Differences in clinical manifestations of ALRTIs with s-RSV, s-HRV, and co-infection
In infants and young children, ALRTIs are most frequently caused by respiratory viruses, such as RSV and HRV, both of which play a significant role in pediatric respiratory tract infections [
20,
21]. Co-infection is common in ALRTIs, while RSV and HRV are the most common viruses in co-infections, with a rate higher than 50% [
22]. Our findings provide details on the characteristics of s-RSV, s-HRV and co-infection of the two viruses among children under 3 years of age in Beijing Children’s Hospital. Our study showed that the peak months for s-HRV and s-HRV infection were January. And the mean age of children in s-HRV group was older than those in the other groups, but most cases in every group were less than 1 year. The s-RSV cases were more likely to experience the respiratory failure and had the highest demand of nasal catheter oxygen inhalation and NCPAP. These results were consistent with the disease score and indicated that s-RSV cases was more severe than co-infection groups. Another study also suggested that RSV infection was more likely to cause coughing, wheezing, and shortness of breath than HRV infection [
23].
It’s controversial about the role of co-infection of viruses in the severity of disease. Martin et al. found that comparing with children infected with a single virus, children with mixed viruses infection were less frequently admitted to the inpatient ward or to the intensive care unit and less likely to require supplemental oxygen or hospital stays longer than 3 days [
24]. Nascimento et al. found that co-infections were not associated with poorer outcomes [
25]. A prospective analysis including 322 hospitalized infant patients with acute respiratory disease (ARD) revealed that co-infections were significantly more common in mild respiratory diseases [
26]. Brand et al. also found that the severity of illness in children with bronchiolitis is not associated with multiple viruses infection [
27]. These results are coincident with that of our study, and demonstrated that co-infection in ALRTIs could not cause more severe condition. A most recent Italian research showed that infants with co-infection seemed to mount a lower inflammatory response [
28], the antagonism caused by non-specific innate immune responses stimulated by co-infection virus maybe a possible reason.
However, other studies had different results. Calvo et al. reported that patients with mixed viruses infection had more frequent fever, longer hospital stays, and more antibiotic treatment than patients infected with RSV alone [
29]. Aberle et al. also reported that co-infection (HRV and HAdV) with RSV was associated with the severity of illness, hypoxemia, and fever [
30]. Richard et al. found that dual viral infection was a relevant risk factor for admission to PICU [
31]. The different results of co-infection of viruses on the severity of disease may be associated with several reasons, such as study population, research design, and standard of evaluation and so on. Multicenter studies are needed.
Incidences of subsequent wheezing/asthma in childhood
A large number of studies have identified a link between RSV/HRV infection and an increased likelihood to develop either recurrent wheezing or asthma. Previous studies showed that with RSV infection, the risk of developing recurrent wheezing was from 28.1 to 30% [
32,
33], and for asthma, the rate was from 30 to 38.4% [
32,
34]. For HRV-infected children, the risk for developing asthma at 6 years of age being more than four-fold higher compared with HRV-negative cases [
35]. In the large, prospective Childhood Origins of Asthma (COAST) study performed in children at increased risk of developing allergies and asthma, HRV infections represented a significantly increased risk (OR = 10) for developing asthma by 6 years of age [
10]. From our study, the rate of recurrent wheezing of the three group was 41.1% (s-RSV), 22.2% (s-HRV) and 41% (co-infection), while the rate of asthma was 7.5% (s-RSV), 11.1% (s-HRV) and 12.8% (co-infection). Taking the number of enrolled cases into account, especially s-HRV and co-infection cases were small in our study and this may also a potential bias of the result. So, further studies are needed to explore the mechanism of different immune response to RSV and HRV infection in infants.
We found that there were no significant differences in the development of asthma among subgroups of the three groups with or without family history of wheezing. And only s-RSV group with positive family history had a tend to have recurrent wheezing than those without. This result is consistent with that of the following studies. A Japanese study found no connection between RSV-based ALRTIs in infants and childhood asthma [
36]. Kusel, et al. reported that RSV and HRV infections in the first year after birth were associated with wheezing and asthma at the age of 5 years, with no difference between the two groups [
37]. Uppala R.et al. reported that the specific pathogens (RSV/HRV) did not account for a statistically significant difference in subsequent wheezing or asthma development [
38].
However, some studies supported that RSV or HRV infection in early childhood was associated with chronic airway diseases, especially in the subsequent development of wheezing and asthma. From some population-based birth cohort studies, RSV bronchiolitis was found to be associated with subsequent wheezing and asthma, especially in children with family histories of atopy and asthma [
32,
39]. Another high-risk birth cohort study showed that among outpatients viral wheezing illnesses in infancy and early childhood, those associated with HRV infections were the most significant risk factors of subsequent development of asthma at the age of 6 years [
10]. We found the different immune response induced by RSV and HRV may be the cause of this result. For instance, IL-8 level in the nasal aspirate is higher in ALRTIs associated with RSV in children than those associated with HRV, and higher respiratory tract IL-8 level was associated with hypoxia and need for ventilation in infants [
40,
41]. Another previous research reported that RSV bronchiolitis, with higher nasal levels of IFN-λ than HRV infection, and higher nasal IFN-λ levels were associated with increased disease severity [
42,
43], and severe bronchiolitis was the risk factor for recurrent wheezing [
44]. Other studies suggested that IL-5 was significantly elevated in the HRV group compared with the RSV group in both serum and nasal secretions [
45], and as we all know, IL-5 has the effect of inducing eosinophil accumulation in airways.