Evaluating the long-term effect of respiratory syncytial virus (RSV) infection on children: a prospective longitudinal birth cohort study in Bangladesh

Abstract

BACKGROUND: Respiratory Syncytial Virus (RSV) is a leading cause of illness among neonates and young infants. In 2019, an estimated 33 million [95% CI: 21·6-50·3) RSV-associated acute lower respiratory infected (RSV-ALRI) episodes occurred worldwide in children younger than five years, and 101,400 of them died [1]. Children from all parts of the world suffer from RSV-associated illnesses. Nevertheless, those who are from the developing part of the world are disproportionately affected, as 93% of all RSV-associated acute lower respiratory infections (RSV-ALRI) and 99% of RSV-ALRI mortality occurs among children living in developing world countries. Evidence also suggests that children with RSV infection during early infancy are at increased risk for asthma and recurrent wheezing in subsequent years. Nevertheless, few studies have assessed the long-term impact of RSV infection in developing healthcare settings, and none of the previous studies focussed on neonates. This PhD thesis aimed to evaluate the long-term effects of RSV infection within 0-59 days of life in a resource-poor setting. RESEARCH PLAN: In this thesis study, I assessed the respiratory health of a cohort of children aged 6-8 years with known RSV infection exposure during 0-59 days of life to evaluate the association between RSV infection and recurrent wheezing and asthma. I evaluated whether RSV infection during the young infant period (0-59 days) affects lung functions and physical growth of the children. Finally, I evaluated the diagnostic value of the peripheral blood eosinophil level for the diagnosis of childhood asthma. METHODS: I enrolled study participants from a rural community in Bangladesh, a country in South Asia. Children of 6-8 years old with known RSV infection information during 0-59 days of life (RSV+'ve cohort) were enrolled at their household and followed for 12 months. In this study, I leveraged the findings of population-based surveillance on the aetiology of neonatal infection in South Asia (ANISA study), which identified the RSV infection cases in young infants in a rural community with an annual birth cohort of 10,000 neonates. The RSV infection cases were identified in the ANISA study through prospective community-based disease surveillance. Control children (RSV-'ve cohort) had no illness signs (i.e., asymptomatic) during 0-59 days of life. I followed the study participants for 12 months to collect health-related information. During the follow-up period, research assistants (RAs) visited the study participants three times; each visit was scheduled within six months intervals. RAs collected health-related data of the study participants from their respective caregivers using structured questionnaires. The lung function of the participants was assessed using spirometry at the outreach clinics. An open-air 6-minute running exercise test was performed to assess the exercise-related airway hyper-reactivity. The height and weight of the children were collected to monitor the growth of the participants. Capillary blood was collected to determine the blood eosinophil level. The primary outcome measure was "current asthma", which I defined as ≥3 episodes of wheezing in the past 12 months or ≥1 episode of wheezing with repeated cough during the night when the child did not have a cold or chest infection. Additional outcome measures included "asthma ever", "doctor-diagnosed asthma", "wheezing ever", "current wheezing", different lung function parameters (i.e., FVC, FEV1, FEV1/FVC ratio), stunting, and underweight. RESULTS: I enrolled 534 children in this study; of these, 179 children had RSV infection within 0-59 days of life (RSV+'ve cohort), and the other 355 children were controls (RSV-'ve cohort) who were healthy during the same period of life without known RSV infection episode. The primary outcome of this study was “current asthma” at follow-up age (asthma at age 6-8 years) was 4.4%, [95% CI: (-)1.8-10.5] higher among the children in the RSV+'ve cohort [15.1%, 95% CI: 10.5-21.1] compared to those in the RSV-'ve cohort [10.7%, 95% CI: 7.8-14.3], but the difference was not statistically significant. Even though the "current asthma" prevalence was not statistically significantly higher among the children in the RSV+'ve cohort, all other asthma phenotypes that I investigated were significantly higher in this group compared to the controls. The prevalence of "asthma ever" was (significantly) 14% higher [95% CI: 5.8-22.3] among the RSV+'ve cohort children [36%, 95%: 29.0-43.1] compared to the RSV-'ve cohort [22%, 95% CI: 9.7-15.2]. There was also a significantly higher prevalence of "current wheezing" [10%, 95% CI: 2.5-17.3] among the children in RSV+'ve cohort [25.1%, 95% CI: 19.3-32.0] compared to those in the RSV-'ve cohort [15.2%, 95% CI: 11.8-19.4]. Parental asthma [Odds Ratio [OR) 2.15; 95% CI: 1.22-3.79] and household crowding index ≥3 [OR 1.83; 95% CI: 1.04-3.21] were found as the risk factors for "current asthma" among the study participants. In general, the different lung function parameters of the participants that were measured in this study were significantly lower than the expected values, but no significant differences were found between the children in RSV+'ve and RSV-'ve cohorts. Children in the RSV+'ve cohort had a mean Forced Vital Capacity (FVC) of 1.41 litres, 92% of the predicted mean, which was 1.29 litres for the children in the RSV-'ve cohort, 91% of the predicted mean. The mean Forced Expiratory Volume in one second (FEV1) of the children in RSV+'ve cohort was 1.31 litres, 96% of the predicted mean, compared to 1.21 litres, 95% of the predicted mean for the children in the RSV-'ve. There was a high burden of stunting (29.2%) and underweight (40.3%) among the study population, but the differences were not statistically significant between the children in the RSV+'ve and RSV-'ve cohorts. About 71% of the participants had >300 eosinophils cells/µl blood without any notable difference between the RSV+'ve and RSV-'ve cohorts. Also, there was no significant difference in the blood eosinophil level among children with and without current asthma. DISCUSSION: This study demonstrates the association of RSV infection during 0-59 days of life with an increased risk of subsequent asthma in childhood in rural Bangladesh. However, the strength of the association between RSV infection and asthma was not significant after 6-8 years of infection. Thus, RSV intervention would likely have little impact in controlling asthma in children, but the high prevalence of current wheezing, doctor-diagnosed asthma, asthma ever and wheezing ever, suggest that RSV-specific interventions may have a broader impact and should be evaluated using all these definitions to ensure that potential benefit can be captured. Additionally, understanding the possible interaction between RSV infection and genetic and environmental risk factors may help intervene in childhood asthma development. CONCLUSIONS: The burden of RSV-associated illness and asthma among children substantiates the continued research on the association between these two conditions. Future studies on the interactions between host, environment, and RSV infections in developing asthma phenotypes and establishing their causality could contribute to articulating a single intervention to control both RSV-associated illness and asthma, which has greater public health importance