Successful treatment of human metapneumovirus pneumonia using combination therapy with intravenous ribavirin and immune globulin

In his review, ‘The challenge of respiratory virus infections in recipients of haemopoietic stem cell transplants (HSCT)’Boeckh (2008) referred to the aetiological role of the recently described human metapneumovirus (HMPV) in serious respiratory infections in patients following stem cell transplants. Boeckh stated that ‘there is no established treatment of HMPV disease’ and ‘there are no reports on treatment with ribavirin’ We report the case of a child on chemotherapy for acute lymphoblastic leukaemia (ALL) with proven HMPV pneumonia, who was successfully treated with a combination of intravenous ribavirin and immunoglobulin. A four-year-old girl, diagnosed with ALL in August 2008, was commenced on the UKALL 2003 treatment protocol, receiving regimen B because of a high presenting white cell count. She remained clinically well throughout induction and by day 28 she was in full morphological remission. At week 6 she commenced consolidation therapy. During this phase she had two admissions with sepsis. The first admission was for fever and diarrhoea, which resolved within a few days and she was discharged on continuing chemotherapy. The second occurred 2 weeks into the consolidation block. The patient presented with febrile neutropenia and a persistent cough. On examination of the chest there were added sounds in right upper and midzone. The patient was treated with standard neutropenic sepsis protocol and antifungal cover was added on day 4 of the illness due to persistent fever and non-specific changes on the chest X-ray. A computed tomography (CT) scan of the thorax was normal. Nasopharyngeal aspirates were negative. Due to persistent chest signs, a bronchoalvelolar lavage (BAL) was performed and samples sent for bacteriology, virology and mycology. No organisms were found. The patient recovered spontaneously and completed consolidation therapy as an outpatient. She was continued on viral prophylaxis with acyclovir, fungal prophylaxis with voriconazole and pneumocystis prophylaxis with septrin. One week into interim maintenance therapy during October 2008, the patient was admitted once again with febrile neutropenia and cough. A younger sibling had recently been diagnosed with a chest infection. On examination she had crepitations audible over the right lung field. She was commenced on broad spectrum antibiotics for neutropenic sepsis and prophylactic therapy with voriconazole, septrin and acyclovir therapy was continued. She remained febrile with a persistent cough and on day 4 of the admission had repeated desaturations on pulse oximetry and was commenced on oxygen via facemask. A chest X-ray demonstrated consolidation in the right midzone and right basal shadowing. CT scan of the thorax showed multiple areas of patchy consolidation in the right anterior cardiophrenic recess, right lower lobe and wedge consolidation in the left anterior cardiophrenic recess. There were no pulmonary nodules or bronchiectasis. There was no cavitation or specific features to suggest opportunistic or fungal infection. Over the next 5 days the patient continued to have an oxygen requirement. A BAL was performed. While awaiting results, she was commenced on prednisolone 1 mg/kg/day (for a total of 4 days). Forty-eight hours later there was no change in her clinical condition. At this point the results from the BAL revealed HMPV by polymerase chain reaction in samples from both lungs. No other bacterial, viral or fungal pathogen was detected. She was commenced on intravenous ribavirin (5 mg/kg tds for 5 days) and alternate day intravenous immunoglobulin (IVIG, Vigam from Bioproducts Laboratory, Elstree, UK; 0·5 g/kg for 5 days). Within 2 days of commencing ribavirin and immunoglobulin therapy her fever subsided and it was possible to discontinue oxygen therapy. Daily blood checks during ribavirin therapy did not show any evidence of haemolysis. She made a full clinical recovery and was discharged home 5 days later. HMPV usually affects immunocompetent children and adults, causing a self-limiting respiratory illness. However, even in otherwise normal subjects, the infection may occasionally cause pneumonia, usually in children younger than 2 years of age. Seroprevalence studies have shown that the virus has a worldwide distribution, shows seasonal variation and is acquired early in life with around 70% of children having antibodies to HMPV by the age of 5 years (Mahalingam et al, 2006). In immunocompromised patients the effects of HMPV infection are heterogeneous, ranging from symptomless carriage in the upper respiratory tract to a serious, and in most cases, fatal lower respiratory tract disease, most often seen in immunosuppressed HSCT patients (Englund et al, 2006; Oliveira et al, 2008). Fatality due to HMPV infection has also been described in a child on treatment for ALL (Pelletier et al, 2002). Although lower respiratory tract infections with HMPV are a potentially serious threat to immunocompromised patients, there is as yet no definitive guide to the treatment of these patients. We successfully treated a 4-year-old ALL patient who developed HMPV pneumonia, using a combination of intravenous ribavirin and immunoglobulin. There are also two further reports in the literature describing the successful use of this same combination therapy in severe HMPV infections in adults; the first case in a lung transplant recipient and the second in an immunosuppressed HSCT recipient with HMPV pneumonia (Kamble et al, 2007; Kashif et al, 2007). Both these individuals made a full recovery. Although there is no pharmaceutical agent approved for treatment of HMPV in immunocompromised adults or children, these three cases all demonstrated clinical resolution of symptoms using intravenous ribavirin and immunoglobulin therapy. There are data from in-vitro studies that give theoretical support to the use of this combination of ribavirin and immunoglobulins. A mouse model has been used to demonstrate that both ribavirin alone or in combination with glucocorticoid causes a significant decrease in the viral loads of HMPV infected mice and a parallel decrease in lung inflammation (Hamelin et al, 2006). However glucocorticoid alone has not been found to be beneficial in either the mouse model or in HSCT patients with pneumonia attributable to HMPV (Hamelin et al, 2006; Kamble et al, 2007). There is also evidence that standard IVIG contains relatively high titres of HMPV neutralising antibody and so may theoretically be useful in the control of clinical HMPV infection. However there are no reports to suggest IVIG used as sole therapy provides effective treatment for HMPV infection (Wyde et al, 2003). The diagnosis of HPMV should be considered in any immunocompromised patients with persistent and/or worsening lower respiratory tract symptoms with no other evident cause. Although the combination of ribavirin and immunoglobulin for the treatment of established HMPV infection remains unproven, in-vitro studies and three case reports may make this therapy worth considering in affected immunosuppressed patients.