Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease.

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA-rich mucus plugs are characteristic features of severe RSV-LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first-line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti-viral effect in vitro. Second, we studied NET formation in vivo during severe RSV-LRTD in infants and bovine RSV-LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV-LRTD. Detailed histopathological examination of calves with RSV-LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV-LRTD contributes to airway obstruction.

WITHDRAWN: Inhaled corticosteroids during acute bronchiolitis in the prevention of post-bronchiolitic wheezing.

BACKGROUND: Acute bronchiolitis in infants and young children is associated with long-term airway disease also known as post-bronchiolitic wheezing. Two major hypotheses have been proposed to explain the association between bronchiolitis and PBW. The first hypothesis considers bronchiolitis to be the first manifestation of recurrent wheezing in infants and children who are susceptible to obstructive airway disease. The second hypothesis suggests that the infection and concomitant inflammatory reaction in the acute phase leads to airway epithelium injury resulting in long-term obstructive airway disease. In line with the latter hypothesis, corticosteroids may have a beneficial effect on the prevention of post-bronchiolitic wheezing. OBJECTIVES: The objective of this review was to evaluate the effect of inhaled corticosteroids, started during the acute phase of bronchiolitis, on the prevention of post-bronchiolitic wheezing. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, issue 3) which contains the Cochrane Acute Respiratory Infections Group's trials register, MEDLINE (1966 to September 2006), EMBASE (1980 to September 2006) and Current Contents (September 2006). Abstracts and reports of congresses (ERS 1999 to September 2005, ATS 1999 to September 2005) were obtained. We contacted experts in the field and pharmaceutical companies for ongoing or unpublished studies. SELECTION CRITERIA: Randomised placebo-controlled trials studying the effect of inhaled corticosteroids in children younger than two years of age with the clinical diagnosis of acute bronchiolitis were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality using the Jadad 5-point scale. MAIN RESULTS: Five studies matched the inclusion criteria, with a median Jadad score of 4 (Inter Quartile Range 3 to 4), involving 374 infants. Pooling of the data was limited, due to the clinical diversity of the studies. However, no effect of inhaled corticosteroids in the prevention of wheezing (diary records or GP diagnosed), hospital re-admissions or use of corticosteroids or bronchodilators could be demonstrated. Duration of therapy, length of follow up or causative agent (respiratory syncytial virus or not) did not influence the pooled effect. In the three studies that also evaluated the adverse events, none were reported. AUTHORS' CONCLUSIONS: This review does not demonstrate an effect of inhaled corticosteroids given during the acute phase of bronchiolitis in the prevention of post-bronchiolitic wheezing. The small number of included participants and the inability to pool all clinical outcomes precludes us from making strong recommendations.