Respiratory Syncytial Virus Pathophysiology and Affect of Palivizumab in Special Populations: Cystic Fibrosis and Immunosuppression

Cystic Fibrosis

As noted by Prescott et al. in this issue of the journal, viral respiratory infections play an important role in the development and progression of pulmonary disease in patients with cystic fibrosis (CF). This appears to be due to an exaggerated pulmonary inflammatory response, particularly seen with Respiratory Syncytial Virus lower-respiratory-tract infection (RSV LRTI).^1–9 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.¹⁰ In CF mice, clearance of RSV is further impaired and a much exaggerated inflammatory response is seen compared to non CF mice.¹¹

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.^12–16 NF-kappaB dimers exist as inactive complexes in the cytoplasm of unstimulated cells by virtue of their interaction with inhibitory proteins (IκBs). These inhibitory proteins are phosphorylated by cellular kinase complexes. This seems to be regulated through activation of the IkappaB kinase alpha (IKK-α) in lung tissue. RSV infection activates IKK-α and IKK-β.¹⁶ In the CF human airway gland cells this exaggerated response of NF-KappaB also can be caused by elevated sodium chloride content.¹⁷ Exposure of non-CF cells to hypotonic sodium chloride solution, compared to isotonic or hypertonic sodium chloride solutions, inhibited activated IKK-α and IL-8 levels. While interleukin (IL) 8 (IL-8) levels were inhibited by hypotonic saline solution in CF cells, marked inhibition of the IKK-α system did not occur.¹⁷ Abnormally high sodium chloride levels within the lung also act to inactivate human β-defensin-1, a naturally occurring antibiotic, and change the antimicrobial characteristics of epithelial surface fluid.^18,19 Respiratory viruses also can cause induction of inflammatory cytokines in human bronchial cells by activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway.²⁰ RSV infection inhibits granulocyte apoptosis via kinase and NF-kappaB dependent mechanisms.²¹ Lastly, in the mouse model, RSV infection increases expression of inducible nitric oxide synthase and nitric oxide production adding to the inflammatory burden.²²

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.^23,24 Palivizumab also has been shown to decrease neurogenic RSV induced inflammation even when given 72 hours after virus inoculation in this same model.²⁵ Further, Piedra and co-workers have demonstrated that a purified fusion protein vaccine can increase RSV neutralizing and binding antibodies in children with CF. In those children who received the vaccine a 17% to 19% reduction in RSV infection was observed.²⁶

Thus, in theory, palivizumab prophylaxis should have a salutatory effect in the CF patient by decreasing the inflammatory effect caused by RSV LRTI. Unfortunately, no well designed prospective studies have been performed in either the CF murine model or in humans with cystic fibrosis to determine what role, if any, palivizumab might have. Randomized controlled human trials are necessary to determine whether palivizumab administration or an alternative therapy would most benefit the CF patient.

Immunosuppression

As noted by Prescott et al. in this issue of the journal, RSV is a major cause of disease among immunocompromised children and adults. Immunocompromised children less than 2 years age and under treatment for acute myeloid leukemia and before or after hematopoietic stem cell transplant appear to be at the most risk for RSV LRTI and death.²⁷ Patients with acute lymphoblastic leukemia, solid tumors or severe combined immunodeficiency syndrome were shown to have an increased risk of RSV LRTI but not death.²⁷ An independent predictor of severe lower respiratory tract infections, but not death, was profound lymphopenia, with absolute lymphocyte counts of < 100 cells per mm³. Similarly, other pediatric immunocompromised populations without leucopenia do not seem to have an increased risk of death.²⁸

As reported by Ottoline et al, there is a high degree of viral replication found in the profoundly leukopenic murine model.²⁹ This increased replication and heightened inflammatory response noted in immunocompromised patients can be related to impaired T-cell function. Infected T cell deficient nude mice have longer lasting and higher levels of viral replication compared to immunocompetent controls. They also have larger numbers of pulmonary macrophages and NK cells as well as higher levels of tumor necrosis factor-α (TNF- α), IL-12 and IL-10.³⁰ In a patient with severe combined immunodeficiency syndrome (SCIDS), RSV clearance has been shown to improve at the time of reconstitution of presumed RSV-specific CD8⁺ cells.³¹ Also, a lack of pulmonary CD8⁺ effector cells has been found in immunocompetent infants with fatal RSV pneumonia.³² The neutralizing and fusion inhibitory activity of palivizumab may be overwhelmed and ineffective in the T-cell compromised host when administered at the standard dosage. Theoretically, in the non T-cell deficient immunocompromised individual, palivizumab may be beneficial. However, like the cystic fibrosis cohort, there are no randomized controlled trials that have examined the effectiveness of palivizumab in this population.

ABBREVIATIONS

CF

cystic fibrosis

IKK-α

IkappaB kinase alpha

IL

interleukin

LRTI

lower respiratory tract infection

NF

nuclear factor

RSV

respiratory syncytial virus

TNF-α

tumor necrosis factor-alpha