Bone Marrow Transplantation (2007) 40, 699–700 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
www.nature.com/bmt
LETTER TO THE EDITOR
Human metapneumovirus infection in a hematopoietic transplant recipient Bone Marrow Transplantation (2007) 40, 699–700; doi:10.1038/sj.bmt.1705781; published online 30 July 2007
Recently, a new paramyxovirus with worldwide distribution, designated as human metapneumovirus (hMPV), has been implicated in 5–10% of respiratory infections in immunocompetent children and adults.1 The clinical manifestations are similar to that of human respiratory syncytial virus (hRSV), and range from mild upper respiratory symptoms to severe bronchiolitis and pneumonia. Little is known about the clinical significance of hMPV after hematopoietic stem cell transplantation (HSCT).2 A retrospective analysis of bronchoalveolar lavage (BAL) fluid and lung tissue in 163 HSCT patients identified hMPV in 3 and 3.8% of samples respectively as determined by PCR amplification.3 All five patients had a fatal outcome. We now report the first successful treatment of hMPV pneumonia in an HSCT recipient. A 55-year-old male with stage IV follicular lymphoma with large cell transformation and refractory relapse received a 6/6 HLA-matched unrelated allogeneic transplant with fully ablative conditioning, comprising cyclophosphamide (60 mg/kg 2), total body irradiation (1200 cGY) and alemtuzumab (10 mg 3). We infused 1.78 106/kg peripheral blood CD-34 þ stem cells and gave tacrolimus for prophylaxis of GVHD. Neutrophil and platelet engraftment was on days 17 and 13 respectively, with 100% donor chimerism. Grade III acute GVHD developed on day 20 involving skin (grade II), gut (grade III) and liver (grade II). Prednisone (2 mg/ kg/day) treatment was followed by infliximab (10 mg/kg twice a week 4 doses) and gradual steroid tapering. At day 94, he developed exacerbation of his skin, liver and gut GVHD, which was successfully treated with rituximab (375 mg/m2 weekly 4 doses). The patient was maintained on prednisone 15–20 mg/day and tacrolimus (1 mg/day) for non-progressive chronic extensive GVHD involving skin and gut. On day 294 after transplant, the patient presented with a 5-day history of nasal congestion, rhinorrhea, headache, flu-like symptoms and non-productive cough. He was afebrile. Although nasal washings were negative for RSV, influenza, para-influenza and adenovirus, he received treatment with oseltamivir (Tamiflu, Roche, Utley, NJ, USA) for 5 days, at which time he developed dyspnea, diffuse pulmonary infiltrates and hypoxia with encephalopathy. A high-resolution CT scan of chest revealed diffuse alveolar and interstitial disease involving both lower lobes. Bronchoalveolar lavage was negative for gross blood, Pneumocystis jiroveci pneumonia, bacterial, fungal and CMV, RSV, influenza, para-influenza and adenovirus. Blood cultures were negative and peripheral blood viral
studies for CMV (antigen and PCR), toxoplasma PCR, JC virus PCR and HHV6 PCR were negative. The patient received broad-spectrum antibacterial (cefepime and vancomycin), antifungal (voriconazole and caspofungin) and antiviral (acyclovir) coverage. In the absence of a documented infectious process, the patient was treated for possible pulmonary GVHD with methylprednisolone 4 mg/kg 2 days with rapid taper over 7 days. However, the patient progressively deteriorated and required ventilatory support. A tracheal aspirate analyzed at two independent virology laboratories tested positive by direct fluorescence assay (DFA) for metapneumovirus (D3 hMPV ASR, Diagnostic Hybrids Inc., Athens, OH, USA), showing bright, punctate staining of respiratory epithelial cells (Figure 1a). To confirm the presence of the virus, we used RT-PCR, in which a 750 base-pair fragment of the fusion open reading frame was amplified using previously published primer pairs4 (Access System, Promega Corporation, Madison, WI, USA) (Figure 1b). Nucleic acid extraction was performed manually using QiAmp columns (Qiagen, Valencia, CA, USA), as per the manufacturer’s protocol. Finally, the tracheal aspirate sample was inoculated onto cell culture monolayers (HFF, A549, RHMK
a
b 750 bp
1
2
3
4
5
Figure 1 Laboratory detection of hMPV. (a) Direct fluorescence assay photomicrograph ( 1000) illustrating bright, punctuate intra-cellular staining by FITC-conjugated monoclonal antibodies specific for hMPV. (b) Gel electrophoresis of RT-PCR products: lane 1, 100 bp ladder; lanes 2 and 5, positive hMPV controls; lane 3, negative hMPV control; lane 4, patient sample.
Letter to the Editor
700
and LLMCK) and incubated at 351C. Viral cytopathic effect characteristic for hMPV was observed during the third week of incubation, first on LLMCK and secondly on HFF monolayers. Virus specific immunofluorescence confirmed the active replication virus in the sample to be hMPV. Nucleic acid amplification studies on CSF were negative for HHV6, toxoplama, JC virus, varicella-zoster virus and herpes simplex virus. An EEG revealed diffuse slowing, but an MRI of the brain was normal. CSF analysis for hMPV was not performed. The patient started intravenous ribavirin (loading dose 30 mg/kg followed by 16 mg/kg/day 4 days) and intravenous immunoglobulin (500 mg/kg 5 days). After 4 days, we discontinued ribavirin owing to the development of moderate hemolytic anemia. Seven days after starting treatment, repeat DFA and RT-PCR testing for hMPV were both negative. Serial chest X-rays revealed progressive improvement in pulmonary infiltrates and the patient was successfully extubated 17 days after the treatment began, and was subsequently discharged. We believe this is the first reported successful outcome of hMPV after HSCT. A positive DFA and PCR analysis from the tracheal aspirate allowed prompt diagnosis and treatment and a positive viral culture provided confirmatory evidence of an active infectious process in this patient. No agent has been approved for the treatment of hMPV in the immunocompromised host, but this patient’s clinical and virologic response to ribavirin therapy is supported by murine data.5 In the absence of any CSF analysis for hMPV, hMPV encephalitis cannot be confirmed or excluded. While at least six cases of probable hMPV-associated encephalitis have been reported,6–8 only one describes clinical outcome and provides evidence of virally infected central nervous system tissues.7 The diagnosis of hMPV disease is confounded by the recent demonstration of asymptomatic nasopharyngeal persistence of the virus in 85% of allogeneic transplant recipients.9 Therefore, the diagnostic consideration of hMPV disease requires exclusion of other pathogens and pathology. Given the risk of mortality for hMPV disease in the immunocompromised host3,7,10 and the availability of potentially effective therapy with ribavirin, the possibility of hMPV infection should be entertained with high index of suspicion in immunocompromised patients with relevant respiratory/neurological symptoms. RT Kamble1, C Bollard1, G Demmler2, PR LaSala3 and G Carrum1 1 Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, TX, USA;
Bone Marrow Transplantation
2
Diagnostic Virology Laboratory, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA and 3 Division of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX, USA E-mail:
[email protected]
References 1 Williams JV, Harris PA, Tollefson SJ, Halburnt-Rush LL, Pingsterhaus JM, Edwards KM et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004; 350: 443–450. 2 Martino R, Porras RP, Rabella N, Williams JV, Ramila E, Margall N et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005; 11: 781–796. 3 Englund JA, Boeckh M, Kuypers J, Nichols WG, Hackman RC, Morrow RA et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med 2006; 144: 344–349. 4 van den Hoogen BG, Herfst S, Sprong L, Cane PA, ForleoNeto E, de Swart RL et al. Antigenic and genetic variability of human metapneumoviruses. Emerg Infect Dis 2004; 10: 658–666. 5 Hamelin ME, Prince GA, Boivin G. Effect of ribavirin and glucocorticoid treatment in a mouse model of human metapneumovirus infection. Antimicrob Agents Chemo 2006; 50: 774–777. 6 Glaser CA, Honarmand S, Anderson LJ, Schnurr DP, Forghani B, Cossen CK et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 2006; 43: 1565–1577. 7 Schildgen O, Glatzel T, Geikowski T, Scheibner B, Matz B, Bindl L et al. Human metapneumovirus RNA in encephalitis patient. Emerg Infect Dis 2005; 11: 467–470. 8 Kaida A, Iritani N, Kubo H, Shiomi M, Kohdera U, Murakami T. Seasonal distribution and phylogenetic analysis of human metapneumovirus among children in Osaka City, Japan. J Clin Virol 2006; 35: 394–399. 9 Debiaggi M, Canducci F, Sampaolo M, Marinozzi MC, Parea M, Terulla C et al. Persistent symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients. J Infect Dis 2006; 194: 474–478. 10 Cane PA, van den Hoogen BG, Chakrabarti S, Fegan CD, Osterhaus AD. Human metapneumovirus in a haematopoietic stem cell transplant recipient with fatal lower respiratory tract disease. Bone Marrow Transplant 2003; 31: 309–310.
