The Topic of This Month Vol. 30, No. 1 (No. 347)

Enterovirus infections in association with aseptic meningitis in Japan, as of December 2008
(IASR 30: 1-3, January 2009)

Japan has experienced outbreaks of aseptic meningitis in every summer.  Echoviruses (E), group B coxsackieviruses (CB) and other enteroviruses occupied 80-90% of the causative agents (Fig. 4).  Their prevalent serotypes changed from year to year.  Regional variation in the prevalent types has been noted.  Prognosis of aseptic meningitis caused by the enteroviruses is generally good, and acute encephalitis is rather rare.  However, during the enterovirus 71 (EV71)-related hand, foot and mouth disease (HFMD) epidemic in the Asia-Pacific region, frequency of complications involving the central nervous system was elevated, and there were very severe or even fatal cases (see p. 9 of this issue).

Aseptic meningitis is a category V infectious disease under the Infectious Diseases Control Law enacted in April 1999.  For the National Epidemiological Surveillance of Infectious Diseases (NESID) under the law, about 470 sentinel points are selected among hospitals with ≥300 beds providing care of the pediatrics and the internal medicine for weekly reporting of clinical aseptic meningitis cases.  Prefectural and municipal public health institutes (PHIs) are responsible for isolation, identification and reporting of etiological agents from specimens (cerebrospinal fluids, stools, pharyngeal swabs, etc.) collected at sentinel points.

Incidence: Fig. 1 shows the weekly report of number of aseptic meningitis cases since April 1999.  There was a large outbreak in 2002 and the cumulative patient number of the year was 2,985 (6.31 cases per sentinel).  Since then, however, the scale of the epidemics has remained small.  In the past 6-7 years, the incidence of the aseptic meningitis has been low (less than one case/sentinel/year) in Hokkaido, Iwate, Miyagi, Ibaraki, Yamaguchi and Kagawa Prefectures.  Other prefectures have experienced outbreaks at one time or another but not simultaneously, indicating no nationwide epidemic has occurred in recent years (Fig. 2).  The age distribution of cases has changed in recent years (Fig. 3).  Until 2003, children under nine years old accounted for around 70% of the cases, but since 2006, cases over ten years old increased and they exceeded a half of the cases in 2008.

Isolation and detection of enteroviruses: In 2002, when aseptic meningitis surged, E13 was predominant, followed by E11, E30, E9 and CB2 (Table 1).  In later years, the predominant types were E30, E6, EV71, E18 and E9 in 2003, E6, E30, CB5, CB1 and E18 in 2004, E9 and CB3 in 2005, E18, E30 and CB5 in 2006, CB5 and E30 in 2007, and E30 in 2008.  Above listed are the types isolated each from more than 50 cases per year (Table 1 and Fig. 4).

Prevalence of each echovirus serotype or EV71 tends to recur with intervals of several years to decades.  E13, unreported until 2000, was isolated abundantly from 2001 to 2002.  It then declined during 2003-2006 and disappeared from the report since 2007.  E30 caused large-scale nationwide outbreaks three times; in 1983 [IASR 4(10): 1, 1983], 1989-1991 (IASR 12: 163, 1991&13: 155, 1992) and 1997-1998 (IASR 19: 174-175, 1998).  Then the epidemic pattern changed to yearly occurrence of local epidemics.  In 2008, however, E30 aseptic meningitis broke out among high school students (see p. 8 of this issue).  EV71 prevalence has recurred every three to four years, and the most recent one was in 2006.

In contrast to the recurrent echovirus prevalence, CB virus types 2-5 have been consistently isolated every year.  A large number of CB5 cases were reported in 2007, and the reported number was the next to that in 1984.

In 2006-2008, E30, E18 and CB5 were viruses most frequently isolated from aseptic meningitis cases.  Fig. 5 shows the age distribution of the isolation sources of E30, E18, CB5 and EV71.  While E30 and E18 were isolated/detected from a wide range of age groups, meningitis cases from which these viruses were isolated were among 0 year infants and among children over 3 years with the highest incidence peak at 5 years.  For CB5, the virus isolation/detection was most frequent from 0-year infants and the isolation from children after school age has been rare.  The peak of the CB5-associated aseptic meningitis was also at 0 year.  EV71 was isolated/detected mostly from the young children with peak ages of 1-2 years.  However, incidence of aseptic meningitis associated with EV71 had two peaks, one at 0-year and the other at 5-years.

E30, E18, CB5 and EV71 were isolated from various sources other than aseptic meningitis.  E30 was isolated/ detected from the upper respiratory tract inflammation and infectious gastroenteritis, E18 from upper respiratory tract inflammation and fever of unknown origin (FOU), CB5 from infectious gastroenteritis and FOU, and EV71 from HFMD.

Table 2 shows specimens from which enteroviruses were isolated or detected during 2006-2008.  Compared with E30, E18 and CB5, EV71 was less frequently isolated/detected from the cerebrospinal fluids (see p. 10 of this issue).

Table 3 also shows isolation/detection methods applied to the enteroviruses identified during 2006-2008.  Recent tendency is increasing application of PCR.  Although PCR is useful for rapid diagnosis, attention must be paid to selecting primers, possible cross-contamination or other technical problems (see p. 4, 10&13 of this issue).  The detection rate of enteroviruses from cerebrospinal fluids by PCR is higher than that by virus isolation in cultured cells or suckling mice (see p. 6 of this issue).  PCR coupled with nucleotide sequencing is now increasingly available.  However, certain important information is available only through virus isolation.  Therefore, conventional virus isolation and identification should be conducted in parallel with the direct molecular detection (see p. 5 of this issue).

Other remarks: Sentinel surveillance of aseptic meningitis started in July 1981 with weekly reporting schedule until December 1986.  It was switched to monthly reporting in January 1987 with expectation of collecting information on causative agents.  It was continued till March 1999.  However, expected information on causative agent(s) was rarely attached to the reports.  In addition, monthly report delayed timely information sharing.  Therefore, weekly reporting scheme was resumed in April 1999.

In the current weekly reporting system, only a small number of reports carry information on infectious agents.  Namely, the current NESID needs further improvement.

From the start of NESID, sentinel hospitals were all designated as pathogen sentinels, i.e., responsible for collecting specimens for laboratory diagnosis (see above).  It is advisable that the health centers request physicians in the sentinel hospitals to send specimens to PHIs for the microbiological diagnosis.

It may happen that non-sentinel hospitals or clinics detect a sign of meningitis outbreak.  Even in such cases, the investigation using laboratory diagnosis should be considered as an active epidemiological investigation.  When EV71 is detected during an epidemic of HFMD, attention is required for possible occurrence of severe neurological complications.

The Infectious Disease Surveillance Center, the National Institute of Infectious Diseases is providing the most recent trend of incidence and virus isolation/detection, which is uploaded on the URLs and  It will be useful information sources for physicians in charge of patient diagnosis and for organizations concerned.

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