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The topic of This Month Vol.39 No.6(No.460)

Viruses detected from aseptic meningitis patients in Japan, through 2017

(IASR Vol. 39 p89-91: June, 2018)

Aseptic meningitis is often characterized by symptoms of acute onset of fever, headache, and vomiting, but may also present with meningeal signs, such as a stiff neck and Kernig’s sign.  However, it is often the case that such manifestations may not be apparent in newborns or infants.  The differentiation from bacterial meningitis is clinically very important, and, in addition to a negative result of bacterial detection from the cerebrospinal fluid (CSF), the following CSF tests are useful for the differentiation: first pressure, cell count and fractionation, CSF/serum glucose ratio, and protein quantity.  Aseptic meningitis is caused by a variety of pathogens, and among viruses, enteroviruses are the most frequent, followed by the mumps virus.  Enteroviruses detected in humans are classified into four species (Enteroviruses A to D), and Enterovirus B (echovirus, coxsackievirus group B) is the most frequently detected in patients with aseptic meningitis, followed by Enterovirus A [e.g., enterovirus A71 (EV-A71)].

According to the National Epidemiological Surveillance of Infectious Diseases (NESID) system based on the Infectious Diseases Control Law, aseptic meningitis is classified as a category V infectious disease. On a weekly basis, approximately 500 designated sentinel sites (hospitals with 300 or more beds; http://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/0000203400.pdf) nationwide report patients that fulfill the notification criteria, based on clinical symptoms and laboratory findings (notification criteria: http://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou11/01-05-40.html). Based on specimens (e.g., CSF, feces, pharyngeal swabs) collected at the designated sentinel sites, prefectural and municipal public health institutes (PHIs) perform isolation/detection and identification of the etiologic agent of aseptic meningitis, and report those results with positive detections. This report describes the occurrence of patients with aseptic meningitis and recent trends in pathogens associated with aseptic meningitis, particularly enteroviruses.

Cases notified under the NESID system: Figure 1 shows the reported number of aseptic meningitis cases per sentinel per week in 2009-2017. In Japan, an increase in aseptic meningitis is reported every year in the summer. The number of reported cases per sentinel site in each prefecture differed by region (reference figure). With regards to the age distribution of aseptic meningitis patients, those under one year of age were the most frequent age group, and while those under 10 years of age made up more than half the cases in 2009-2011, the proportion of those 10 years or older increased since 2012 (Figure 2).

Isolation and detection of enteroviruses: During 2012-2017, enteroviruses, such as echovirus (E) and coxsackievirus group B (CV-B), accounted for 56-84% of the etiologic pathogens (Figure 3).

The annual number of viruses isolated or detected in patients with aseptic meningitis from 2009 to 2017 is shown in the Table. Among these viruses, CV-B5 and E-6 were frequently reported, with a total of 344 and 548 cases detected during the 9-year period, respectively (see pp. 94, 96 & 97 of this issue). E-30 aseptic meningitis outbreaks occurred nationwide in 1983 [IASR 4(10): 1, 1983], 1989-1991 (IASR 12: 163, 1991 & 13: 155, 1992), and 1997-1998 (IASR 19: 174-175, 1998). In 2017, a regional outbreak of E-30-associated aseptic meningitis was reported in Hokkaido, Japan (see p. 91 of this issue). High circulation of E-9 has also been reported from some localities (see p. 93 of this issue). As an etiologic agent of hand, foot, and mouth disease (HFMD), EV-A71 causes nationwide epidemics every 3-4 years, and is known to be frequently involved in central nervous system diseases; EV-A71 was detected in 43 and 30 patients with aseptic meningitis, respectively, in 2013 and 2017. If EV-A71 is detected when HFMD activity is high, attention should be paid to the occurrence of central nervous system diseases, including aseptic meningitis (see p. 94 of this issue).

In addition, the age distribution of cases with E-30, E-18, E-6, CV-B5, or EV-A71 detections reported through the Infectious Agents Surveillance System during 2012-2017, along with the proportion of these cases that were aseptic meningitis, are shown in Figure 4. These distributions differed by virus type. E-6 and E-30 were also detected in children and adults with meningitis, while CV-B5 and EV-A71 were detected mainly in young infants few months of age (IASR 38: 204-205, 2017).

Enteroviruses isolated or detected in patients diagnosed with aseptic meningitis between 2009 and 2017 were predominantly from CSF, feces, or throat swabs (reference table). For those with particularly high isolations/detections, namely E-6, E-18, E-30, and CV-B5 of the Enterovirus B family, CSF comprised 74-80% and feces 20-43% of the samples. In contrast, for aseptic meningitis patients from whom EV-A71 (belonging to the Enterovirus A family) was isolated/detected, 21% were from CSF and 63% from fecal samples. For aseptic meningitis, it is important to examine multiple samples, not only CSF, but also those such as feces and throat swabs. Recently, many enteroviruses have been identified from clinical samples by direct PCR detection and sequencing (see p. 98 of this issue).

Non-enterovirus aseptic meningitis-associated viruses (Figure 3, see pp. 94, 96, 97 & 99 of this issue): Non-enterovirus viruses detected in patients with aseptic meningitis included the mumps virus (12%), rhinovirus (5.8%), and parechovirus type 3 (2.4%) (% values indicated in parentheses for each virus represent the respective proportions among the total number of reported aseptic meningitis cases with isolations/detections of enteroviruses or the aforementioned viruses in 2009-2017, Table). Rhinovirus was detected mostly from throat swabs, and the association with aseptic meningitis was unclear in many cases. Mumps meningitis occurred frequently during mumps epidemic years [IASR 37: 185-186, 2016; median age of 6 years (range, 2-36 years) for 35 verified mumps meningitis cases in 2016 reported from the designated sentinel sites]. Although mumps is a disease that can be prevented by vaccination, the mumps vaccination is voluntary in Japan, and the vaccination coverage is around 30% (according to the National Epidemiological Surveillance of Vaccine-preventable Diseases: https://www.niid.go.jp/niid/ja/y-graphs/7457-mumps-yosoku-vaccine2016.htmlvaccine2016.html), a level inadequate for the control of mumps.

Conclusions:  Aseptic meningitis is an outbreak-prone disease, and identification of the pathogen is important because measures and precautions differ by pathogen.  It is important to strengthen both patient-based surveillance and laboratory-based (pathogen) surveillance on a routine basis.  Under the NESID system, all the designated sentinel sites are to conduct laboratory-based surveillance for aseptic meningitis.  When an outbreak of meningitis is detected in a medical facility, active epidemiological investigation is warranted, based on the Infectious Diseases Control Law.  It should be emphasized that CSF, feces and throat swab samples should be collected at an early stage of aseptic meningitis, in order to enable direct detection of pathogens (e.g. by PCR, isolation), and for neonates, blood samples should also be collected.

Copyright 1998 National Institute of Infectious Diseases, Japan

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