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The topic of This Month Vol.38 No.7(No.449)

Adenovirus infections, 2008 to June 2017, Japan

(IASR Vol. 38 p133-135: July, 2017)

Adenovirus (human mastadenovirus: Ad), is a physicochemically stable non-enveloped double-stranded DNA virus.  Over 80 types have been described, and are currently grouped into 7 species from A to G.  Ads have been reported as serotypes up to Ad51 (denoted as, for example, Ad1), but Ads discovered later (i.e. Ad52 or greater) have been reported based on the whole genome sequencing (see p. 136 of this issue).

Ad infection has been associated with a diversity of clinical manifestations, including respiratory, ophthalmologic [(such as epidemic keratoconjunctivitis (EKC)], gastrointestinal (such as infectious gastroenteritis), and urologic (such as hemorrhagic cystitis and urethritis) syndromes (Table 1 & Table 2). Nationally, Ad infections are monitored syndromically under the National Epidemiological Surveillance of Infectious Diseases (NESID) system, specifically via sentinel surveillance for pharyngoconjunctival fever (PCF) and infectious gastroenteritis at ~3,000 pediatric sentinel sites and for EKC at ~700 ophthalmological sentinel sites. Surveillance for pathogens are also conducted at these sentinel sites (see p. 136 of this issue).

Notifications of pharyngoconjunctival fever (PCF) and epidemic keratoconjunctivitis (EKC): Since surveillance for PCF began in 1987, the largest number of PCF cases were reported in 2006 (Fig. 1). While a summer peak in notifications has been consistently observed, an additional peak in winter has also been observed since 2003 (https://www.niid.go.jp/niid/ja/10/2096-weeklygraph/1645-02pcf.htmlweeklygraph/1645-02pcf.html, https://nesid4g.mhlw.go.jp/Byogentai/Pdf/data27e.pdf). Among the reported PCF cases, the most frequently reported age group was one year olds (Fig. 2).

In contrast, EKC patients monitored at ophthalmological sentinel sites have been reported most frequently during May-August. In 2015-2016, however, notifications increased through the autumn (Fig. 1; https://www.niid.go.jp/niid/ja/10/2096-weeklygraph/1656-15ekc.html). The age distribution of the reported EKC patients has been bimodal, with one peak occurring among 0-4 year olds and the other in adults in their 30s (Fig.2).

Isolation/detection of Ad isolates: From 2008 to June 2017, prefectural and municipal public health institutes (PHIs) reported 15,383 isolates of Ad (Table 2). Ad2 was most frequent (26%), followed by Ad3 (19%) and Ad1 (14%). In contrast, in 2000-2007, among 16,304 Ad isolates, the most frequent was Ad3 (38%), followed by Ad2 (22%) and Ad1 (12%) (IASR 29: 93-94; 2008). Thus, from 2000-2007 to 2008-2017, the proportion of Ad3 halved.

From PCF patients, there was a total of 2,436 Ad isolates, and Ad3, Ad2, Ad1, Ad4 and Ad5 were the most frequently reported (see Table 2 & p. 138 of this issue). From EKC patients, there was a total of 1,570 isolates, and the most frequently reported types were Ad37, Ad3, Ad54, Ad56, Ad4, Ad8, Ad53 and Ad19/64 (Table 2, Fig. 3). Among those where the Ad isolate has not been typed (Ad NT), there is a possibility of including types which have yet to be described (see p. 139 of this issue). From infectious gastroenteritis patients, 2,804 Ad isolates were obtained, and the majority was Ad40 and/or Ad41, belonging to species F (Table 2). There were also 106 isolates of Ad31.

Recent trends in Ad isolates:

1. Ad3 isolated from PCF patients during 2003-2006 had mutations in the hypervariableregion of the hexon gene, a region could associate with neutralizability of the virus (IASR 29: 93-94, 2008). Further mutations have not been observed from Ad3 isolated since 2008.

2. Ad7 belonging to species B is known to cause severe pneumonia. During 1995-1998, when Ad7 was circulating at a high level and there were 863 Ad7 isolations (https://www.niid.go.jp/niid/images/iasr/table/virus/adv91-00.pdf), several fatal cases of Ad7 infections were reported (IASR 17: 99-100, 1996 & 18: 79-80, 1997). During 2008-2013, 33 Ad7 isolates were obtained (Table 2); continued careful monitoring of Ad7 is warranted.

3. Based on serologic cross-reactivity, Ad57 is believed to be serologically related to Ad6, and it is possible that Ad57 may have been classified as Ad6 in the past (see p. 143 of this issue).

4. The main causative agent of EKC has been Ad8 abroad. In Japan, however, Ad8 has decreased and Ad54 has increased in recent years (see Table 2 and p. 144 of this issue). Ad8 and Ad54 partly cross-react antigenically with each other and can both cause severe EKC.

5. Some Ad types have been found to be associated with non-chlamydial non-gonoccocal urethritis (see p. 145 of this issue).

The pathogenicity of many of Ads, however, remain to be elucidated (Table 1, see pp. 140 & 141 of this issue).

Laboratory diagnosis: The sensitivity of Ad detection generally increases going from antigen-detecting immunochromatography (IC), virus isolation, to PCR (Fujimoto, et al., JCM, 2004). While IC kits cannot discriminate Ad types, they are useful for quick bedside diagnosis. They are used widely in Japan with approximately 2,700,000 kits utilized a year, and the sensitivity has been improving.

More recently, laboratory diagnosis has shifted from serotyping to genotyping. In the routine laboratory testing at PHIs, partial sequencing of the penton, hexon and fiber regions are done. For species B and D with frequent recombination events, more than one region needs to be sequenced (see pp. 136 & 140 of this issue). However, for species C and E with rare recombination events, a partial sequencing of the hexon region is sufficient for routine laboratory diagnosis (see p. 143 of this issue) (Laboratory manual for diagnosis of PCF and EKC, ed. 3, https://www.niid.go.jp/niid/images/lab-manual/Adeno20170215.pdf).

Therapy and prevention: No anti-viral agent specifically against Ad is currently available in Japan. Establishing therapeutic measures against Ad infection is in urgent need, as Ad infection may be fatal in patients whose immune capacity is suppressed after organ transplantation (see p. 147 of this issue).

As Ad is transmitted via contact or droplets, hand hygine is important for infection prevention. It should be reminded that the infected patients’ eye discharge and tear contain large amounts of Ad; healthcare workers, especially those in ophthalmology, are advised to follow the guidelines for ophthalmologists (http://www.nichigan.or.jp/member/guideline/conjunctivitis.jsp). Guidance for children is available from Schoold health and Safety Act and Infection Control Guideline in Nurseries (http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000123472.html).

Copyright 1998 National Institute of Infectious Diseases, Japan

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