Viral etiology of community-acquired pneumonia among adolescents and adults with mild or moderate severity and its relation to age and severity

Community-acquired pneumonia (CAP) remains a common disease associated with significant morbidity and mortality. Mortality varied from <1% to 48% and is associated with advanced age, co-morbid conditions, and CAP severity [1]. Clear etiology is essential for the management of CAP patients [2]. Although CAP guidelines acknowledge respiratory viruses (RVs) as a “cause” of adults pneumonia [3], few recommendations are made regarding management, largely due to the short of data regarding prevalence and clinical severity, as most relevant data concern infants and children [4,5]. In addition, the emergence of severe acute respiratory syndrome (SARS), avian influenza A (H5N1) virus, and the pandemic influenza A 2009 (pH1N1) virus has emphasized the important role of RVs as causes of CAP [6]. Thus, much better knowledge of the potential role of RVs present in adolescents and adults patients with pneumonia is needed.

In general, compared to conventional viral diagnostic methods (culture, antigen detection, and serological assays), PCR-based methods are 2–5 times more sensitive to detect RVs [6]. Moreover, use of PCR has augmented detection of viruses that are difficult to identify with conventional methods, including human rhinovirus (HRV), human coronavirus (hCoV), human metapneumovirus (hMPV), and human bocavirus [7,8]. Recently, development of several multiplex assays has enabled simultaneous detection of up to 15 different viruses, and use of these tests is becoming standard for identification of respiratory viruses [9-11].

In an attempt to better characterize the viral etiology of CAP in adolescents and adults, a multi-center, prospective surveillance was conducted in 12 general hospitals of Beijing, from November 2010 to April 2012, using a multiplex RT-PCR assay covering all common RVs associated with CAP [12]. We also sought to evaluate age and severity of disease related to different pathogens.

To our knowledge, this is the largest scale investigation of common RV infections in China in adolescents and adults with CAP, using PCR-based method. The CAP patients in our group were different from other CAP studies with specific feathers as below, (1) young, mean (SD) age was 45.24 (19.478) years; (2) 82.3% of the patients’ PSI classes wereI-III; (3) low numbers of ICU admission and deaths; (4) 9 of 12 teaching hospitals functioned as primary care facilities. Our results indicated that 27.5% of CAP patients have evidence of viral infection. It has been generally assumed that for respiratory infections due to viruses, the optimal specimen is the nasopharyngeal aspirate, rather than throat swabs we used here [16]. Actually, the detection rate was higher than 22% reported by Ruuskanen O et al. [6] based on 2910 CAP patients from 10 studies, also higher than 5–20% reported by other studies that had not used PCR-based assays [17].

IFV A was the first ranking viral pathogen. Among 94 cases, 68 (72.3%) had IFV A as the only identified pathogen, 20 (21.3%) had co-infection with bacteria, and six (6.4%) had co-infection with other RVs. Similar with other reports [18,19], the analysis of subtypes of IFV A revealed that pH1N1 virus was circulating along with sH3N2 virus, as this surveillance was carried out from the post-pandemic period of pH1N1 [20]. It has been reported that younger age and more severe respiratory compromise are key features of patients with pH1N1-associated pneumonia compared with seasonal influenza pneumonia [21]. Here, oppositely, pH1N1 infected patients were mostly distributed in patients older than 45 years, which was coincident with the findings reported by Viasus D et al. [22]. This upward shift in age distribution is probably due to a higher seropositivity against A (H1N1) pdm09 virus in young adult patients. On the other side, although IFV A infected cases distributed through all PSI groups, all cases in high risk group were determined as pH1N1 (accounting for 16.7%, p < 0.05). And 93.3% of sH3N2 positive patients were found in low risk group, without high-risk cases. Two of four dead patients were caused by pH1N1. These findings suggest that the severity of pH1N1-associated CAP is still higher [22]. Four co-infection cases of pH1N1 and H3N2 were presented with PSI I-II, the reason was unclear. Further analysis of corresponding viral load and antiviral treatment might be needed.

In agreement with our results (HRV, 4.3%), two recently reports using PCR assays suggested that HRV was important cause in CAP, with infection rates of 4.9% [23] and 7% [24]. Among 41 infections, 27 patients (65.9%) had HRV as the only identified pathogen, ten (24.4%) had co-infection with bacteria, and four (9.7%) had co-infection with other RVs. These results stand in contrast to those of previous studies, which reported that HRV commonly occurred with bacterial co-infection (approximately 41.9–57.1%) [25,26]. Moreover, it is reported that HRV single or mixed HRV /pneumococcal infection should be an independent cause of severe pneumonia [25-27]. In our study, oppositely, HRV infections occurred in all age and severity groups.

The incidence of adenovirus was 4.2%, which was in the upper scale of the range of < 1% - 4% as reported [12]. Although most infected cases are self-limited, adenovirus is recognized as one of the first viruses clearly linked with pneumonia [12]. David Lieberman’s team had found that 1.6% of adults CAP patients caused by adenovirus, and no such cases had been detected in healthy controls or non-pneumonia low respiratory tract infection cohort [23]. Few studies reported on the co-infection of adenovirus with other pathogens, here, we found four with MP and four with other RVs, accounting for 20%. Lauderdalea et al. reported that all infections of AdV were found in 17–44 years-old patients [28]. Similarly, the incidence was significantly higher in adolescents and younger adults (p < 0.001).

Regarding on other important viruses, the frequencies of PIVs, RSV, hMPV and HCoVs were lower than that of Dr. Andrew T. Pavia’s report [12]. Since most respiratory viruses are highly seasonal, the frequencies might be influenced by the variation in intensity of the study period, age of the population and region.

In this surveillance, CAP patients due to MP, an important atypical bacterial pathogen, were common in 14 ~ 44 years-old patients and recognized by PSI as a low-risk condition, which is in consistent with the previous findings [29,30]. Just as Roson et al. reported, the patients with bacterial infections were usually associated with increased severity and mortality [31]. The analysis of typical bacterial pathogens indicated that the incidence increased along with age and PSI classes of the patients. And one patient died from co-infection of Streptococcus pneumoniae and Klebsiella pneumoniae. However, bacterial pneumonia might be underdiagnosed in this study [1,32] due to the reasons: (1) we focused on viral pathogens, therefore patients unavailable with a blood or sputum culture were not excluded. Only 533 patients were detected for typical bacterial pathogens, though urinary antigen test was conducted in all patients; (2) the defined population was young and had low or moderate severity; (3) the rate of antimicrobial treatment before enrollment was high (65.5%).

Our study is subject to two limitations. First, as reported by David Lieberman [23], RVs could be detected in 7.1% of 450 controls without respiratory complaints. Healthy controls were not included to clarify the clinical significance of RVs, especially for the cases of triple and quadruple infections. Second, clinical relevance of viral load in the specimens could not be analyzed since the study was carried out in qualitative assays.

The proportion of RV involvement in CAP is higher than previously reported. Influenza virus A pneumonia are usually found in patients older than 45 years, while, adenovirus pneumonia are commonly found in adolescents and young adult patients. Pandemic H1N1 virus is still recognized by PSI as a high-severity pathogen. The findings contribute baseline data on viral CAP study in China.