Background
Both well-known and emerging viruses affect human health by causing various diseases, and sometimes they even have a devastating impact on the entire society, such as the newly emerged human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Adenoviruses (AdVs), members of the family
Adenoviridae, are non-enveloped double-stranded DNA viruses, found widely in the biosphere. Since they were first discovered by Rowe et al. in 1953 [
1], AdVs have been the focus of intense research. AdVs can infect various tissues and organs, sometimes with serious consequences, especially in children. The infectivity and cell entry mechanism of AdVs make them suitable for drug delivery, vaccination and gene therapy for many diseases including cancer [
2]. Research on adenoviruses has greatly contributed to the fields of life sciences and medicine over the past decades.
Currently, about 110 human adenovirus (HAdV) genotypes are recognized; these are classified into seven species (A–G) in the genus
Mastadenovirus based on their physical, chemical and biological properties [
3]. HAdV direct or indirect transmission of occurs through throat, faeces, eyes or urine, depending on the virus type. Certain HAdV types are predominantly associated with specific pathologies, such as acute respiratory outbreaks (HAdV-B/C/E) [
4,
5], epidemic keratoconjunctivitis (HAdV-D) [
6,
7], gastroenteritis, and/or acute hemorrhagic cystitis (HAdV-F/G) [
8,
9]. The major disease-associated HAdV genotypes detected in various countries and regions differ and change over time [
10]. Although most HAdVs cause only mild symptoms, some can cause severe infections, most of which occur in children, the elderly, and people with severely compromised immune systems [
11‐
13]. However, there have also been reported cases of severe pneumonia and death in adults with normal immunity caused by HAdV-55 [
14]. HAdVs can cause outbreaks, which usually occur in crowded places, such as hospitals, nursing homes, military bases, schools, and swimming pools, and these have been reported in several countries [
15‐
19]. HAdV-B (HADV-3, -7, -14, and -55) cause outbreaks of respiratory-related diseases [
4,
16,
20,
21], whereas HAdV-D (HAdV-8, -19, -37, -53, and -54) cause outbreaks of epidemic keratoconjunctivitis [
18,
22,
23].
HAdV-G is a novel species that has been typed and named by using whole genome sequencing and phylogenetics rather than by applying traditional serology. At present, the specific and frequently mutated hexon gene of HAdV has been widely used in the molecular diagnosis and genotyping of this virus. Owing to the frequent recombination of HAdVs, as exemplified by HAdV-85/89 in Japan, HAdV-D56 in France, and the HAdV-55 and CBJ113 strains in China [
15,
24‐
28], whole-genome sequencing remains the gold standard for proper classification of HAdVs [
28]. Among them, HAdV-55, reconstituted from HAdV-B11 and HAdV-B14, has repeatedly caused outbreaks in densely populated areas such as schools and the military in China [
15,
16]. The purpose of this study was to evaluate the epidemiological, clinical, and molecular characteristics of HAdV infections occurring among hospitalized children with respiratory tract infections (RTIs) in Beijing Friendship Hospital in China from April 2018–March 2019. In addition, this work explored the relationship between HAdV infection and RTI symptoms to provide information for the control and prevention of HAdV infection in China.
Discussion
The respiratory tract-related clinical symptoms caused by HAdV infections are similar to those caused by infection with IFA, HRSV and other respiratory pathogens. Consequently, correct diagnosis of HAdV infection is often difficult. In this study, qPCR and Sanger sequencing were used to analyse the phylogenetic sequence of the hexon gene, and the epidemiological characteristics and genotypic diversity of HAdVs in children hospitalized during the period from April 2018–March 2019 in Beijing, China were investigated. Of the 1572 collected specimens, 90 (5.73%) were positive for HAdV; this HAdV detection rate is very similar to that of the previous year in this hospital (5.64%) [
31] and is also consistent with those reported from China and other countries (3.71%–35.5%) [
31,
38‐
42]. The HAdV detection rate was 3.71% in Hebei Province, China. However, it was slightly higher among hospitalized children with RTIs in southern China; the HAdV detection rate in hospitalized children with RTIs during the period from 2009 to 2012 in Chongqing was 8.55%, and that in Hunan Province was 9.4%. It should be noted that different HAdV detection rates may be the result of differences in detection method, sample collection site, collection time and other factors. Thus, it is necessary to establish a unified and continuous epidemiological surveillance over a wider area.
The HAdV detection rate was not significantly affected by patient sex, but it was significantly affected by patients age (P = 0.008). The main age group affected by HAdV was children aged ≤ 5 years (73.3%, 66/90), specifically, the group of patients aged 3–5 years had the highest HAdV detection rate (10.11%, 27/267), whereas the group aged 2–3 years had the lowest (3.35%, 11/328). The reason for this difference remains to be determined.
Previous studies have shown that the HAdV detection rate is positively correlated with monthly average temperature, sunshine hours, and air temperature [
39]. The number of HAdV infections in southern China reaches its peak during summer. In this study, the HAdV detection rate in Beijing had an obvious seasonal distribution difference (
P = 0.001), and peaking in autumn (9.33%), which is consistent with a previous report by Duan et al. [
43].
The clinical symptoms caused by HAdV infection in our patients were similar to those commonly caused by infections with other respiratory viruses, such as HRSV and IFV; their most common clinical symptoms and signs were fever and cough, and a few cases of HAdV also experienced gastrointestinal symptoms, such as vomit and nasal obstruction. The most common diagnosis among our HAdV-positive subjects was bronchopneumonia (68.89%, 62/90). The duration of hospital stay was generally less than 7 days, which is consistent with the results of previous studies. The co-infection of HAdVs and other respiratory viruses has been reported many times [
39,
40]. In this study, the co-infection rate was 61.11% (55/90), and the viruses with the highest frequency of mixed infection were HRSV and HRV. No significant difference was observed in clinical symptoms and duration of hospitalization between the mono- and co-infections. The severity of HAdV infection is affected by many factors, including the patient age, immune status, and socioeconomic status. Although, some studies have shown that HAdV-7 may cause a more severe infection [
44]; others have found that the HAdV type has no obvious influence on the severity of respiratory tract infection in children. Additionally, HAdV-infected patients with a long-lasting fever often experience more serious disease [
40]. In agreement with previous work, this study found that there was no significant association between the HAdV genotype and disease severity (Additional file
1: Table S3), and only one child who was co-infected with HRSV had dyspnea. In the analysis of HAdV simple infection, the viral load in NPAs had no significant statistical association with patient age, sex or hospital stay duration, but children with a high viral load were more likely to have a high fever and elevated WBC count.
The most common species of HAdV worldwide, affecting the respiratory tracts of both adults and children, are HAdV-B, HAdV-C and HAdV-E, among which HAdV-B3 and HAdV-B7 are the main epidemic strains [
44‐
46]. HAdV-55, which often causes outbreaks, is also detected at high rates in cases of adult respiratory tract infection [
4,
6]. The prevalent HAdVs in China are mainly genotypes HAdV-2, -3 and -7. The dominant genotypes in northern China are HAdV-3 and -7, while those in southern China were HAdV-2 and 3 [
43]. In this study, hexon gene sequencing and phylogenetic analysis were performed on 55 samples. The results show that HAdV species B and C were the most common species, accounting for 63.64% (35/55) and 29.10% (16/55) of HAdV cases, respectively. HAdV-B3 was the most common genotype (43.64%, 24/55), followed by HAdV-B7 (20.00%, 11/55), HAdV-C1 (10.91%, 6/55), and HAdV-E4 (9.09%, 9/55), which is consistent with other reports. HAdVs are prone to gene mutation and recombination [
7,
25,
45,
47], and the CBJ113 strain isolated in Beijing in 2016 contained HAdV-C2, HAdV-C6, HAdV-C1, HAdV-C5 and HAdV-C57 sequences, which were recombined in several genes, including the hexon and fiber genes. Notably, three of the hexon sequences detected here were on the same branch as strain CBJ113, and they showed maximum homology with strain CBJ113. This study demonstrates that there are at least eight different HAdV genotypes circulating in Beijing; and that the HAdV species C strain CBJ113 has been prevalent in China for a long time. The hexon gene is commonly used for typing and is common in many molecular epidemiological studies of HAdV [
48,
49]. However, because adenoviruses are prone to mutating and recombining, it is more accurate to use the whole genotype, which is a limitation of this study.
Our data allows CDC and health officials to understand the importance of adenovirus infection more deeply, thereby the government will give more attention and financial support to adenovirus research. In addition, our study can also provide clinicians more information of adenovirus infection, and patients can get the accurate diagnosis and better treatment for viral infection.
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