Successful High-Dose Ribavirin Treatment of Respiratory Syncytial Virus-Induced Tracheobronchitis and Pneumonia Occuring Pre-Engraftment in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Respiratory syncytial viruses (RSV) frequently cause severe respiratory disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Within the first post-transplant month, progression of upper respiratory tract infection to life-threatening bronchiolitis and pneumonia is common and mortality rates of up to 80% have been reported if left untreated. Aerosolized ribavirin plus/minus immunoglobulins is considered the treatment of choice for RSV pneumonia. With this regimen, the 30-day all cause mortality is still 40% in immunosuppressed HSCT patients. In addition, nebulizing ribavirin may induce toxic side effects on patients and staff.

Concurrent with an outbreak in the community, RSV infection was diagnosed in 10 out of 29 patients (34%) undergoing allogeneic HSCT in the winter season 2008. Diagnosis was based on RSV-specific PCR of routinely collected throat swaps. Intravenous ribavirin was dosed according to Schleuning et al., 2003 (day 1: 33 mg/kg, day 2-5: 4×16 mg/kg, day 6-10: 3×8 mg/kg) for 8-10 days, followed by oral ribavirin (1800 mg per day) until recovery from symptoms. Airflow obstruction (AFO) was defined as a FEV1/FVC ratio <0.7 or a drop in FEV1 >20% from baseline. All RSV-infected patients (median age 60 years) had undergone reduced-intensity conditioning HSCT for high-risk acute myeloid leukemia (1st CR: n=2; subsequent CR: n=3; untreated or refractory relapse: n=5). GvHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil with (n=8) or without (n=2) antithymocyte globulin. Donors were HLA-idential siblings (n=1), matched (n=8) or mismatched unrelated donors (n=1).

Median time from HSCT to detection of RSV was 15 (range, 1-40) days. In 7 out of 10 patients, RSV infection was diagnosed pre-engraftment during neutropenia. Four patients had bronchiolitis or pneumonia and 6 patients suffered from tracheobronchitis. High-dose intravenous ribavirin was administered to all patients with pneumonia and/or diagnosis of RSV infection within 7 days after transplantation (n=5). These patients had hypoxia and required oxygen supplementation. Treatment with oral ribavirin was initiated in the other five patients with tracheobronchitis diagnosed on days 12-40 after HSCT. With a median follow up of 6 months, 9 out of 10 patients are alive and in complete remission of their AML. All 9 patients became RSV-negative in throat swabs after a median time of 22 days from start of therapy. Severe AFO caused by RSV pneumonia occurred in 2 patients and improved after treatment. Despite severe lymphopenia, no patient treated for tracheobronchitis progressed to RSV pneumonia. Neutrophil recovery was delayed in the three patients diagnosed with RSV pneumonia pre-engraftment until days 26, 28+ and 111 after HSCT, due to high-dose intravenous ribavirin and/or RSV infection itself. One of these patients died of septic shock associated with pseudomonas aeruginosa-induced pneumonia on day 28 after HSCT in prolonged neutropenia. No other ribavirin-associated toxicity such as hepatotoxicity or clinically relevant hemolysis was observed. Three patients developed acute intestinal GvHD, 2 of them recovering upon steroid treatment and one proceeding to chronic disease despite salvage therapy. One additional patient had steroid-responsive acute GvHD of the skin.

High-dose intravenous or oral ribavirin therapy appears to be safe and effective even if administered to neutropenic allogeneic HSCT recipients. None of these patients with RSV infection in the early post-transplant period developed bronchiolitis obliterans or persistent AFO. Based on our favourable results, further studies are required. Meanwhile, we suggest to treat all patients with symptomatic RSV infections in the early post-transplant phase with oral or intravenous ribavirin.

Off Label Use: Ribavirin is approved for inhalative treatment of RSV infections but not for systemic therapy..