Outbreak of Aseptic Meningitis Associated with Multiple Enterovirus Serotypes --- Romania, 1999

In August 1999, the Ministry of Health of Romania (MOH) reported to the World Health Organization (WHO) an outbreak of aseptic meningitis that began in early July 1999. CDC and the Robert Koch-Institute in Berlin, Germany, were invited by WHO and MOH to assist in the investigation of this outbreak. Virologic findings of the investigation showed that the etiologic agents of the outbreak were three separate enterovirus serotypes. This report summarizes the epidemiologic findings of the investigation.

MOH defined a case of aseptic meningitis as fever, headache, other meningeal signs (e.g., vomiting, malaise, and stiff neck and back), increased cell counts in the cerebro-spinal fluid (CSF) of up to 1000 cells/mm³ that are mainly lymphocytes, and no bacterial etiology identified. During late June and early July, MOH received physician reports of increased numbers of hospital admissions for aseptic meningitis. In response to physician reports, on July 19, MOH began active surveillance for persons hospitalized with aseptic meningitis. From July 19 through September 8, physicians in Romania reported 4734 hospitalized persons with aseptic meningitis. The incidence of new cases peaked during August 17--20. By September 8, the incidence was declining steadily, and the investigation ended.

The highest attack rates were concentrated within six of the 40 counties in Romania (five of which are in the northeastern section of the country). The range of attack rates within these six counties was 43.5--126.4 per 100,000 population. On August 6, Romanian health authorities initiated a case series investigation to assess risk factors for illness and define disease characteristics; reports were received for 343 hospitalized persons who had illnesses that met the case definition from 18 counties. Of the 343 case-patients, 185 (54%) were male. The median age was 13 years (range: <1--72 years); 93% of case-patients were aged <30 years. Symptoms most commonly reported were fever (98%), headache (97%), vomiting (80%), eye pain (79%), nausea (52%), photophobia (38%), and myalgia (28%).

To determine risk factors for aseptic meningitis, a matched case-control study was conducted in four counties. For each case-patient, two control-patients matched for age and date of hospital admission were selected from noninfectious disease hospital wards. The case-control study included 241 case-patients and 480 controls. The number of participating case per county ranged from 34 to 106. The factors consistently associated with illness within all four participating counties were contact with a body of water (i.e., swimming, bathing, and working), contact with a confirmed case of viral meningitis, contact with a person displaying meningeal signs or symptoms (all p<0.01), male sex (p=0.04), and lack of organized household garbage disposal (p=0.02). No association was found between illness and other possible risk factors such as household size, source of drinking water, or type of toilet facilities (all p>0.4).

Lumbar punctures were performed on patients suspected to have aseptic meningitis. CSF or stool specimens or both were obtained for enteroviral isolation studies from approximately 100 hospitalized case-patients. Viral isolation studies have been completed for 114 specimens received from eight counties. Echovirus type 4 was isolated from eight CSF specimens and 12 stool specimens, echovirus type 7 was isolated from three CSF specimens and three stool specimens, and echovirus type 30 was isolated from 17 CSF specimens and 32 stool specimens. One case-patient was positive for both echovirus type 4 and type 7 from a single CSF specimen.

In response to this outbreak, MOH initiated control measures that included a vigorous, nationwide education campaign that emphasized preventive measures. These measures included short-term closing of schools in the most affected counties, improved hygiene practices, and avoiding public swimming areas.

Reported by: Preventive Medicine Dept, Ministry of Health, Romania Field Epidemiologists Association Institute of Preventive Medicine; Cantacuzino Institute, Bucharest, Romania. Div of Emerging and Other Communicable Diseases Surveillance and Control, World Health Organization, Geneva, Switzerland. European Program for Intervention Epidemiology Training, United Kingdom and Germany. Robert Koch-Institute, Berlin, Germany. Respiratory and Enteric Viruses Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases; and an EIS Officer, CDC.

Editorial Note:

Aseptic meningitis is the most common infectious syndrome affecting the central nervous system (1,2). Nonpolio enteroviruses are the leading infectious cause of this syndrome in the United States, accounting for >80% of all cases in which a pathogen is identified (3). The etiologic agents identified in this outbreak were enteroviruses; three different echovirus serotypes (4, 7, and 30) were isolated from CSF specimens, indicating a possible multiserotype outbreak. Several enterovirus serotypes may co-circulate in the same community during the summer and fall months, but a large epidemic of aseptic meningitis associated with three different serotypes is unusual. This outbreak represents one of the largest focal aseptic meningitis outbreaks ever reported. In 1991, a nationwide epidemic of aseptic meningitis caused by echovirus 30 in Japan resulted in 4061 total cases, the largest number of cases ever attributed to a single virus type (4).

Enteroviruses are usually spread through the fecal-oral route, and children often play an important role in transmission. In temperate climates, the incidence of infection is higher during the summer and fall; in tropical climates, infections are more evenly distributed throughout the year (5). This outbreak occurred during the usual season of greatest enterovirus activity. Virologic surveillance data from Romania indicated that the last large outbreak of aseptic meningitis was in 1970 and was attributed to echovirus 4 (M. Popa, M.D., MOH, personal communication, 1999). The 1999 outbreak may have resulted from simultaneous circulation of three enterovirus serotypes that have not been present in this population for several years, resulting in high rates of susceptibility to at least one of the three serotypes.

Typically, enterovirus infections are either asymptomatic or result in mild disease, and fewer than one in 500 infections result in aseptic meningitis (5). Age is one of the most important determinants of infection, with illness often being more severe in older persons. Because of the low case-to-infection ratio, effective control measures should not be based on response to individual cases. Effective measures are aimed at interrupting transmission by encouraging strict adherence to hygienic practices (e.g., handwashing).

The findings from the case-control study are subject to at least three limitations. First, all control patients were chosen from noninfectious disease wards of hospitals and may not have had equal opportunity for exposure to enteroviruses. Although this may have protected them from infection, it was difficult to interpret disease associations with specific activities such as swimming. Second, cases were defined clinically rather than by serologic or virologic evidence of infection. Because of the low case-to-infection ratio, power to identify risk factors may have been reduced. For example, the investigation failed to identify known risk factors such as household size or toilet facilities. Finally, the case-control study was conducted late in the outbreak, when the primary mode of transmission may have changed.

This outbreak demonstrates the potential for enteroviruses to cause widespread community disease with substantial public health impact. A major component of the public health response to an enterovirus outbreak is public education that stresses the role of personal hygiene (e.g., handwashing and avoiding sharing of eating utensils and drinking containers) in interrupting virus transmission.

References

1. Nicolosi A, Hauser WA, Beghi E, Kruland LT. Epidemiology of central nervous system infections in Olmsted County, Minnesota, 1950--1981. J Infect Dis 1986;154:399--408.
2. Rantakallio P, Leskinen M, Von Wendt L. Incidence and prognosis of central nervous system infections in a birth cohort of 12,000 children. Scand J Infect Dis 1986;18:287--94.
3. Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am 1990;4:599--622.
4. Yamashita K, Miyamura K, Yamedera S, et al. Epidemics of aseptic meningitis due to ECHO virus 30 in Japan. Jpn J Med Sci Biol 1994;47:221--39.
5. Morens DM, Pallansch MA, Moore M. Polioviruses and other enteroviruses. In: Belshe RB, ed. Textbook of human virology. 2nd ed. St. Louis: Mosby Yearbook, 1991:427--97.

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