6
Measles and Mumps Vaccines

BACKGROUND AND HISTORY

Measles

Measles formerly afflicted virtually all children before they reached adolescence. It is a viral infection caused by a member of the paramyxovirus group. Conventionally, the diagnosis of measles is made clinically on the basis of its signs and symptoms, which include a characteristic rash. The diagnosis can be confirmed by a laboratory test that detects antibodies to the measles virus. It is also possible to isolate the measles virus, but this effort often fails. Therefore, failure to isolate the virus is not an argument against the diagnosis. A diagnosis of measles based solely on clinical appearance could be erroneous, because a number of other exanthematous diseases can resemble measles.

The disease can be quite debilitating, and its complications are among the most serious consequences of childhood exanthematous infections (Robbins, 1962). These include otitis media, croup, diarrhea, hemorrhagic rash, pneumonia, parainfectious encephalitis, and subacute sclerosing panencephalitis. Whatever its toll in industrialized countries, where the measles fatality rate is 1 per 10,000 cases (Babbott and Gordon, 1954), measles has been a far greater scourge in developing countries, with case fatality rates as high as 1,000 per 10,000 cases (Morley, 1974).

For these reasons, efforts to prevent measles have been extraordinary.



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 6 Measles and Mumps Vaccines BACKGROUND AND HISTORY Measles Measles formerly afflicted virtually all children before they reached adolescence. It is a viral infection caused by a member of the paramyxovirus group. Conventionally, the diagnosis of measles is made clinically on the basis of its signs and symptoms, which include a characteristic rash. The diagnosis can be confirmed by a laboratory test that detects antibodies to the measles virus. It is also possible to isolate the measles virus, but this effort often fails. Therefore, failure to isolate the virus is not an argument against the diagnosis. A diagnosis of measles based solely on clinical appearance could be erroneous, because a number of other exanthematous diseases can resemble measles. The disease can be quite debilitating, and its complications are among the most serious consequences of childhood exanthematous infections (Robbins, 1962). These include otitis media, croup, diarrhea, hemorrhagic rash, pneumonia, parainfectious encephalitis, and subacute sclerosing panencephalitis. Whatever its toll in industrialized countries, where the measles fatality rate is 1 per 10,000 cases (Babbott and Gordon, 1954), measles has been a far greater scourge in developing countries, with case fatality rates as high as 1,000 per 10,000 cases (Morley, 1974). For these reasons, efforts to prevent measles have been extraordinary.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality The initial method of prevention depended on postexposure prophylaxis with immune gamma globulin (Stokes et al., 1944). This method, although quite effective, was marred by several difficulties. It required vigilance with respect to exposure and almost immediate action, because if gamma globulin was given more than 4 days after the exposure, it was no longer effective at preventing disease, although it did attenuate it. Moreover, the prevention it afforded was short-lived, because the injected antibodies tended to disappear within about 2 months. An effort to allow the infection to take place, but in an attenuated form, by injecting less immune globulin was usually successful. The consequence of this was a milder case of clinical measles and a resulting lifelong immunity. However, the titration was not always perfect, and in some children the disease was inadvertently prevented, and therefore, they were soon susceptible again, whereas other children developed nearly full-blown measles, with all the risks of serious morbidity and complications. The next step in prevention efforts was the development of a killed vaccine. The killed vaccine was derived from the Edmonston strain, which was originally isolated in 1954 (Enders and Peebles, 1954). The component antigen was the virus inactivated by formalin and precipitated by alum. Although this vaccine was in use for nearly 4 years (1963 to 1967), it was abandoned when analysis indicated that it provided only short-lived immunity and it was found that formerly vaccinated children developed severe reactions called ''atypical measles'' after their immunity waned and they became infected with the wild-type measles virus (Centers for Disease Control, 1967). Development of a live attenuated measles vaccine began a new era in the prevention of this disease. The initial vaccine was derived from the Edmonston strain, which was attenuated by serial passage in various tissue cultures and ultimately grown in chicken embryo cells. The resulting variant was named the Edmonston B strain. It was quite immunogenic, but it was not free of side effects. One-third of the recipients developed high fever, and half of the recipients had a rash. Nevertheless, none of the recipients acted ill. Administration of the vaccine with immune globulin of the proper titer attenuated the reaction without interfering with the induction of permanent immunity. In the meantime, two vaccines derived from the Edmonston B strain were developed by additional serial passage in chicken embryo cells that were maintained at a lower than optimal temperature. The resulting more-attenuated Enders strain (Hilleman et al., 1968a,b) was the product of an additional 40 passages of the Edmonston B strain; the Schwarz strain was the product of an additional 85 passages of the Edmonston B strain (Schwarz, 1964). Each vaccine induced immunity, and the side effects from these further attenuated vaccines were substantially reduced. The more-attenu-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality FIGURE 6-1 Derivation of measles vaccine strains. Sources:  Adapted from Plotkin and Mortimer (1988, p. 189) and Hirayama M. (1983). ated Enders strain vaccine is currently in use in the United States; the Schwarz strain is used elsewhere in the world. Other strains have been developed and used in various smaller population groups. 'Figure 6-1 illustrates the derivation of many measles vaccines from the Edmonston strain. Table 6-1 lists the measles vaccines used in the United States. TABLE 6-1 Measles Vaccines Used in the United States Attenuation Strain Trade Name Manufacturer Years in Use Live attenuated Edmonston B Rubeovax Merck Sharpe & Dohme 1963-1975     M-Vac Lederle 1963-1975     Pfizer-vax; Pfizer 1963-1975     Measles-L         Generic Lilly, Parke Davis, Philips Roxane 1963-1975 Live, more attenuated Schwarz (derived from Edmonston A) Lirugen Pitman Moore-Dow 1965-1976   More-attenuated Enders (derived from Edmonston B) Attenuvax Merck Sharp & Dohme 1968-presen   Source: Adapted from Plotkin and Mortimer (1988, p. 189).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Mumps Unlike measles, mumps is not considered a globally devastating disease. Nevertheless, because of its complications, it was targeted for prevention by use of a vaccine. The complications that prompted this were epididymoorchitis, aseptic meningitis, meningoencephalitis, and deafness (usually, but not exclusively, unilateral) (Coll, 1974). Before a vaccine was developed, there was no effective means of preventing this disease. Mumps is rare in the first year of life, and its rarity has been attributed to the passive protection rendered by maternal antibodies (Meyer, 1962). Nevertheless, immune globulin injections administered after exposure do not prevent mumps (Reed et al., 1967). Development of mumps vaccine had two stages. Initially, there was an inactivated vaccine (Enders, 1946). It was not sufficiently effective, in that it offered protection only to some 80 percent of the recipients and the protection lasted for less than 1 year. Therefore, investigators undertook efforts to develop an attenuated strain of mumps virus that could be used as a live vaccine. The Jeryl Lynn strain, the mumps virus strain used in mumps vaccines in the United States, came about by numerous passages in vitro, first in embryohated ben's eggs and then in chicken embryo cells (Buynak and Hilleman, 1966). The seroconversion rate was nearly 97 percent. Subsequently, two other strains were developed by similar attenuation of a wild-type isolate. They are Leningrad-3-Parkow and Urabe AM9, which were generated in the former Soviet Union and Japan, respectively. The American Academy of Pediatrics recommends that measles-mumps-rubella vaccine (MMR) be given at age 15 months and at entry into middle or junior high school. The Advisory Committee on Immunization Practices recommends that MMR be administered at 15 months and then again at school entry at age 4 to 6 years. ("MMR" is used in this report to indicate any multivalent vaccine preparation directed against measles, mumps, and rubella. No association with a specific manufacturer is intended or should be inferred.) BIOLOGIC EVENTS FOLLOWING IMMUNIZATION Measles Although the measles vaccine is administered by injection rather than by the natural, respiratory route of infection, the host response is similar to that evoked by the wild-type virus in all but two respects. The immunized subject develops humoral and cellular immune responses some 48 hours earlier than the naturally infected host, and the recipient of the vaccine does

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality not develop clinical measles. Three classes of immune globulin (IgA, IgG, and IgM) are produced and are detectable in the serum and nasal mucus of vaccinated subjects (Bellanti et al., 1969). The standard test of immunity to measles is based on the detection of serum antibodies by the enzyme-linked immunosorbent assay method. Although the titers of these antibodies induced by the vaccine tend to be somewhat lower than those resulting from natural infection (Schwarz and Anderson, 1965), immunity acquired by vaccination is long-lasting (Krugman, 1983). Mumps Following the administration of mumps vaccine, seroconversion is slower and the antibody titers achieved are lower than those following natural infection. A neutralizing antibody response can be detected in some recipients 2 weeks after vaccine administration; in others, it can be delayed for up to 6 weeks (Hilleman et al., 1968a,b). It is assumed that this immunity is long-lasting, but this has not yet been established. ENCEPHALOPATHY AND ENCEPHALITIS Clinical Description Encephalopathy refers to any acute or chronic acquired abnormality of, injury to, or impairment of the function of the brain. Symptoms can include alterations in state of consciousness or behavior, convulsions, headache, and focal neurologic deficits. Encephalitis refers to an encephalopathy caused by an inflammatory response in the brain. This is usually manifested with systemic constitutional symptoms, particularly pleocytosis of the cerebrospinal fluid (CSF). However, the terms encephalopathy and encephalitis have been used imprecisely and even interchangeably in the literature. The discussion that follows uses the terminologies of the authors of the reports. However, if the authors used the term encephalitis, but there was no documentation of pleocytosis in the CSF, "encephalitis" is used in quotation marks. The annual incidence of encephalitis for the years 1950 to 1981 in Olmsted County, Minnesota, was 7.4 per 100,000 people (Beghi et al., 1984; Nicolosi et al., 1986). The incidence in children less than age 1 year was 22.5, in children between ages 1 and 4 years it was 15.2, and in children between ages 5 and 9 years it was 30.2 per 100,000. Other estimates of encephalopathy for children less than age 2 years were somewhat lower than those reported by Beghi et al. and Nicolosi et al. cited above. Other estimates for annual incidence range from 5 per 100,000 people (Walker et al., 1988) to 10 per 100,000 people (Gale et al., 1990). Chapter 3 contains a discussion of encephalopathy.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality History of Suspected Association The occurrence of encephalitis following a natural measles virus infection is well described. The condition is quite severe, often leading to permanent brain damage or even death. There may be no detectable pathologic lesion, but in most cases some edema and demyelination are noted. Early studies of the adverse events associated with measles vaccine concentrated on "encephalitis." These are described below (Landrigan and Witte, 1973; Nader and Warren, 1968). The first report of encephalopathy following vaccination with the live attenuated Edmonston B (Rubeovax) measles vaccine appeared in 1967 (Trump and White, 1967). A 2-year-old girl developed unsteadiness 7 days following vaccination. This was followed by pronounced generalized ataxia (diagnosed as cerebellar ataxia), fever, vomiting, and an exanthem. There was pleocytosis in the CSF 1 month after vaccination. The ataxia persisted for at least 8 months. Because of the child's history and physical and laboratory findings, the investigators attributed the condition to measles vaccination. Two early case series investigations of neuralgic disorders following measles vaccination included reports of "encephalitis." These are discussed below. Mumps affects the central nervous system as well, but it is more likely to cause meningitis than encephalitis (Azimi et al., 1969). This condition tends to be self-limited and has a good prognosis. Cases of pure encephalitis following mumps are rare, but they can be quite severe. Evidence for Association Biologic Plausibility Chapter 3 contains a discussion of the biologic plausibility for certain types of encephalopathies and vaccination. As described above, natural (wild-type) measles virus infection is associated with a well-described, frequently very severe encephalitis. Case Reports, Case Series, and Uncontrolled Observational Studies Many uncontrolled observational studies in the literature describe the occurrence of encephalopathy after administration of measles vaccine. These are reviewed first. Data from similar studies regarding multivalent preparations are described next. Individual case reports and unpublished case reports from U.S. Public Health Service passive surveillance systems are discussed last. There are no data regarding monovalent mumps vaccine and encephalopathy.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Measles Vaccine The first published case of encephalopathy (acute cerebellar ataxia) attributed to measles vaccine was discussed above (Trump and White, 1967). Retrospective analyses of populations who have received measles vaccine have been reported from many countries, including the United States. These uncontrolled observational studies provide no information on the concurrent background rates of encephalopathy. Table 6-2 summarizes case series and uncontrolled observational studies in which the incidence rates of encephalopathy or encephalitis following administration of measles vaccine were calculated by the authors. Two case series addressed early concerns in the United States that measles vaccine might cause encephalitis. The first was a report of 23 cases of neurologic disease following measles vaccination in the United States from January 1965 to February 1967 (Nader and Warren, 1968). The authors characterized 18 of the 23 cases as "encephalitis" (described as including disturbances of sensorium, seizure, major loss of motor function, and cerebral edema; no data are provided regarding pleocytosis in the CSF). The interval from vaccination to the onset of symptoms ranged between 3 and 24 days. Postmortem findings in one case revealed herpes simplex virus in brain tissue. There were two cases of aseptic meningitis, two cases of cerebellar ataxia, and one case of extraocular muscle paralysis. The authors estimated a rate of 1.5 reported cases of "encephalitis" within a 4-week period of vaccination per 1 million doses of vaccine distributed. They compared this with a background rate of 2.8 cases of encephalitis (unrelated to vaccination or known parainfectious causes) per 1 million children for any 4-week period. The authors concluded, ''No single clinical or epidemiologic characteristic appears consistently in the reports of cases of possible neurologic sequelae of measles vaccination" (p. 998). A review of 84 patients with neurologic disorders occurring within 30 days of vaccination against measles virus reported to the Centers for Disease Control from 1963 to 1971 revealed 59 patients with extensive neurologic disorders, which included encephalomyelitis (Landrigan and Witte, 1973). The cases reported by Nader and Warren (1968) and discussed above are a subset of the data of Landrigan and Witte (1973). Although in all 59 patients the onset of symptoms occurred between 1 and 25 days after vaccination, in 45 it coincided with the period of maximal viral replication (6 to 15 days after vaccination). Of 50 patients for whom follow-up information was available (follow-up presumably from 1963 to sometime before 1973), 26 recovered fully, 5 died (2 of the 5 had pathologic features of Reye syndrome), and 19 were left with permanent neurologic damage. Thirteen of the 59 patients were classified as having encephalomyelitis. Long-term follow-up of 12 of the patients showed residual neurologic signs in 3 patients. Long-term follow-up was available for 31 of 36 patients considered to have encephalopathy. Ten of those 31 patients recovered fully, 5 died,

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 6-2 Rates of Encephalitis/Encephalopathy After Measles Vaccination from Uncontrolled Studies Reference Years Covered Measles Vaccine Used Condition No. of Cases Calculated Rate per Million Doses Nader and Warren, 1968 January 1965 to February 1967 Live attenuated Encephalitis 18 1.5 Landrigan and Witte, 1973 (overlaps with Nader and Warren, 1968) 1963 to 1971 Live attenuated Encephalomyelitis (including transverse myelitis) 13 1.2       Encephalopathy 36   Hirayama, 1983 1978 to 1982 (?) Schwarz Encephalitis/ encephalopathy 8 3.7     Biken-CAM   4 2.9 White, 1983 1965 to 1976 Unspecified Encephalitis 7 1.8 Koch et al., 1989 1987 MMR (unspecified) Meningitis/ encephalitis 5 11 Fescharek et al., 1990 1976 to 1989 More attenuated Enders Meningitis/ encephalitis 16 (total) 3     (measles, measles-mumps, MMR)   5* 1 * The authors thought that 5 of the 16 cases were possibly causally related to the vaccine.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality and 16 were left with neurologic residua. The authors calculated rates of "encephalitis" of 1.16 cases per 1 million doses of vaccine distributed. Among the recipients of more than 3 million doses of measles vaccine (various strains, but mostly the Schwarz strain) in the United Kingdom between 1968 and 1974, there were 47 cases of "encephalitis" (Beale, 1974). The report does not discuss the criteria used for the diagnosis. Data on the occurrence of encephalitis in temporal relation to administration of measles vaccine for the years 1965-1976 in Canada showed a rate of 1.79 cases of encephalitis per 1 million doses of vaccine distributed (White, 1983). These data are based on hospital admissions associated with International Classification of Diseases codes for "viral encephalitis unspecified" and "acute viral encephalitis.'' In a report from the former East Germany (Dietzsch and Kiehl, 1976), there were 7 central nervous system (CNS) complications out of 174,725 immunizations with an unstated vaccine, but it was probably one of the strains from the former Soviet Union. Two febrile seizures, four cases of encephalopathy, and one case of encephalitis (there was pleocytosis in the CSF) were reported. Few clinical details were reported. Two of the patients with encephalopathy and the patient with encephalitis recovered completely, one patient with encephalopathy was left with a residual paralysis, and another died of leukemia. A report from the former Soviet Union (Ozeretskovskii and Gurvich, 1991) referred to cases of encephalitis and encephalitic reaction caused by a measles vaccine (probably the Smorodintsev strain), but offered no primary data. The authors quote three rates per 100,000 vaccinees: 0.1, 0.02, and 190 cases. The rate of 0.02 is far below the acknowledged background rate of encephalitis and the rate of 190 is far above any rates quoted anywhere for encephalitis/encephalopathy after receipt of measles vaccine. Considering the imprecision of the definition of "encephalitis" and "encephalitic reaction" and the discrepancy of the rates, it is impossible to interpret that report. A report of adverse events associated with measles vaccine in Japan from 1978 to 1983 cited 12 cases of "encephalitis" or "encephalopathy," without describing them, and derived a rate of 3.7 cases of "encephalitis'' per 1 million vaccinees administered the Schwarz vaccine and 2.9 cases per 1 million vaccinees administered the Biken-CAM vaccine (Hirayama, 1983). A follow-up to that report published 5 years later (Isomura, 1988) mentioned 16 cases of "encephalitis" (4 more cases than the earlier report), but provided no details. The incidence rate for "encephalopathy" and "encephalitis" following measles vaccination appeared to be lower than the observed incidence of encephalitis from all causes among age-matched controls (Hirayama, 1983; Isomura, 1988). This comparison was not derived from a controlled cohort study, however.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Measles Vaccine-Containing Preparations In an analysis of 433 spontaneous reports to a vaccine manufacturer in the Federal Republic of Germany (former West Germany) between 1976 and 1989 (Fescharek et al., 1990), 6 of 16 reports of "meningitis" or "encephalitis" were thought by the authors to be possibly related to measles, measles-mumps, or measles-mumps-rubella vaccine, leading to a rate of 1 case per 1 million doses distributed, as calculated by the authors. The vaccine strains are those currently licensed in the United States, that is, the more attenuated measles vaccine and Jeryl Lynn mumps vaccine. Assuming that all 16 reports of cases of "meningitis'' and "encephalitis" were causally related to the vaccine, the rate would increase to about 3 cases per 1 million doses distributed, which is within the range reported in other countries, as described above. A study based on a new passive surveillance system in Canada reported a rate of 1.1 cases of meningitis or encephalitis, without distinguishing between the two, per 100,000 doses of MMR (Koch et al., 1989). (This high rate was probably due to the inclusion of meningitis in the survey.) It was estimated that more than 8 million doses of MMR were distributed in Canada during the reporting period. A description of 212 adverse events associated with MMR reported to Swedish health authorities from 1982 to 1984 (when an estimated 700,000 doses of MMR were sold) includes 17 reports of transient, serious cases of neurologic symptoms: 3 patients with "encephalitic symptoms" who were treated at the hospital, 7 patients with "encephalitic symptoms" who were not hospitalized, 5 patients with acute symptoms with motor difficulties, 1 patient with seizures and fever, and 1 patient with hemiparesis (Taranger and Wiholm, 1987). "Encephalitic symptoms" included tiredness, whining, irritability, and mood changes with or without fever. No mention of CSF pleocytosis was made. Follow-up of at least 1 year showed that one 18-month-old boy who had developed symptoms of mild encephalitis with balance problems had residua of foot dragging and stumbling when he was tired. Case Reports Many case reports describe encephalitis or encephalopathy following administration of measles vaccine. Because isolation of measles virus is problematic and exposure to wild-type measles virus is common, it is difficult to assess a possible role of measles or measles vaccine in the occurrence of encephalopathy or encephalitis in an individual case. Typical case reports follow. A 5-year-old received a live measles vaccine and developed fever two weeks later (Alves et al., 1992). Three days after the onset of fever, the boy presented with hemiparesis, dysarthria, and a generalized rigid-akinetic syndrome. A spinal tap obtained four days later showed pleocytosis. One month later he was diagnosed with postencephalitic parkinsonism. He responded to levodopa therapy. The parkinsonism persisted for the 2 years

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality between the time of vaccination and publication of the report (Alves et al., 1992). A 14-month-old girl received the wellcome measles vaccine and developed convulsions 12 days later (Barbor and Grant, 1969). She became confused, restless, and then unconscious. Although the authors called this an encephalitis, there was no CSF pleocytosis on days 13 or 21 postvaccination. She made little progress in the 4 months between hospitalization and publication of the report. An electroencephalographic record of slow waves, which are not characteristic of measles encephalitis, and possible slight head trauma 9 days after vaccination suggested a temporal, not a causal, relation between the convulsions and the measles vaccination. A 13-month-old girl was admitted to the hospital with involuntary jerking movements of her limbs 10 days after receiving a further attenuated Enders live measles vaccine (Jagdis et al., 1975). She was afebrile, although she had fever for 2 days prior to admission. The CSF was turbid and showed pleocytosis. She had a convulsion followed by apnea. She died 13 days after vaccination. Postmortem examination suggested viral encephalitis; Cowdry type A inclusion bodies suggested measles virus as the etiologic agent, but no measles virus was isolated. She had no known exposure to wild-type measles virus, but an epidemic in the community was ending. Haun and Ehrhardt (1973) described a boy age 11 months who developed drowsiness, convulsions, and coma 12 days following vaccination with the L-16 SSW measles vaccine (a variant derived from the Soviet strain Leningrad-16). There was pleocytosis in the CSF. He died the same day as onset of symptoms. Autopsy findings were suggestive of disseminated intravascular coagulation as the cause of death. A boy age 2 years was administered live measles vaccine 10 days before the development of persistent convulsions (Starke et al., 1970). The child suffered convulsions accompanied by unconsciousness until his death a month later. He had experienced convulsions in the first year of life during a bout of pneumonia. The autopsy stated there was CNS death, "encephalitis" following measles inoculation, and septic pulmonary infarction. No further details are given. Several reports of encephalopathy following measles vaccination can be found in the Vaccine Adverse Event Reporting System (VAERS) (submitted between November 1990 and July 1992). As with many VAERS reports, the information that is supplied is frequently inadequate to support or reject a diagnosis or to exclude the possibility that other factors are responsible for the disorder, if the case was encephalopathy or encephalitis. The committee found that 17 VAERS reports were suggestive of encephalopathy or encephalitis in vaccinees (mostly MMR) from ages 5 months to 16 years. Reported latencies ranged from 1 to 14 days after immunization. The patients presented with symptoms such as fever, ataxia, somnolence, convulsions, and flaccid paralysis. Several reports contained too little information to suggest a diagnosis or to shed light on causality.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality tive risk is available. Estimates from the studies described above range from 1 per 20,000 to 1 per 1 million doses distributed. The evidence is inadequate to accept or reject a causal relation between mumps vaccine and anaphylaxis. Risk-Modifying Factors Most anaphylactic reactions occur in individuals who have no known risk factors for severe reactions to these vaccines; thus, no special precautions can be taken. Patients who have demonstrated severe systemic reactions to egg protein or neomycin may be at increased risk of anaphylaxis following receipt of measles or mumps vaccines, and guidelines for immunizing such patients have been provided by the Committee on Infectious Diseases of the American Academy of Pediatrics (1991). Patients with allergies to other antigens, including chickens and feathers, are not at increased risk of severe allergic reactions to these vaccines. DEATH A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10. Only the causality argument and conclusions follow. See Chapter 10 for details. Causality Argument The data relating death and measles or mumps vaccine are from case reports and case series. The largest series comes from India, but toxic shock syndrome caused by the unhygienic conditions involved in the immunization program was the apparent cause of death reported for eight of nine patients. Evidence based on RNA sequencing techniques has linked measles vaccine and measles infection to subsequent death in some severely immunocompromised children. In contrast, studies of the immunogenic response to measles vaccine in children infected with human immunodeficiency virus, which causes acquired immune deficiency syndrome, have not recorded any deaths from measles infection. The evidence favors the acceptance of a causal relation between measles vaccine and anaphylaxis. The evidence establishes a causal relation between MMR and thrombocytopenia and anaphylaxis. Anaphylaxis and thrombocytopenia can be fatal. Although there is no direct evidence of death as a consequence of measles vaccine-related anaphylaxis or of MMR-related thrombocytopenia or anaphylaxis, in the committee's judgment measles vaccine could cause fatal anaphylaxis and MMR could cause fatal

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality thrombocytopenia or fatal anaphylaxis. There is no evidence or reason to believe that the case fatality rate of vaccine-related thrombocytopenia or anaphylaxis would differ from the case fatality rates for these adverse events associated with any other cause. Conclusion The evidence establishes a causal relation between vaccine-strain measles virus infection and death. The conclusion is based on case reports in immunocompromised individuals and not on controlled studies. No relative risk can be calculated. However, the risk of death from measles vaccine-strain infection would seem to be extraordinarily low. The evidence establishes a causal relation between MMR and death from anaphylaxis or complications of severe thrombocytopenia. There is no direct evidence for this; the conclusion is based on the potential of thrombocytopenia and anaphylaxis to be fatal. The risk would seem to be extraordinarily low. The evidence favors acceptance of a causal relation between measles vaccine and death from anaphylaxis. There is no direct evidence for this; the conclusion is based on the potential of anaphylaxis to be fatal. The risk would seem to be extraordinarily low. The evidence is inadequate to accept or reject a causal relation between measles and mumps vaccines and death from causes other than those listed above. REFERENCES Abe T, Nonaka C, Hiraiwa M, Ushijima H, Fujii R. Acute and delayed neuralgic reaction to inoculation with attenuated live measles virus. Brain and Development 1985;7:421-423. Afzal MA, Pickford AR, Forsey T, Minor PD. Heterogeneous mumps vaccine. Lancet 1992;340:980-981. Alderslade R, Bellman MH, Rawson NS, Ross EM, Miller DL. The National Childhood Encephalopathy Study: a report on 1,000 cases of serious neurological disorders in infants and young children from the NCES research team. In: Department of Health and Social Security. Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunization. Lond: Her Majesty's Stationery Office; 1981. Alter HJ, Scanlon RT, Schechter GP. Thrombocytopenic purpura following vaccination with attenuated measles virus. American Journal of Diseases of Children 1968; 115:111-113. Alves RS, Barbosa ER, Scarf M. Postvaccinal parkinsonism. Movement Disorders 1992;7:178-180. American Academy of Pediatrics, Committee on Infectious Diseases. The Red Book. Report of the Committee on Infectious Diseases, 22nd edition. Elk Grove, IL: American Academy of Pediatrics; 1991. Asbury AK, Gibbs CJ Jr, eds. Autoimmune neuropathies: Guillain-Barré syndrome. Annals of Neurology 1990;27(Suppl.):S1-S79.

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