DIAGNOSIS

Reye Syndrome Associated with Vaccination with Live Virus Vaccines

An Exploration of Possible Etiologic Relationships

David M. Morens, M.D., Neal A. Halsey, M.D.† Lawrence B. Schonberger, M.D., M.P.H., Joseph V. Baublis, M.D., Ph.D.‡

To determine whether vaccination with live virus vaccines may be etiologi- cally related to Reye syndrome, we examined 404 cases reported to the Center for Disease Control. Fifteen of 269 children with Reye syndrome had been inoculated with live virus vaccines within 30 days before onset of illness. Although this temporal relationship may have occurred by chance, seasonal distribution and clustering of incubation periods suggests that live virus vaccines may occasionally serve as cofactors in the etiology of Reye syndrome through undefined mechanisms.

ANI~I instance of Reye syndromesyndrome related to vascular , and (2) evidence of administration of live vaccine which fatty change of the demonstrated by was reported to the Center for Disease Control or autopsy, or an SCOT or SGPT 3 (CDC) prompted a search of data on file at times normal or a blood ammonia level 1.5 CDC for similar cases. This report summarizes times normal, with (3) no other explanation our findings. for the neurologic or hepatic abnormalities. We examined report forms of 404 cases of Methods Reye syndrome. These reports had been filed between mid-1971 and December 1976 with was defined as an acute Reye syndrome (1) either the CDC Viral Diseases character- Division, noninflammatory Bureau of which maintains a ized by (CSF) containing Epidemiology, voluntary nationwide reporting system of less than 8 white blood cells (WBC) per mem3 Reye syndrome, or with the Immunization or by histologic sections of brain demonstrat- Division, Bureau of State Services, to which ing without meningeai or peri- reports of possible vaccine-related illnesses are sent. Of these forms, 289 contained * Enteric and Neurotropic Disease Branch, Viral to a about &dquo;immunization&dquo; Diseases Bureau of for responses question Division, Epidemiology, Center in the month. Disease Control, Atlanta, Georgia. [sic] previous † Vaccine Evaluation Branch, Immunization Division, Bureau of State Services, Center for Disease Control. ‡ Department of , University of Michigan Results Medical Center, Ann Arbor, MI. Correspondence to: David M. Morens, M.D., Building 7, Room 146, Bureau of Laboratories, Center for Of these 269 children, 23 were stated to Disease Control, Atlanta, GA 30333. have received an &dquo;immunization&dquo; within one 42 TABLE 1. Cases of Reye Syndrome Temporally As.sr~citated with Live Virus Vaccination

* M = measles vaccine; MMR = live measles, , cultured from patient. rubella vaccine; V = vaccinia virus inoculation; OPV ? Mean for 1974-1976 for all children, 10.3 years. = live oral virus vaccine; DTP = diphtheria and § Previously reported.’ tetanus toxoids, and killed pertussis vaccine. ~’ Previously reported.&dquo;’ t Not vaccinated, but vaccine-derived polioviruses were month preceding their illness. Of the 23, four ferred to a large referral center on the 4th day of had received bacterial vaccine (diptheria and illness, she suffered a and was resuscitated with intravenous urea. tetanus toxoids and killed three pertussis); Examination revealed an unconscious child with had received an undetermined of type vaccine; normal fundi and hyperflexia of both upper and in one the diagnosis of Reye syndrome extremities. The liver edge was palpated 4 cm (measles vaccine-associated) was question- below the right costal margin. Her pupils, which -had been fixed and dilated on able-the child may have had . arrival, responded to within minutes of the urea infusion. There were 14 who had been a live virus briskly light given Laboratory studies included a WBC count of vaccine within a month before onset of 12,000 with a marked left shift, serum ammonia prodromal symptoms of Reye syndrome; and 0.3 mg/dl (control, 0.2 mg/dl), SGPT 262 units, one other (Case K, Table 1) who had no history SGOT 209 units, total bilirubin 0.3 rrrg/dl, and 90 units. Skull films and of receiving any vaccinations but vaccine- 2-hour urinary amylase carotid were normal. The electro- derived polioviruses were cultured from him. arteriograms encephalogram was interpreted as being compati- the 14 children known to have received Only ble with Reye syndrome, Grade III on the scale of live virus vaccinations and Case K are discussed Aoki and Lombroso.~ Liver biopsy studies showed in this survey. These 15 cases were distrib- fatty infiltration without significant inflammatory uted in 1 I states and the District of Columbia; response and electron micrographs revealed swollen mitochondria, both as con- occurred at all times of the (Table l ). interpreted they year sistent with Reye syndrome. An monitor was placed Case His~ory through a burr hole, and intravenous urea adminis- tered for repeated &dquo;spikes&dquo; in intracranial pressure. Case I (Pt. A, Table 1). An 18-month-oid Her neurologic status remained poor, however, girl was admitted from the emergency room of a and at the time of discharge, 66 days later, she small community hospital with progression of suffered from marked spasticity, optic atrophy, , , convulsions, and over a 2-day and apparent severe intellectual deterioration. measles She had received live further attenuated Virologic studies performed at the referral measles vaccine 9 days prior to onset of prodromal center laboratory included negative cultures of symptoms, and also rubella vaccine 45 days prior throat, nasopharynx, CSF, rectal swab, urine, and to the onset. liver tissue. The following indirect immuno- WBC count, CSF analysis, and serum electrolyte fluorescent antibody (IFA) studies were negative: levels were within normal limits. While being trans- screen of the CSF for antibodies to V-Z virus, 43 rubella, mumps, and herpes simplex. Serum EB Furthermore, 5 of the 15 children had mild virus titer was less than 1:8. Serum rubella (IFA) respiratory symptoms preceding the onset of titers (IFA) were 1:16 on the 4th, 13th, and 24th one the time days of clinical illness. On the same days, serum neurologic symptoms; during when B was in his com- rubeola titers (IFA) were <1:8, 1:64, and 1:32. prevalent Complement fixation titers of acute and conva- munity. This is suggestive evidence that other lescent sera examined by the Michigan Department etiologic agents may have been involved in at of Health, Bureau of Disease Control and Labora- least some of the cases. However, only 3 of the tory Services, confirmed rubeola seroconversion. 15 live vaccine-associated cases occurred in the There was no evidence of seroconversion to St. Louis Encephalitis virus, LCM virus, herpes 3-month period (January through March) simplex, V-Z virus, mumps, parainfluenza 1, 2, and during which 76 per cent of the Reye 3, influenza A and B, polioviruses l, 2, and 3, Myco- syndrome cases reported to CDC in 1974- or the LGV plasma pneumoniae, agent. 1976 occurred, p < .0001, chi-square, ldf, (Table 1). Discussion There was apparent clustering of disease onset in the second week after the vaccination. Reye syndrome following vaccination with a live virus has been reported infrequently. Two Prodromal symptoms of Reye syndrome in 11 instances between 7 and 12 possible cases of measles vaccine-associated began days after the vaccination. If the three cases with Reye syndrome were described by Landrigan unknown dates are distributed and Witter one case of which is included here vaccination (Case B, Table l ~. The other child did not randomly throughout the 30.46 days of the meet our case definition. Reviews of the average month, the likelihood of the other Unites States experience with vaccinia virus I cases’ clustering within any 7-day period is not binomial If inoculation by Neff et al. and Lane et at.5 re- great (p < .01, expansion). recall bias were one would vealed no instances of Reye syndrome, operative, expect although in the earliest of these series marked a more direct relationship between recentness cerebral edema was noted in all four of the of vaccination and onset of Reye syndrome. it is difficult to the autopsied cases of &dquo;postvaccinal encephalitis.&dquo; Thus, reject hypothesis In a later series, at least two children had that live virus vaccines may serve as cofactors in the occurrence of illnesses similar to Reye syndrome. A case of Reye syndrome, though Reye syndrome associated with vaccine- the available data do not determine whether such a be derived poliovirus was reported in a 7-year- relationship might secondary solely 6 or to interaction of old contact by Brunberg and Bell. to primary infection, the Assuming that the inactive components of the vaccine virus with other infectious agents the vaccines play no role in the etiology acquired naturally. of there are at least 3 reason- Reye syndrome, References able of the explanations temporal relationship 1. Aoki, Y., and Lombroso, C. T.: value of virus vaccination and Prognostic between live Reye electroencephalography in Reye’s syndrome. syndrome: (1) It is coincidental. (2) The virus Neurology 23: 333, 1973. in the vaccine is the sole infectious 2. Kindt, G. W., Waldman, J., Kohl, S.,et al.: Intra- agent cranial in the disease. The virus in pressure Reye syndrome. Monitoring with (3) and control. JAMA 231: 822, 1975. the vaccine acts as an etiologic cofactor in con- 3. Landrigan, P. J., and Witte, J. J.: Neurologic dis- with one or more other infectious orders following live measles-virus vaccination. junction JAMA 233: 1459, 1973. agents. 4. Neff, J. M., Lane, J. M., Pert, J. H., et al.:Complica- When exploring these possibilities, we tions of smallpox vaccinations. I. National survey looked at the of viral diseases in in the , 1963. N. Engl. J. Med. 276: prevalence 125, 1967. at the time of illness. With the communities 5. Lane, J. M., Ruben, F. L., Neff, J. M.,et.: al Complica- 6 of the 15 cases, other viruses reported in tions of smallpox vaccination, 1968: National sur- the to have veillance in the United States. N. Engl. J. Med. past preceded Reye syndrome 281: 1201, 1969. were known to have been recently present, 6. Brunberg, J. A., and Bell, W. E.: Reye syndrome: including influenza B in two instances and An association with type 1 vaccine-like poliovirus. Arch. Neurol. 30: 1974. influenza A in another. Perhaps these or other 304, 7. Roe, C. R., Schonberger, L. B., Gelbach, S. H.,et al.: a role in devel- undetected viruses played the Enzymatic alterations in Reye’s syndrome: Prog- opment of Reye syndrome in these patients. nostic implications. Pediatrics 55: 119, 1975. 44