It is not known why respiratory syncytial virus (RSV) is associated with prolonged sequelae in many children. Measles virus (also a paramyxovirus), acute stress in sepsis, and cardiac bypass all cause lymphopenia. Using a retrospective analysis of records of children in Bristol with RSV infections over 5 years, we found that children with RSV had lower lymphocyte counts than unstressed, stable children prior to cardiac surgery. Children who required intensive care had the lowest lymphocyte counts. Neutrophil counts were raised in RSV-infected children. These data may offer an insight into pathological mechanisms, and suggest new research avenues.

SUMMARYRespiratory syncytial virus (RSV) infection may have an effect on the development of T cell memory responses. RSV bronchiolitis in infants is associated with a transient decline in circulating lymphocytes. We hypothesized that the mechanism underlying this lymphopenia is apoptosis. Blood was taken from 32 infants during primary RSV bronchiolitis and three months later. Using flow cytometry, we found that absolute numbers of both CD3+/CD4+ T-helper lymphocytes ( P = 0·029) and CD3+/CD8+ cytotoxic lymphocytes (CTL) ( P = 0·043) were significantly reduced during acute infection. Up-regulated expression both of Fas ( P < 0·001) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ( P < 0·001) was found during acute illness on both CD3+/CD4+ and CD3+/CD8+ lymphocytes, when compared with convalescent samples. Expression of Fas on CD4+ lymphocytes was inversely related to CD4+ number ( P = 0·03). Plasma levels of soluble Fas ligand ( P = 0·028) and caspase-1 ( P = 0·037), determined by enzyme-linked immunosorbent assay, were increased during bronchiolitis. Plasma interleukin-18, a product of caspase-1 activity, was not raised. Taken together, these data suggest that in acute RSV infection, CD4+ helper lymphocytes and CD8+ cytotoxic lymphocytes are primed to undergo apoptosis. This is a mechanism through which lymphopenia may occur and T cell memory may be altered.

Respiratory syncytial virus (RSV) infection is associated with epithelial cell death and vigorous inflammation. In mouse models, and in immunosuppressed patients, CD8(+) T cells are necessary for RSV clearance. In vitro, RSV has been shown to induce expression of several proteins on the respiratory epithelial cell, including RSV proteins, ICAM-1, and MHC class I, that can potentially interact with CD8(+) T cells in initiating apoptosis of the target cell. One mechanism of T-cell-directed cell death is the interaction of FasL on the CD8(+) T lymphocytes and Fas expressed on the target cell. In order to determine the ability of RSV to induce Fas on the respiratory epithelium, we studied the RSV infection of a human respiratory epithelial cell line (A549) in vitro. Fas mRNA and protein levels are increased two-to-fourfold following RSV infection, and transcriptional upregulation of Fas was demonstrated using promoter/reporter gene constructs. RSV infection directly resulted in cellular apoptosis, and the frequency of apoptotic cells was further increased by cross-linking with antibodies to Fas. These data demonstrate that RSV infection induces cellular apoptosis and suggest that interactions of surface Fas with T cells may further augment this process in vivo.

Whereas the effect of intensive care (mechanical ventilation and medication) could not be controlled for, our results suggest that there is an association between the neuroendocrine hormone response, severity of illness and degree of lymphopenia.