Study on pathogen spectrum of 1,046 hospitalized children with respiratory tract infections during COVID-19

Introduction

Respiratory tract infections (RTIs) in humans can evolve from common colds to severe pneumonia, representing a pressing public health challenge and a major global health burden in developing countries and especially among children in socio-economic disadvantaged situations [1]. The 2019 Global Burden of Diseases (GBD) study showed that pneumonia and bronchiolitis caused by respiratory pathogens affected 489 million people globally and children under 5 years were the populations mainly affected by pneumonia [2]. In China, S. pneumoniae, Haemophilus influenzae, S. aureus, RSV, and HRV were the most commonly reported respiratory pathogens in the epidemiological survey of children RTIs in the recent five years [3, 4]. S. pneumoniae mainly caused otitis media, pneumonia, septicemia, and meningitis. It was one of the key contributors to child mortality [5]. More than 90% of invasive H. influenzae infections occurred in children under 5 years of age (4). S. aureus had become a common reason for community-acquired pneumonia (CAP) in children, and rising rate of methicillin-resistant staphylococcus aureus (MRSA) had increased the burden of treatment for the disease. One study showed that 81% of S. aureus -induced CAP patients required intensive care, with a mortality rate of 29% [6]. RSV was found to be the predominant viral-causing LRTIs in childhood, accounting for 65% of hospitalized cases [7]. HRV was the second leading cause of RTIs after RSV, causing major diseases including bronchitis, asthma, and pneumonia. HRV infection in children was seasonal and susceptible, with mild or asymptomatic clinical symptoms, so it was easy to be ignored [8].

At the end of 2019, COVID-19 was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, it has posed an enormous health burden worldwide. To curb transmission, population-level non-pharmaceutical interventions have been rolled out on a large scale, including wearing masks in public, stay-at-home orders, and encouragement of social distancing. Studies from France, Japan and Mexico showed that these measures could also curb the spread of influenza at the same time compared to previous seasons before COVID-19 [9], [10], [11]. However, little research has been done on the prevalence of other respiratory pathogens, including bacteria, during epidemics.

Hospitalized children with RTIs tended to be more severe, and the majority of these patients had secondary bacterial infections with viral respiratory infections. This study analyzed the pathogen spectrum of infected pathogens containing bacteria and viruses among hospitalized children in Shenzhen, China, during the COVID-19 outbreak. This survey will help parents and pediatricians to develop new therapies or preventive measures and improve interventional approaches that may modify respiratory health outcomes in advance.

Materials and methods

Results

Monthly and seasonal distribution of pathogens

There was a significant difference that existed in the overall incidence of viruses in four seasons (χ2=16.818, p<0.05). However, the difference in the incidence of bacteria in four seasons was not obvious (χ2=0.758, p>0.05). HRV, RSV, HPIV, S. aureus, M. catarrhalis, and S. pneumoniae were the main epidemic pathogens all year round. HRV and HPIV were mainly -circulated in autumn with a peak in November (28.6 and 45.7% respectively). RSV was prevalent in summer and autumn with two peaks In July and October (28.2 and 32.2% respectively). S. aureus and M. catarrhalis circulated mainly in autumn with a peak in November (30.1 and 37.8% respectively). S. pneumoniae mainly circulated in autumn with a peak in October (31.6%) (Figure 1). From the above analysis, Autumn, especially in November, was the season with a high incidence of HRV, HPIV, S. aureus, and M. catarrhalis. More attention should be paid to RSV infections during the summer.

Figure 1:

Monthly and seasonal distribution of respiratory pathogens from October 2020 to October 2021 (A) monthly distribution of bacteria (B) monthly distribution of virus (C) seasonal distribution of mainly infected bacteria (D) seasonal distribution of mainly infected viruses.

Co- infection types of respiratory pathogens

Pathogens with high detection rates were also susceptible to co-infection. Bacterial-bacterial co-infections accounted for 73 cases, an incidence of 8.8% (73/829). Of the types of bacterial-bacterial co-infections, S. aureus co-infections accounted for 65.8%. Of the S. aureus co-infection, S. aureus + M. catarrhalis (46%) was the most frequent; followed by S. aureus + S. pneumoniae (19%) (Figure 2A). A total of 67 specimens were detected as viral-viral co-infection with an incidence of 6.5% (67/1,037). The types of viral-viral co-infections were complex. Among them, HRV-coinfections accounted for 91%. Of the HRV co-infection, the HRV + HPIV coinfection (43%) was the most frequent; followed by HRV + RSV (21%) and HRV + HMPV (10%) (Figure 2B). Of the 1,046 eligible specimens, 822 patients underwent tests for bacteria and viruses. Among them, bacterial-virus co-infection accounted for 249 cases with an incidence of 30.3% (249/822). Of these co-infections, double infection was most commonly caused by S. aureus + RSV (10.0%, 25/249). S. aureus + HRV and S. pneumoniae + RSV were followed, with 22 samples of both. The PDR of triple infection was relatively low and mainly caused by M. catarrhalis + S. aureus + HRV (2.8%, 7/249) (Table 3). Thus, pathogens with a high detection rate of single pathogen infection also had a high co-infection rate. More attention should be paid to S. aureus and HRV in cases of -co-infection.

Figure 2:

Co-infection of common pathogens (A) distribution of S. aureus co-infection (B) distribution of HRV co-infection.

Table 3:

The bacteria-virus co-infections in respiratory infection cases.

Bacteria/virus co-infections	Number of cases	Constituent ratio, %
S. aureus + RSV	25	10.0
S. aureus + HRV	22	8.8
S. pneumoniae + RSV	22	8.8
M. catarrhalis + HPIV	14	5.6
S. aureus + HPIV	9	3.6
S. aureus + HMPV	8	3.2
M. catarrhalis + HRV	7	2.8
S. pneumoniae + HRV	7	2.8
S. pneumoniae + HPIV	6	2.4
M. catarrhalis + RSV	6	2.4
M. catarrhalis + S. aureus + HRV	7	2.8
M. catarrhalis + S. aureus + HPIV	5	2.0
M. catarrhalis + S. aureus + RSV	5	2.0
Others	106	42.6
Total	249	100.0

Discussion

This study was to investigate the pathogen spectrum of respiratory pathogens, including bacteria and viruses, in hospitalized children with RTIs in Shenzhen, China, after the COVID-19 outbreak.

In our study, children aged 1–3 years had the highest respiratory infection rate. One possible reason was that pandemic containment measures such as school closures, home quarantines and reduced social interaction have largely reduced outdoor activities for older children (1–12 years). However, children aged 1–3 years had poor adherence to preventive measures such as mask use hand washing, and gel alcohol use before and after contact with others, which also made children in this age group more susceptible to respiratory pathogens.

The prognosis of patients with COVID-19 depends on the severity of the LRTIs caused by SARS-CoV-2 [12]. Timely understanding of the epidemic trend of respiratory bacterial infection is beneficial to the prevention and treatment of LRTIs in communities. During the COVID-19 pandemic, S. aureus, M. catarrhalis, S. pneumoniae, and H. influenzae were the major pathogens responsible for respiratory tract infections in children. The detection rates of S. aureus and M. catarrhalis showed an increasing trend year by year [13]. In addition, Zhu et al. (14). reported a significant increase in respiratory M. catarrhalis infection among children in Chengdu, China, in 2020 compared with 2019. In our study, a total of 42.1% of the RTIs cases were detected as bacteria-positive. S. aureus was the most frequently detected bacterium in Shenzhen in 2020–2021, followed by M. catarrhalis, S. pneumoniae, H. influenzae and others. Common bacteria during the pandemic may be associated with bacterial structure changes [14]. In addition, studies have found that family members and the home environment play a key role in the transmission of S. aureus. Therefore, increased time spent in the home quarantine may help stabilize the incidence of S. aureus infection during the COVID-19 epidemic [15, 16].

A total of 65.6% of RTIs cases were tested positive for the virus. HRV has been known to be the major virus for RTIs in children, with a PDR as high as 10–30% in many studies [17, 18]. Our study showed that HRV was the most frequently detected virus in Shenzhen during the 2020–2021 period, with a PDR of 28%. RSV was the second common virus in our study, followed by HPIV and HMPV. These viruses were the common causes of LRTIs, mainly occurred in children under 3 years, and the prevalence of these viruses decreased with age. Studies in Austria and Japan had also reported a high incidence of HRV infections during the COVID-19 epidemic [19, 20]. HRV is a non-enveloped virus that resists disinfectants containing ethanol and can survive in the environment for long periods of time. HRV can also be transmitted between family members [21, 22]. These factors may lead to HRV infection being less affected by epidemic prevention policies. A significant increase in the rate of RSV infection was reported during the winter of 2020 in Australia (19). Studies had also shown that higher rates of RSV infection have not been detected during COVID-19 [23, 24]. However, the mechanism behind these findings is unclear. Xu [23] et al. found that the detection rates of HPIV and HMPV increased significantly in the winter of 2020, and the infection rate of HPIV was even higher than that in the same period of 2019. A study in Shenzhen also reported higher rates of HPIV and HMPV detection in the winter of 2020 [25]. One study suggested that interference between influenza viruses and other respiratory viruses could affect host viral infection, especially the reduction of influenza virus infection due to epidemic prevention measures, which partly explains the higher detection rates of HPIV and HMPV [26]. Both influenza and COVID-19 are spread between humans through contact and droplets [27]. Therefore, non-pharmaceutical interventions related to reducing COVID-19 transmission would also significantly reduce influenza infection rates. Competition for resources between viruses, immune responses or interference with viral proteins may also play some role [28], [29], [30]. Therefore, the results of these studies suggest that after the COVID-19 outbreak, attention should be focused on HRV, RSV, HPIV and HMPV infections in children, especially those under 3 years of age.

Seasonal climate is a significant factor affecting pathogen transmission. Our study found regular seasonality for S. aureus, M. catarrhalis, S. pneumoniae, HRV, RSV, and HPIV. The detection rates of S. aureus, M. catarrhalis, and S. pneumoniae were highest in autumn and peaked in November. However, reports from Beijing and Shanghai found that respiratory bacterial infections were more likely to occur in winter [31, 32]. The detection rates of RHV, HRV, and HPIV were highest in autumn in our study. A study from India [17] found RHV, and HRV was more prevalent in the summer, followed by the rainy season, which was not consistent with our results. These differences in seasonal detection may be related to local climate and demographic factors. Wang [33] found the detection rate of HPIV was highest in autumn in Shenzhen, which was consistent with our results. The detection rate of RSV was highest in summer and autumn, peaking in July and October. Cold and humidity are risk factors for RSV infection. Shenzhen is located in southern China; It has a typically subtropical monsoon climate, where RSV infection increases primarily during the wet months. A report from Vietnam found that RSV was prevalent in the summer [34], which was similar to our results.

Co-infection is common in RTIs. In our study, S. aureus, HRV, and RSV were the most frequently detected co-infection pathogens. The classical view is that viruses pave the way for bacterial infection by promoting bacterial adhesion to respiratory epithelial cells [35]. Of the co-infections, S. aureus + M. catarrhalis, HRV + HPIV, S. aureus + RSV, and S. aureus + HRV combinations were the most common, which was consistent with the high PDR of these pathogens. Thus, the pathogen with a high PDR in a single infection will also have a high PDR in a co-infection.

Since our study is a retrospective study rather than a prospective analysis, it has the following limitations. (1) Not all 1,046 enrolled patients were tested for both bacteria and viruses, which may lead to an underestimation of some pathogens’ burden. (2) The surveillance time was not enough. COVID-19 is still difficult to be eradicated now, and epidemiological analysis of respiratory pathogens will be needed over the next few years to validate our results and implement effective preventive measures against RTIs in children.

Conclusions

Non-pharmaceutical interventions such as vaccination, home quarantine, reduced social interaction, hand hygiene and environmental disinfection can help address the spread of COVID-19 while also reducing the spread of seasonal epidemic-related pathogens. This information is important for planning strategies to prevent future epidemics of respiratory-related pathogens. In our study, S. aureus, M. catarrhalis, S. pneumoniae, HRV, RSV, and HPIV were the main pathogens of RTIs in children during the COVID-19 epidemic. Positive rates of S. aureus and HRV in RTIs are highest in children, who were prone to co-infection. Children under 3 years were susceptible to respiratory bacteria and viruses. Autumn was the season of high incidence of RTIs. The results of this study can guide the prevention and control decisions for RTIs in children during the epidemic. We will continue to statistically analyze the epidemiological characteristics of respiratory pathogens in hospitalized children with RTIs during the COVID-19 pandemic to obtain a clearer pathogen spectrum.