Human adenoviruses (HAdV), belonging to the family Adenoviridae and the Mastadenovirus genus, are associated with a broad spectrum of clinical diseases, including uncomplicated acute respiratory and gastrointestinal infections in humans, especially in children and immunodeficient individuals . HAdV are non-enveloped particles with linear double-stranded DNA. On the basis of biological properties and DNA sequence homology, more than 65 types of HAdV have been characterized and classified into seven species (A–G) [2, 3]. HAdV species B is classified into two subspecies B1 (types 3, 7, 16, 21, and 50) and B2 (types 11, 14, 34, and 35). Subspecies B1 cause respiratory infections, whereas subspecies B2 is usually associated with kidney and urinary tract infections but sometimes also associated with respiratory diseases [4, 5].
Shaanxi province, located in northwestern China, has had a few epidemic outbreaks of HAdV in recent years. HAdV-11a (HAdV-55) was reported in high school students in 2006, while HAdV-7 was reported in infants in 2009 [6, 7]. In present study, we report a HAdV-7 outbreak in a military training camp that affected about 200 soldiers. This is the first report about a HAdV outbreak in military recruits in China.
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The present study describes an outbreak of febrile respiratory illness (176 affected) in a military training unit in Shaanxi, China, in early spring of 2012. From the epidemical survey and laboratory examination, the etiological pathogen of the reported outbreak was confirmed as HAdV-7.
HAdV are classified into more than 60 types belonging to seven species. HAdV subspecies B1 (types 7, 3, 21) and species E (type 4) cause outbreaks in military and civilian communities . Stress, fatigue, and crowding are important factors facilitating the transmission, and increase the susceptibility of different diseases in a military training unit [11, 12]. Many outbreaks have been reported in military units in the USA, the Netherlands and Portugal [13-16]. This is the first report of an outbreak with a definite pathogen from a Chinese military training camp and indicates the need for close surveillance in the future. Adenoviral respiratory disease has been recognized as a frequent cause of illness in US active duty military populations, particularly in basic training installations, for more than several decades [17, 18]. In 1971, the US army started a vaccination program against HAdV types 4 and 7 [17, 19] that was ceased in 1996–1999 . In the vaccination period, there were only five reported adenovirus (HAdV-4 and -7)-associated deaths. In the post-vaccine period (1999–2010), eight HAdV-associated deaths have been reported . After a 12-year absence, the HADV vaccination program has been resumed for military recruits since October 2011 . Vaccination programs for Chinese military recruits include vaccination against hepatitis B, measles, tetanus and Neisseria meningitides. HAdV vaccines are unavailable in China now, and indigenous HAdV vaccines should be developed from the lessons of this outbreak.
A series of HAdV outbreaks have been reported from Shaanxi province recently [6, 7]. In March 2006, the causative pathogen of an acute respiratory outbreak in Qishan county, Baoji prefecture, was found to be HAdV-11A, later renamed HAdV-55 . During this infection, 254 people including 247 senior high school students were infected, which resulted in the death of one patient who had bone marrow megaloblastic anemia . In February 2009, an outbreak of severe lower respiratory tract disease in infants in Xixiang county, Hanzhong prefecture, located in the southwest part of Shaanxi province, was due to HAdV-7 . In July and August 2009, an outbreak of HAdV-3 infection caused pharyngo-conjunctival fever in 67 pupils while another outbreak of HAdV-4 infection caused acute upper respiratory tract disease in 11 students (15–18 years old) in Xi'an, located in central Shaanxi (data not published). The isolated strains of HAdV-7 in Shaanxi (n = 4, three from this outbreak and one from Hanzhong in 2009) showed high similarity in sequences (99.8–100%) and indicated the possibility of the same ancestor. It is interesting that several types of HAdV are circulating in Shaanxi province which indicates the need for a surveillance network for adenovirus infections.
Different HAdV-7 genome types have predominated in different areas and 13 (7p, 7a–7l) genome types have been found . The prototype strain Gomen of HAdV-7p was isolated in an outbreak of ARD among new military recruits in California in 1955, while 7a was isolated in 1958, 7b from Paris in 1956, 7c from South Africa in 1958, 7d from China in 1980, 7e from Brazil, 7f from the former Soviet Union, 7g from China, 7h from South Africa, 7i from Korea in 1999, 7k from Israel in 1968, 7l from Korea in 1996, and 7m has recently been mentioned [24-33]. Both epidemiological and molecular evidence strongly suggest that unique patterns of genome type shifts are restricted to geographic areas. Therefore, surveillance for HAdV genome types in China should be strengthened.
The IgA antibody plays an important role in the diagonosis of HAdV infection [6, 7]. As we know that IgM antibody predominates in early immune responses, this is always used as an early diagnosis for infection. However, Kornadt et al. found that in adenoviruses infections, fewer antibody rises and weak reactions were observed in the IgM test than in the IgA test. A test for IgM antibodies was found to be unrewarding and IgM antibodies were present in individuals without fresh HAdV infection. Therefore, the IgM antibodies test was not suitable for the early diagnosis of HAdV infection . Previous reports from the 2006 and 2009 outbreaks have shown 83.3% and 35% IgA positivity rates, respectively. Similarly, serum samples from the acute phase in this study showed 50% IgA positivity. From 30 IgA-positive samples, 29 were also positive for IgG both in the acute phase and in the convalescence phase. IgG in the acute phase and in the convalescence phase showed no obvious change, whereas the neutralization antibody was significantly different in various phases. It was also noted that IgA against HAdV was negative in all samples in the first 3 days of disease onset, but all were positive on the 8th day. From 15 samples that were HAdV positive by PCR, IgA antibody was not present. It was noted that PCR could detect HAdV within 5 days from onset. Two individuals from the control group (apparently healthy) were also positive for IgA, indicating a possible non-apparent HAdV infection.
To confirm HAdV infection, the 30 paired sera titers of neutralization antibody against the viral strain isolated in this outbreak were detected. Although most (22/30) titers of sera increased, in our study, three samples were found to be decreased. A decrease in neutralization antibody has been reported previously, but the reason is unknown . We assume that personal differences may play a role in this finding, but this needs to be studied in future work.
From the present study, it is concluded that the etiological agent of an outbreak in military recruits in Shaanxi province in the spring of 2012 was HAdV-7. The nucleotide sequence, virus isolation, IgA antibody, and neutralization antibody were all attributed to the HAdV infection. IgA antibody began to appear on the 4th day after onset and showed 100% positivity on the 8th day. The virus strain in this outbreak was highly similar to the virus isolated in Hanzhong prefecture, Shaanxi in 2009. Recent outbreaks of HAdV in Shaanxi province indicate that vaccine development, and enhanced epidemiological and virological surveillance of HAdV infections are necessary in Shaanxi as well as in China.