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Acute respiratory tract infections (ARTIs) are a persistent and pervasive public health problem in both developed and developing countries. They cause a great burden of disease worldwide. Especially in developing countries including China, ARTIs, mainly pneumonia, are the leading cause of death among children under the age of 5 years.[1, 2] A great variety of pathogens can cause ARTIs, and viruses have been considered as the predominant pathogens in this children population.[3, 4] The most frequently reported viruses include respiratory syncytial virus (RSV), influenza viruses A and B (IAV, IBV), parainfluenza viruses (PIVs), human rhinovirus (HRV) and adenovirus (ADV), which are responsible for most episodes of ARTIs in children. In the past decade, several new viruses associated with ARTIs such as human metapneumovirus (HMPV), novel strains of coronaviruses (SARS-CoV, HCoV-NL63 and HKUI), human bocavirus (BOV), WU polyomavirus (WUPoyV) and KI polyomavirus (KIPoyV) have been discovered in human respiratory tract specimens. Among them, some have been identified to be causative pathogens of ARTIs.[1, 4, 5]
Currently, there are no approved vaccines or medications available for most of the respiratory viruses. A better understanding of the epidemiology of viral respiratory tract infections in children plays a key role for the prevention, control and treatment of ARTIs. Studies showed that many viral respiratory infections exhibited predictable seasonal variations. However, the epidemiological profiles of viral respiratory infections from different climate zones or different countries in the same climate zone may be varied.[6-12]
China is a large country crossing three climate zones, and great differences in climate are found from region to region. A better understanding of the epidemiology of ARTIs in different regions could be helpful to develop effective surveillance, prevention and treatment strategies. Although some studies on the epidemiology of ARTIs have recently been reported in big cities such as Beijing, Shanghai and Hong Kong,[13-16] the epidemic characteristics of viruses in ARTIs are still not well established all around China, especially in other cities and rural areas.
Shenzhen is the largest migratory city of China with high population density and population mobility. It is located in southern China at 22°27′–22°52′N and 113°46′–114°37′E, immediately north of Hong Kong, with a typical subtropical monsoon climate. The annual average temperature and relative humidity of Shenzhen are about 23°C (12–33°C) and 77%, respectively. The purpose of this study is to investigate the prevalence, seasonality and clinical characteristics of acute viral respiratory infections in hospitalized children in Shenzhen and to provide insights into etiologies of ARTIs in local infants and children.
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- Materials and methods
- Conflict of interest
Very few long-term prospective studies were performed for viral etiologies of ARTIs among hospitalized children. In this present study, the infection frequency, seasonality, co-infection pattern and clinical features of viral respiratory infections were investigated based on prospective analysis of three consecutive year's data from hospitalized children with ARTIs. Our results provided a distinctive epidemiological profile of viral respiratory infections in hospitalized children with ARTIs in the study areas, which was different from those in the big cities in northern China such as Beijing and Shanghai and also different from that in adjacent Hong Kong.
Overall, 48·0% of our cases were positive for respiratory virus infections, which resembled the latest study in the same city. A similar incidence rate has been obtained in neighboring regions[13, 22] and other cities such as Rome and Milan, but it was different from other studies.[10-12] In China, the overall positive rate reported varied from 27·3 to 74·8% depending on different areas and detection methods.[15, 16, 25-31] The rate of respiratory viral infections varied worldwide, and many factors such as geographic distribution, study design and detection protocols could lead to these variations.[1, 7, 8, 32] In our study, leukocyte count was used as an indicator of inclusion criteria and it probably affected the positive rate. Viruses not considered in the study, for example coronaviruses, would underestimate the positive rate.
Most studies showed that RSV or HRV was the most prevalent viruses in children with viral respiratory tract infection. In this study, IAV was the most frequently detected respiratory virus, followed by RSV and HRV. IAV (H1N1) outbreak in 2009 could explain this shift. Data showed that about 60% of IAV infections were detected during the outbreak period. Studies showed that the H1N1 outbreak could change viral distribution patterns.[24, 29, 33] Regardless of the IAV (H1N1) outbreak, RSV and HRV were the two most common viral pathogens in ARTIs, which was consistent with most previous studies.[1, 10, 15, 16, 22, 25-29] Our study further confirmed the importance of RSV and HRV in children with ARTIs, especially in children < 4 years of age.[10, 14, 23]
Our results also showed that 12·7% of viral pathogens detected were PIV1 and PIV3, which implied that PIVs played an important role in children with ARTIs. Similar findings were obtained in the studies conducted in Shanghai,[14, 34] Changsha, Harbin, Hong Kong and Rome. The prevalence of PIV3 was twofold higher than that of PIV1, particularly in infants, which was similar with other reports,[25, 26, 30, 35] implying that infants could be more vulnerable to infection with PIV3 than PIV1.
HMPV has been proven to be one of the main viral pathogens responsible for ARTIs in children. The positive rate found in the study was consistent with previously published results.[10, 36, 37] In China, the infection rate of HMPV varied from 3·2 to 10·6%.[22, 26, 28, 29, 31] The seasonality of HMPV in this study was mainly from March to May, similar to that in Hong Kong, but different from other places.[5, 37] In our study, 4·9% of cases were positive for BOV, which coincided with 5·0% in Hong Kong and higher than Guangzhou and eastern Guangdong. Our result suggested that BOV might be present throughout the year with no seasonal distribution. However, seasonal distribution was noted from September to February in Hong Kong and May and June in Guangzhou.
The use of multiple PCR made it possible to simultaneously detect a broad spectrum of viruses with excellent sensitivity, at the same time, with increased viral detection rate and co-infection rate for ARTIs.[12, 40] Among our positive cases, co-infection rate was 31·1%, which was similar to 27·9% reported by Do et al. Co-infection rate reported elsewhere varied widely from 25·4 to 47·9%. The relatively lower co-infection rates ranging from 0·24 to 26·9% were reported in the studies conducted in various cities of China.[22, 25-31] In most of these studies, immunofluorescence kits were used to test a lower number of respiratory viruses. It was worth to note that in the study by Peng et al. in Wuhan, China, 69·5% of co-infection rate was reported with immunofluorescence kit. These variations might be attributed to geographic differences, diagnostic methods for viral agents and study design.[12, 32, 34, 41, 42] Pathogens in those negative patients need to be further investigated as only ten common and newly identified viruses were included in our study, which might underestimate positive rate or co-infection rate. It was notable that the correlation between co-infection rate and positive rate was not observed.
Of multiple infections, dual infection was predominant in this study whether or not considering the IAV (H1N1) outbreak in 2009, which was consistent with previous studies.[28, 32, 42, 43] Similar with the studies conducted in the cities of Guangzhou and Wuhan, China,[28, 29] our study showed that IAV, RSV and HRV were the main viruses involved in multiple infections. High co-infection rate between these three viruses could be explained from the overlap of their seasonal distributions. A variety of predominant multiple infection patterns between respiratory viruses were observed in different studies.[12, 32, 42, 43] For example, it was shown in Martin et al.'s study that ADV and coronaviruses were the most common co-infection pattern. Our study showed that RSV and HRV were the two most viruses involved in multiple infection, followed by IAV and PIVs, regardless of IAV infection in the H1N1 outbreak period. It was difficult to explain the variations of co-infection patterns based only on seasonal distribution. A recent study suggested that co-infection patterns were not random and certain pathogens had higher frequency of co-infection. As molecular assays only detect nucleic acid and positive result does not mean the presence of the pathogen, when studying co-infection patterns of respiratory viruses, the ability to differentiate the real causative pathogens needs to be solved first. Viral load detection could provide some clues for solving this issue.[43, 44]
Although high co-infection rates have been reported in various studies, the associations among multiple infections, hospitalization rate and severity of ARTIs were still not clear with inconsistent results in different studies.[42, 43, 45] Our data suggested that multiple infection had less association with the severity of disease, consistent with Peng et al.'s study. The relationship between co-infection rates and age group was also investigated in our study, and little correlation was observed. Several previous studies observed that co-infection rates were more frequent in a certain age group, but results were varied.[32, 43]
In contrast to temperate region, where most viruses had winter-spring seasonality, the respiratory viral infections in tropical and subtropical regions appeared mainly to be spring-summer seasonality. In this study, due to the high detection rate and similar seasonality of RSV, HRV, IAV, PIV and HMPV, an overall spring-summer seasonality of viral respiratory infections in children was concluded. Studies conducted in Hong Kong showed that a clear seasonal peak was from April to September,[36, 46] with a longer duration than our study. The overall seasonality in this study was also different from the studies conducted in northern or central cities of China, in which the seasonality of most viruses presented in autumn-winter and/or winter-spring.[15, 25-27, 30] The winter-spring seasonality was also observed in Guangzhou, a city about 150 kilometers north of Shenzhen. Different seasonal onset and duration were observed in various studies conducted in (sub-) tropical regions. In these studies, ambient temperature, humidity and rainfall were widely used to explain these differences in seasonality, but inconsistent results were observed.[9, 46, 47] Although most studies demonstrated that the seasonality of viral respiratory infections was correlated with increased rainfall, effects of climate factors such as humidity and temperature on the seasonality were complex and interactive.[9, 46, 48] The study areas have four indistinct seasons, and the coldest month usually emerges in January (average 12°C). During the period from March to May, the weather featured warm ambient temperature (average 18–25°C), high relative humidity (average 85%-90%) and increasing rainfall. These meteorological conditions were perhaps conducive to viral survival.[9, 48] In addition, intensive temperature fluctuations during seasonal alternation could increase the susceptibility to infections.
As reported in other studies in temperate, tropical and subtropical regions, viral infection rates in children population showed an inverse correlation with age, with younger individuals experiencing higher viral infection rates.[3, 4, 6, 9, 24] Our results suggested that children younger than 4 years of age, particularly <6 months, were at higher risk of hospitalization for ARTIs, compared with older children. This was particularly substantiated in RSV infection. Our presumption was supported by other studies.[14, 25-28] Of course, this speculation needed to be validated by the population-based study. The findings reported elsewhere suggested that more males than females were affected by ARTIs, which were not observed in our study.
Notably, our study occurred over a span of 3 years, which included the IAV (H1N1) outbreak in 2009. The impact of the outbreak on the results should be considered. Data showed that the detection rate of IAV increased significantly and co-infection rate during outbreak months was much higher than average co-infection rate. Unfortunately, we did not type these influenza strains based on the original study design. It was most likely that these strains contributed to the relatively high proportion of IAV. Relatively higher single and multiple infections of RSV, HRV and PIVs were also observed during the outbreak of IAV. Increased susceptible population and awareness, intensive testing and altered patient and physician behavior could lead to these increases. These factors could partly explain the relatively high proportion of pneumonia cases in the study. Furthermore, studies showed that the outbreak of IAV (H1N1) could increase the risk of other viral infections such as RSV and HRV.[24, 33] Other limitations also existed in this study. First, molecular methods allowed the detection of only viral nucleic acid even without virus replication, which complicates the interpretation of positive detection results. Second, the subtype identification of some common respiratory viruses such as IAV and HRV was not performed in our study, particularly during the IAV (H1N1) outbreak in 2009.
In summary, despite those aforementioned limitations, this three consecutive years' surveillance would provide a basic profile of the spectrum, seasonality, age and gender distribution, co-infection patterns as well as clinical association of viral respiratory infections in hospitalized children in the study sites. It could help the prediction, prevention and control of ARTIs in children.