Respiratory syncytial virus pathophysiology and affect of palivizumab in special populations: cystic fibrosis and immunosuppression.

monary disease in patients with cystic fibrosis (CF). This appears to be due to an exaggerated pulmonary inflammatory response, particularly seen with Respiratory Syncytial Virus lowerrespiratory-tract infection (RSV LRTI). In the normal mouse, infection with RSV leads to increased lymphocytes, neutrophils, and inflammatory cytokines recovered from bronchoalveolar lavage and chronic pulmonary inflammatory infiltrates may last up to 154 days after inoculation. In CF mice, clearance of RSV is further impaired and a much exaggerated inflammatory response is seen compared to non CF mice. As observed using in vitro and in vivo models, RSV causes an exaggerated nuclear factor (NF)kappaB activation and subsequent elevated cytokine and chemokine production. NF-kappaB dimers exist as inactive complexes in the cytoplasm of unstimulated cells by virtue of their interaction with inhibitory proteins (IjBs). These inhibitory proteins are phosphorylated by cellular kinase complexes. This seems to be regulated through activation of the IkappaB kinase alpha (IKK-a) in lung tissue. RSV infection activates IKK-a and IKK-b. In the CF human airway gland cells this exaggerated response of NF-KappaB also can be caused by elevated sodium chloride content. Exposure of non-CF cells to hypotonic sodium chloride solution, compared to isotonic or hypertonic sodium chloride solutions, inhibited activated IKK-a and IL-8 levels. While interleukin (IL) 8 (IL8) levels were inhibited by hypotonic saline solution in CF cells, marked inhibition of the IKK-a system did not occur. Abnormally high sodium chloride levels within the lung also act to inactivate human b-defensin-1, a naturally occurring antibiotic, and change the antimicrobial characteristics of epithelial surface fluid. Respiratory viruses also can cause induction of inflammatory cytokines in human bronchial cells by activation of the p38 mitogenactivated protein kinase (MAPK) signaling pathway. RSV infection inhibits granulocyte apoptosis via kinase and NF-kappaB dependent mechanisms. Lastly, in the mouse model, RSV infection increases expression of inducible nitric oxide synthase and nitric oxide production adding to the inflammatory burden. Palivizumab exhibits both neutralizing and fusion inhibitory activity against RSV. This inhibits RSV replication and appears to decrease the severity of LRTI in high risk human populations. When given in a non-CF murine model 24 hours before RSV inoculation, significant decreases in the number of RSV recovered in bronchoalveolar lavage and histopathological inflammatory scores are observed. Airway obstruction, mucus production and airway hyper-responsiveness also are less than in controls. Palivizumab also has been shown to decrease neurogenic RSV induced inflammation even when given 72 hours after virus inoculation in this same model. Further, Piedra and co-workers have demonstrated that a purified fusion protein vaccine can increase RSV neutralizAddress correspondence to: Michael E. Speer, MD, 6621 Fannin Street, WT 6 – 104, Houston, TX 77030, email: mspeer@bcm.tmc.edu 2011 Pediatric Pharmacy Advocacy Group