RSV bronchiolitis in healthy term infants: prediction and pathogenesis

The global estimated annual numbers of non-severe and severe (i.e. hospitalized) respiratory syncytial virus (RSV) infections in children younger than five are 34 and 3.4 million. Most children with RSV bronchiolitis are treated outside the hospital and most children with RSV bronchiolitis are healthy term infants. This thesis is based on the Netherlands Amniotic Fluid Cohort, which was initiated to gain insight in the etiology of RSV bronchiolitis and to contribute to its prediction in healthy term infants. We found the following predictive factors for RSV bronchiolitis in healthy term infants: presence of siblings / day-care attendance, birth in April to September, birth weight >4 kg, and highly educated parents. Abundant viral exposure (i.e. siblings, day-care) appeared to be the strongest predictor of RSV bronchiolitis in healthy term infants. The derived prediction rule could differentiate between children with low risk (3%) of RSV bronchiolitis and high risk (32%). Children with RSV bronchiolitis had an increased prevalence of recurrent wheezing and reduced health-related quality of life during the first year of life. In addition, vitamin D deficiency at birth was also associated with an increased risk of RSV bronchiolitis. RSV viral load was positively associated with disease severity in primary RSV infections. A high correlation with RSV viral load was found for single RSV infections and for RSV co-infections. In line with these findings, the sensitivity of the nasal swab for the molecular detection of RSV infection in the community was generally moderate, but high in case of more severe RSV infection. Term spontaneous onset of labor vaginal delivery was associated with high levels amniotic fluid pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and a high prevalence of histological chorioamnionitis. Fetal exposure to higher levels of amniotic fluid pro-inflammatory cytokines (IL-8, TNF-α) appeared to be associated with a decreased risk of medically attended RSV bronchiolitis in the first year of life. In addition, in the group of children that developed RSV bronchiolitis, the number of days with wheezing symptoms in the first year of life was inversely associated with the amniotic fluid concentration of IL-8. Finally, newborn airway compliance was positively correlated with the amniotic fluid concentration of sLAIR-1, which is considered a marker of general immune activation. Additionally, children exposed to a high level of amniotic fluid sLAIR-1 had a decreased incidence of recurrent wheezing. Given the finding that a firm pro-inflammatory profile was present in amniotic fluid of the majority of physiologic term deliveries, one could speculate on the role of exposure of the fetal mucosa to these inflammatory signals. Maybe these signals instruct the local mucosal immune system to prepare for the invasions of several pathogens, allergens and pollutants after birth. Since the impressive inflammatory response is present during term deliveries on such a large scale, it is likely that the beneficial effect found is not specific for RSV bronchiolitis, but also holds true for other childhood respiratory condition, such as viral-induced wheezing and asthma. Maybe the origin of common human respiratory disorders should be sought antenatally