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ARTICLE
Clinical Outcomes of Paramyxovirus Infections in Lung Transplant Recipients Treated With Oral Ribavirin: A Two-Center Case Series

Objectives: Paramyxoviruses contribute to morbidity and mortality after lung transplant and are associated with bronchiolitis obliterans syndrome. Oral ribavirin has been used off-label for treatment of paramyxo-viruses in immunosuppressed patients; however, data supporting its use for this purpose are lacking.

Materials and Methods: We conducted a retrospective review to evaluate clinical outcomes of lung transplant recipients infected with paramyxoviruses and received treatment with oral ribavirin at 2 tertiary referral centers. Patients who were diagnosed with paramyxo-virus infection by polymerase chain reaction testing between January 2011 and December 2014 and who received oral ribavirin were included. Clinical outcomes included pulmonary function testing, infection severity, and adverse events related to treatment.

Results: Twenty-six patients were diagnosed with a paramyxovirus and received oral ribavirin. The changes in mean forced expiratory volume 1 second from preinfection to infection onset and from infection onset to postinfection were significant (1.79 ± 0.13 to 1.61 ± 0.12 L and 1.61 ± 0.12L to 1.74±0.12 L; P = .0001). Similar results were seen in subgroup analysis when respiratory syncytial virus and parainfluenza infections were evaluated independently.

Conclusions: Use of oral ribavirin for treatment of paramyxovirus infections in lung transplant recipients was safe and associated with recovery of lung function.


Key words : Bronchiolitis obliterans syndrome, Pulmonary function testing, Respiratory syncytial virus

Introduction

Community-acquired lower respiratory tract viral infections with paramyxoviruses, including respira-tory syncytial virus (RSV), parainfluenza, and human metapneumovirus (HMV) can result in significant morbidity and mortality in immunosuppressed individuals, particularly after allogeneic hematopoi-etic stem cell or lung transplant.1-3 Prior studies have cited mortality rates as high as 10% to 20% for lung transplant patients infected with RSV. In addition, infection with paramyxoviruses is associated with an increased risk of the development of bronchiolitis obliterans syndrome (BOS).3-5

Although there is consensus that treatment of RSV is essential in the lung transplant population, there remains a lack of data to conclude the best mode of therapy, and treatment of other paramyxo-viruses is even less well studied.6,7 Ribavirin is a synthetic nucleoside analog with in vivo and in vitro evidence supporting its activity against a range of viruses, including RSV, parainfluenza, and HMV.8-13 Prior case series have described bone marrow and lung transplant patients infected by RSV who used inhaled, intravenous, or oral ribavirin with or without the addition of corticosteroids, intravenous immunoglobulin, and palivizumab. However, these studies have been limited by small sample sizes, lack of control groups, and single-center retrospective study designs.5-8,14

Intravenous ribavirin is not commercially available in the United States, and the clinical utility of inhaled ribavirin is limited for multiple reasons, including its high cost, its need for a negative pressure room due to potential toxicity to health care providers as it is a known teratogen, the potential for bronchospasm, and its ability to obstruct the ventilator circuit.5,8 Oral ribavirin is well tolerated, is a lower cost medication approved for the treatment of hepatitis C virus, and is increasingly being utilized for the treatment of RSV infections in lung transplant recipients. There are limited data to show that any formulation of ribavirin is clinically superior in the treatment of paramyxovirus infections in lung transplant recipients. In this study, we describe a 2-center experience in the use of oral ribavirin for lung transplant recipients diagnosed with community-acquired lower respiratory tract paramyxovirus infections.

Materials and Methods

Study design
A retrospective chart review of 2 lung transplant centers was performed. Medical records of all lung transplant recipients from both centers were reviewed, and all patients diagnosed with symp-tomatic paramyxovirus who received ribavirin were included. Patients were excluded on the basis of having received a non-oral formulation of ribavirin or if there was incomplete spirometry in the 6 months before, during, or 6 months after the diagnosis of viral infection.

Definitions
A patient was identified as having a symptomatic paramyxovirus infection based on clinical symptoms of fever, cough, dyspnea, shortness of breath, or increased oxygen requirement and a positive polymerase chain reaction (PCR) either by naso-pharyngeal swab or by bronchoalveolar lavage. Severity of viral infection was based on previously defined criteria with grade 1 (mild) requiring no change in oxygen therapy from baseline, grade 2 (moderate) requiring new or increased oxygen requirements, and grade 3 (severe) requiring mechanical ventilation. Baseline lung function was defined as the most recent spirometry data obtained in the 6 months before infection diagnosis, and follow-up spirometry was generally obtained at 6 months after completion of therapy.

Patient population and characteristics
Between January 2011 and January 2015, 32 patients were identified as having symptomatic paramyxo-virus infections with positive PCR testing. Two of these patients were excluded on the basis of having received inhaled ribavirin, and 4 patients had incomplete spirometry either in the 3 months before or after their infection and were precluded from the study. Patient characteristics, including reason for transplant, age at time of viral infection, time since transplant, type of paramyxovirus, grade of infection severity, and pulmonary function, were obtained (Table 1).

Treatment protocol
Patients infected with a paramyxovirus were given oral ribavirin at a dose of 400 to 600 mg either twice per day or 3 times per day using standard weight-based dosing for 7 to 10 days pending clinical recovery. Patients were monitored for signs of known adverse effects, including anemia, gastroenteritis, and transaminitis.

Statistical analyses
Statistical analysis was performed using GraphPad Prism version 6.0c (GraphPad Software, Inc., San Diego, CA, USA). Continuous variables were described using means with standard errors or medians with ranges as sample sizes were small; variables were analyzed using t test as data were nonparametric. The patients’ baseline forced expiratory volume in 1 second (FEV1) and forced expiratory flow at 25% to 75% (FEF25-75%) at the time of infection onset and at 3 months before and after infection were compared. All statistical tests were 2-sided, and P < .05 was considered statistically significant.

Results

There were a total of 26 lung transplant recipients diagnosed with a paramyxovirus pulmonary infection and who received treatment with oral ribavirin identified between January 2011 and January 2015 at our centers. Of these patients, 3 received single-lung transplants for idiopathic lung fibrosis. There were 14 cases of RSV, 8 cases of parainfluenza, and 4 cases of HMV. These were diagnosed by nasopharyngeal PCR in 23 patients and by PCR testing of bronchoalveolar lavage fluid in 3 patients. Cases were primarily seasonal, with 15 cases occurring in the winter and 6 in the early spring, whereas 3 cases occurred in the fall and 2 in the summer. Of 26 patients, 6 patients were female and 20 were male. Median age of patients was 60 years (range, 38-71 y) at the time of infection, with the viral infections occurring at a median of 1173 days after transplant (range, 37-3365 d). There were 18 cases of grade 1 infection, 8 of grade 2 infection, and no cases of severe grade 3 infection. No adverse events related to ribavirin therapy were identified during the treatment period.

Pulmonary function was evaluated using FEV1 and FEF25-75% as clinical outcome measures. For the purpose of analysis, clinical outcomes were evaluated in all patients who presented with a paramyxovirus and then subgrouped based on the specific viral infection treated with oral ribavirin.

Among all patients diagnosed with a paramyxo-virus, the change in mean FEV1 was significant from preinfection to infection onset (1.79 ± 0.13 to 1.61 ± 0.12 L; P = .0001) and from infection onset to postinfection (1.61 ± 0.12 to 1.74 ± 0.12 L; P = .0001). In addition, among all patients diagnosed with a paramyxovirus, the decline in mean FEF25-75% from preinfection to infection onset (1.32 ± 0.17 to 1.11 ± 0.15L; P = .0006) was significant; the improve-ment between infection onset to postinfection was also significant (1.11 ± 0.15 to 1.31 ± 0.18 L; P = .0006). No significant difference was seen in this group for either FEV1 or FEF25-75% when comparing pre- and postinfection (P > .05) (Figure 1).

In subgroup analysis based on specific viral infection, with regard to FEV1 in patients with RSV, there was a significant change from preinfection to infection onset (1.73 ± 0.20 to 1.58 ± 0.19 L; P = .0001) and from infection onset to postinfection (1.58 ± 0.19 to 1.72 ± 0.19 L; P = .0006), with no difference between pre- and postinfection (P > .05). With respect to FEF25-75%, there was no significant change from preinfection to infection onset (1.18 ± 0.24 to 1.07 ± 0.22 L; P > .05), but there was a significant difference from infection onset to postinfection onset (1.07 ± 0.22 to 1.27 ± 0.25 L; P = .05); again, no difference between pre- and postinfection (P > .05) was identified (Figure 2).

Among patients who were diagnosed with parainfluenza, there was a significant change in FEV1 from preinfection to infection onset (1.57 ± 0.14 to 1.41 ± 0.11 L; P = .02) and from infection onset to postinfection (1.41 ± 0.11 to 1.52 ± 0.10 L; P = .01), and no difference between pre- and postinfection (P > .05). Similar findings were seen with respect to FEF25-75% as there was a significant change from preinfection to infection onset (1.25 ± 0.23 to 0.91 ± 0.22 L; P = .007) and from infection onset to postinfection onset (0.91 ± 0.22 to 1.10 ± 0.26 L; P = .03), and again no difference between pre- and postinfection (P > .05) was identified (Figure 2).

Among patients diagnosed with HMV, no significant differences in FEV1 were identified between preinfection and infection onset (2.45 ± 0.30 to 2.14 ± 0.31 L), between infection onset and postinfection (2.14 ± 0.31 to 2.25 ± 0.38 L), and between pre- and postinfection (P > .05 for all comparisons). Similarly, no differences in FEF25-75% were seen between preinfection and infection onset (1.96 ± 0.63 to 1.61 ± 0.52 L), between infection onset and postinfection (1.61 ± 0.52 to 1.89 ± 0.67 L), and between pre- and postinfection (P > .05 for all comparisons) (Figure 2).

Discussion

Paramyxoviruses, particularly RSV, have been associated with both acute and chronic lung allograft dysfunction and development of BOS in lung transplant recipients. Enhancements in viral PCR techniques have resulted in improved identification of these paramyxoviruses in lung transplant recipients.15-17 Despite improved diagnostic yield, there remains a lack of well-studied definitive therapies for management of these viruses in our patients.18 Several primarily small, single-center studies have described short-term outcomes of different formulations of ribavirin for the treatment of paramyxoviruses in lung transplant recipients.8,14 Our study has several unique features. We provide medium-term clinical outcomes in patients treated with oral ribavirin at 2 centers. In addition, our data also include the outcomes of oral ribavirin treatment in non-RSV paramyxovirus infections.

Our findings demonstrated that treatment of paramyxovirus infections in lung transplant recipients with oral ribavirin is safe and is associated with clinical recovery that appears similar to previous reports that utilized nonoral formulations of ribavirin for the same purpose.8,14,19,20 This is of significance since prior studies demonstrating allograft stability after paramyxovirus infection have primarily utilized inhaled or intravenous ribavirin formulations that are more expensive and more cumbersome modes of delivery.14

No severe grade 3 infections were seen in our patients, which recapitulates the findings of prior work. Despite this finding, paramyxoviruses, especially RSV, have been associated with the development of both acute and chronic allograft dysfunction.3,6,8,10,14 Use of oral ribavirin in our patients was associated with a return to baseline pulmonary function after treatment at 6-month follow-up. However, due to the lack of a control arm and short follow-up period, the full effects of oral ribavirin on posttreatment recovery and risk of BOS development remain uncertain. Nevertheless, this study is the first to evaluate outcomes at more than a single center and describes the outcomes of a strictly oral ribavirin-based therapy in a variety of different paramyxoviruses, showing no identified adverse events related to ribavirin treatment. A prospective study with longer follow-up that will evaluate the efficacy of oral ribavirin for treatment of paramyxoviruses in lung transplant recipients is warranted.


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DOI : 10.6002/ect.2017.0133


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From the 1Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama-Birmingham, Birmingham, Alabama, USA; the 2Division of Pulmonary and Critical Care, University of Florida, Gainesville, Florida, USA; and the 3Division of Pulmonary and Critical Care, Indiana University, Indianapolis, Indiana, USA
Acknowledgements: All authors contributed to the study design, participated in data analysis/interpretation and critical review and revision of the manuscript, and approved the final draft for submission. The authors have no sources of funding for this study and have no conflicts of interest to declare. Bryan Garcia, Nirmal Sharma, Juan Salgado, and Keith Wille contributed equally to the production of this manuscript.
Corresponding author: Bryan Garcia, 1900 University Blvd, THT 422, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama-Birmingham, Birmingham, AL 35294, USA
Phone: +1 205 994 4328
E-mail: bgarcia@uabmc.edu