Treanor, 2010). Following an average incubation period of 2 days but ranging from 1 to 4 days, adults and children remain infectious for approximately 5 days after the onset of the illness (CDC, 2002). Children, who generally have the highest attack rate and serve as the major source of transmission within communities (Glezen and Couch, 1978; Monto and Kioumehr, 1975), can be infectious for longer periods both before and after the onset of illness (Belshe et al., 2008). Uncomplicated influenza often begins abruptly with systemic symptoms of fever, chills, headaches, myalgia, malaise, anorexia, and fatigue. These symptoms persist for the duration of the fever— typically for 3 days (Treanor, 2010). Respiratory symptoms such as dry cough, sore throat, and nonproductive cough may also occur and usually persist for 2 weeks or more (Belshe et al., 2008; Treanor, 2010). Fevers tend to be higher in children and can lead to febrile seizures, while elderly individuals may experience afebrile disease with lassitude or confusion (Babcock et al., 2006; Bridges et al., 2008; Neuzil et al., 2003). The risk of complications from influenza is higher in children and the elderly and those with certain underlying conditions (Barker, 1986; Bridges et al., 2008; Simonsen et al., 2000; Thompson et al., 2004). The most common complications include primary influenza viral pneumonia, secondary bacterial pneumonia, and the exacerbation of chronic pulmonary and cardiopulmonary diseases such as asthma and congestive heart failure (Bridges et al., 2008).

The influenza viruses were first isolated in the early 1900s by Smith and his associates (influenza A, 1933), Francis (influenza B, 1939), and Taylor (influenza C, 1950) (Francis, 1940; Smith et al., 1933; Taylor, 1951). In 1936, Burnet discovered that the virus could be grown in embryonated hen eggs, and in the 1950s animal cell culture systems were developed (Burnet, 1936; Mogabgab et al., 1954; Treanor, 2010). In 1943, the first commercial influenza vaccines were approved for use in the United States, and consisted of inactivated virus grown in chicken eggs (Treanor, 2010). With a few adaptations, propagation of influenza viruses in chicken eggs remains the primary means for growing virus for vaccine production and biomedical research (Treanor, 2010).

Currently, two types of vaccines are available in the United States—the trivalent, inactivated influenza virus (TIV) vaccine, and the live, attenuated, cold-adapted influenza virus (LAIV) vaccine (also trivalent). TIV vaccines, which were first licensed for use in the United States in 1943, are inactivated (killed) virus vaccines that provide immunity against the viruses without causing any signs or symptoms of the infection (Treanor, 2010). The LAIV vaccine is a live but attenuated virus vaccine that is capable of causing mild signs and symptoms of vaccine virus infection (Treanor, 2010). Approved in 2003, LAIV is a live virus vaccine that is cold-adapted (attenuated) so that it does not replicate in the warmer body temperature of the lower airways (CDC, 2003; Treanor, 2010). It is capable of causing mild signs and symptoms of wild-type influenza infection (Treanor, 2010). TIV is administered through an intramuscular injection, while LAIV is administered intranasally via an aerosol sprayer. Both vaccines contain two influenza A and one influenza B subtypes which are recommended by the World Health Organization (WHO) Global Influenza Programme—for example A/California/7/2009 (H1N1)-like,1 A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60-2008-like for the 2010–2011 season (WHO, 2010).

The Advisory Committee on Immunization Practices (ACIP) recommends that all persons 6 months or older receive an annual influenza virus vaccine (CDC, 2010b). For healthy, nonpregnant persons aged 2 to 49 years either TIV or LAIV vaccine is recommended without preference (CDC, 2010b). LAIV is not recommended for children under 2 years of age, pregnant women, adults over 50 years of age, and persons with a history of hyper sensitivity to eggs or LAIV vaccine components (CDC, 2010b). It is also not recommended for persons with asthma and children between 2 and 4 years of age with a history of asthma or wheezing episodes in the 12 months prior to vaccination (CDC, 2010b). For these individuals and individuals with chronic conditions such as hematologic, hepatic, metabolic, neurologic or neuromuscular, pulmonary, or renal disorders; the immunosuppressed; and those between the ages of 6 months and 18 years receiving aspirin or other salicylates; ACIP recommends use of the age-appropriate TIV vaccine (Table 6-1) (CDC, 2010b).

TABLE 6-1. Influenza Vaccines Licensed and Available in the United States.

TABLE 6-1

Influenza Vaccines Licensed and Available in the United States.

In the 2008–2009 season, influenza vaccination was received by 29.1 percent of all persons aged 6 months to 18 years (CDC, 2010a). Thirty-three percent of individuals aged 19 to 49 years, who were considered high-risk for this age group, were vaccinated in comparison to 19.7 percent of individuals who were not considered high-risk for influenza (CDC, 2010a). The vaccine was administered to 51.5 percent of high-risk adults aged 50 to 64 years and 34.2 percent of non-high-risk adults in this age group (CDC, 2010a).

ENCEPHALITIS AND ENCEPHALOPATHY

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of encephalitis or encephalopathy after the administration of influenza vaccine. One study (Nakayama and Onoda, 2007) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population. Three controlled studies (France et al., 2004; Goodman et al., 2006; Hambidge et al., 2006) had very serious methodological limitations that precluded their inclusion in this assessment. The studies by France et al. (2004), Goodman et al. (2006), and Hambidge et al. (2006) were unable to find any cases of encephalopathy or encephalitis following influenza vaccination using a case-crossover or case-control design, so no conclusions could be drawn from these analyses.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and encephalitis or encephalopathy.

Mechanistic Evidence Regarding Encephalitis

The committee identified 11 publications reporting meningoencephalitis or encephalitis after administration of an influenza vaccine. Ten publications did not provide evidence beyond temporality (Blanco et al., 1999; Buchner et al., 1988; Chhor et al., 2008; Drouet et al., 2002; Ehrengut and Allerdist, 1977; Gross et al., 1978; Rosenberg, 1970; Saito and Yanagisawa, 1989; Turkoglu and Tuzun, 2009; Utumi et al., 2010). One publication attributed the development of encephalitis after vaccination to a concomitant infection with herpes simplex virus (Utumi et al., 2010). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Froissart et al. (1978) described a 29-year-old woman presenting with vomiting, fever, and a stiff neck leading to a diagnosis of meningoencephalitis 2 days after administration of an influenza vaccine. The previous year the patient presented with similar symptoms 2 days after receiving an influenza vaccine.

Weight of Mechanistic Evidence

While rare, infection with influenza has been associated with encephalitis (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication, described above, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of encephalitis after administration of an influenza vaccine. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of encephalitis, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Viral infection and viral reactivation may contribute to the symptoms of encephalitis; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and encephalitis as weak based on knowledge about the natural infection and one case.

Causality Conclusion

Conclusion 6.1: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and encephalitis.

Mechanistic Evidence Regarding Encephalopathy

The committee identified five publications reporting encephalopathy after administration of an influenza vaccine. Three publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Ehrengut and Allerdist, 1977; Morimoto et al., 1985; Woods and Ellison, 1964).

Described below are two publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Boutros and Keck (1993) described a 75-year-old woman presenting with confusion 12 days after receiving an influenza vaccine. Physical examination showed anorexia, insomnia, hallucinations, and delirium. High signal lesions in the white matter were revealed upon magnetic resonance imaging. The symptoms resolved upon treatment with thiothixene. One year prior to the current episode the patient developed similar symptoms 21 days after receiving an influenza vaccine.

Warren (1956) described a 19-year-old man presenting with profuse rhinorrhea, wheezing, feverishness, soreness behind the eyes, shaking chills, and aching of the arms, back, and head hours after receiving an influenza vaccine. Two hours later the patient was weak, dizzy, unable to sit upright, and began to black out. Physical examination revealed the patient to be semicomatose and delirious. One year prior to the current episode the patient had presented with severe malaise 2 days after receiving an influenza vaccine.

Weight of Mechanistic Evidence

The publications described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of encephalopathy after administration of an influenza vaccine. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of encephalopathy, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Viral infection and viral reactivation may contribute to the symptoms of encephalopathy; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and encephalopathy as weak based on two cases.

Causality Conclusion

Conclusion 6.2: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and encephalopathy.

SEIZURES

Epidemiologic Evidence

The committee reviewed eight studies to evaluate the risk of seizures after the administration of influenza vaccine. Four studies (D'Heilly et al., 2006; Izurieta et al., 2005; McMahon et al., 2005; Rosenberg et al., 2009) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

The four remaining controlled studies (France et al., 2004; Goodman et al., 2006; Greene et al., 2010; Hambidge et al., 2006) were included in the weight of epidemiologic evidence and are described below.

France et al. (2004) conducted a case-crossover study in 251,600 children (younger than 18 years of age) enrolled in five health maintenance organizations (HMOs) participating in the Vaccine Safety Datalink (VSD). The study investigated the occurrence of adverse events (reported as outpatient, inpatient, and emergency department visits) within 14 days of TIV administration from January 1993 through December 1999. Two control periods were defined as 15 to 28 days before vaccination (control period 1) and 15 to 28 days after vaccination (control period 2). The inclusion criteria required participants to be enrolled in the HMO 28 days before and 28 days after receiving TIV, and have a record of an adverse event in either the risk period or one of the two control periods. Study participants were excluded from the analysis if they experienced an event during both the risk period and one of the control periods, which limited the analysis to discordant pairs. Multiple vaccinations in an individual were treated as independent in the analysis and the pre- and postvaccination control periods in the same individual were analyzed independently, which would tend to increase the number of associations found to be significant by chance alone (type I error). Seizures were observed in 81 children, but no significant associations were reported for outpatient, inpatient, and emergency department visits for seizures during the 14-day risk period when compared to the prevaccination control period or postvaccination control period. Additional analyses with liberalized significance criterion (.05 < p ≤ .20) were used to identify potentially overlooked associations, but seizures remained nonsignificant.

Hambidge et al. (2006) conducted case-crossover analysis to examine the risk of seizures after influenza vaccination in 45,356 children (6 to 23 months of age) enrolled in eight medical care organizations (MCOs) participating in the VSD. The study investigated the occurrence of adverse events (reported as outpatient, inpatient, and emergency department visits) within 14 days (primary analysis) of TIV administration from 1991 through 2003. Two control periods were defined as 15 to 28 days before vaccination (control period 1) and 15 to 28 days after vaccination (control period 2). Only discordant pairs were analyzed, and participants that experienced an event during both the risk period and one of the control periods were excluded. Half of the study population overlapped the patients observed in the study by France et al. (2004), but separate analyses for the unique subgroups presented in this paper (1991–1992 and 2000–2003) were not performed. A total of 24 seizures were observed in the 14-day risk window; 22 were found to be febrile seizures, and 17 were reported during the same period that has been associated with febrile seizures following measles, mumps, and rubella (MMR) immunization (7–14 days postvaccination). Children who received MMR vaccine on the same day as TIV were excluded from the analysis (nine cases and one control). The matched odds ratio for seizures within 14 days of TIV administration was 1.36 (95% CI, 0.63–2.97). The authors concluded that after excluding children who received MMR vaccine on the same day, TIV administration was not associated with an increased risk in febrile seizures. They also noted that no signal of seizures within 3 days of TIV administration was observed.

Goodman et al. (2006) conducted a nested case-control study in children (6 to 23 months of age) enrolled in the HealthPartners Medical Group (HPMG) during the 2002–2003 and 2003–2004 influenza seasons. Vaccination histories were obtained from the HPMG vaccine registry and the investigators coded whether the TIV injection was a first or second dose during the given influenza season. Seizure diagnoses were verified by reviewing the medical charts. The risk window was defined as 0–42 days following vaccination, but the investigators also analyzed 0–3-day, 4–14-day, and 14–42-day windows. The cohort included 13,383 children, of whom 3,697 received TIV during the study period. Cases were matched to three controls (children who did not have the outcome of interest) on date of birth and gender; the index date for the controls was the date the event was observed in the matched case. The authors did not report how many cases and controls were included in the seizure analysis or list characteristics of these two groups. The hazard ratio for seizures within 42 days of a first dose of TIV was 1.17 (95% CI, 0.36–3.86), and within 42 days of a second dose of TIV the hazard ratio was 1.026 (95% CI, 0.19–5.56). Shorter time windows did not have the power to assess the hazard ratio for seizures following TIV and were not listed in the study. The authors concluded that TIV administration is not associated with an increased rate of seizures.

Greene et al. (2010) conducted a retrospective cohort study in children (6 months to 17 years of age) and adults (≥ 18 years of age) enrolled in eight MCOs participating in the VSD. The study investigated the occurrence of adverse events (reported as inpatient and emergency department visits) after receipt of influenza vaccine from September through April of the 2005–2006, 2006–2007, and 2007–2008 influenza seasons. The risk period for the seizures analysis (0 to 7 days after vaccination) of the given season was compared to the control period (8 to 15 days after vaccination) of the same season. The number of vaccine doses administered to children during the 2005–2006 season was 317,108; during the 2006–2007 season was 415,446; and during the 2007–2008 season was 462,998. The relative risk of seizures in children within 7 days of influenza vaccination was 1.35, 0.80, and 0.98 for the 2005–2006, 2006–2007, and 2007–2008 influenza seasons, respectively. The number of vaccine doses administered to adults during the 2005–2006 season was 1,429,974; during the 2006–2007 season it was 1,598,880; and during the 2007–2008 season it was 1,742,858. The relative risk of seizures in adults within 7 days of influenza vaccination was 0.99, 0.96, and 1.09 for the 2005–2006, 2006–2007, and 2007–2008 influenza seasons, respectively. None of the associations reached the critical value of the log-likelihood ratio, and none of the relative risks achieved statistical significance. This paper also included an analysis comparing rate ratios in the current year with the cumulative ratios in prior comparison years. All of these comparisons also found no increase in seizures in the risk period.

Weight of Epidemiologic Evidence

Analyses from four studies (one retrospective cohort, one case-control, and two case-crossover designs) were included in the epidemiologic evidence. France et al. (2004) did not find a statistically significant association between seizures and TIV, even with liberalized significance criterion (.05 < p ≤ .20). The study by Hambidge et al. (2006) observed a null association in seizures within 14 days of TIV administration when children who received MMR simultaneously with TIV were removed from the case-crossover analysis. The case-control study by Goodman et al. (2006) found no association between seizures and TIV, but the precision was low. Greene et al. (2010) did not find a statistically significant association among the analyses for children and adults; however, the control period was within the risk period of the other papers. Although power was limited in all the studies, they were generally well done and results were consistent, supporting the committee's conclusion that the evidence overall reached a moderate level of confidence for a null association. See Table 6-2 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-2. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Seizures.

TABLE 6-2

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Seizures.

The committee has a moderate degree of confidence in the epidemiologic evidence based on four studies with sufficient validity and precision to assess an association between influenza vaccine and seizures; these studies consistently report a null association.

Mechanistic Evidence

The committee identified five publications reporting the development of seizures after administration of an influenza vaccine. The publications did not provide evidence beyond temporality (Chhor et al., 2008; Hirtz et al., 1983; Kennedy et al., 2002; Marine and Stuart-Harris, 1976; Wright et al., 1976). In addition, Kennedy et al. (2002) attributed seizure development to the corticosteroid therapy used to treat respiratory problems in the patient. One publication reported a cell culture study using an influenza vaccine. Takahashi et al. (2006) reported the isolation of lymphocytes reactive to both the neuronal molecule GluRɛ2 and influenza vaccine from a patient diagnosed with Rasmussen syndrome who had developed a febrile seizure upon infection with influenza A. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of seizure. In some instances fever may contribute to the development of seizures; however, the publications did not provide evidence linking this mechanism to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and seizures as lacking.

Causality Conclusion

Conclusion 6.3: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and seizures.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of acute disseminated encephalomyelitis (ADEM) after the administration of influenza vaccine. These two studies (Izurieta et al., 2005; Nakayama and Onoda, 2007) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and ADEM.

Mechanistic Evidence

The committee identified 15 publications reporting the development of ADEM after administration of an influenza vaccine. The publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved (Antony et al., 1995; Buchner et al., 1988; Garea Garcia-Malvar et al., 2004; Huynh et al., 2008; Iyoda et al., 2004; Kavadas et al., 2008; Kepes, 1993; Nagano et al., 1988; Nakamura et al., 2003; Ravaglia et al., 2004; Rosenberg, 1970; Saito et al., 1980; Selvaraj et al., 1998; Vilain et al., 2000; Yahr and Lobo-Antunes, 1972). In addition, two publications reported concomitant infections making it difficult to determine the precipitating event (Kavadas et al., 2008; Nagano et al., 1988). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

While rare, influenza infection has been associated with the development of ADEM (Yiu and Kornberg, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of ADEM. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of ADEM; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and ADEM as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 6.4: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and ADEM.

TRANSVERSE MYELITIS

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of transverse myelitis after the administration of influenza vaccine. This study (Vellozzi et al., 2009) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and transverse myelitis.

Mechanistic Evidence

The committee identified six publications reporting the development of transverse myelitis after administration of an influenza vaccine. The publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved (Bakshi and Mazziotta, 1996; Buchner et al., 1988; Larner and Farmer, 2000; Nakamura et al., 2003; Sugimoto et al., 1968; Wells, 1971). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

Influenza infection has, rarely, been associated with the development of transverse myelitis (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of transverse myelitis. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of transverse myelitis; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and transverse myelitis as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 6.4: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and transverse myelitis.

OPTIC NEURITIS

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of optic neuritis (ON) after the administration of influenza vaccine. The two controlled studies (DeStefano et al., 2003; Payne et al., 2006) contributed to the weight of epidemiologic evidence and are described below.

DeStefano et al. (2003) conducted a case-control study to evaluate the association between influenza vaccination and optic neuritis using data from three HMOs participating in the VSD. The optic neuritis analysis included 108 cases and 228 controls. The cases had a documented physician's diagnosis from 1995 through 1999, and were matched to controls from the HMO on date of birth (within 1 year) and sex. The authors evaluated the date of disease onset using data described in the medical record or reported in the telephone interview. The immunization status was obtained from vaccination records, medical records, and telephone interviews. The study had high rates of self-reported vaccinations from outside the HMO system (32 percent of cases and 39 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever vaccinated with influenza before optic neuritis diagnosis was 1.2 (95% CI, 0.6–2.3). The authors concluded that influenza vaccination did not appear to be associated with an increased risk of optic neuritis in adults.

Payne et al. (2006) used the Defense Medical Surveillance System (DMSS) to conduct a case-control study among U.S. military personnel. The study included 1,131 cases with a first diagnosis of optic neuritis from 1998 through 2003, and 3,393 controls. The cases and controls were matched on sex, military service (e.g., active or reserve), and deployment within 18 weeks of diagnosis date. The vaccination status and date of first symptom of optic neuritis were obtained from the DMSS and reviewed by a neuroophthalmologist. About 15 percent of the cases (173 patients) and controls (510 patients) received influenza vaccine within the 18-week risk period, which suggested that possible confounders related to the decision to vaccinate were present. Although the authors considered three exposure times—6, 12, and 18 weeks after vaccination—only the odds ratio for optic neuritis diagnosis within 18 weeks of influenza vaccination was given (OR, 1.01; 95% CI, 0.79–1.29). The authors noted without presenting results that similar conclusions were obtained using 6- and 12-month exposure times. The authors concluded that vaccination against influenza does not appear to increase the risk of optic neuritis in adults.

Weight of Epidemiologic Evidence

Neither of the two case-control studies included in the evidence assessment found evidence of an association between influenza vaccine and the onset of ON in adults even after adjustment for potential confounders. However, DeStefano et al. (2003) did not define a specific exposure time and had no short-term assessment in their primary analysis. The authors performed secondary analyses considering the timing of the influenza vaccination (< 1 year, 1–5 years, and > 5 years) relative to the ON onset, which also showed no significant association, but they did not state how they handled the timing of vaccination for those who had more than one influenza vaccine before the onset of ON or when influenza was given in combination with other vaccines. In both studies (DeStefano et al., 2003; Payne et al., 2006), the proportion of cases and controls who had influenza vaccination was around 15–16 percent, which suggests possible confounders related to the decision to vaccinate may be present. Payne et al. (2006) is a study with a better design and analysis. The authors mentioned adjusting for other vaccines in their analysis of anthrax vaccine, but it is not clearly stated that they adjusted for other vaccines in their analysis of the safety of the influenza vaccine, which is the interest in this review. The confidence intervals for the odds ratio from DeStefano et al. (2003) were wide while those from Payne et al. (2006) were relatively narrow around 1. Considering the limitations of the studies, the small number of studies, and the width of the confidence intervals, the committee has limited confidence in the epidemiologic evidence. See Table 6-3 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-3. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Optic Neuritis.

TABLE 6-3

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Optic Neuritis.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between influenza vaccine and optic neuritis.

Mechanistic Evidence

The committee identified six publications reporting the development of optic neuritis after administration of an influenza vaccine. Four publications did not provide evidence beyond temporality (Huynh et al., 2008; Ray and Dreizin, 1996; Tan et al., 2010; Vilain et al., 2000). These publications did not contribute to the weight of mechanistic evidence.

Described below are publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

A Vaccine Adverse Event Reporting System (VAERS) report, identified in Vellozzi et al. (2009), describing the development of optic neuritis after administration of influenza vaccines in back-to-back years, was obtained via a Freedom of Information Act (FOIA) request (FDA, 2010). The patient was a 61-year-old woman presenting with transient blindness 20 and 17 days after receiving influenza vaccines in 1992 and 1993, respectively. Evidence of causality beyond a temporal relationship between administration of the vaccines and development of transient blindness was not provided.

Hull and Bates (1997) described a 59-year-old woman presenting with decreased visual acuity. Physical examination showed light perception in the right eye, the ability to count fingers at one foot in the left eye, and bilateral disk edema 2 weeks after administration of an influenza vaccine. The patient's visual acuity recovered with intravenous corticosteroid treatment. One year later the patient presented with deterioration of vision to light perception in both eyes 17 days after receiving an influenza vaccine. After intravenous corticosteroid treatment visual acuity improved in the patient's right eye but remained unchanged in the left eye.

Weight of Mechanistic Evidence

The publications, described above, did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of optic neuritis after administration of an influenza vaccine. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of optic neuritis, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Autoantibodies, T cells, immune complexes, and molecular mimicry may contribute to the symptoms of optic neuritis; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and optic neuritis as weak based on two cases.

Causality Conclusion

Conclusion 6.6: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and optic neuritis.

NEUROMYELITIS OPTICA

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of neuromyelitis optica (NMO) after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and NMO.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of NMO developing after administration of an influenza vaccine.

Weight of Mechanistic Evidence

Autoantibodies, T cells, complement activation, and molecular mimicry may contribute to the symptoms of NMO; however, the committee did not identify literature reporting evidence of these mechanisms after administration of influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and NMO as lacking.

Causality Conclusion

Conclusion 6.7: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and NMO.

MULTIPLE SCLEROSIS ONSET IN ADULTS

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of onset (date of first symptom) of multiple sclerosis (MS) in adults after the administration of influenza vaccine. Two controlled studies (Lauer and Firnhaber, 1990; Ramagopalan et al., 2009) had very serious methodological limitations that precluded their inclusion in this assessment. The control group used in the study by Lauer et al. (1990) was flawed, and the authors may have selected a group at greater or lesser likelihood to receive the vaccine. Ramagopalan et al. (2009) did not attempt to validate self-report vaccination data or confirm the timing of vaccination, and the choice of spousal controls could have introduced selection bias.

The two remaining controlled studies (DeStefano et al., 2003; Hernan et al., 2004) contributed to the weight of epidemiologic evidence and are described below.

The study by DeStefano et al. (2003) was described in detail in the section on optic neuritis. This case-control study evaluated the association between influenza vaccination and MS or optic neuritis onset using data from three HMOs participating in the VSD. The MS analysis included 332 cases and 722 controls. Although there is a large number of cases and controls, the study had high rates of self-reported vaccinations from outside the HMO system (32 percent of cases and 39 percent of controls) that could not be verified, which may have biased the results. The odds ratio for ever versus never vaccinated with influenza before MS onset was 0.7 (95% CI, 0.5–1.1). The authors concluded that influenza vaccination does not appear to be associated with an increased risk of MS onset in adults.

Hernan et al. (2004) used the General Practice Research Database (GPRD) to perform a nested case-control study. Cases with a confirmed MS diagnosis from 1993 through 2000, and a minimum of 3 years follow-up in the database, were selected and matched with controls. The study included 163 cases and 1,604 controls; all participants were over 18 years of age, except for one unvaccinated control that was 16 years of age. The date of first symptom of MS and influenza vaccination status were identified in the medical record. The rates of vaccination were very low among the cases and controls (6.1 percent and 6.0 percent, respectively), which raised the possibility that subjects selected for vaccination were different in relevant ways. The odds ratio for MS onset within 3 years of influenza immunization compared to never vaccinated was 1.0 (95% CI, 0.5–2.0). The authors concluded that influenza immunization did not appear to be associated with an increased risk of MS onset in adults, but the confidence intervals in the study were quite broad, including a potential doubling of risk with vaccination.

Weight of Epidemiologic Evidence

Neither of the two case-control studies considered in the assessment of epidemiologic evidence found an association between influenza vaccine and onset of MS in adults. However, there are some concerns about the study designs and analyses. DeStefano et al. (2003) did not define a specific exposure time and had no short-term assessment in their primary analysis. The authors performed secondary analyses considering the timing of the influenza vaccination (< 1 year, 1–5 years, and > 5 years) relative to the MS onset, which showed no significant association, but they did not state how they handled the timing of vaccination for those who had more than one influenza vaccine before the onset of MS or when influenza was given in combination with other vaccines. Hernan et al. (2004) considered a fixed exposure time of 3 years within the onset of MS but did not present results on any subanalysis considering the timing of the influenza vaccination. In addition, the rates of vaccination were very low among the cases and controls (around 6 percent). Finally, the confidence intervals of the study were fairly broad and a clinically relevant association could not be ruled out. Given these study limitations and the small number of studies, the committee has limited confidence in the overall evidence. See Table 6-4 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-4. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Onset in Adults.

TABLE 6-4

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Onset in Adults.

The committee has limited confidence in the epidemiologic evidence based on two studies that lacked validity and precision to assess an association between influenza vaccine and onset of MS in adults.

Mechanistic Evidence

The committee identified three publications reporting the onset of MS in adults after administration of an influenza vaccine. Rabin (1973) reported the development of MS after administration of an influenza vaccine in one patient but did not provide clinical, diagnostic, or experimental evidence, including the time frame between administration of the vaccine and development of symptoms. Two publications did not provide evidence beyond temporality (Nakajima et al., 2003; Yahr and Lobo-Antunes, 1972). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The symptoms described in the publications referenced above are consistent with those leading to the onset of MS in adults. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and onset of MS in adults as lacking.

Causality Conclusion

Conclusion 6.8: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and onset of MS in adults.

MULTIPLE SCLEROSIS RELAPSE IN ADULTS

Epidemiologic Evidence

The committee reviewed three studies to evaluate the risk of relapse of MS in adults after the administration of influenza vaccine. One controlled study (Mokhtarian, 1997) had very serious methodological limitations that precluded its inclusion in this assessment. Mokhtarian (1997) conducted a placebo-controlled trial with 19 MS patients, but the study was too small to be informative, and the author did not state if the treatment was assigned randomly.

The two remaining controlled studies (Confavreux et al., 2001; Miller et al., 1997) contributed to the weight of epidemiologic evidence and are described below.

Miller et al. (1997) conducted a double-blind, randomized controlled trial in 104 patients with relapsing-remitting MS identified at five MS centers in the United States. The participants were randomized at each center to receive influenza vaccination (49 patients) or placebo injection (54 patients). Injections took place during the autumn of 1993, and then patients were followed for 6 months for evidence of MS relapse. At 4 weeks and 6 months, patients were examined by a blinded neurologist, and at 1 week and 3 months a blinded nurse conducted a telephone assessment. Comparisons of MS relapse were performed at 28 days after and 6 months after vaccine or placebo injection. During the 28-day period, MS exacerbations were reported in three vaccine patients and two placebo patients. Over the 6-month period, 11 vaccine patients and 6 placebo patients experienced MS exacerbations. The difference in MS relapse was not statistically significant for either risk period. The authors concluded that influenza vaccination did not appear to be associated with an increased risk of relapse in MS patients.

Confavreux et al. (2001) conducted a case-crossover study in adults attending neurology centers affiliated with the European Database for Multiple Sclerosis. The study included 643 adults with definite or probable MS diagnoses and at least one relapse of symptoms that occurred from 1993 through 1997. The relapse was confirmed during outpatient visits or during hospitalizations at the neurology centers. For each patient, information on immunizations received was obtained from telephone questionnaires and confirmed with vaccination records or written confirmation from the physician. Vaccinations were confirmed for 260 participants, not confirmed for 57, and 326 reported receiving no vaccinations during the study period. The risk period was defined as any time within 2 months before the relapse, and the four control periods were outlined as 2-month intervals prior to the risk period (2–10 months before the relapse). The relative risk of relapse of MS within 2 months of influenza vaccination was 1.08 (95% CI, 0.37–3.10). The authors concluded that vaccination against influenza does not appear to increase the risk of MS relapse in adults.

Weight of Epidemiologic Evidence

The two studies considered in the assessment of the epidemiologic evidence did not find evidence of an association between influenza vaccine and relapse of MS. However, both studies had methodological issues. Neither of the studies were adequately powered to rule out a clinically relevant association. Furthermore, the study by Confavreux et al. (2001) could not adequately control for a potential association between influenza infection and MS relapse, which could have been affected by vaccination and would tend to mask a causative influence of vaccination in a subset of patients. See Table 6-5 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-5. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Relapse in Adults.

TABLE 6-5

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Relapse in Adults.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between influenza vaccine and relapse of MS in adults.

Mechanistic Evidence

The committee identified three publications reporting the administration of an influenza vaccine to patients with MS. Moriabadi et al. (2001) did not report MS relapse after vaccination. Salvetti et al. (1995) reported fewer MS relapses in the year after vaccination than during the year preceding vaccination. The authors did not report the latency between administration of the vaccine and MS relapse after vaccination. Kepes (1993) did not provide evidence beyond temporality. The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

There is strong evidence that several viral infections trigger flare-ups in patients with MS. Whether influenza virus triggers these flare-ups is less certain. Given that vaccination triggers inflammatory responses, and inflammation is associated with exacerbations of MS, it is possible that vaccination could exacerbate clinical symptoms in MS patients. However, clinical studies with cohorts of MS patients generally do not support a causal relationship between TIV and exacerbations of MS. Case reports are few, but generally time is the only connection between MS flare-up and vaccination. Thus, there is no mechanistic evidence to support an association between influenza vaccines and MS relapse in adults.

The symptoms described in the publications referenced above are consistent with those leading to the relapse of MS in adults. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of MS; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and relapse of MS in adults as lacking.

Causality Conclusion

Conclusion 6.9: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and relapse of MS in adults.

GUILLAIN-BARRÉ SYNDROME

Epidemiologic Evidence

The committee reviewed 21 studies to evaluate the risk of Guillain-Barré syndrome (GBS) after the administration of influenza vaccine.2 Nine studies (Geier et al., 2003; Haber et al., 2004; Izurieta et al., 2005; Johnson, 1982; Muhammad et al., 2011; Nakayama and Onoda, 2007; Souayah et al., 2007, 2009; Vellozzi et al., 2009) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. Three controlled studies (Hambidge et al., 2006; Lasky et al., 1998; Wu et al., 1999) had very serious methodological limitations that precluded their inclusion in this assessment. The study by Hambidge et al. (2006) was unable to find any cases of GBS within the defined risk period following influenza vaccination using a case-crossover design, so no conclusions could be drawn from this analysis. The random-digit-dialing telephone survey used by Lasky et al. (1998) to define the population rates of vaccination was problematic, and the results suggested confounding by age may be present. Wu et al. (1999) conducted a case-control study, but provided inadequate information on how the controls and exposure were classified.

The nine remaining controlled studies (Burwen et al., 2010; Greene et al., 2010; Hughes et al., 2006; Hurwitz et al., 1981; Juurlink et al., 2006; Kaplan et al., 1982; Roscelli et al., 1991; Stowe et al., 2009; Tam et al., 2007) contributed to the weight of epidemiologic evidence and are described below.

Hurwitz et al. (1981) conducted a cohort study in GBS patients based on data from a voluntary surveillance system that analyzed disease onset from September 1978 through March 1979. During the study period, 1,813 neurologists (37 percent of the American Academy of Neurology members) submitted surveillance forms reporting new cases of GBS. The surveillance form listed the patient's date of birth, race, sex, county of residence, date of GBS onset, and date and type of any vaccinations received within 8 weeks of disease onset. Cases of GBS that did not receive an influenza vaccination within 8 weeks of onset were classified as unvaccinated, whereas those that received influenza vaccine during this period were listed at vaccinated. Since only neurologists participated, cases reported or seen in other settings were missed in this analysis. The vaccinated patients tended to be older than the unvaccinated (median age of 55 years compared to 35 years of age, respectively) and included a higher percentage of women (69 percent compared to 44 percent). The analysis was restricted to adults (≥ 18 years of age) and included 12 vaccinated and 393 unvaccinated cases. U.S. population estimates were used from the Bureau of the Census, and an estimate of the number of vaccinated adults was obtained from a national immunization survey conducted by the Opinion Research Corporation. Incidence rates were calculated for the vaccinated and unvaccinated groups, and expressed as 0.52 and 0.38 cases per million persons per month, respectively. The relative risk of onset of GBS within 8 weeks of influenza vaccination was 1.4 (95% CI, 0.7–2.7). The authors concluded that there was no increased risk of GBS onset within 8 weeks of immunization during the 1978–1979 influenza season.

Kaplan et al. (1982) conducted a cohort study in GBS patients and used the same methods as Hurwitz et al. (1981) to analyze the onset of disease from September through March of the 1979–1980 and 1980–1981 influenza seasons. A total of 1,648 neurologists submitted surveillance forms in 1979–1980, and 1,557 participated in 1980–1981. Cases not reported or seen by neurologists were missed in this study. The analysis included 7 vaccinated and 412 unvaccinated adults (≥ 18 years of age) with GBS onset during 1979–1980, and 12 vaccinated and 347 unvaccinated during 1980–1981. The relative risk of GBS onset within 8 weeks of vaccination during the 1979–1980 influenza season was 0.6 (95% CI, 0.45–1.32), and during the 1980–1981 season it was 1.4 (95% CI, 0.80–1.76). The authors concluded that there was no increased risk of GBS onset within 8 weeks of immunization during the 1979–1980 or 1980–1981 influenza season.

Roscelli et al. (1991) conducted a retrospective cohort study in active duty soldiers with health statistics from the U.S. Army Health Services Command database and vaccination information from the office of the Surgeon General of the U.S. Army. A total of 289 patients were hospitalized for onset of GBS at U.S. Army Medical Treatment Facilities from 1980 through 1988. The risk period was defined as cases of GBS occurring during November of 1980 to 1988, and the control period included cases reported in non-November months during these years. By looking at diagnoses in November, the onset of GBS was assumed to occur 1 month after vaccination (the U.S. Army requires annual immunization during the last week of October). A total of 23 cases occurred in November, and a mean of 24.18 cases were reported for non-November months. The monthly incidence of GBS was calculated by estimating the annual number of active duty army soldiers eligible for influenza vaccination (780,000 soldiers) and the number that received vaccine (624,000 based on an 80 percent compliance rate). For the month of November, the monthly incidence of GBS was 3.3 per million (95% CI, 2.0–4.6); during the non-November months, the incidence was 3.4 per million (95% CI, 3.0–3.8). No significant difference was observed between the risk and control periods. The authors concluded that influenza vaccination during 1980 through 1988 was not associated with an increased incidence in GBS in active duty U.S. Army soldiers. GBS is generally more frequent in winter months and has been associated with influenza infection itself, and these confounders could mask an association between vaccination and GBS. However, there was no evidence of seasonal differences in rates in the non-November months in this study.

Hughes et al. (2006) conducted a self-controlled case-series study in patients (0 to 100 years of age) registered in the GPRD from January 1992 through December 2000. A total of 228 new cases of GBS were identified from medical diagnostic codes in the medical records. If multiple diagnostic codes were present for one patient, the first recorded code was considered the date of disease onset. The immunization status was also found in the medical record. Cases of GBS occurring within 42 days of vaccination (risk period) were compared to diagnoses occurring at any other time during the study period (control period). Three cases occurred in the risk period and 225 cases occurred in the control period. The adjusted relative risk of GBS onset within 42 days of influenza vaccination was 0.99 (95% CI, 0.32–3.12). The authors concluded that vaccination against influenza does not increase the risk of GBS incidence within 42 days of immunization, but noted the study was underpowered to assess a small increase in the background incidence.

Juurlink et al. (2006) conducted a self-controlled case-series study in adults (≥ 18 years of age) from April 1993 through March 2004. Vaccination records were obtained from the Ontario Health Insurance Plan database and linked to hospital admissions information from the Canadian Institute for Health Information Discharge Abstract Database. To identify new cases of GBS and avoid misclassification of patients with chronic inflammatory demyelinating polyneuropathy, the authors excluded cases that had any previous admission for GBS. Any general vaccination that was provided to adults during October and November of each season was classified as an influenza immunization (the authors noted that influenza vaccinations rarely received specific codes). The analysis was restricted to patients who received a vaccination and were hospitalized for GBS onset during the 43 weeks of follow-up. The primary risk and control periods were defined as 2 to 7 weeks and 26 to 43 weeks after vaccination, respectively. A total of 51 cases were observed in the risk period and 141 cases were observed in the control period. The relative risk of a hospitalization for GBS onset during the 2 to 7 weeks after influenza immunization was 1.45 (95% CI, 1.05–1.99). Three additional sensitivity analyses using a longer risk period, shorter control period, or longer control period were conducted to evaluate the seasonal variations in GBS incidence and the results were consistent. The authors also performed an ecological analysis at the population level using a time series in the period between June 1, 1991, and March 31, 2004, to determine if there was an increase in GBS hospitalizations after introduction of universal influenza immunization program. The authors found no significant increase in hospitalization for GBS onset in adults after the mass influenza vaccination program; however, the analysis failed to adequately control for confounding by influenza season.

Tam et al. (2007) used the GPRD to perform a nested case-control study in 553 GBS patients with onset from 1990 through 2001, and 5,445 randomly selected, matched controls. The enrolled cases had a consultation for GBS in their medical record (repeat consultations were excluded) and at least 1 year of follow-up in the GPRD. Any cases with consultations within 4 months of joining a new clinic or less than 2 months of follow-up from the date of GBS onset were excluded from the analysis. A total of 10 controls were matched to each case on general practice clinic, sex, birth year, and an assigned date of GBS consultation. The controls also had to meet the same inclusion criteria that were described above for the GBS cases. The date of influenza immunization was obtained from the medical record and the risk period was defined as 60 days prior to the GBS consultation (or assigned date in controls). The odds ratio for GBS onset within 60 days of immunization against influenza was 0.16 (95% CI, 0.02–1.25). The authors concluded that influenza vaccination is not associated with an increased risk of GBS in adults; however, they noted that this association was not the primary goal of the study. Also, differences between those selected for vaccination and others could have contributed to the association reported.

Stowe et al. (2009) conducted a self-controlled case-series study in GBS patients (all ages) registered in the GPRD from 1990 through 2005. Patients with a first or new consultation for GBS in their medical records were identified, and the date of influenza immunization was recorded. Cases that received at least one influenza vaccination had to complete a two-stage validation process to verify the date of diagnosis and to assess if an earlier date of onset was present in the medical record. The study controlled for season by using the calendar month of vaccination and controlled for age by using 12 age periods in the analysis. A total of 775 episodes occurred in 690 enrolled patients, of which 169 had at least one influenza vaccination. The primary risk period was defined as 0–90 days after vaccination, and 12 and 157 cases occurred within the risk and control periods, respectively (the control period was not defined). The relative risk of GBS onset within 90 days of influenza vaccination was 0.76 (95% CI, 0.41–1.40). The authors concluded that vaccination against influenza does not increase the risk of GBS incidence, and suggested that an association with influenza-like illness may explain the increase of GBS cases often observed during the influenza season.

Burwen et al. (2010) conducted a retrospective cohort study in 22.2 million adults (< 65 and ≥ 65 years of age) who received an influenza vaccination from September through December of 2000 and 2001 according to Medicare claims data. Cases of GBS were identified using hospital claims data from Medicare files, and diagnoses that occurred within 18 weeks of vaccination were reviewed by a physician. The cases were classified as definite, probable, or possible GBS, or not a case. Definite or probable case definitions required exclusion of other diagnoses in the information available. The date of GBS onset was obtained from the medical record. The authors compared the incidence rate of GBS during the risk period (0 to 6 weeks after vaccination) to the incidence rate during the control period (9 to 14 weeks after vaccination). The authors excluded weeks 7 and 8 from the analysis to avoid misclassification of cases in the control period if the risk of GBS extended beyond week 6. In 2000, a total of 33 cases and 10,206,581 person-periods were reported in the risk period, and 38 cases and 10,137,566 person-periods were reported in the control period. In 2001, a total of 51 cases and 11,972,259 person-periods were reported in the risk period, and 42 cases and 11,895,891 person-periods were reported in the control period. The relative risk of onset of GBS (definite or probable) within 6 weeks of influenza vaccination during the 2000 study period was 0.86 (95% CI, 0.52–1.41), and during the 2001 study period it was 1.21 (95% CI, 0.79–1.86). The authors concluded that influenza vaccine was not associated with GBS in adults (≥ 65 years of age) during the 2000–2001 or 2001–2002 influenza season. However, the study was unable to control for the seasonal variation in influenza, a potential confounder.

The study by Greene et al. (2010) was described in detail in the section on seizures. This retrospective cohort study investigated the occurrence of adverse events after influenza vaccination in children and adults enrolled in eight MCOs participating in the VSD. The authors used a Poisson-based approach (applying a maximized sequential probability ratio test [ MaxSPRT]) to assess the risk of GBS after influenza vaccination. The study included cases of GBS reported during outpatient, inpatient, and emergency department visits after receipt of influenza vaccine from September through April of the 2005–2006, 2006–2007, and 2007–2008 influenza seasons. The analysis was restricted to new cases of GBS (the first event of its type) that occurred in the year of interest. The risk period for the GBS analysis (1 to 42 days after vaccination) of the current season was compared to the risk period of the previous seasons (historical risk period). The relative risk of GBS (in all ages) reported 1 to 42 days after influenza vaccination was 0.83 during the 2005–2006 season, 1.13 during the 2006–2007 season, and 1.37 during the 2007–2008 season; none of the associations was significant. The authors concluded that the risk of GBS after influenza vaccination was not significantly elevated compared to no vaccine during the 2005–2006, 2006–2007, and 2007–2008 seasons. However, annual variations in timing and severity of influenza may have affected GBS rates and confounded these associations.

Weight of Epidemiologic Evidence

Of the nine epidemiologic studies reviewed, none were from a randomized clinical trial. GBS has a known seasonal variation, and some studies (see for instance Juurlink et al., 2006; Stowe et al., 2009) have demonstrated an association between GBS and influenza infection, so the risk of confounding by seasonal variation is very high. Only one paper (Juurlink et al., 2006) found a significantly increased risk of GBS associated with influenza vaccine, but results are limited by possible seasonality confounding. Furthermore, the authors noted that the absolute risk is very low. A recently published cohort study (Burwen et al., 2010) using a larger data set for analysis from two influenza seasons did not find a significant increased risk in GBS. One study (Hughes et al., 2006), which also showed no significant association, had a good study design, but the source data used for this analysis did not have enough power to assess an association. Taken together, the nine controlled studies did not support that influenza vaccination is associated with GBS. There are a relatively large number of studies showing lack of evidence of an association between influenza vaccine and GBS, and they were generally well done. All the studies were potentially limited by confounding by seasonality and by the association between influenza itself and GBS, which could mask an association between vaccine and GBS. In addition, strains of influenza targeted by the vaccine vary each year and associations with GBS also may vary. See Table 6-6 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-6. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and GBS.

TABLE 6-6

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and GBS.

The committee has a moderate degree of confidence in the epidemiologic evidence based on nine studies with sufficient validity and precision to assess an association between influenza vaccine and GBS; these studies generally report a null association, but the findings are variable across these studies.

Mechanistic Evidence

The committee identified 16 publications reporting the development of GBS after administration of an influenza vaccine. Fifteen publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved (Blanco-Marchite et al., 2008; Brooks and Reznik, 1980; Eckert et al., 2005; Haber et al., 2004; Hajiabdolbaghi et al., 2009; Kao et al., 2004; Kavadas et al., 2008; Kuitwaard et al., 2009; Liu et al., 2006; Moon and Souayah, 2006; Muhammad et al., 2011; Nakashima et al., 1982; Pelosio et al., 1990; Pritchard et al., 2002; Thaler, 2008). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. One publication also reported the concomitant administration of vaccines making it difficult to determine which, if any, vaccine could have been the precipitating event (Thaler, 2008). In addition, two publications reported preceding illnesses that could have contributed to the symptoms (Haber et al., 2004; Muhammad et al., 2011). These publications did not contribute to the weight of mechanistic evidence.

Described below are two publications, reporting clinical or experimental evidence that contributed to the weight of mechanistic evidence.

Bedard Marrero et al. (2010) described in case number 1 a 68-year-old man, with a history of hypertension, who presented with tingling sensation of the hands and feet 2 weeks after receiving an influenza vaccine. The patient later developed respiratory difficulties, the inability to void, flaccid paralysis in all four extremities, and decreased sensation in cranial nerve V with decreased corneal and gag reflexes leading to a diagnosis of GBS. Immunoglobulin (Ig) G anti-GM1 ganglioside antibodies were demonstrated in the patient.

Nachamkin et al. (2008) immunized mice with influenza vaccines to determine if Campylobacter jejuni (C. jejuni) contamination of influenza vaccine induced GBS by eliciting antiganglioside antibodies. Mice were immunized twice with C. jejuni (positive control), C. jejuni waaF knockout mutant (negative control), A/NJ/1976 influenza vaccine (1976 swine influenza vaccine), 1991–1992 influenza vaccine, or the 2004–2005 influenza vaccine; the immunizations were separated by 21 days. Antibodies to hemagglutinin were demonstrated in mice immunized with influenza vaccine but neither the positive nor negative controls. To determine if the vaccine preparations were contaminated with C. jejuni, the authors tested the serum samples from influenza-vaccine-immunized mice for antibodies to C. jejuni and performed polymerase chain reaction (PCR) on the vaccine preparations to amplify prokaryotic ribosomal ribonucleic acid. The serum tests and PCR were negative suggesting the vaccine preparations were not contaminated with C. jejuni. However, IgM and IgG anti-GM1 ganglioside antibodies were demonstrated in mice immunized with an influenza vaccine or the positive control. Furthermore, the concentration of anti-GM1 IgM and IgG antibodies demonstrated in mice immunized with the A/NJ/1976 influenza vaccine were statistically significant on days 7, 21, and 35 after immunization compared to the day of immunization. The antiganglioside antibody-positive mice did not present with clinical disease.

Weight of Mechanistic Evidence

While rare, infection with influenza viruses A and B have been associated with the development of GBS (Davis, 2008). The committee considers the effects of natural infection one type of mechanistic evidence.

The publications described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of GBS after administration of an influenza vaccine. The presence of antiganglioside antibodies has been associated with many cases of GBS that were not precipitated by C. jejuni infections (Willison, 2005). The mechanism appears to be a cross-reaction to viruses. The presence of antibodies in the case described in Bedard Marrero et al. (2010) is consistent with GBS but does not provide an etiologic connection with the vaccine. Furthermore, Bedard Marrero et al. (2010) did not rule out other possible etiologies of the GBS. Nachamkin et al. (2008) ruled out C. jejuni contamination of the 1976 influenza vaccine. In addition, Nachamkin et al. (2008) reported antiganglioside antibodies in mice immunized against the 1976 influenza vaccine and non-GBS-associated influenza vaccines. However, the mice with antiganglioside antibodies did not have clinical disease and the vaccine dose was higher by body weight than the human vaccine dose (Nachamkin et al., 2008). Furthermore, Nachamkin et al. (2008) did not include a negative influenza control virus that does not induce anti-GM1 antibodies in the study. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of GBS. Autoantibodies, complement activation, immune complexes, T cells, and molecular mimicry may contribute to the symptoms of GBS; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and GBS as weak based on knowledge about the natural infection, one case, and experimental evidence.

Causality Conclusion

Conclusion 6.10: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and GBS.

Although the epidemiologic evidence is graded moderate-null, the committee does not feel the evidence is adequate to favor rejection of an association because of the potential for confounding by season and influenza infection and because of the yearly differences in influenza strains included in the vaccine. While the weight of epidemiologic evidence does not support a causal link between influenza vaccinations evaluated over the last 30 years, an association cannot be confidently ruled out, particularly for future vaccine strains.

CHRONIC INFLAMMATORY DISSEMINATED POLYNEUROPATHY

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of chronic inflammatory disseminated polyneuropathy (CIDP) after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and CIDP.

Mechanistic Evidence

The committee identified five publications reporting CIDP after administration of an influenza vaccine. Four publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved (Brostoff et al., 2008; Kelkar, 2006; Pritchard et al., 2002; Wells, 1971). The publications did not contribute to the weight of mechanistic evidence.

Described below is one publication that contributed to the weight of mechanistic evidence.

Three VAERS reports, identified in Vellozzi et al. (2009) describing the development of CIDP after administration of influenza vaccines were obtained via a FOIA request (FDA, 2010). In two reports the patients developed CIDP after administration of influenza vaccines in two different years. Symptoms developed between 1 and 10 days after administration of the influenza vaccines. In a third report an influenza vaccine was administered to a patient with a history of CIDP. Evidence beyond a temporal relationship between administration of the vaccine and development of CIDP after vaccination was not provided in any of the reports.

Weight of Mechanistic Evidence

The publication described above did not provide evidence sufficient for the committee to conclude the vaccine may be a contributing cause of CIDP. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of CIDP, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of CIDP; however, the publications did not provide evidence linking these mechanisms to the vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and CIDP as weak based on two cases.

Causality Conclusion

Conclusion 6.11: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and CIDP.

BELL'S PALSY

Epidemiologic Evidence

The committee reviewed five studies to evaluate the risk of Bell's palsy after the administration of influenza vaccine. Two studies (Izurieta et al., 2005; Zhou et al., 2004) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study (Mutsch et al., 2004) investigated the association of a vaccine product that is no longer in use and was not included in the epidemiologic evidence.

The two remaining controlled studies (Greene et al., 2010; Stowe et al., 2006) contributed to the epidemiologic weight of evidence and are described below.

Stowe et al. (2006) conducted a self-controlled case-series study in patients (2 to 95 years of age) enrolled in the GPRD. Eligible patients received at least one inactivated influenza vaccine and had a consultation for Bell's palsy from July 1992 through June 2005. Multiple consultations were counted as a single episode if the second consultation occurred within 6 months of the first visit. Follow-up ended on the date the patient left the practice, the date data were last obtained from the practice, date of death, or June 30, 2005, whichever occurred first. The risk period was defined as 1–91 days after vaccination, with separate analyses for 1–30 days, 31–60 days, and 61–91 days. The authors expected a reduced number of events 14 days prior to vaccination and an increased number of events on the day of vaccination because of increased opportunity to record cases, so these were analyzed as separate risk periods. The control period included all other time not attributed to the risk periods. Analyses were adjusted for age (5-year categories), influenza season (defined as July through June), and calendar time (by quarter). A total of 2,128 patients were included in the analysis; they experienced 2,263 Bell's palsy episodes, and received 8,376 doses of influenza vaccine. The relative risk of Bell's palsy within 1–91 days of influenza vaccination was 0.92 (95% CI, 0.78–1.08). Additionally, no significant increased risk was observed when the risk period was separated into 30-day intervals or when the analyses were separated into three age groups (0–44 years, 45–64 years, ≥ 65 years). The authors concluded that influenza vaccine is not associated with an increased risk of Bell's palsy within 3 months of vaccination.

The study by Greene et al. (2010) was described in detail in the section on seizures. This retrospective cohort study investigated the occurrence of adverse events after influenza vaccination in children and adults enrolled in eight MCOs participating in the VSD. The study included cases of Bell's palsy reported during outpatient, inpatient, and emergency department visits after receipt of influenza vaccine from September through April of the 2005–2006, 2006–2007, and 2007–2008 influenza seasons. The risk period for the Bell's palsy analysis (1 to 42 days after vaccination) of the given season was compared to the control period (15 to 74 days before vaccination) of the same season. Because the prevaccination period tended to always be in the earliest part of the season, residual confounding owing to the lack of adjustment for different seasonal risks of infection was present. The relative risk of Bell's palsy in children within 1–42 days of influenza vaccination was 0.67, 1.81, and 1.27 for the 2005–2006, 2006–2007, and 2007–2008 influenza seasons, respectively. The relative risk of Bell's palsy in adults within 1–42 days of influenza vaccination was 1.06, 1.07, and 0.99 for the 2005–2006, 2006–2007, and 2007–2008 influenza seasons, respectively. None of the associations was significant. This paper also included an analysis comparing rate ratios in the current year with the cumulative ratios in prior comparison years. All of these comparisons also found no increase in Bell's palsy in the risk period.

Weight of Epidemiologic Evidence

Analyses from one retrospective cohort study and one self-controlled case-series study were included in the epidemiologic evidence. Neither of these studies (Greene et al., 2010; Stowe et al., 2006) found a significantly increased risk of Bell's palsy after influenza vaccination. The studies were generally well done and the results were consistent, supporting the committee's conclusion that the evidence overall reached a high level of confidence for a null association. See Table 6-7 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-7. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Bell's Palsy.

TABLE 6-7

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Bell's Palsy.

The committee has a high degree of confidence in the epidemiologic evidence based on two studies with validity and precision to assess an association between inactivated influenza vaccine and Bell's palsy; these studies consistently report a null association.

Mechanistic Evidence

The committee identified two publications reporting Bell's palsy after administration of an influenza vaccine. The publications did not provide evidence beyond temporality, some too short based on the possible mechanisms involved (Chou et al., 2007; Philippin et al., 2002). The publications did not contribute to the weight of mechanistic evidence.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and Bell's palsy as lacking.

Causality Conclusion

Conclusion 6.12: The evidence favors rejection of a causal relationship between inactivated influenza vaccine and Bell's palsy.

BRACHIAL NEURITIS

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of brachial neuritis after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and brachial neuritis.

Mechanistic Evidence

The committee identified two publications reporting brachial neuritis after administration of an influenza vaccine. The publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Hansen, 2005; Wells, 1971).

Weight of Mechanistic Evidence

The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of brachial neuritis. Autoantibodies, T cells, and complement activation may contribute to the symptoms of brachial neuritis; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and brachial neuritis as lacking.

Causality Conclusion

Conclusion 6.13: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and brachial neuritis.

SMALL FIBER NEUROPATHY

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of small fiber neuropathy after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and small fiber neuropathy.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of small fiber neuropathy developing after administration of an influenza vaccine.

Weight of Mechanistic Evidence

Autoantibodies, T cells, and molecular mimicry may contribute to the symptoms of small fiber neuropathy; however, the committee did not identify literature reporting evidence of these mechanisms after administration of influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and small fiber neuropathy as lacking.

Causality Conclusion

Conclusion 6.14: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and small fiber neuropathy.

ANAPHYLAXIS

Epidemiologic Evidence

The committee reviewed eight studies to evaluate the risk of anaphylaxis after the administration of influenza vaccine. Seven studies (Bohlke et al., 2003; D'Heilly et al., 2006; DiMiceli et al., 2006; Izurieta et al., 2005; Muhammad et al., 2011; Nakayama and Onoda, 2007; Peng and Jick, 2004) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations.

The one remaining controlled study (Greene et al., 2010) contributed to the weight of epidemiologic evidence and is described below.

The study by Greene et al. (2010) was described in detail in the section on seizures. This retrospective cohort study investigated the occurrence of adverse events after influenza vaccination in children and adults enrolled in eight MCOs participating in the VSD. The study included cases of anaphylaxis reported during inpatient and emergency department visits after receipt of influenza vaccine from September through April of the 2005–2006, 2006–2007, and 2007–2008 influenza seasons. The risk period for the anaphylaxis analysis (0 to 2 days after vaccination) of the given season was compared to the control period (7 to 9 days after vaccination) of the same season. The relative risk of anaphylaxis in individuals of all ages within 2 days of influenza vaccination was 3.00, 4.00, and 1.00 for the 2005–2006, 2006–2007, and 2007–2008 influenza seasons, respectively. None of the associations was significant.

Weight of Epidemiologic Evidence

The committee has limited confidence in the epidemiologic evidence, based on one study that lacked validity and precision, to assess an association between influenza vaccine and anaphylaxis.

Mechanistic Evidence

The committee identified 10 publications reporting anaphylaxis after the administration of an influenza vaccine. One publication reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Ball et al., 2001). This publication did not contribute to the weight of mechanistic evidence.

Described below are nine publications reporting clinical, diagnostic, or experiment evidence that contributed to the weight of mechanistic evidence.

Coop et al. (2008) describe a 37-year-old man presenting with a warm sensation over the entire body, face tingling and redness, postnasal drip, pruritus, and lip numbness 15 minutes after receiving an influenza vaccine. Lip swelling, heart burn, and worsening facial flushing developed over the next 15 minutes. The patient was treated with epinephrine and ranitidine. Subsequent skin prick testing showed positive responses to influenza vaccine and gelatin, and a minimal response to egg. Bands corresponding to the molecular weights of gelatin, hemagglutinin from the influenza vaccine, and ovalbumin from chicken egg were observed on the patient's IgE immunoblot.

Chung et al. (2010) performed a retrospective chart review of egg allergic children (6 months to 18 years) receiving an influenza vaccine during the influenza seasons 2002–2003 through 2008–2009. Patients receiving an influenza vaccine skin test, the two-dose graded administration of the vaccine, or both were identified in each of the influenza seasons. Between the 2002–2003 and 2006–2007 influenza seasons 91 of 146 patients developed a positive response to an influenza vaccine skin test. Between the 2006–2007 and 2008–2009 influenza seasons 24 of 115 patients developed localized or systemic reactions after receiving the two-dose graded influenza vaccine. In addition, 12 of the 56 patients vaccinated, after skin testing, with the influenza vaccine developed localized or systemic reactions. Six systemic reactions involved the development of wheezing, eczema exacerbation, or hives on the face or chest 30 minutes after vaccination.

James et al. (1998) conducted a multicenter clinical trial to investigate the two-dose administration of influenza vaccines to egg allergic individuals. Eighty-three of the 207 subjects recruited into the investigation had a history of egg allergy. All 83 egg allergic subjects developed a positive response to skin prick testing with egg, and four of the 83 subjects developed positive responses to skin prick testing with the influenza vaccine. All 83 egg allergic subjects were administered the influenza vaccine using the two-dose protocol without developing serious immediate or delayed reactions.

DiMiceli et al. (2006) searched the VAERS database from July 1990 to July 2004 for reports mentioning a history of yeast allergy present prior to vaccination. The authors identified 107 reports mentioning a history of yeast allergy. Of the 107 reports, two reported anaphylaxis after vaccination against influenza. Case 1 (13 in the report) describes a 64-year-old woman presenting with oral edema and itchy watery eyes 15–45 minutes after vaccination against influenza. Case 2 (14 in the report) describes a 29-year-old woman presenting with numbness, tachycardia, and difficulty breathing 20 minutes after administration of an influenza vaccine.

Izurieta et al. (2005) reviewed adverse events, reported to VAERS, after administration of a live attenuated influenza vaccine during the 2003–2004 and 2004–2005 influenza seasons. The authors identified seven cases of possible anaphylaxis. Throat swelling developed in four individuals, and periorbital swelling developed in one individual. In all seven reports symptoms developed less than 3 hours after vaccination, and in five reports the symptoms developed in 20 minutes or less.

Lasley (2007) describes a 2.5-year-old boy presenting with hives scattered on the body shortly after receiving his first dose of an influenza vaccine. One month later the patient presented with hives scattered on the body, wheezing, and coughing 10 minutes after receiving a booster dose of influenza vaccine. The patient was treated with diphenhydramine and albuterol. The mother recalls the patient developing perioral hives after eating gummy candy fruit snacks. The patient developed positive responses to skin prick testing with Knox gelatin and liquefied gummy fruit snack. Furthermore, serum testing showed antibovine gelatin IgE.

Muhammad et al. (2011) reviewed reports of adverse events after administration of a trivalent influenza vaccine submitted to VAERS from January 1990 through June 2006, of 2- to 17-year-old children and from July 2008 through June 2009, of 5- to 17-year-old children. The authors identified six cases of anaphylaxis developing after administration of an influenza vaccine from 1990 through 2006. Two of the six did not receive other vaccines and developed chest tightness or wheezing and erythema or hives on the day of vaccination. The remaining four developed symptoms either after the day of vaccination or after administration of multiple vaccines.

Peng and Jick (2004) conducted a population-based study of anaphylaxis using computer records from the GPRD for the period of January 1994 through December 1999. The authors identified two cases of anaphylaxis developing after administration of influenza vaccines. One patient was resuscitated in the emergency department immediately after vaccination.

Zheng et al. (2007) describes a 31-year-old woman with a history of seasonal allergic rhinitis and irritable bowel syndrome who developed conjunctival erythema and pain after using a thimerosal-containing contact lens solution. A booster dose of tetanus toxoid and a thimerosal-free pediatric influenza vaccine were administered without incident. The patient developed a positive response to skin prick testing with a full strength adult influenza vaccine. Generalized pruritus, throat tightness, and a dry cough developed 20 minutes after the skin prick test. The patient was treated with epinephrine.

Weight of Mechanistic Evidence

The publications, described above, presented clinical evidence sufficient for the committee to conclude the vaccine was a contributing cause of anaphylaxis after administration of influenza vaccines. The clinical descriptions provided in many of the publications establish a strong temporal relationship between administration of the vaccine and anaphylactic reactions. In addition, two publications reported the isolation of antigelatin IgE, and two reported positive reactions upon prick skin testing with gelatin. In addition, one publication reported the development of symptoms to vaccination against influenza on two occasions. The vast majority of anaphylactic reactions with evidence of IgE antibodies to constituents within the vaccine have occurred in egg allergic individuals. However, in recent years, vaccine manufacturers have markedly reduced the egg protein content of vaccines and a few recent studies have demonstrated the safety of these vaccines in egg allergic patients.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and anaphylaxis as strong based on 22 cases presenting temporality and clinical symptoms consistent with anaphylaxis.

Causality Conclusion

Conclusion 6.15: The evidence convincingly supports a causal relationship between influenza vaccine and anaphylaxis.

INACTIVATED INFLUENZA VACCINE AND ASTHMA EXACERBATION OR REACTIVE AIRWAY DISEASE EPISODES IN CHILDREN AND ADULTS

Epidemiologic Evidence

The committee reviewed eight studies to evaluate the risk of asthma or reactive airway disease episodes after TIV administration in children and adults with a prior diagnosis of asthma. One controlled study (Kramarz et al., 2000) had very serious methodological limitations that precluded its inclusion in the assessment. Kramarz et al. (2000) inadequately defined the control group and comparison time periods used in their retrospective cohort study.

The seven remaining controlled studies (Bueving et al., 2004; Castro et al., 2001; Kmiecik et al., 2007; Nicholson et al., 1998; Pedroza et al., 2009; Stenius-Aarniala et al., 1986; Tata et al., 2003) were included in the weight of epidemiologic evidence and are described below.

Stenius-Aarniala et al. (1986) conducted a double-blind, randomized controlled trial in 318 patients aged 15 to 73 years, with moderate to severe asthma recruited at nine centers in Finland. The patients were randomly assigned to TIV or placebo groups, and asked to record their peak expiratory flow (PEF) values, medications, and symptom scores throughout the study. A total of 27 patients were lost to follow-up, and it was not clear whether they were balanced across the vaccine and placebo groups. No difference was observed between the PEF values reported among the vaccine and placebo groups during the 7 days after injection. Additionally, there was no difference between the severity of asthma (PEF values, symptom scores, changes in medication, or hospitalization due to asthma) observed in the groups during the 8-month follow-up period from September 1981 through April 1982. The authors concluded that TIV administration does not induce asthma exacerbations in adults with moderate to severe asthma.

Nicholson et al. (1998) conducted a double-blind, randomized controlled crossover trial in patients (18 to 75 years of age) with a history of asthma, recruited from nine respiratory centers and two asthma clinics in the United Kingdom. A total of 255 participants were included in a paired data analysis. These patients received TIV and placebo injections (vaccine then placebo or placebo then vaccine, separated by 2 weeks) and completed symptom diaries postinjection. The authors did not provide information on the characteristics of patients lost to follow-up or the results from appropriate intention-to-treat analysis. The primary outcome was exacerbation of asthma within 72 hours of injection (defined as a decrease in PEF values). Asthma exacerbations were observed in 11 patients after TIV (4.3 percent; 95% CI, 2.2 percent to 7.6 percent) compared to 3 patients after placebo (1.2 percent; 95% CI, 0.2 percent to 3.3 percent). Moderate or severe exacerbations were more common after first-time vaccinations compared to repeat vaccinations (1 in 16 and 1 in 83, respectively), which suggests that an initial TIV exposure is more likely to exacerbate asthma or that patients who experience an exacerbation after TIV are more likely to avoid further doses. The authors concluded that TIV may increase the risk of pulmonary complications in asthmatic patients, although this risk is very small.

Castro et al. (2001) conducted a double-blind, randomized controlled crossover trial in asthmatic patients (3 to 64 years of age) recruited from 19 American Lung Association Asthma Clinical Research Centers from September through November 2000. A total of 1,952 patients received TIV and placebo injections (vaccine followed by placebo or placebo followed by vaccine) and completed symptom diaries for the 14 days following each injection. The mean time between injections was 22 days. The rates of asthma exacerbations in the vaccine group (28.8 percent) were equivalent to the placebo group (27.7 percent) for the 14 days after injection (absolute difference, 1.1 percent; 95% CI, –1.4 percent to 3.6 percent). The authors concluded that TIV does not increase the rate of exacerbations in asthmatic patients.

Tata et al. (2003) conducted a self-controlled case-series study in 6,000 patients with asthma and 6,000 patients with chronic obstructive pulmonary disease (65 to 79 years of age) who were randomly selected from the GPRD. The study used patient records to assess the association between TIV and disease exacerbations for the 1991–1992, 1992–1993, and 1993–1994 influenza seasons. Only patients who experienced at least one event during one of the three risk periods (the day of vaccination, 1 to 2 days after, and 3 to 14 days after vaccination) were included in the analysis. The frequency of diagnostic codes for asthma exacerbation, any asthma diagnosis, and asthma drug prescription use during the risk periods was compared to corresponding rates during the remaining influenza season (defined as October 1 through April 30). In observation of multiple outcomes (asthma exacerbation, asthma diagnosis, and increased medication use) over three influenza seasons and three risk periods, no rate ratio showed an increased risk of the outcome following influenza vaccination. The authors concluded that vaccination with TIV does not increase the risk of asthma exacerbations in patients with asthma. However, the statistical power of the study was reduced by lower than expected vaccination rates (40 percent were vaccinated) and low reporting rates of asthma exacerbation (less than 5 percent of all asthma diagnosis codes).

Bueving et al. (2004) conducted a double-blind, randomized controlled trial in 696 children (6 to 18 years of age) with asthma who were enrolled from general practices in the Netherlands during the 1999–2000 and 2000– 2001 influenza seasons. The study participants were randomly assigned to TIV (347 children) or placebo groups (349 children); the groups had similar baseline characteristics. The patients recorded any asthma symptoms during the 7 days after injection, and each child only participated in one influenza season. No differences in asthma symptoms were reported between the TIV and placebo groups within 7 days of injection. Additionally, the two groups did not differ in the use of medication and number of physician consultations, school absenteeism, and work absenteeism after injection. The authors concluded that asthmatic children have no severe local or general adverse reactions to TIV administration in general practice.

Kmiecik et al. (2007) conducted a double-blind, randomized controlled crossover trial in patients (18 to 65 years of age) with a history of asthma, enrolled at four centers in Poland from October 2004 through January 2005. The study participants were randomized to receive TIV at visit one and placebo at visit two (group A), or placebo at visit one and TIV at visit two (group B). The visits were separated by 14-day intervals. During the 14 days after each injection, patients recorded any asthma exacerbations on diary cards. A total of 286 patients (144 from group A and 142 from group B) were included in the analysis; they received the TIV and placebo injections and completed both 14-day observation periods. The difference in the asthma exacerbation rates after TIV compared to placebo was 2.8 percent (95% CI, 1.9 percent to 4.2 percent) for any exacerbation and 1.7 percent (95% CI, 1.0 percent to 2.7 percent) for severe exacerbations. These small differences were less than the 5 percent difference that the authors considered clinically significant, as well as being less than the study was designed to be able to detect with adequate statistical power. The authors reported that significantly more asthma exacerbations were observed in groups A and B during the first 14-day interval compared to the second 14-day interval; however, results from appropriate repeated measures analyses (required for crossover study designs) were not provided, making the finding somewhat difficult to interpret.

Pedroza et al. (2009) conducted a double-blind, randomized controlled trial in 163 children (5 to 9 years of age) with a diagnosis of mild intermittent or moderate persistent asthma. The study participants were enrolled from the outpatient clinics of the Instituto Nacional de Pediatria, Mexico, and randomized to receive two doses of TIV (132 children) or placebo (31 children) during the 2001–2002 influenza season. The injections were separated by 28-day intervals. Evaluation of adverse events and measurement of the forced expiratory volumes (FEVs) at 1, 2, and 3 seconds (FEV1, FEV2, and FEV3, respectively) were assessed at baseline (visit one), 3 to 5 days after the first injection (visit two), and 3 to 5 days after the second injection (visit four). The authors did not adjust for differences in baseline FEV values between the vaccine and placebo groups; the placebo group had higher FEV values at visit one. There were no significant differences in changes in FEV1, FEV2, or FEV3 among the TIV and placebo groups between visits one and two, or visits one and four. The authors concluded that TIV administration in children with asthma is not associated with a significant change in pulmonary function tests.

The committee reviewed four studies evaluating the risk of asthma or reactive airway disease episodes after TIV administration in children without regard to any prior diagnosis of asthma. One study (Rosenberg et al., 2009) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population. One controlled study (Benke et al., 2004) had very serious methodological limitations that precluded its inclusion in the assessment. The study by Benke et al. (2004) was a cross-sectional survey that could not establish the temporal sequence between influenza vaccination and asthma episodes, and since the survey was based on self-reported recall of past events, vaccinations were not validated.

The two remaining controlled studies included in the weight of epidemiologic evidence (France et al., 2004; Hambidge et al., 2006) had overlapping study populations and are described below.

The study by France et al. (2004) was described in detail in the section on seizures. This case-crossover study investigated the occurrence of adverse events within 14 days of TIV administration in children enrolled in five HMOs participating in the VSD from January 1993 through December 1999. Information regarding any prior diagnosis of asthma was not ascertained. Significant negative associations were reported for outpatient, inpatient, and emergency department visits for asthma during the 14-day risk period when compared to the prevaccination control period (OR, 0.72; 95% CI, 0.68–0.76) and postvaccination control period (OR, 0.87; 95% CI, 0.82–0.93). When children aged 6 to 23 months were analyzed separately, a negative association was observed for outpatient and emergency department asthma visits 14 days after vaccination compared to the prevaccination control period (OR, 0.73; 95% CI, 0.63–0.85) and postvaccination control period (OR, 0.84; 95% CI, 0.72–0.99). Separate analyses were not provided for asthma episodes among children with a prior diagnosis of asthma or without a prior diagnosis. The authors concluded that TIV does not increase the risk of asthma in children during the 14 days after vaccination.

The study by Hambidge et al. (2006) was described in detail in the section on seizures. This case-crossover analysis examined the occurrence of adverse events within 14 days of TIV administration in children enrolled in eight MCOs participating in the VSD from 1991 through 2003. Half of the study population overlapped the patients observed in the study by France et al. (2004), but separate analyses for the additional time periods presented in this paper (1991–1992 and 2000–2003) were not performed. Significantly fewer outpatient visits for asthma occurred in children aged 6 to 23 months within 14 days of vaccination compared to pre- and postvaccination periods (control period 1 OR, 0.69; 95% CI, 0.63–0.76; control period 2 OR, 0.80; 95% CI 0.73–0.87). Separate analyses were not provided to distinguish asthma episodes among children with a prior diagnosis of asthma or without a prior diagnosis. The authors concluded that the lower risk of asthma observed within 14 days of TIV administration may be due to the healthy vaccine effect or reflect a change in asthma therapy during the vaccination visit.

Weight of Epidemiologic Evidence

The seven studies reviewed (of which six were randomized controlled trials and four had negligible limitations in research methodology) for asthma or reactive airway disease episodes after TIV administration in children and adults with a prior diagnosis of asthma reported consistent findings across a broad age range of children and adults. The studies suggest no clinically or statistically significant increase in asthma exacerbation episodes occurs after TIV administration, regardless of whether episodes were measured by objective pulmonary function tests, prescription drug use, clinic visits, hospitalizations, absence from school or work, or subjective symptom diaries. In one randomized trial with serious losses to follow-up and other methodological limitations (Nicholson et al., 1998), a significant but relatively small reduction in PEF was reported, but only among first-time vaccinated asthma patients. The two overlapping studies (France et al., 2004; Hambidge et al., 2006) that followed large samples of children without regard to any prior diagnosis of asthma both reported consistently negative (protective) associations across a broad age range of children, suggesting no clinically or statistically significant increase in asthma episodes following TIV administration. Both studies were potentially confounded by the healthy vaccine effect and neither differentiated between asthma episodes in children with a prior asthma diagnosis or without a prior diagnosis. Under the assumption that a prior asthma diagnosis has no modifying effect (i.e., the influence of inactivated influenza vaccination on a child's risk of an asthma-like episode is the same regardless of any prior diagnosis of asthma), these reports add to the evidence described in the paragraphs above for asthma episodes in individuals with a prior asthma diagnosis. However, these two reports are unable to shed any light on whether inactivated influenza vaccine may have a differential effect on asthma or wheezing episodes in children depending on the presence or absence of a prior diagnosis of asthma. See Table 6-8 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-8. Studies Included in the Weight of Epidemiologic Evidence for Inactivated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children and Adults.

TABLE 6-8

Studies Included in the Weight of Epidemiologic Evidence for Inactivated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children and Adults.

The committee has a high degree of confidence in the epidemiologic evidence based on nine studies with validity and precision to assess an association between inactivated influenza vaccine and asthma exacerbation or reactive airway disease episodes in children and adults; these studies consistently report a null association.

Mechanistic Evidence

The committee identified 17 publications studying or reporting asthma or reactive airway disease episodes after the administration of an inactivated influenza vaccine. Reizis et al. (1987) did not provide evidence beyond temporality between vaccination and the development, not exacerbation, of asthma. Fischer et al. (1982) reported no change in theophyl-line levels and did not report disease activity in asthmatic patients after administration of an inactivated influenza vaccine. Hanania et al. (2004) reported that the humoral immune response to an inactivated influenza vaccine was not adversely affected by corticosteroid treatment in asthmatics. The authors did not report disease activity following vaccination. Ouellette et al. (1965) reported changes in airway hyperreactivity after methacholine challenge in asthmatics administered an inactivated influenza vaccine. The authors did not observe changes in airway hyperreactivity after administration of the vaccine in the absence of methacholine challenge. Ahmed et al. (1997) reported that pre- and postsymptom scores were not significantly different in asthmatics administered an inactivated influenza vaccine. Three publications did not report asthma exacerbation after administration of an inactivated influenza vaccine (Albazzaz et al., 1987; Chiu et al., 2003; Sener et al., 1999). Eight publications did not provide evidence beyond temporality between vaccine administration and dyspnea, bronchial reactivity, decreased peak expiratory flow rates, bronchospasm, increased use of an inhaler, asthma attacks, wheezing, and asthma exacerbation (Bell et al., 1978; Esposito et al., 2008; Innes et al., 2000; Kava and Laitinen, 1985; Kava et al., 1987; Migueres et al., 1987; Murphy and Strunk, 1985; Nicholson et al., 1998). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

De Jongste et al. (1984) reported significant differences in histamine-induced bronchial hyperreactivity pre- and postvaccination in nine of nine asthmatic patients receiving LAIV and six of nine asthmatic patients receiving the inactivated influenza vaccine. The change in bronchial hyperreactivity occurred in individuals receiving killed virus as well as live virus; therefore, this was not considered to reflect the same mechanism for asthma exacerbation that occurs with natural infection.

Weight of Mechanistic Evidence

Infection with influenza viruses is associated with exacerbation of asthma (Treanor, 2010). Furthermore, morbidity and mortality rates associated with influenza virus infection are high in individuals with asthma (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of asthma exacerbation or reactive airway disease episodes in children and adults after administration of an inactivated influenza vaccine. The symptoms described in the publications referenced above are consistent with those of asthma exacerbation. Viral infection and IgE-mediated hypersensitivity may contribute to asthma exacerbation; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between inactivated influenza vaccine and asthma exacerbation or reactive airway disease episodes in children and adults as weak based on six cases.

Causality Conclusion

Conclusion 6.16: The evidence favors rejection of a causal relationship between inactivated influenza vaccine and asthma exacerbation or reactive airway disease episodes in children and adults.

LIVE ATTENUATED INFLUENZA VACCINE AND ASTHMA EXACERBATION OR REACTIVE AIRWAY DISEASE EPISODES IN CHILDREN YOUNGER THAN 5 YEARS OF AGE

Epidemiologic Evidence

The committee reviewed six studies to evaluate the risk of asthma or reactive airway disease episodes in children younger than 5 years of age with and without a prior diagnosis of asthma after LAIV or CAIV administration. Four papers that reported analyses from two separate controlled studies (Belshe et al., 2004; Bergen et al., 2004; Gaglani et al., 2008; Piedra et al., 2005) and two additional controlled studies that compared LAIV to TIV (Ashkenazi et al., 2006; Belshe et al., 2007) contributed to the weight of epidemiologic evidence and are described below. Concern for a possibly greater risk of asthma episodes following LAIV or CAIV in the subgroup of children younger than 5 years of age arose from age-specific (i.e., stratified) analyses that were reported in two published papers based on the same study population of children between 1 and 18 years of age (Belshe et al., 2004; Bergen et al., 2004).

Bergen et al. (2004) conducted a double-blind, randomized controlled trial in healthy children and adolescents (1 to 18 years of age) selected from the Kaiser Permanente (KP) health plan. A total of 9,689 participants were enrolled from October through December 2000 and randomized (2:1 ratio) to receive cold-adapted, trivalent intranasal influenza virus vaccine (CAIV) or placebo. Among the children aged 1 to 8 years, 3,769 were immunized with CAIV and 1,868 received placebo; this age group also received a second dose of the assigned agent 28 to 42 days after the first dose. Of the children aged 9 to 18 years, 2,704 received CAIV and 1,348 received placebo. The investigators reviewed the KP database to assess any hospitalizations, emergency visits, or clinic visits among the cases and controls within 42 days of vaccine or placebo administration. Serious adverse events required additional review of the medical record or contact with the patient's physician or parents. Elevated risk ratios for asthma episodes were observed in children aged 18 to 35 months: the relative risk of asthma episodes (all settings combined) within 42 days after CAIV (all doses combined) was 4.06 (90% CI, 1.29–17.86). Although history of asthma or possible asthma (by parent report) was an exclusion criterion, the authors noted that upon review of the study participants' medical records, 8.8 percent had previous visits for asthma/reactive airway disease. The authors also reported that among the 18- to 35-month age group, 7 of the 16 children experiencing asthma after CAIV had a prior visit for asthma listed in their medical record. In an analysis restricted to participants with prior asthma/reactive airway visits, the relative risk of asthma diagnosis within 42 days of CAIV vaccination was 1.11 (90% CI, 0.59–2.14); however, the analysis was not simultaneously separated or adjusted by age (e.g., 18 to 35 months).

Belshe et al. (2004) conducted a post hoc analysis of the study by Bergen et al. (2004). In the post hoc analysis, the risk of medically attended events for asthma or reactive airway disease within 42 days of CAIV administration was assessed for different age groups. The relative risk of asthma or reactive airway disease episodes within 42 days of administration of dose one of CAIV in children aged 12 to 59 months was 3.5 (90% CI, 1.09–15.54); however, no statistically significant increased risk was observed for children aged 36 to 59 months. There is a concern for the lack of simultaneous adjustment for age and history of asthma or reactive airway disease visits, which was discussed above in Bergen et al. (2004). The authors note the lack of temporal clustering of asthma or reactive airway disease episodes within 42 days of vaccination for any age group suggests the observed increased risk of asthma may not be a result of vaccine administration.

It is important to note that the increased rates of asthma or reactive airway disease episodes following CAIV administration reported by Bergen et al. (2004) and Belshe et al. (2004) for children younger than 5 years of age were based on analyses of the same study population (albeit stratified by slightly different age cut-points); the subgroup was small and the observed increases in relative risk (4.06 and 3.5, respectively) did not achieve statistical significance at the conventional 0.05 level. The authors chose to report 90 percent rather than conventional 95 percent confidence limits, which may have heightened concern for the potential medical or public health significance of the increased relative risks computed for these small subgroups despite their instability and lack of statistical significance. Several subsequent papers examined different study populations for asthma exacerbation following LAIV or CAIV administration in children younger than 5 years of age.

Piedra et al. (2005) conducted a retrospective cohort study of children (18 months to 18 years of age) from the Scott & White Health Plan (SWHP) in Texas. The study included healthy children and children with a history of wheezing or mild intermittent asthma. It excluded children who had a previous hospital or emergency room visit for asthma, reactive airway disease, or wheezing within 6 to 12 months of enrollment. All study participants received one LAIV each year they were enrolled from 1998 through 2002. Two risk periods (defined as 0 to 14 days and 15 to 42 days after vaccination) were compared to a prevaccination reference period (defined as start date of vaccination program to date of vaccination). Adverse events during visits to clinics, emergency departments, and hospitals were ascertained by searching the SWHP administrative database. While the authors adjusted for the activity of respiratory viruses during each enrollment year, the prevaccination period tended to always be in the earliest part of the season and residual confounding owing to the lack of adjustment for different seasonal risks of infection was still present. No significant increased risk of asthma was reported 0 to 14 days after LAIV administration in children aged 18 months to 4 years. One significant increased risk was observed in this age group 15 to 42 days after vaccination in year 1 (RR, 2.85; 95% CI, 1.01–8.03), but not in the other 3 vaccine years. The authors concluded that the observed increased risk of asthma in the 18-month to 4-year age group during the 15 to 42 days after LAIV administration was most likely due to chance effect because of the large number of comparisons made without adjustment.

Gaglani et al. (2008) conducted a reanalysis of the study from Piedra et al. (2005). The reanalysis focused on exacerbation of existing mild intermittent asthma, reactive airway disease, or wheezing among study participants and new onset of asthma in those without a history of wheezing, reactive airways disease, or asthma. Two risk periods (defined as 0 to 14 days and 0 to 42 days after LAIV vaccination) were compared to a reference period that included events observed before vaccination and after the defined risk periods. One main concern with the analysis is the possibility for confounding due to residual seasonal differences in the risk period comparisons (postvaccination risk period compared to the combination of a pre- and postvaccination reference period). The authors did not find an increased risk of asthma exacerbation or new onset asthma during the 0-to-14-day or 0-to-42-day risk period after LAIV administration in the 18-month to 4-year age group during any of the 4 study years. The authors concluded that LAIV administration does not increase the risk of health care utilization for new-onset asthma or asthma exacerbation in children aged 18 months to 4 years.

Ashkenazi et al. (2006) conducted a randomized controlled trial in children (6 to 71 months of age) to assess the safety of CAIV in comparison to TIV in 10 countries (Belgium, Czech Republic, Finland, Germany, Israel, Italy, Poland, Spain, Switzerland, and the United Kingdom). The study participants were randomly assigned in a 1:1 ratio to receive two doses of CAIV-T or TIV; the doses were administered approximately 35 days apart. A total of 1,107 and 1,080 children received dose 1 CAIV-T and TIV, respectively; 1,068 and 1,046 children received dose 2 of CAIV-T and TIV, respectively. The two treatment groups had similar characteristics; a history of wheezing was reported among 47.1 percent of the CAIV-T group and 44.5 percent of the TIV group, and a history of asthma diagnosis was observed in 22.5 percent of the CAIV-T group and 22.8 percent of the TIV group. Wheezing was recorded after vaccination by parental use of diary cards (0 to 10 days); active surveillance consisting of telephone calls, clinic visits, or home visits (11 to 41 days); and reports by medical practitioners (11 to 41 days). The incidence of wheezing within 41 days of vaccination was similar in both treatment groups for dose 1 (incidence difference, -0.8; 90% CI, -3.1–1.6) and for dose 2 (incidence difference, 1.4; 90% CI, -1.0–3.8).

Belshe et al. (2007) conducted a randomized controlled trial in children (6 to 59 months of age) to assess the safety of LAIV in comparison to TIV in 16 countries (the United States, 12 countries in Europe and the Middle East, and 3 countries in Asia). The study participants were randomly assigned to LAIV (4,179 children) or TIV (4,173 children) based on a 1:1 ratio, and an intramuscular or intranasal placebo was administered with the corresponding vaccine. The study participants and the clinical, biostatistical, and data-management staff did not know the treatment assignments. Children with wheezing recorded more than 42 days before enrollment or mild asthma were included in the study, whereas children with recent wheezing (less than 42 days before enrollment) or severe asthma were excluded. The subjects' parents recorded adverse events during the 42 days after vaccination. The authors only included in the analysis those subjects who completed the study and did not provide any data on the characteristics of the study withdrawals that would enable assessment of bias due to differential withdrawal across study groups. No significant difference in medically significant wheezing was observed between the LAIV and TIV groups for children aged 6 to 59 months, less than 24 months, or greater than or equal to 24 months. When children with or without a history of recurrent wheezing were analyzed separately, no significant difference was observed. The only observed difference in medically significant wheezing (within 42 days of vaccination) was in children less than 12 months of age, where 12 additional episodes of wheezing were reported after LAIV compared to TIV (3.8 percent and 2.1 percent, respectively).

Weight of Epidemiologic Evidence

In examining evidence for an association of asthma with TIV or LAIV immunization, the committee addressed asthma or wheezing episodes in study populations with and without a prior diagnosis of asthma. The majority of the studies enrolled persons with prior histories of asthma episodes. The diagnosis of asthma in a child usually involves a clinical judgment following repeated episodes of wheezing. Most children with asthma are atopic, having demonstrable IgE antibodies to specific antigens. The age at which wheezing is first diagnosed is variable and often accompanies a viral illness or antigen exposure, which are not causative, but rather stimulate a pathway that already existed, as described in the weight of mechanistic evidence below.

Four of the papers described above, representing two discrete cohorts in which LAIV is compared to a control population or a control time period, reported what may appear to be inconsistent findings for children younger than 5 years of age owing largely to the choice and emphasis in the first two papers on 90 percent rather than the conventional 95 percent confidence intervals. Bergen et al. (2004) and Belshe et al. (2004) analyzed age-stratified data from a large double-blind randomized controlled trial (RCT) with serious limitations. The study protocol excluded children with known asthma diagnosis, but when the study was analyzed it was found that 8.8 percent of the participants in fact had an asthma diagnosis or symptoms in the past. In the Bergen et al. (2004) analysis, there was an increased risk of wheezing in the 42 days after LAIV administration among children 18–35 months of age (including seven children with prior asthma and nine children without prior asthma); and in the Belshe et al. (2004) analysis, increased wheezing was observed in the 12- to 59-month age group in the 42 days after LAIV administration. The relative risk estimates for the youngest subgroups of children in the original study (Bergen et al., 2004) and the reanalysis (Belshe et al., 2004) were very unstable and were not significantly increased at the conventional 0.05 level. For example, for the 3.5-fold increased relative risk reported in Belshe et al. (2004), the 95% CI would be 0.59–20.61; and for the 4.06-fold increased relative risk reported in Bergen et al. (2004), the 95% CI would be 0.36–23.72. Neither of these are statistically significant at the conventional 0.05 level. The lack of temporal clustering of asthma within the 42 days following vaccination decreases confidence that there is a causal association. In the second set of papers from Piedra et al. (2005) and Gagliani et al. (2008) the prevaccination season was used as the comparison period in the analysis. If wheezing rate is different in different seasons, this could obscure the effect of vaccine (e.g., if wheezing is expected to be higher in the winter, the lack of increased wheezing would suggest a protective effect of vaccine). Although the papers did not account for possible seasonal variation in wheezing, it is noteworthy that wheezing episodes did not increase following vaccination. Two papers comparing TIV and LAIV found no difference in likelihood of wheezing or asthma episodes after immunization in children with a prior history of wheezing or asthma (Ashkenazi et al., 2006; Belshe et al., 2007). Since TIV vaccination compared to no vaccination showed a consistent null association with asthma episodes in children younger than 5 years of age (France et al., 2004; Hambidge et al., 2006) (see prior section on inactivated influenza vaccine and asthma or reactive airway disease episodes in children and adults), the two LAIV versus TIV studies provide further support for a null association. See Table 6-9 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-9. Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children Younger Than 5 Years of Age.

TABLE 6-9

Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children Younger Than 5 Years of Age.

The committee has a moderate degree of confidence in the epidemiologic evidence based on six studies with sufficient validity and precision to assess an association between LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age; these studies generally report a null association.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of asthma or reactive airway disease episodes in children younger than 5 years of age with and without a prior diagnosis of asthma after LAIV or CAIV administration.

Weight of Mechanistic Evidence

Infection with influenza is associated with exacerbations of asthma (Treanor, 2010). Furthermore, morbidity and mortality rates associated with influenza infection are high in individuals with asthma (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

Viral infections, IgE-mediated hypersensitivity reactions to allergens, and response to environmental pollutants may contribute to exacerbations of asthma in individuals predisposed to developing airway hyper-responsiveness. Both viral infections and environmental allergens and pollutants result in inflammation in the airway leading to the recruitment of immunomodulatory cells that release inflammatory mediators resulting in airway hyperresponsiveness and remodeling. Reviews by Holgate (2008) and Jackson and Johnston (2010) provide detailed descriptions of the cells and mechanisms involved in the pathogenesis of asthma, including abnormal responses of airway epithelial cells and the innate immune system, which promote inflammation and remodeling. The committee did not identify literature reporting evidence of these mechanisms after administration of LAIV.

The committee assesses the mechanistic evidence regarding an association between LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age as weak based on knowledge about the natural infection.

Causality Conclusion

Conclusion 6.17: The evidence is inadequate to accept or reject a causal relationship between LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age.

LIVE ATTENUATED INFLUENZA VACCINE AND ASTHMA EXACERBATION OR REACTIVE AIRWAY DISEASE EPISODES IN PERSONS 5 YEARS OF AGE OR OLDER

Epidemiologic Evidence

The committee reviewed six studies to evaluate the risk of asthma or reactive airway disease episodes in persons 5 years of age or older after LAIV or CAIV administration. One study (Izurieta et al., 2005) was not considered in the weight of epidemiologic evidence because it provided data from a passive surveillance system and lacked an unvaccinated comparison population.

Four papers that reported analyses from two separate controlled studies (Belshe et al., 2004; Bergen et al., 2004; Gaglani et al., 2008; Piedra et al., 2005) and one additional controlled study that compared LAIV to TIV (Fleming et al., 2006) contributed to the weight of epidemiologic evidence and are described below.

The study by Bergen et al. (2004) was described in detail in the section on LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age. This randomized controlled trial did not observe an increased risk of asthma episodes in the 1- to 8-year or 9- to 17-year age group within 42 days of CAIV administration. Since the authors only reported relative risks for positive associations, specific risk ratios were not available for these subgroup analyses.

Belshe et al. (2004) conducted a post hoc analysis of the study by Bergen et al. (2004). This study is described in detail in the section on LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age. The authors report relative risks of asthma or reactive airway disease episodes within 42 days of CAIV administration in children aged 5 to 17 years after dose one (RR, 0.74; 90% CI, 0.42–1.33) and after dose two (RR, 0.33; 90% CI, 0.10–0.96). The authors concluded that the administration of CAIV in children 5 to 17 years of age does not increase the risk of asthma.

The study by Piedra et al. (2005) was described in detail in the section on LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age. This retrospective cohort study did not observe an increased risk of asthma 0 to 14 days or 15 to 42 days after LAIV administration in children aged 5 to 9 years or 10 to 18 years during any of the four study periods.

Gaglani et al. (2008) conducted a reanalysis of the study from Piedra et al. (2005). This reanalysis is described in detail in the section on LAIV and asthma exacerbation or reactive airway disease episodes in children younger than 5 years of age. The authors did not find an increased risk of asthma exacerbation or new-onset wheezing during the 0- to 14-day or 0- to 42-day risk period after LAIV administration in the 5- to 9-year or 10- to 18-year age group during any of the 4 study years.

Fleming et al. (2006) conducted a randomized controlled trial in children (6 to 17 years of age) with a clinical diagnosis of asthma. The study took place in 13 countries (Belgium, Finland, Germany, Greece, Israel, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Switzerland, and the United Kingdom) from October 2002 through May 2003. The study participants were randomized 1:1 to receive CAIV (1,114 children) or TIV (1,115 children), and daily asthma symptoms were recorded by their parents for 15 days postvaccination. Asthma events were also recorded during a surveillance phase (from day 14 through May 2003) that consisted of telephone calls, home visits, and clinic visits. No significant differences in the incidence of asthma exacerbations were observed between the CAIV and TIV groups after vaccination. The percentage point difference of incidence of asthma exacerbation within 42 days of CAIV administration compared to TIV was -0.1 (90% CI, -2.4–2.2; 95% CI, -2.8–2.6). The authors noted the majority of subjects that received CAIV and TIV reported no asthma symptoms within 15 days postvaccination.

Weight of Epidemiologic Evidence

In examining evidence for an association of asthma with TIV or LAIV immunization, the committee addressed asthma episodes in study populations with varying asthma histories. The majority of the studies enrolled persons with prior histories of asthma episodes. The diagnosis of asthma in a child usually involves a clinical judgment following repeated episodes of wheezing. Most children with asthma are atopic, having demonstrable IgE antibodies to specific antigens. The age at which wheezing is first diagnosed is variable and often accompanies a viral illness or antigen exposure, which are not causative, but rather stimulate a pathway that already existed, as described in the weight of mechanistic evidence below.

The five studies that reported observations from three different data sets showed consistent results. Belshe et al. (2004) and Bergen et al. (2004) report on a large retrospective cohort with appropriately defined control periods and found no association between LAIV and wheezing in children over 5 years of age. Although preexisting asthma was an exclusion criterion, 8.8 percent of the participants had a record of prior asthma diagnosis or symptoms. In these children receipt of CAIV was not associated with an increased risk of an asthma or reactive airway disease episode in the 42 days after vaccination (RR, 1.11; 90% CI, 0.59–2.14). The retrospective cohort analyzed in Piedra et al. (2005) and Gaglani et al. (2008) included children with prior asthma, and no increase in wheezing was seen in children over 5 years in either group. Interpretation of this study is limited by the fact that the control period was consistently earlier in the year, when asthma and wheezing risk may be different. However, if wheezing rates vary across different seasons and wheezing is expected to be higher in the winter, the lack of increased wheezing could suggest a protective effect of vaccination. The study comparing CAIV and TIV groups (Fleming et al., 2006) has the advantage of observing children during the same season, and finds no difference in asthma exacerbation or wheezing. Since TIV has been shown to not be associated with asthma episodes (see prior section on inactivated influenza vaccine and asthma or reactive airway episodes in children or adults), this finding of no difference provides support for our weight of evidence of no association of LAIV or CAIV and asthma. See Table 6-10 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-10. Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Persons 5 Years of Age or Older.

TABLE 6-10

Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Persons 5 Years of Age or Older.

The committee has a moderate degree of confidence in the epidemiologic evidence based on five studies with sufficient validity and precision to assess an association between LAIV and asthma exacerbation or reactive airway disease episodes in persons 5 years of age or older; these studies consistently report a null association.

Mechanistic Evidence

The committee identified five publications studying LAIV and asthma or reactive airway disease episodes in persons 5 years of age or older. Two publications did not observe exacerbation of asthma after administration of LAIV (Atmar et al., 1990; Storms et al., 1976). Two publications did not provide evidence beyond temporality (Kava and Laitinen, 1985; Redding et al., 2002). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

De Jongste et al. (1984) reported significant differences in histamine-induced bronchial hyperreactivity pre- and postvaccination in all nine asthmatic patients receiving LAIV and six of nine asthmatic patients receiving the inactivated influenza vaccine. The change in bronchial hyperreactivity occurred in individuals receiving killed virus as well as live virus; therefore, this was not considered to reflect the same mechanism for asthma exacerbation that occurs with natural infection.

Weight of Mechanistic Evidence

Infection with influenza viruses is associated with exacerbation of asthma (Treanor, 2010). Furthermore, morbidity and mortality rates associated with influenza virus infection are high in individuals with asthma (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present evidence sufficient for the committee to conclude the vaccine may be a contributing cause of asthma exacerbation or reactive airway disease episodes in persons 5 years of age or older after administration of LAIV. The symptoms described in the publications referenced above are consistent with those of asthma exacerbation. Viral infections, IgE-mediated hypersensitivity reactions to allergens, and response to environmental pollutants may contribute to exacerbations of asthma in individuals predisposed to developing airway hyperresponsiveness. Both viral infections and environmental allergens and pollutants result in inflammation in the airway leading to the recruitment of immunomodulatory cells that release inflammatory mediators resulting in airway hyperresponsiveness and remodeling. Reviews by Holgate (2008) and Jackson and Johnston (2010) provide detailed descriptions of the cells and mechanisms involved in the pathogenesis of asthma, including abnormal responses of airway epithelial cells and the innate immune system, which promote inflammation and remodeling. The committee did not identify literature reporting evidence of these mechanisms after administration of LAIV.

The committee assesses the mechanistic evidence regarding an association between LAIV and asthma exacerbation or reactive airway disease episodes in persons 5 years of age or older as weak based on knowledge about the natural infection and nine cases.

Causality Conclusion

Conclusion 6.18: The evidence is inadequate to accept or reject a causal relationship between LAIV and asthma exacerbation or reactive airway disease episodes in persons 5 years of age or older.

ONSET OR EXACERBATION OF SYSTEMIC LUPUS ERYTHEMATOSUS

Epidemiologic Evidence

The committee reviewed four studies to evaluate the risk of systemic lupus erythematosus (SLE) after the administration of influenza vaccine; the studies assessed the risk of SLE exacerbation in patients with preexisting disease. These four controlled studies (Abu-Shakra et al., 2000; Del Porto et al., 2006; Stojanovich, 2006; Williams et al., 1978) contributed to the weight of epidemiologic evidence and are described below.

Williams et al. (1978) conducted a double-blind, randomized controlled trial in patients with SLE to investigate changes in disease activity following influenza immunization. A total of 40 patients who met the American Rheumatism Association diagnosis criteria for SLE were randomized to receive a bivalent whole influenza vaccine or saline injection. The authors noted that the two groups were balanced for age, sex, treatment, clinical manifestations, and prevaccination disease activity. Clinical evaluations were conducted at 1, 2, 4, and 6 weeks following injection, and then monthly through 20 weeks of follow-up. Between weeks 15 and 20, one patient from the vaccinated group and one patient from the placebo group required hospitalization for disease flare-ups. The authors concluded that influenza vaccination does not increase the disease activity of SLE patients, but noted they had limited information to adequately assess this risk.

Abu-Shakra et al. (2000) conducted a cohort study (presumably retrospective, however the cohort design was not further described) in patients with SLE who were enrolled from October through November 1998. A total of 48 consecutive patients who met the American College of Rheumatology diagnosis criteria for SLE were included in the study; 24 patients received influenza vaccine, and 24 patients were not vaccinated during the study period. The exposed and unexposed groups had similar characteristics (age, sex, ethnic origin, disease duration, and disease activity at diagnosis), but the authors failed to describe the exclusion criteria (especially for unvaccinated patients). SLE activity was evaluated using the SLE Disease Activity Index (SLEDAI) at vaccination and during follow-up assessments at 6 and 12 weeks postvaccination. Multivariate analysis of variance was performed to compare the repeated SLEDAI measurements. Changes in SLEDAI score for the vaccinated and unvaccinated patients were not statistically different after the three assessments (p = .29). There was a significant decrease in the SLEDAI score within each group at 6 and 12 weeks postvaccination compared to the time of vaccination (p = .02). The authors concluded that influenza vaccine does not adversely influence the disease activity of SLE patients.

Del Porto et al. (2006) conducted a prospective cohort study in SLE and rheumatoid arthritis (RA) patients enrolled at an outpatient clinic from 2003 through 2004. The exposed group included 14 SLE patients and 10 RA patients who met the American College of Rheumatology diagnostic criteria and agreed to receive influenza vaccine during the study period. The unexposed group included 14 SLE patients and 10 RA patients who were randomly selected from the patients that did not consent to vaccine administration. Disease activity of the 28 SLE patients was evaluated before vaccination and at 1, 3, and 6 months after vaccination. The investigators assessed the SLEDAI scores, number and severity of flare-ups, and local or systemic clinical adverse events for the exposed and unexposed groups. No systemic clinical adverse events were observed in the vaccinated patients. The SLEDAI scores did not significantly increase among the vaccinated and unvaccinated SLE patients during the 6 months of follow-up. Additionally, the number and severity of flare-ups were not significantly different among the two groups (OR, 2.17; 95% CI, 0.1–137.49), and were observed in two vaccinated patients and one unvaccinated patient. The authors concluded that influenza vaccination does not adversely influence the disease activity of SLE patients.

Stojanovich (2006) conducted a cohort study in 69 SLE patients. A total of 23 patients received influenza vaccine in November 2003, and 46 patients remained unvaccinated. The exposed and unexposed groups had comparable characteristics (age, gender, disease activity, manifestations of main disease, and immunoserological parameters) at time of vaccination. The investigators assessed the disease activity (SLEDAI scores) and occurrence of viral and bacterial infections for 1 year following vaccination. The authors noted that the disease activity did not worsen in vaccinated SLE patients, but measures of disease activity were not provided. The unvaccinated SLE patients experienced more viral and bacterial infections and worsening of disease activity, which was attributed to changes in the medical management of SLE necessitated by treatment (e.g., antibiotics) for the infections. The authors concluded that influenza vaccination does not adversely influence the disease activity of SLE patients, and noted that unvaccinated patients are at higher risk of disease exacerbation resulting from viral and bacterial infections.

Weight of Epidemiologic Evidence

The studies considered in the epidemiologic evidence consist of one small RCT comparing influenza vaccine and no vaccine in SLE patients (Williams et al., 1978) and three observational studies that include unvaccinated patients (Abu-Shakra et al., 2000; Del Porto et al., 2006; Stojanovich, 2006). The observational studies are variably limited by size and adjustment for confounding. Changes in disease activity pre- and postvaccination are reported based on SLE symptom scales (SLEDAI scores). The results in each of the four studies are consistent with no change in disease activity or a negative association with disease activity (Stojanovich, 2006) following influenza vaccination. See Table 6-11 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-11. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of SLE.

TABLE 6-11

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of SLE.

The committee has limited confidence in the epidemiologic evidence, based on four studies that lacked validity and precision, to assess an association between influenza vaccine and exacerbation of SLE.

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and onset of SLE.

Mechanistic Evidence

The committee identified nine publications reporting or studying the onset or exacerbation of SLE after administration of an influenza vaccine. Five publications either did not observe exacerbation of SLE after administration of an influenza vaccine or did not provide evidence beyond temporality between vaccine administration and exacerbation of SLE (Brodman et al., 1978; Holvast et al., 2009b; Ichikawa et al., 1983; Wallin et al., 2009; Wiesik-Szewczyk et al., 2010). Four publications did not provide evidence beyond temporality between administration of influenza vaccine and diagnosis of SLE (Brown et al., 1994; Ichikawa et al., 1983; Older et al., 1999; Vainer-Mossel et al., 2009). In addition, Older et al. (1999) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that merits greater discussion.

Augey et al. (2003) described a 65-year-old woman, with a history of hypertension and thrombosis of the retina, presenting with nonpruritic bubbles on the chest and arms 7 days after receiving an influenza vaccine. The rash spontaneously resolved within 6 months. One year later, the patient presented with similar symptoms, except the bubbles were more numerous and larger, 4 days after receiving an influenza vaccine. A biopsy of a bubble showed granulocytes, neutrophils, and eosinophils. The biopsy also showed inflammation of the dermis with a primarily lymphocytic infiltrate in the perivascular nodules. Deposits of IgA, IgG, IgM, and C3 were revealed by direct immunofluorescence. SLE was diagnosed based on the histology. There were no data linking the diagnosis of SLE to the vaccine, and there was no proposed mechanism.

Weight of Mechanistic Evidence

There are data suggesting that natural infections, but not influenza viruses per se, can exacerbate symptoms in patients with SLE (Doria et al., 2008). Vaccination, like natural infection, triggers an inflammatory response, and inflammation is present during exacerbations of SLE. It is important to note, however, that not all inflammation is infectious so lupus flare-ups may also be associated with sterile inflammation as would be the case with an inactivated influenza vaccine. Autoantibodies, T cells, complement activation, and immune complexes may contribute to the onset or exacerbation of SLE; however, the publications did not provide evidence linking these mechanisms to influenza vaccine. Notably, the time for progression to SLE is thought to be many years. Therefore, a person with no history of SLE who presents with SLE symptoms shortly after receiving an influenza vaccine would not have had a vaccine-induced initiation of the disease process. The committee finds temporality, which is insufficient to conclude a causal relationship, the only association between SLE and influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and onset or exacerbation of SLE as lacking.

Causality Conclusion

Conclusion 6.19: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and onset or exacerbation of SLE.

ONSET OR EXACERBATION OF VASCULITIS

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of exacerbation of vasculitis after the administration of influenza vaccine. These two controlled studies (Holvast et al., 2009a; Stassen et al., 2008) contributed to the weight of epidemiologic evidence and are described below.

Stassen et al. (2008) conducted a retrospective cohort study in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Consecutive AAV patients (mainly with Wegener's granulomatosis) with at least 1 year of medical record follow-up between 1999 and 2004 were enrolled in the study. Influenza vaccination histories were obtained from interviews conducted in 2004 using a standardized questionnaire and supplemented with additional data from the patients' general practitioners. Disease relapse was assessed by reviewing the medical charts for new or increased disease activity and was attributed to influenza vaccination if the vaccine was administered within 1 year of the relapse. The analysis provided relapse rates each year for the vaccinated and unvaccinated groups. A total of 230 AAV patients with at least 1 year of follow-up were included in the study; 156 were vaccinated at least once and 74 were never vaccinated. The exposed group was significantly older, had longer disease duration before enrollment, and used a lower dosage of immunosuppressive medication than the unexposed group. The relapse rate per 100 patients at risk during 1999–2004 was 3.4 and 6.3 for the vaccinated and unvaccinated groups, respectively (RR, 0.54). The authors concluded that influenza vaccination does not increase the occurrence of disease relapse in AAV patients.

Holvast et al. (2009a) conducted a randomized controlled trial in Wegener's granulomatosis patients with quiescent disease from October through December 1995. Patients with active disease were excluded from the study. A total of 72 patients were randomized in a 2:1 ratio to receive influenza vaccine (49 patients) or serve as controls (23 patients). Disease activity was assessed at entry, 1 month postvaccination, and 3–4 months postvaccination. At each visit, the Birmingham vasculitis activity score (BVAS), visual analogue score (VAS), and ANCA titers were measured. The patients completed standardized questionnaires to record any adverse effects from influenza vaccination, and both groups reported comparable events. One vaccinated and one unvaccinated patient developed active disease within 1 month of follow-up; no vaccinated and two unvaccinated patients developed active disease within 4 months of follow-up. The ANCA titers, fourfold increase in ANCA titers, and VAS did not differ among the vaccinated and control groups during the 4 months of follow-up. The authors concluded that influenza vaccination does not increase the occurrence of disease relapse in Wegener's granulomatosis patients with quiescent disease; however, they noted the study was underpowered to adequately detect this effect.

Weight of Epidemiologic Evidence

Two studies are considered in the epidemiologic evidence. One is a larger observational study of consecutive AAV patients with 1 year of follow-up. The results show a negative association with moderate precision; however, the exposure was not randomly allocated and the analysis did not adjust for potential confounders. The second study is a smaller RCT with 3–4 months of follow-up (Wegener's patients randomized to vaccine or no vaccine). The pre- and postvaccination disease scores are the same or lower in the vaccine group, but the study may be underpowered to adequately assess this outcome. See Table 6-12 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-12. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of Vasculitis.

TABLE 6-12

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of Vasculitis.

The committee has limited confidence in the epidemiologic evidence, based on two studies that lacked validity and precision, to assess an association between influenza vaccine and exacerbation of vasculitis.

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and onset of vasculitis.

Mechanistic Evidence

The committee identified 48 publications reporting or studying onset or exacerbation of vasculitis after administration of an influenza vaccine. Holvast et al. (2010) did not report differences in cell-mediated immune responses between Wegener's granulomatosis patients undergoing treatment with immunosuppressants, those not undergoing treatment with immunosuppressants, and healthy controls. Three publications did not provide clinical, diagnostic, or experimental evidence, including the time frame between vaccination and development of symptoms (Gburek and Gozdzik, 2002; Gerth, 1992; Spaetgens et al., 2009). Forty-three publications did not provide evidence beyond temporality, some too long or too short based on the possible mechanisms involved (Bedard and Gascon, 1999; Begier et al., 2004; Bellut et al., 2001; Birck et al., 2009; Blumberg et al., 1980; Cannata et al., 1981; Famularo et al., 2006; Finsterer et al., 2001; Garcia Robledo et al., 2010; Gavaghan and Webber, 1993; Ghose et al., 1976; Guillevin and Levy, 1983; Herron et al., 1979; Houston, 1983; Hu et al., 2009; Hyla-Klekot et al., 2005; Iyngkaran et al., 2003; Jover-Saenz et al., 2008; Kasper et al., 2004; Kelsall et al., 1997; Liozon et al., 2000; Lohse et al., 1999; Mader et al., 1993; Molina et al., 1990; Mormile et al., 2004; Patel et al., 1988; Perez et al., 2000; Pou et al., 2008; Reizis et al., 1987; Ritter et al., 2003; Shuster, 2006; Tavadia et al., 2003; Uji et al., 2005; Ulm et al., 2006; Vaglio et al., 2009; Verschuren and Blockmans, 1998; Vial et al., 1990; Wada et al., 2008; Walker et al., 2004; Watanabe and Onda, 2001; Wattiaux et al., 1988; Wharton and Pietroni, 1974; Yanai-Berar et al., 2002). Long latencies between vaccine administration and development of symptoms make it impossible to rule out other possible causes. One publication also reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event (Houston, 1983). Furthermore, four publications reported concomitant infections, making it difficult to determine which could have been the precipitating event (Finsterer et al., 2001; Liozon et al., 2000; Verschuren and Blockmans, 1998; Wada et al., 2008). These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Two VAERS reports, identified in Vellozzi et al. (2009), describing the development of vasculitis after administration of influenza vaccines were obtained via a FOIA request (FDA, 2010). One patient reported the development of vasculitis 8 days after administration of influenza vaccines on two occasions. One patient reported the development of leukocytoclastic vasculitis on the day of vaccination on two occasions. These reports potentially represent cases of rechallenge. Evidence of causality beyond a temporal relationship between administration of the vaccines and development of transient blindness was not provided. The influenza vaccine changes yearly, but generally includes some strains from the previous year.

Weight of Mechanistic Evidence

The publication described above did not provide evidence sufficient for the committee to conclude the vaccine may be a contributing cause of vasculitis. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of vasculitis, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Autoantibodies, T cells, complement activation, and immune complexes may contribute to the symptoms of vasculitis; however, the publications did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and exacerbation of vasculitis as weak based on two cases.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and onset of vasculitis as lacking.

Causality Conclusion

Conclusion 6.20: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and vasculitis.

POLYARTERITIS NODOSA

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of polyarteritis nodosa (PAN) after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and PAN.

Mechanistic Evidence

The committee identified one publication reporting the development of PAN after administration of an influenza vaccine. The publication did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Wharton and Pietroni, 1974).

Weight of Mechanistic Evidence

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of PAN. Autoantibodies, T cells, complement activation, and immune complexes may contribute to the symptoms of PAN; however, the publication did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and PAN as lacking.

Causality Conclusion

Conclusion 6.21: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and PAN.

ONSET OR EXACERBATION OF ARTHROPATHY

Epidemiologic Evidence

The committee reviewed two studies to evaluate the risk of onset or exacerbation of arthropathy after the administration of influenza vaccine. These two studies (Chalmers et al., 1994; Harrison et al., 1997) had very serious methodological limitations that precluded their inclusion in this assessment. The study by Chalmers et al. (1994) assessed the association between influenza vaccine and disease flare-ups in RA patients, but the authors did not use a clear measure for the outcome of interest, and the results were difficult to compare across groups. Harrison et al. (1997) conducted a case-control study in patients with inflammatory polyarthritis, but the methods for selecting controls were not well described, and differential assessment of the cases could have led to biased ascertainment of the exposure.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and onset or exacerbation of arthropathy.

Mechanistic Evidence

The committee identified 12 publications either reporting or studying the onset or exacerbation of arthropathy after administration of an influenza vaccine. Three publications did not report exacerbation of rheumatoid arthritis after administration of an influenza vaccine to patients receiving treatment (Elkayam et al., 2010; Salemi et al., 2010; Van Assen et al., 2010). Eight publications did not provide evidence beyond temporality between vaccine administration and the development or exacerbation of arthropathies (Asakawa et al., 2005; Biasi et al., 1994; Brown et al., 1994; Harrison et al., 1997; Kato et al., 2006; Malleson et al., 1993; Pou et al., 2008; Yoo, 2010). In addition, Pou et al. (2008) reported the concomitant administration of vaccines, making it difficult to determine which, if any, vaccine could have been the precipitating event. Furthermore, Brown et al. (1994) reported the development of a flu-like illness in the same time frame, making it difficult to determine the precipitating event. These publications did not contribute to the weight of mechanistic evidence.

Described below is one publication reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

Thurairajan et al. (1997) reported a 78-year-old man, with a history of chronic obstructive airway disease and ischemic heart disease, presenting with malaise, swollen joints, stiffness of the hands, ankles, and knees, and pyrexia leading to a diagnosis of polyarthropathy 2 hours after receiving an inactivated influenza vaccine. The symptoms spontaneously resolved within 1 week. One year prior the patient developed similar symptoms 2 hours after administration of an influenza vaccine with spontaneous resolution of symptoms within 1 day.

Weight of Mechanistic Evidence

Arthralgia is commonly observed during infection with influenza (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The publication described above did not present clinical evidence sufficient for the committee to conclude the vaccine may be a contributing cause of arthropathy after vaccination against influenza. The symptoms described in the publications referenced above are consistent with those leading to a diagnosis of arthropathy, but the only evidence that could be attributed to the vaccine was recurrence of symptoms upon vaccine rechallenge. Autoantibodies, T cells, complement activation, immune complexes, and infection may contribute to the symptoms of arthropathy; however, the publications did not provide evidence linking these mechanisms to the vaccine.

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and onset or exacerbation of arthropathy as weak based on one case and knowledge about the natural infection.

Causality Conclusion

Conclusion 6.22: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and onset or exacerbation of arthropathy.

STROKE

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of stroke after the administration of influenza vaccine. This one controlled study (Smeeth et al., 2004) contributed to the weight of epidemiologic evidence and is described below.

The study by Smeeth et al. (2004) was described in detail in the section on influenza vaccine and myocardial infarction. This self-controlled case-series study included patients who were enrolled in the GPRD for at least 1 year and had a stroke diagnosis at least 6 months after enrollment; patients were excluded if vascular events listed in their medical records appeared to be recorded retrospectively. A total of 19,063 patients with a validated date of a first stroke and influenza vaccination were included in the analysis. Age-adjusted incidence ratios (IRs) were calculated for a first stroke occurring within 1–3 days (IR, 0.77; 95% CI, 0.61–0.96), 4–7 days (IR, 0.72; 95% CI, 0.59–0.88), 8–14 days (IR, 0.84; 95% CI, 0.73–0.96), 15–28 days (IR 0.88; 95% CI, 0.80–0.97), and 29–91 days (IR, 1.01; 95% CI, 0.96–1.06) following vaccination. The authors concluded that influenza vaccination is not associated with an increased risk of stroke.

Weight of Epidemiologic Evidence

The committee has a moderate degree of confidence in the epidemiologic evidence based on a single study with sufficient validity and precision to assess an association between influenza vaccine and stroke; this study reports a decreased risk within 1 month following vaccination.

Mechanistic Evidence

The committee identified one publication reporting ischemic stroke after administration of an influenza vaccine. The publication did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Vainer-Mossel et al., 2009).

Weight of Mechanistic Evidence

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of ischemic stroke. Alterations in the coagulation cascade may contribute to the symptoms of ischemic stroke; however, the publication did not provide evidence linking this mechanism to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between inactivated influenza vaccine and ischemic stroke as lacking.

Causality Conclusion

Conclusion 6.23: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and stroke.3

MYOCARDIAL INFARCTION

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of myocardial infarction after the administration of influenza vaccine. This one controlled study (Smeeth et al., 2004) contributed to the weight of epidemiologic evidence and is described below.

Smeeth et al. (2004) conducted a self-controlled case-series study in patients (? 18 years of age) enrolled in the GPRD from 1987 through 2001. Eligible patients were enrolled in the GPRD for at least 1 year and had a myocardial infarction at least 6 months after enrollment; patients were excluded if vascular events listed in their medical records appeared to be recorded retrospectively. Vaccination histories were obtained from the GPRD, and participants were classified as vaccinated if they received an influenza vaccine from September through March of a given influenza season. The risk period included the 1–91 days following vaccination and was subdivided into five smaller periods (1–3 days, 4–7 days, 8–14 days, 15–28 days, and 29–91 days after vaccination). The control period consisted of all other time outside the risk period not including the time before a participant's first influenza vaccination, since influenza vaccine is indicated for patients with preexisting cardiovascular disease. Participants who received multiple influenza vaccinations during the study period were followed for 91 days after each exposure. A total of 20,486 patients with a validated date of a first myocardial infarction and influenza vaccination were included in the analysis. Age-adjusted incidence ratios were calculated for a first myocardial infarction occurring within 1–3 days (IR, 0.75; 95% CI, 0.60–0.94), 4–7 days (IR, 0.68; 95% CI, 0.56–0.84), 8–14 days (IR, 0.73; 95% CI, 0.63–0.85), 15–28 days (IR 0.87; 95% CI, 0.79–0.96), and 29–91 days (IR, 1.03; 95% CI, 0.98–1.08) following vaccination. The authors concluded that influenza vaccination is not associated with an increased risk of a first myocardial infarction.

Weight of Epidemiologic Evidence

The committee has a moderate degree of confidence in the epidemiologic evidence based on a single study with sufficient validity and precision to assess an association between influenza vaccine and myocardial infarction; this study reports a decreased risk within 1 month following vaccination.

Mechanistic Evidence

The committee identified one publication reporting myocardial infarction after administration of an influenza vaccine. The publication did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Ritter et al., 2003).

Weight of Mechanistic Evidence

While rare, influenza infection has been associated with myocardial infarction (Treanor, 2010). The committee considers the effects of natural infection one type of mechanistic evidence.

The symptoms described in the publication referenced above are consistent with those leading to a diagnosis of myocardial infarction. Viral infection and alterations in the coagulation cascade may contribute to the symptoms of myocardial infarction; however, the publication did not provide evidence linking these mechanisms to influenza vaccine.

The committee assesses the mechanistic evidence regarding an association between LAIV and myocardial infarctions as weak based on knowledge about the natural infection.

The committee assesses the mechanistic evidence regarding an association between inactivated influenza vaccine and myocardial infarction as lacking.

Causality Conclusion

Conclusion 6.24: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and myocardial infarction.4

FIBROMYALGIA

Epidemiologic Evidence

No studies were identified in the literature for the committee to evaluate the risk of fibromyalgia after the administration of influenza vaccine.

Weight of Epidemiologic Evidence

The epidemiologic evidence is insufficient or absent to assess an association between influenza vaccine and fibromyalgia.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of fibromyalgia after administration of an influenza vaccine.

Weight of Mechanistic Evidence

The committee assesses the mechanistic evidence regarding an association between influenza vaccine and fibromyalgia as lacking.

Causality Conclusion

Conclusion 6.25: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and fibromyalgia.

ALL-CAUSE MORTALITY

Epidemiologic Evidence

The committee reviewed one study to evaluate the risk of all-cause mortality following the administration of influenza vaccine. This one controlled study (Kokia et al., 2007) contributed to the weight of epidemiologic evidence and is described below.

Kokia et al. (2007) conducted a retrospective cohort study in adults (55 years of age and older) enrolled in the Maccabi Healthcare Services HMO in Israel during the 2006–2007 influenza season. The influenza vaccination date was obtained from computerized physician and nurse treatment files; 3,064 cases were excluded because the exact date of vaccine administration could not be determined from the files. The outcome was defined as death due to any cause. The National Insurance Institute provided the date of death, which was included in the HMO membership files. One case was excluded because of a reporting error that listed the date of death before the vaccination date. The vaccinated group included patients who received an influenza vaccine during October 2006. The nonvaccinated group included patients who did not receive an influenza vaccine during October 2006 (some of whom were vaccinated later in the 2006–2007 influenza season). Follow-up began after the index date (date of vaccination for exposed and October 1 for unexposed) and ended after 14 days. A total of 259,781 patients were included in the survival analysis; 31,043 were vaccinated and 228,738 did not receive influenza vaccine in October 2006. The hazard ratio model was adjusted for factors associated with higher mortality risk (age, history of diabetes or cardiovascular disease, and homebound status). The adjusted hazard ratio for all-cause mortality within 14 days of administration of influenza vaccine was 0.33 (95% CI, 0.18–0.61). The authors concluded that influenza vaccination is not associated with an increased risk of death in the short term.

Weight of Epidemiologic Evidence

The committee has a moderate degree of confidence in the epidemiologic evidence based on a single study with sufficient validity and precision to assess an association between influenza vaccine and all-cause mortality; this study reports a decreased risk.

Mechanistic Evidence

The committee did not identify literature reporting clinical, diagnostic, or experimental evidence of all-cause mortality after administration of an influenza vaccine.

Weight of Mechanistic Evidence

Infection with wild-type influenza viruses is associated with excess mortality (Treanor, 2010). Increases in all-cause excess mortality are observed during epidemics of influenza (Treanor, 2010).

The committee assesses the mechanistic evidence regarding an association between LAIV and all-cause mortality as weak based on knowledge about the natural infection.

The committee assesses the mechanistic evidence regarding an association between inactivated influenza vaccine and all-cause mortality as lacking.

Causality Conclusion

Conclusion 6.26: The evidence is inadequate to accept or reject a causal relationship between influenza vaccine and all-cause mortality.5

OCULORESPIRATORY SYNDROME

Epidemiologic Evidence

The committee reviewed seven studies to evaluate the risk of oculorespiratory syndrome (ORS) after the administration of influenza vaccine. Two studies (De Serres et al., 2003, 2005) were not considered in the weight of epidemiologic evidence because they provided data from passive surveillance systems and lacked unvaccinated comparison populations. One controlled study (Skowronski et al., 2006) had very serious methodological limitations that precluded its inclusion in this assessment. Skowronski et al. (2006) conducted a retrospective cohort study based on a household telephone survey that did not validate self-reported vaccination data, and the choice of household controls could have introduced selection bias.

The four remaining controlled studies (De Serres et al., 2004; Hambidge et al., 2006; Scheifele et al., 2003; Skowronski et al., 2003a) contributed to the weight of epidemiologic evidence and are described below. Scheifele et al. (2003) and Skowronski et al. (2003a) conducted concurrent studies; patients who had not previously experienced ORS were enrolled in Scheifele et al. (2003), and patients who had ORS following influenza vaccination during the 2000–2001 season were included in Skowronski et al. (2003a).

Scheifele et al. (2003) conducted a randomized controlled crossover trial in adults (30–59 years of age) residing in provinces of Canada where Fluviral S/F influenza vaccine was exclusively supplied during the 2000– 2001 influenza season. Patients were excluded if they experienced ORS symptoms after a previous influenza vaccination. The participants were randomly assigned to receive Fluviral S/F vaccine then placebo, or placebo then Fluviral S/F vaccine. The injections were given 5 to 7 days apart during September 2001. The nurse or pharmacist administering the injection and the patient were blinded to the treatment assignments. Patients were contacted by telephone 24 hours and 6 days after each injection, and a team member collected data on ORS symptoms (bilateral conjunctival redness, facial swelling, sore throat, hoarseness, difficulty swallowing, coughing, wheezing, difficulty breathing, and chest discomfort) and duration of illness. Of the 622 doses of vaccine and 626 doses of placebo administered, 620 and 624 patients completed the telephone interview, respectively. The vaccine-attributable risk of ORS symptoms within 24 hours of injection (with resolution of symptoms within 48 hours of onset) was 2.9 percent (95% CI, 0.6–5.2). The ORS symptoms observed in the study were mild and generally short lived.

Skowronski et al. (2003a) conducted a randomized controlled crossover trial in adults (≥ 19 years of age) enrolled from Quebec, Manitoba, Alberta, and British Columbia provinces of Canada. Patients were eligible if they had ORS following the administration of Fluviral S/F vaccine during the 2000–2001 influenza season. The participants were randomly assigned to receive Fluviral S/F vaccine then placebo, or placebo then Fluviral S/F vaccine. The injections were given 5 to 7 days apart during September 2001. The nurse or pharmacist administering the injection and the patient were blinded to the treatment assignments. Patients were contacted by telephone the evening of the injection day, and 24 hours and 6 days after each injection. A team member collected data on ORS symptoms (bilateral conjunctival redness, coughing, wheezing, chest discomfort, difficulty breathing, difficulty swallowing, hoarseness, sore throat, and facial swelling) and duration of illness. The study was stopped early because the vaccine-attributable ORS recurrence rate exceeded 10 percent. A total of 61 patients received a first injection and completed a follow-up interview when the study ended; 34 patients received vaccine and 27 patients received placebo. The vaccine-attributable risk of ORS symptoms within 24 hours of injection with no time limit for resolution of symptoms was 33 percent (95% CI, 10–53 percent), and with resolution of symptoms within 48 hours of onset it was 27 percent (95% CI, 5–47 percent). Odds ratios were also calculated for the occurrence of ORS symptoms within 24 hours of injection with no time limit for resolution of symptoms (OR, 4.0; 95% CI, 1.4–37.8) and with resolution of symptoms within 48 hours of onset (OR, 5.0; 95% CI, 1.1–30.0). Most ORS symptoms were considered mild and easily tolerated.

De Serres et al. (2004) conducted a randomized controlled crossover trial in adults (≥ 18 years of age) enrolled from Vancouver, Quebec City, and the Montérégie area in Canada during the 2002–2003 influenza season. Patients were eligible if they had ORS after receiving the 2000–2001 influenza vaccine and were not revaccinated (group A), had ORS after receiving the 2000–2001 influenza vaccine and were revaccinated in 2001–2002 (group B), or had a first occurrence of ORS after receiving the 2001–2002 influenza vaccine (group C). A total of 281 patients were eligible, of whom 150 (53 percent) agreed to participate; 146 were included in the analysis (46 in group A, 50 in group B, and 50 in group C). The patients in each group were randomly assigned to receive Fluviral S/F vaccine then placebo, Vaxigrip vaccine then placebo, placebo then Fluviral S/F vaccine, or placebo then Vaxigrip vaccine. The two injections were given 7 days apart, and the immunizing nurse and patient were blinded to the content of the injections. Patients were contacted by telephone 24 hours and 7 days after each injection, and a trained nurse collected data on ORS symptoms (bilateral red eyes, sore throat, difficulty swallowing, cough, breathing difficulty, chest tightness, wheezing, and facial or palpebral edema) and duration of illness. The vaccine-attributable risk of ORS symptoms in the first 24 hours of injection (with no time limit for resolution of symptoms) was 34 percent (95% CI, 21–47 percent) in patients receiving Fluviral S/F vaccine and 15 percent (95% CI, 2–28 percent) in patients receiving Vaxigrip vaccine. Only the association between ORS and Fluviral S/F vaccine remained statistically significant when the case definition was restricted to include at least one edema or ocular symptom and at least one respiratory symptom. After the 2002–2003 influenza vaccination, the highest risk of ORS was observed in group A patients (41 percent) compared to patients in groups B and C (16 percent and 18 percent, respectively). Overall, 86 percent of the patients described their ORS symptoms as mild.

The study by Hambidge et al. (2006) was described in detail in the section on seizures. This case-crossover analysis examined the occurrence of adverse events after TIV administration in children enrolled in eight MCOs participating in the VSD from 1991 through 2003. The investigators looked for episodes of ORS symptoms (red eyes, respiratory symptoms, or facial swelling) during four risk periods (0–2 or 1–3 days, 1–14 days, 15–42 days, and 1–42 days) after influenza vaccination, but were limited to predefined codes in the MCO databases. The authors state that “no increased signal” of conjunctivitis (individual code or part of aggregate code for eye symptoms) was observed in any cohort or medical setting after administration of a U.S. influenza vaccine, but they do not provide data as to the actual number of cases of conjunctivitis in the risk windows or the control periods. The weakness of the study is that since ORS symptoms are mild, subjects may not have sought medical attention; thus, in the absence of the active surveillance conducted in the three Canadian studies above, no conclusions can be drawn about the incidence of ORS symptoms following this U.S. immunization program.

Weight of Epidemiologic Evidence

Of the four papers described above, three are well-designed randomized controlled crossover clinical studies. One randomized study (Scheifele et al., 2003) examining ORS occurrence after Fluviral S/F vaccine compared to placebo showed significant evidence of an increased risk of ORS after influenza vaccine. Two randomized trials (De Serres et al., 2004; Skowronski, et al., 2003a) examined the recurrence of ORS following repeat influenza vaccination in people who had experienced ORS following prior vaccination in Canada, and showed highly significant increased risk of recurrence of ORS. Although De Serres et al. (2004) included Vaxigrip in their trial, the risk of ORS did not remain statistically significant when a more narrow case definition (ocular symptoms or edema plus respiratory symptoms) was employed. Scheifele, Skowronski, and De Serres indicated that the ORS symptoms were mild and easily resolved—an important consideration in weighing the risk versus the benefit of these influenza vaccines. One case-crossover study by Hambidge et al. (2006) did not observe an increased frequency of conjunctivitis symptoms following influenza vaccine in the United States. However, this study did not conduct active surveillance of ORS symptoms, relying instead on evidence from predefined diagnosis codes from medical records. Since ORS symptoms reported by other studies were mild, and often did not lead subjects to seek medical care, the study by Hambidge et al. (2006) only allows the conclusion that ORS symptoms severe or persistent enough to lead subjects to seek medical care did not occur more frequently following influenza immunization. Thus, the evidence is limited to observations following the administration of two particular vaccines used in Canada in the first 3 years of the 21st century, and does not offer useful information as to the risk of ORS following influenza vaccination in the United States. See Table 6-13 for a summary of the studies that contributed to the weight of epidemiologic evidence.

TABLE 6-13. Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Oculorespiratory Syndrome.

TABLE 6-13

Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Oculorespiratory Syndrome.

The committee has a moderate degree of confidence in the epidemiologic evidence based on three studies with sufficient validity and precision to assess an association between ORS and two particular vaccines used in three particular years in Canada; these studies consistently report an increased risk.

Mechanistic Evidence

The committee identified eight publications of ORS postvaccination against influenza. Two publications did not provide evidence beyond temporality and therefore did not contribute to the weight of mechanistic evidence (Skowronski et al., 2003b,c).

Described below are six publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence.

De Serres et al. (2004) performed a placebo controlled clinical trial in which patients were divided into three groups. In two groups patients developed ORS postinfluenza vaccination in 2000–2001; one group was revaccinated in 2001–2002 while the other was not. The third group consisted of patients that developed ORS, for the first time, postinfluenza vaccination in 2001–2002. Each patient received the placebo and the 2002–2003 vaccine, either Fluviral S/F or Vaxigrip, 7 days apart. Fifty-two of the 146 patients participating in the study developed a recurrence of ORS symptoms after receiving the 2002–2003 vaccine. Of the patients who developed ORS symptoms after vaccination in 2000–2001, 12 patients experienced a recurrence of symptoms after receiving the 2001–2002 vaccine, and 13 patients experienced a recurrence of symptoms after receiving the 2002–2003 vaccine. ORS symptoms were more frequent in patients receiving Fluviral S/F than in those receiving Vaxigrip.

De Serres et al. (2005) produced a report on the development of ORS postvaccination during four influenza seasons (2000–2003) using vaccine-associated adverse event data reported to public health units in Quebec, Canada. The Fluviral vaccine was the only influenza vaccine distributed in 2000 and made up 99 percent of the doses administered in 2003. Fluviral and Vaxigrip were distributed in 2001 and 2002. The authors identified 1,488 cases of ORS. Recurrent ORS symptoms were reported by 17, 43, and 11 patients in 2001, 2002, and 2003, respectively. Five patients developed symptoms of ORS after each of three vaccinations while three patients developed symptoms after each of four vaccinations.

Fredette et al. (2003) described six patients presenting with symptoms of ORS developing 1.5 to 12 hours postinfluenza vaccination. All of the patients reported red eyes, three reported a sensation of palpebral fullness, and three reported ocular pruritus. Five patients complained of ocular secretions and two reported photophobia and blurred vision. Four patients complained of a sore throat. Levels of total hemolytic complement (CH50) were at or lower than the low reference point for the normal range in four patients. Likewise, C3 and C4 levels were at or lower than the low reference points for the normal ranges in four patients and three patients, respectively.

Skowronski et al. (2002) conducted a survey of British Columbia residents that reported an adverse event postinfluenza vaccination during the 2000–2001 season. Of the survey participants, 398 developed ORS after vaccination during the 2000–2001 season. One hundred twenty-two participants that developed ORS during the 2000–2001 season were vaccinated against influenza during the 2001–2002 season; approximately 5 percent experienced a recurrence of symptoms.

Skowronski et al. (2003a) conducted a randomized, double-blind, placebo-controlled trial to determine the risk of recurrence of ORS. Seventy-three participants, of whom 61 met the inclusion and exclusion criteria, were enrolled in the study when it was halted because the early stopping rule was exceeded. Forty-four percent of the 34 individuals who received the Fluviral S/F influenza vaccine experienced a recurrence of ORS symptoms.

Skowronski et al. (2005) conducted a survey of children in British Columbia, Canada, to assess the development of adverse events post-influenza vaccination in 2000–2001. A total of 1,074 children were vaccinated during the 2000–2001 influenza season. Of the 39 children who received two doses of influenza vaccine, 10 experienced ORS. The symptoms were described as being worse or the same after the first dose compared to the second dose by 8 of the 10 children.

Weight of Mechanistic Evidence

The six publications described above, when considered together, presented clinical evidence sufficient for the committee to conclude the vaccine may be a contributing cause of ORS after vaccination against influenza. Evidence from these publications include latency of ≤ 24 hours between vaccination and the development of symptoms, complement activation, and importantly, recurrence of symptoms after vaccine rechallenge in six publications. In addition, the activation of the complement cascade by influenza viruses directly through binding of its matrix (M1) protein (Zhang et al., 2009) or through immune complex formation with preformed nonprotective antibodies leading to tissue pathology has been reported (Monsalvo et al., 2011).

The mechanistic evidence, described above, suggests that complement activation may be a mechanism for ORS after influenza vaccination.

The committee assesses the mechanistic evidence regarding an association between ORS and two particular vaccines used in three particular years in Canada as intermediate based on experimental evidence and cases6 presenting clinical evidence.

Causality Conclusion

Conclusion 6.27: The evidence favors acceptance of a causal relationship between ORS and two particular vaccines used in 3 particular years in Canada.

CONCLUDING SECTION

Table 6-14 provides a summary of the epidemiologic assessments, mech anistic assessments, and causality conclusions for influenza vaccine.

TABLE 6-14. Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Influenza Vaccine.

TABLE 6-14

Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Influenza Vaccine.

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Footnotes

1

A/California/7/2009 (H1N1)-like is derived from the 2009 pandemic influenza A (H1N1) virus. This strain was included in the trivalent vaccine in 2010. The monovalent vaccine developed for the pandemic is not covered under the National Vaccine Injury Compensation Program (VICP); it is covered under the Countermeasures Injury Compensation Program and is therefore beyond the scope of this report.

2

The committee does not include in this review any of the studies of the 1976–1977 swine influenza vaccine and its relationship to GBS. This association is accepted as causal by most analysts and a previous IOM committee (Institute of Medicine, 2004).

3

In order for the evidence to favor rejection of a causal relationship, the committee's framework requires two or more epidemiologic studies with negligible limitations (indicating a null association or decreased risk) to reach a high degree of confidence in the epidemiologic evidence. Only one epidemiologic study with negligible methodological limitations that reports a decreased risk is included in the weight of evidence for this causality conclusion.

4

In order for the evidence to favor rejection of a causal relationship, the committee's framework requires two or more epidemiologic studies with negligible limitations (indicating a null association or decreased risk) to reach a high degree of confidence in the epidemiologic evidence. Only one epidemiologic study with negligible methodological limitations that reports a decreased risk is included in the weight of evidence for this causality conclusion.

5

In order for the evidence to favor rejection of a causal relationship, the committee's framework requires two or more epidemiologic studies with negligible limitations (indicating a null association or decreased risk) to reach a high degree of confidence in the epidemiologic evidence. Only one epidemiologic study with negligible methodological limitations that reports a decreased risk is included in the weight of evidence for this causality conclusion.

6

Due to the use of the same sample population in some studies it is likely that some of the cases were presented in more than one publication; thus, it is difficult to determine the number of unique cases.

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