Viral Infection and Respiratory Exacerbation in Children: Results from a Local German Pediatric Exacerbation Cohort

Abstract

Respiratory viruses play an important role in asthma exacerbation, and early exposure can be involved in recurrent bronchitis and the development of asthma. The exact mechanism is not fully clarified, and pathogen-to-host interaction studies are warranted to identify biomarkers of exacerbation in the early phase. Only a limited number of international exacerbation cohorts were studied. Here, we have established a local pediatric exacerbation study in Germany consisting of children with asthma or chronic, recurrent bronchitis and analyzed the viriome within the nasopharyngeal swab specimens derived from the entire cohort (n = 141). Interestingly, 41% of exacerbated children had a positive test result for human rhinovirus (HRV)/human enterovirus (HEV), and 14% were positive for respiratory syncytial virus (RSV). HRV was particularly prevalent in asthmatics (56%), wheezers (50%), and atopic (66%) patients. Lymphocytes were decreased in asthmatics and in HRV-infected subjects, and patients allergic to house dust mites were more susceptible to HRV infection. Our study thus confirms HRV infection as a strong 'biomarker' of exacerbated asthma. Further longitudinal studies will show the clinical progress of those children with a history of an RSV or HRV infection. Vaccination strategies and novel treatment guidelines against HRV are urgently needed to protect those high-risk children from a serious course of disease.

Keywords: asthma; bronchitis; children; exacerbation; human rhinovirus; infection; respiratory syncytial virus; virus.

Figure 1

Frequency of infection in different groups. The frequency of infection with each of the studied viruses was compared between asthmatics or wheezers and age-matched controls. Rhinovirus infection levels are significantly higher in asthmatics than in older healthy controls. There is also a substantial difference in RSV infection levels between wheezers and younger controls. The pairwise comparisons were conducted with Fisher’s exact test, then the p-values were corrected using the FDR method. *** p < 0.001. Abbreviations: AdV = adenovirus, CoV = coronavirus, HRV/HEV = human rhinovirus/human enterovirus, MPV = metapneumovirus, RSV = respiratory syncytial virus).

Figure 2

Subjects infected by HRV or by RSV as a function of atopy status. (a) The correlation between infection and atopic status was tested within each group or with all groups combined using Fisher’s exact test. Additionally, Woolf tests were conducted to assess if the odds ratio of infection versus atopy status differed between asthmatics and healthy controls older than 5 or between wheezers and healthy controls younger than 5. After all the tests, p-values were corrected using the FDR method. Atopy significantly increased HRV infection levels in all groups combined (p = 0.000031). (b) There was no significant correlation between atopy status and RSV infection levels. *** p < 0.001.

Figure 3

Lymphocytes decreased in HRV/HEV-infected subjects. Post-hoc pairwise comparisons of infected versus non-infected subjects were conducted within each group using the Mann–Whitney U, non-parametric test. *** = p < 0.001.

Figure 4

Patients with house dust mite allergies are susceptible for rhinovirus infection. We hypothesized that dust mite allergy levels, as measured by ImmunoCAP, influence the susceptibility to viral infections. We restricted our analysis to HRV/HEV and RSV and to wheezers and asthmatics since too few healthy controls accepted to undertake ImmunoCAP. For each group and each virus, we conducted a Mann–Whitney U test to assess if the viral infection status correlated with dust mite allergy levels. We found that dust mite allergies increased in HRV/HEV infected asthmatics compared with non-infected asthmatics (p = 0.031). * p < 0.05.

Figure 5

Bacterial profiles in patients with human rhinovirus (HRV) or respiratory syncytial virus (RSV) infections (a,b). In each cohort subset, we compared bacteria colonization between groups for each selected bacteria and location and between bacteria and location with all groups combined. We used chi-square tests of independence and corrected all p-values using the FDR method. Pairwise comparisons were conducted using Fisher’s exact test (Haemophilus influenzae = Haemophilus influenzae + Haemophilus parainfluenzae, S. aureus = Staphylococcus aureus, S. pneumonia = Streptococcus pneumonia, M. catarrhalis = Moraxella catarrhalis). * p < 0.05; ** p < 0.01; *** p < 0.001.