The Topic of This Month Vol. 29, No. 4 (No. 338)

Adenovirus infections, 2000-2007
(IASR 29: 93-94, April 2008)

Human adenovirus is a non-enveloped, double-stranded DNA virus with icosahedral symmetry and a size of approximately 80 nm and stable to chemical or physical agents.  To date, there are 51 immunologically distinct serotypes grouped into six species (A-F) (adenoviruses are denoted, e.g. adenovirus serotype 3 as Ad3). 

Adenoviruses manifest such variegated clinical features as pharyngoconjunctival fever (PCF), pharyngitis, tonsillitis, pneumonitis, epidemic keratoconjunctivitis (EKC), gastroenteritis, hemorrhagic cystitis, hepatitis, pancreatitis, and encephalitis (see p. 95 of this issue). 

The National Epidemiological Surveillance of Infectious Diseases (NESID) conducts adenovirus surveillance for the pathogen of PCF and infectious gastroenteritis reported by pediatric sentinel clinics, and of EKC reported by eye disease sentinel clinics.

The causative agents of such respiratory illnesses as upper respiratory inflammation (URI) are principally species B (Ad3 & 7), species C (Ad1, 2, 5 & 6) and species E (Ad4).  Of these, Ad7 has the highest pathogenicity and often causes pneumonia.  During the Ad7 epidemic from 1995 to 1998, fatal cases were seen (IASR 17: 99-100, 1996 and 18: 79-80, 1997).  During 2006-2007, serious respiratory infection occurred in the US due to an Ad14 variant (species B) [MMWR 56 (45): 1181-1184, 2007 and IASR 29: 24-25, 2008].  Ad14 has not been detected recently in Japan (Table 1) and invasion into this country is concerned.  Ad8, 19 & 37 of species D cause EKC and Ad40 and 41 of species F infectious gastroenteritis.  Adenoviruses have a high infectivity and its infection control is important (see p. 95 of this issue).

PCF and EKC case reports in NESID: In the previous topic of adenovirus (IASR 25: 94-95, 2004), it was reported that the number of PCF cases per sentinel in 2003 was the largest since 1987 when totaling case numbers from pediatric sentinel started.  In 2004 and 2006, the number of cases exceeded that of 2003 (Fig. 1).  A large peak of PCF epidemic has been seen in summer and apparent peaks have been seen even in winter after 2003 (Fig. 1 and p. 100 of this issue).  In PCF cases by prefecture (Fig. 2), the outstanding feature in 2006, the year of large-scale epidemic, was that cases per sentinel were more than 20 in all prefectures other than Aomori, Iwate, Miyagi, Tochigi and Yamanashi Prefectures.  In the next year 2007, prefectures with more than 20 cases per sentinel decreased to 18.

Isolation/detection reports: During 8 years from 2000 to 2007, prefectural and municipal public health institutes (PHIs) reported 16,304 detections of adenovirus (Table 1 and Table 2).  By serotype, Ad3 was most frequently detected (6,152), followed by Ad2 (3,555) and Ad1 (1,894).  Not typed accounted for 7. 3% (1,184), the fourth most frequent, indicating that serotyping adenovirus is not necessarily simple. 

Detection from URI, PCF, influenza-like illness (ILI), and lower respiratory inflammation numbered 4,607, 2,490, 1,600 and 1,030, respectively.  Ad3 was most prevalent, followed by Ad2, Ad1 and Ad5 in this order.  Yearly variation was small in detection of Ad1, 2 and 5, but large in that of Ad3.  In 2001 and 2003-2006, when Ad3 detection was frequent, PCF epidemics were prominent (Fig. 1, and 

Conventional ELISA kits to detect Ad40/41 antigens directly from stools of gastroenteritis cases were unable to differentiate Ad40 from Ad41.  Recently, report of Ad41 by genetic analysis has increased.  During 2000-2007, detection of Ad31 numbered 35, and 21 of them were from infectious gastroenteritis cases (see p. 96 of this issue).

Detection of Ad8, 19 & 37 during 2000-2007 numbered 275, 197, and 510, respectively, and most of them were from EKC cases.  Ad8 was detected most frequently in 2005, Ad19 in 2002, and Ad37 in 2003, thus epidemic year of each type differedisee p. 98 & 99 of this issue, and 

Epidemics of Ad3: Factors affecting the nationwide epidemic of PCF due to Ad3 starting in 2003 and becoming the largest scale in the past in 2006 has not been clarified.  However, it has been shown that Ad3 causing a large-scale epidemic of PCF in Korea during 1998-1999 possessed a variation in amino acid sequence of the hyper variable regions (HVRs) of the hexon gene carrying the neutralizing antigenicity.  It has been suggested that Ad3 having amino acid sequences homologous to this Korean strain was first detected in Japan in 2000 and prevailed widely since 2003 (see p. 100 of this issue and JJID 61: 143-145, 2008).

Laboratory diagnosis: It is known that the positive rate of tests differs depending on the time of specimen collection and that the rate is high with the samples taken within 4 days after onset.  The sensitivity of detection depending on the test method is generally in the order of PCR and real-time PCR > virus isolation > immunochromatography (IC) and ELISA.  IC kits are useful to get bedside diagnosis in approximately 15 minutes, but have such weak points as low detection sensitivity and not applicable for typing.  In addition to identification and serotyping by conventional virus isolation and neutralization, reports of detection by PCR and sequencing are on the increase recently (see Table 2 and p. 96 of this issue).  Nevertheless, it is necessary to perform virus isolation and molecular epidemiological analysis utilizing epidemic strains for detailed analysis of epidemics (see p. 98-100 of this issue).  The detection sensitivity largely differs depending upon cultured cells in virus isolation and upon primers in PCR.  Selection of appropriate specimens (Table 2) and appropriate cells for virus isolation (see p. 101 of this issue), and choice of the primers for PCR are important. The National Institute of Infectious Diseases and also reference centers of PHIs in six prefectures (Niigata, Tokyo, Fukui, Osaka, Hiroshima, and Miyazaki) have engaged with standardization of laboratory tests for adenoviruses and improvement in accuracy of the methods. 

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