Oski and Naiman1 were the first to demonstrate a causal relationship between immunization with the Schwarz strain of live-attenuated measles virus and thrombocytopenia (TP). The cases described were transient and mild; the lowest recorded platelet count was 64 000/mm3, indicating that spontaneous hemorrhage and serious complications were unlikely to occur as the result of postimmunization TP. In contrast a recent report from Finland described severe thrombocytopenia after immunization with measles-mumps-rubella (MMR) vaccine (Virivac®); children in this series had platelet counts <20 000/mm3 and hemorrhagic complications.2
The current experience with postimmunization TP in the United States is less well known. The Institute of Medicine reviewed 12 US cases reported to the Vaccine Adverse Events Reporting System (VAERS) between 1990 to 1992 which also indicated that severe but transitory decreases in platelet counts sometimes follow primary immunization with measles-containing vaccines.3 It is also important to know whether postimmunization TP can recur when additional doses of measles vaccine are administered. Although adverse reactions to any subsequent dose(s) may be similar to those seen with primary immunization, it is believed that these reactions would most likely be limited to the subset of children who were nonimmune before immunization.4 However, rechallenge with the Schwarz strain of measles virus caused repeat episodes of TP in one child indicating that individuals thus primed may be at risk for additional episodes of TP if they are again exposed to vaccine.1, 3
Recently a cluster of reports documenting severe TP after MMR II immunization was received by VAERS which prompted a review of the database to evaluate the severity of this adverse event resulting from primary and secondary immunization with measles-containing vaccines. This summary of VAERS data provides a review of 55 cases of TP after measles immunization in the US in order to increase awareness and recognition of this rare but potentially serious adverse event.
Methods. VAERS, established under the National Childhood Vaccine Injury Act of 1986, is the joint responsibility of the Centers for Disease Control and Prevention and the US Food and Drug Administration. Data on adverse reactions have been entered into the database since July, 1990 and since that time >44 000 reports have accrued. Each reported event is coded using COSTART (Coding Symbols for the Thesaurus of Adverse Reaction Terms). For this review all reports coded thrombocytopenia or thrombocytopenic purpura for measles-containing vaccines entered between July, 1990, and December 30, 1994, were retrieved. The following data were summarized: age at the time of immunization; sex; day of onset postimmunization and, if mentioned, duration of thrombocytopenia; lowest platelet count; occurrence after the first or second dose of measles vaccine; need for hospitalization; therapy (intravenous immunoglobulin, steroids and/or splenectomy); complications of the thrombocytopenia; and pertinent medical history such as antecedent illness and concurrent administration of other vaccines.
Results. Fifty-six reports coded thrombocytopenia or thrombocytopenic purpura were retrieved from 8581 reports for measles-containing vaccines. One described a child with a platelet count of 5000/mm3 at the time of vaccine administration: this report was eliminated from analysis leaving 55 reports for review. There were 51 reports for individuals receiving measles-mumps-rubella, 3 individuals had received monovalent measles vaccine and 1 report after administration of measles-mumps vaccine.
The age distribution for vaccinees with TP is listed in Figure 1, with a range of 1 to 40 years; 55% of the cases occurred in children <2 years old. Cases were evenly distributed between males (28 cases) and females (27 cases). Onset of TP, available in 48 of 55 reports, occurred 1 to 83 days postimmunization; 42 cases began 3 to 32 days after vaccination (median time to diagnosis, 12 days).
Forty-one reports indicated that the vaccinee required hospitalization. VAERS reports indicated that 17 individuals were given intravenous immunoglobulin and/or steroids for treatment of TP; one 12-year-old male had a splenectomy. Two serious complications were reported: a 1-year-old male (platelet count, 1000/mm3, 12 days after immunization) had severe gastrointestinal hemorrhage and required blood transfusions; a 15-month-old male (platelet count, 5000/mm3, interval after immunization not reported) had pulmonary hemorrhage.
There were 2 fatalities. A 17-year-old male with a history of recurrent episodes of TP secondary to antiphospholipid syndrome died of sepsis 4 days after immunization and a 4-year-old male child died 7 days after immunization after the acute onset of Escherichia coli 0157:H7 infection complicated by pseudomembranous colitis. It cannot be ascertained from the data reported whether immunization contributed to TP in these cases or whether TP was solely associated with the underlying disease. Platelet counts were reported for 42 individuals, ranging from 1000 to 102 000/mm3; 29 had platelet counts ≤20 000/mm3 (see Figure 1 for summary of platelet counts).
Most reports did not indicate whether the vaccine was administered for primary immunization or represented Dose 2 in the currently recommended series. Thirty-five reports for children <2 years old are likely to represent primary immunization. TP occurred after the second dose in 3 children (ages 4, 9 and 14 years old with platelet counts of 6000, 11 000 and 6500/mm3, respectively) and one of these cases represented a positive rechallenge. Antecedent acute respiratory illnesses were reported for only 2 children: sore throat in a 15-year-old; and upper respiratory infection in a 10.5-year-old. Fourteen of 15 patients older than 6 years received only MMR or monovalent measles vaccine on the day of immunization; one 15-year-old received MMR and Td. Other vaccines, including diphtheria-tetanus toxoids-pertussis (7 children), oral poliovirus vaccine (7 children), Haemophilus influenzae type b conjugate vaccine (15 children) or hepatitis B vaccine (2 children), were administered concurrently to 21 of 40 children ≤6 years old. Bone marrow biopsies were reported for 5 individuals and interpreted as “normal” or consistent with a diagnosis of immune thrombocytopenic purpura. One of 2 children tested had antiplatelet antibodies. Most VAERS reports did not specify whether the TP resolved or the time to resolution. Five reports indicated that normal platelet counts were reached by Days 7, 8, 9, 19 and 81 after diagnosis.
Discussion. Thrombocytopenia may follow infection caused by wild-type measles, mumps or rubella viruses and one prospective study documented occurrence after measles immunization with the Schwarz strain of attenuated vaccine virus.1 The data summarized here agree with the findings of Nieminen et al. in Finland who similarly documented severe TP in children who were immunized with Virivac containing the MORATEN strain of live, attenuated measles virus; these investigators estimated from their series that TP occurred at a rate of 1 case/30 000 doses of vaccine administered.
The current report extends these findings to older age groups and indicates that severe TP may occur in US children and may on rare occasions lead to gastrointestinal or pulmonary hemorrhage. TP may occur after the second dose of vaccine and has been documented to precipitate repeat episodes in one individual listed in the VAERS database, a finding initially observed by Oski and Naiman1 in their evaluation of recurrent TP after repetitive challenge with measles vaccine. The data summarized from VAERS do not prove a causal relationship between immunization with measles-mumps-rubella-containing vaccines and postimmunization TP for each vaccinee. Four cases reported other possible etiologies, such as sepsis or antecedent viral illness. However, immunization was the only risk factor reported to VAERS that could be linked to TP for the majority of cases.
These findings suggest that individuals with a history of TP, regardless of the etiology, may have recurrent episodes of thrombocytopenia after immunization and deserve a careful risk-benefit analysis before receiving vaccine. Immunization with MMR II or the monovalent components may be contraindicated for those who experienced severe TP after the first dose because there are no data in this series or in published reports that would allow us to conclude that seropositive individuals would be less likely to experience TP upon reexposure to vaccine antigen. Therefore serologic screening may be indicated to confirm the measles, mumps and/or rubella antibody status in order to determine the need for additional dosages of vaccine in persons with a history of vaccine-associated TP. Patients receiving intravenous immunoglobulin and/or immunosuppressive doses of steroids for vaccine-associated TP should also be serologically tested to be certain that these treatments do not abrogate the response to these live attenuated viral vaccines. VAERS reports provide inadequate information to assess the effectiveness of therapy. Untreated, postimmunization TP after immunization with Schwarz vaccine virus usually resolves in 3 to 6 weeks.1
The reports summarized here represent 0.07% of the reports for measles-containing vaccines that were received by VAERS and suggest that postvaccination TP may be a rare event; passive surveillance, however, does not provide a basis for estimating incidence rates. This report should not deter immunization with measles-containing vaccines but may provide a cautionary note for the use of these vaccines in children and adults with a history of thrombocytopenia.
Acknowledgments. We thank the physicians, health care providers and parents who filed these reports with VAERS. We are grateful to Drs. Bascom Anthony, Susan Ellenberg and Peter Patriarca for their critical review of the manuscript.
Judy Beeler, M.D.; Frederick Varricchio, M.D.; Robert Wise, M.D., M.P.H.
Divisions of Viral Products (JB) and Biostatistics and Epidemiology (FV, RW)
Center for Biologics Evaluation and Research
US Food and Drug Administration
1. Oski FA, Naiman JL. Effect of live measles vaccine
on platelet count, N Engl J Med 1966;275:352-6.
2. Nieminen U, Peltola H, Syrjala MT, Makipernaa A, Kekomaki R. Acute thrombocytopenic purpura following measles mumps and rubella vaccination: a report on 23 patients. Acta Paediatr 1993;82:267-70.
3. Stratton KR, Howe CJ, Johnston RB Jr., eds. Adverse events associated with childhood vaccines: evidence bearing on causality. Washington, DC: Institute of Medicine, National Academy Press, 1994.
4. Report of the Committee on Infectious Diseases. Evanston, IL; American Academy of Pediatrics, 1994:317.