Abstract
Human metapneumovirus (hMPV) is an emerging human pulmonary pathogen that is genetically related to respiratory syncytial virus. It has been increasingly associated with respiratory illnesses over the last few decades. Immunocompromised patients are particularly susceptible with resultant morbidity and mortality. We describe our experience with 9 immunocompromised patients diagnosed with pneumonia secondary to hMPV, 2 of whom were successfully treated with aerosolized and oral ribavirin along with intravenous immunoglobulin (IVIG).We suggest that hMPV should be considered in the differential diagnosis of immunocompromised patients with acute respiratory illness. Ribavirin (oral and aerosolized) with IVIG is potentially an effective treatment option for those with severe disease.
Keywords: human metapneumovirus, immunosuppression, hematopoietic stem cell transplant, lung transplant, ribavirin, cellular rejection
Background
Human metapneumovirus (hMPV) is an RNA virus that was first reported in 2001 (1). It was subsequently described as a seasonal virus affecting all age groups.The clinical manifestations range from asymptomatic carriage to accelerated lung transplant rejection and acute respiratory distress syndrome (ARDS) in susceptible individuals. There is no established treatment for hMPV infection; however, successful treatment with intravenous (IV) ribavirin and IV immunoglobulin (IVIG) has been reported (2).
Patients and methods
A retrospective review of the electronic medical records for 9 documented cases of hMPV infection was carried out. This study was approved by the institutional review board. Immunocompromised patients who presented to the Indiana University-Clarian Health Partners campus and who were diagnosed with hMPV infection between the years 2008 and 2009 were evaluated in this series. Patients presented with a broad spectrum of symptoms including cough, signs of upper respiratory infections, occasionally fever, and in a few of them, symptoms severe enough to cause respiratory failure. Taking into account the degree of immunosuppression and the severity of the symptoms, patients were either admitted and managed in the hospital or observed on an outpatient basis.
Results
Nine patients were included in this review (Tables 1 and 2). Six of them had hMPV as a single pathogen. Four nasal swab specimens, 1 nasopharyngeal swab, and 6 bronchoalveolar lavage (BAL) samples were evaluated. Two of the nasal swab samples initially tested negative for hMPV rapid antigen test and then, after more evaluation, BAL returned positive for the hMPV antigen. Seven specimens were tested with the rapid viral antigen test with DFA metapneumovirus identification kit (Diagnostic Hybrids Inc., Athens, Ohio, USA), which uses immunofluorescence assay with a blend of 3 monoclonal antibodies to detect the hMPV antigen. Two other patients tested positive by reverse transcriptase-polymerase chain reaction (RT-PCR) (XTAG® Respiratory Viral panel, Luminex Corp., Austin, Texas, USA). This method is a qualitative nucleic acid multiplex RT-PCR/array bead hybridization procedure. It is intended for simultaneous detection and identification of 12 viral targets (of which MPV is one) in specimens collected from individuals with suspected respiratory tract infections.
Table 1.
Demographic and clinical description: lung transplant and other immunosuppressed patients
Age (years)/ gender |
Underlying disease | Significant medications |
Time of diagnosis |
Presenting symptoms |
Radiographic findings |
Method of diagnosis |
Microbiologic studies |
Treatment | Outcome |
---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
|
|
|
52/M | COPD, lung transplant 10/07, acute cellular rejection | Prednisone, tacrolimus | March 2009 | Productive cough, dyspnea | Chest CT: small nodular and tree-in-bud opacities | Flexible bronchoscopy, BAL | BAL positive for hMPV Ag | Supportive | Died of respiratory failure |
66/F | COPD, lung transplant 1/05, acute cellular rejection | MMF, prednisone, tacrolimus | March 2009 | Productive cough, dyspnea | Chest CT: no pathologic findings | Flexible bronchoscopy, BAL | BAL positive for hMPV Ag, Pseudomonas aeruginosa and Escherichia coli | Supportive+antimicrobial treatment | Partial recovery; worsened lung function |
53/F | COPD, lung transplant 1/04, acute cellular rejection | MMF, prednisone, sirolimus, thymoglobulin | February 2008 | Fever, dyspnea, cough | Chest CT:1 patchy airspace disease and ground glass opacities | Nasopharyngeal swab | BAL positive for hMPV Ag | Supportive | Died of respiratory failure |
68/M | COPD, lung transplant 7/06, acute cellular rejection | MMF, prednisone, sirolimus | May 2009 | Productive cough, dyspnea | CXR: patchy airspace interstitial disease | Flexible bronchoscopy, BAL | BAL was positive for hMPV PCR and P. aeruginosa | Supportive+antimicrobial treatment | Partial recovery; worsened lung function |
27/F | Fibrosing mediastinitis | Previous treatment with steroids and cyclophosphamide | February 2009 | Fever, dyspnea, productive cough | Chest CT: scattered airspace opacities | Nasal swab | Positive for hMPV Ag | Supportive | Alive |
66/F | Breast cancer | No recent treatment | April 2009 | Dry cough, dyspnea | CXR: airspace opacities | Nasal swab | Positive for hMPV Ag | Supportive | Alive |
See Figure 2.
M, male; COPD, chronic obstructive pulmonary disease; CT; computed tomography; BAL, bronchoalveolar lavage; hMPV, human metapneumovirus; Ag, antigen; F, female; MMF, mycophenolate mofetil; CXR, chest x-ray; PCR, polymerase chain reaction.
Table 2.
Demographic and clinical description: hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients
Age (years)/ gender |
Underlying disease |
Time of diagnosis |
Presenting symptoms |
Radiographic findings |
Method of diagnosis |
Microbiologic studies |
Treatment | Outcome | BMT conditioning |
Steroid during treatment |
Treatment of GVHD |
GVHD prophylaxis |
---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
|
|
|
|
|
|
|
73/M | CLL, GVHD, Matched unrelated HSCT 8/06 | March 2009 | Productive cough, fever, dyspnea | Chest CT1: bibasilar tree-in-bud nodularity and ground glass opacities | Flexible bronchoscopy, BAL | BAL positive for hMPV Ag | Aerosolized and oral ribavirin+IVIG | Recovered | TBI, fludarabine, and alemtuzumab, DLI 4/07 | Yes, prednisone 60 mg orally daily | Prednisone and tacrolimus, then prednisone and MMF | Unknown |
43/F | AML, M2, GVHD, Matched unrelated HSCT 8/07 | March 2009 | Productive cough, dyspnea, rhinorrhea | Chest CT: Scattered foci of alveolar opacities and ground glass opacities | Flexible bronchoscopy, BAL | BAL positive for hMPV Ag, Pseudomonas aeruginosa and Aspergillus species | Aerosolized and oral ribavirin+IVIG+antifungal and antimicrobial treatment | Recovered | Busulfan, clofarabine | Yes, methylprednisolone 50 mg IV daily | Methylprednisolone 50 mg, sirolimus, and tacrolimus | MTX, cyclosporine |
65/F | MM, IgA, autologous HSCT 12/05 | April 2009 | Productive cough, dyspnea, chest pain | Chest CT: Scattered small nodules in the right upper lobe | Flexible bronchoscopy, BAL | BAL positive for hMPV Ag | Supportive | Recovered | Melphalan | No | NA | NA |
See Figure 1.
BMT, bone marrow transplant; GVHD, graft-versus-host disease; M, male; CLL, chronic lymphocytic leukemia; CT, computed tomography; BAL, bronchoalveoloar lavage; IVIG, intravenous immunoglobulin; TBI, total body irradiation; DLI, donor lymphocyte infusion; MMF, mycophenolate mofetil; AML, acute myelogenous leukemia; M2, a subtype of AML; hMPV, human metapneumovirus; Ag, antigen; IV, intravenous; MTX, methotrexate; MM, multiple myeloma; IgA, immunoglobulin A; NA, not applicable.
Two of these 9 patients, both with hematopoetic stem cell transplant (HSCT), were admitted to the bone marrow transplant unit and treated with inhaled and oral ribavirin along with IVIG. Two other patients, both with lung transplant, were admitted to the hospital and managed with aggressive supportive care. Unfortunately, they both died with ARDS and acute graft rejection (Figs. 1 and 2).
Fig. 1.
Bilateral nodular infiltrates and ground glass opacities in hematopoietic stem cell transplant recipient.
Fig. 2.
Patchy airspace disease and ground glass opacities in lung transplant recipient.
Discussion
Since hMPV was isolated in 2001 (1), many reports have highlighted this virus in an attempt to actually determine its pathologic role. MPV is mainly a seasonal virus with incidence throughout the year. It may affect all age groups with more severe disease in children, elderly, and immunocompromised patients. Radiographic findings are nonspecific, and the diagnosis relies on detection of the antigen or nucleic material in fresh respiratory secretions. PCR is a more sensitive test and might detect hMPV infection in cases of negative viral culture results (3), which might improve the disease management and have a better outcome in the high-risk population.
In lung transplant recipients, hMPV is a common cause of respiratory illness and is thought to increase the risk of acute and chronic graft rejection (4). Viral infections increase the risk of developing bronchioloitis obliterans in lung transplant recipients (5) and that impacts their survival significantly.
HSCT recipients and patients with hematologic malignancies (6) are at risk for conducting respiratory viral infections including hMPV. The spectrum of symptoms may vary. Peck et al. (7) showed evidence of asymptomatic parainfluenza virus in HSCTpatients when they were followed for 100 days post transplant. MPV-infected patients may have minimal symptoms or remain asymptomatic when they are followed over a period of time (8, 9), and in other cases, they may exhibit signs of respiratory failure and their course gets complicated with fatal pulmonary infections (10, 11).
Although the natural course of this disease can be associated with full recovery, children may have severe disseminated disease with poor outcomes (12), as well as immunocompromised patients (10), who may benefit from early intervention (13). To date, there are no trials examining specific treatments for hMPV. Ribavirin, which disrupts viral purine metabolism and inhibits RNA polymerase, has been shown to be active against hMPV in vitro (14). In a mouse model, ribavirin had a significant effect on both hMPV replication rate and the pulmonary inflammation (15). Adding a corticosteroid to the treatment did not change the outcome significantly. Ribavirin in combination with IVIG was reported to be effective in treating hMPV pneumonia in a lung transplant recipient (2), and in another immunocompromised patient (16). Ribavirin has demonstrated in vitro inhibition of tumor necrosis factor-α, interferon-γ, and interleukin (IL)-10, suggesting a downregulation in Th1 and Th2 cytokine production and an increase of IL-2 production by peripheral blood mononuclear cells (17). One hypothesis is that ribavirin may augment or terminate Tcell immune-mediated damage caused by viral infections.
We treated our immunocompromised patients with oral and inhaled ribavirin owing to the severity of the disease, and lack of other treatment options, as IV ribavirin is not available in the United States. We also thought ribavirin was appropriate, given their disease severity. Clinical improvement was noted, especially in our patient with isolated hMPV infection.
Ribavirin is teratogenic and administration by nebulization must be carried out by a trained respiratory therapist via a SPAG-2 small particle aerosol generator. Additionally, health care providers who are pregnant or attempting to become pregnant should avoid contact with patients receiving treatment with aerosolized ribavirin.
Conclusion
We report the first successful treatment to our knowledge of hMPV infection in 2 immunocompromised patients using oral and aerosolized ribavirin with IVIG. Until more studies determine the optimal treatment for hMPV, this combination is a potential therapeutic option in immunosuppressed patients with severe infection.
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