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Treatment of Respiratory Syncytial Virus in Lung Transplant: Fifty Shades of Gray


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Angela Logan, PharmD
Tampa General Hospital
Tampa, FL, USA
ALogan@tgh.org



The outcomes of treatment for respiratory syncytial virus (RSV) in the setting of lung transplant have remained unclear due to the lack of robust data published for this population. Implications of increased morbidity and mortality in the immunocompromised population make this a significant complication. As with many aspects of lung transplantation, clear black and white guidelines for RSV management do not exist; the challenges in a consensus for treatment are painted with fifty shades of gray.

The Black and White

Respiratory syncytial virus (RSV) is a single-stranded RNA paramyxovirus with seasonal outbreaks occurring primarily in the winter months. The incidence of infection in the lung transplant population ranges from 6-21% with mortality rates of 20%. Whereas mortality rates are 70% in the bone marrow transplant population; however, there is comprehensive published support in early treatment to reduce mortality for this population [1]. The clinical impact of community respiratory viruses has been shown to result in a decrease in FEV1 at 3 months after infection and an increased incidence of acute rejection episodes; which lends towards an inclination for specific RSV treatment rather than supportive therapy alone [2].

The Shades of Gray

In comparing the ribavirin treatment options for RSV infection, the clinical endpoints most commonly examined include clearance of viral infection, return of lung graft function to baseline, incidence of acute cellular rejection and bronchiolitis obliterans syndrome (BOS) development. However, the common limitations to studies include small sample sizes, non-randomized design, differences in follow up time, and few head to head comparisons.

Generally, more practitioners are inclined to treat rather than rely mainly on supportive therapy of oxygen and bronchodilators due to the immunologic impact of viral infections, which in lung transplant recipients (LTRs) have increased difficulty in clearing viral infections due to lack of mucociliary clearance and impaired cough reflex. A progression to BOS development after infection has been reported as high as 60% in patients without any specific treatment [3], and allografts that have higher stages of BOS (≥1) at time of infection may have more detrimental effects on lung function [4].

Ribavirin is a purine nucleoside analog that has in vitro activity against RNA viruses including, but not limited to, RSV. The routes of administration include inhaled, oral, and intravenous, with inhaled ribavirin having an FDA approved indication for treatment in the pediatric population. Inhaled ribavirin has been the preferred route with the most published literature in LTRs and consists of dosages of either 6g daily over 12-18 hours for 3-5 days or 2g over 2-4 hours every 8 hours for 3-5 days [5]. The limitations to its use include the specialized respiratory delivery apparatus which may not be available in all institutions, as well as the exorbitant costs associated with the drug and hospitalization days for treatment. McKurdy's study in a cohort of 15 patients showed a return of FEV1 back to baseline in 70% of the patients by 90 days after inhaled ribavirin treatment. This study examined outcomes specifically in lower respiratory infections (RTI) in patients who presented with a median 25% decline in FEV1 during time of infection, and the author highlighted that the 3 patients that did not have a return to lung function all had underlying IPF, and 2 (14%) patients died within 30 days of diagnosis of infection. On the other hand, aerosolized delivery poses an increased teratogenic risk to female staff of child-bearing age.

Oral ribavirin is available primarily for use in hepatitis C treatment with hemolytic anemia serving as one of the main adverse effects with its use. The use of oral ribavirin in RSV treatment in LTRs was first described by Paelez and colleagues for its use on 5 patients. In this study, oral ribavirin was dosed at 15-20mg/kg/day for 10 days with confirmed viral clearance through nasal swabs in patients with lower RTIs. The patients presented with an average decrease in FEV1 by 21% at time of infection with a return to baseline in all 5 patients; additionally, no evidence of BOS was seen in this small cohort. In another study, where therapy was chosen by provider preference, a direct comparison of inhaled versus oral in 21 patients showed no difference between inhaled and oral in FEV1, mortality, or progression of BOS. However, this again was limited by a small sample, a short 6 month follow up time period, and a non-randomized design [6]. While the preponderance of clinical support is with inhaled ribavirin, the oral option is more economically favorable with a reported cost comparison of $700 versus $14,000 for drug cost alone [7].

Intravenous ribavirin is currently only available in the US through compassionate use in hemorrhagic fevers, and its use in RSV infection has only been reported in one study of eighteen symptomatic LTRs dosed at 33mg/kg in 3 divided doses, every 8 hours for 1 day; then maintained on 20mg/kg divided into 3 doses until a negative nasopharyngeal and throat swab was obtained. The average length of therapy was 8 days and all patients recovered to baseline FEV1 by 3 months. The reported cost savings was $15,913 per 8 day course compared to the nebulized therapy [8].

50 Shades Darker

The sequel to this saga has yet to be written as more data is necessary to more objectively tailor therapies and elucidate the outcomes of therapies. Individual programs will have to weigh in on the financial burden of the current preferred aerosolized therapy. Perhaps a stratification of patients by severity of symptoms, upper versus lower RTI, degree of baseline graft function, % change in FEV1, and current immunologic risk are factors to take into account in order to individualize the decision of inhaled versus oral therapy. Other treatment options not detailed in this article include palivizumab and IVIG, which have not had much documented success. While prevention continues to be the preferred option, ultimately, the ideal 'treatment' is the development of a vaccine in the near future. ■

Disclosure Statement: The author has no conflicts of interest to disclose


References:

  1. McCurdy L, Milston A, and Dummer S. Clinical features and outcomes of paramyxoviral infections in lung transplant recipients treated with ribavirin. J Heart Lung Transplant 2003;22:745-53.
  2. Kumar D, Erdman D, Keshavjee S, et al. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. J Heart Lung Transplant 2005;5:2031-36.
  3. Uckay I, Gashe-Soccal P, Kaiser L, et al. Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy. J Heart Lung Transplant 2010;29:299-305.
  4. Liu V, Dhillon GS, Weill D. A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients.Transpl Infect Dis 2010;12:38-44.
  5. Hynicka L, Ensor C. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother 2012;46:558-66.
  6. Li L, Avery R, Budv M, et al. Oral versus inhaled ribavirin therapy for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant 2012;31:839-44.
  7. Pelaez A, Lyon M, Force S, et al. Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant 2009;29:67-71.
  8. Glanville A, Scott A, Morton J, et al. intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transplant 2005;24:2114-19.




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