Human metapneumovirus (hMPV) was first identified in 2001 from 28 nasopharyngeal isolates from Dutch children with upper respiratory infections symptom. Its electron micrographic structure, biochemical properties and cytopathic effects position hMPV in the Paramyxoviridae family [1]. No similar virus was identified in 400 children without respiratory symptoms suggesting its role in symptomatic upper respiratory tract infection (URI). Reverse transcriptase PCR (RT-PCR) and direct fluorescent antibody (DFA-Abs) testing proved this was a novel virus. Its RNA did not amplify with primers associated with other members of Paramyxoviridae family. In addition, anti-sera of animals exposed to hMPV did not react with viral particles of known members of Paramyxoviridae family. A year after its discovery, Boivin et al. studied 11 nasopharyngeal and bronchoalveolar lavage (BAL) specimens and isolated hMPV for the first time in adults [2]. This study also demonstrated the first evidence of re-infection when the investigators found a single child had two different hMPV strains in two different winter seasons.

The clinical manifestations relate to hMPV-infected dendritic cells (DCs) releasing soluble matrix proteins from virus. These matrix protein bind activated DCs inducing their maturation and production of cytokines and subsequent activation of T lymphocytes. In addition, hMPV causes hyperplasia of the respiratory epithelium resulting in airway obstruction and hyper responsiveness to methacholine challenge. This suggests the possibility of asthma exacerbation with hMPV infection similar to other respiratory tract viral infections [3]. The clinical manifestations of hMPV infection in adults and children are identical. The infection usually presents with cough, nasal congestion, rhinorrhea, dyspnea, hoarseness and wheezing. Immunocompromised hosts present similarly but may also have fever [1] .

There are two major modalities for the diagnosis of hMPV: Reverse transcription (RT-PCR) and (Direct fluorescent antibody assay). Though RT-PCR is the most sensitive method of diagnosis, it has limitations including the possibility of false positive results in asymptomatic carriers. The other method for diagnosis is antibody assay which detects hMPV antigens by immunofluorescence on nasopharyngeal or bronchoalveolar lavage specimen. This assay uses a blend of three fluorescein labeled murine monoclonal antibodies (MAbs). Though not successful in detecting new antigenic variants, this test has a very high specificity and can be performed rapidly [1] .

Supportive therapy is the main stay of treatment for hMPV. To date, there are no FDA-approved treatment options for individuals with hMPV infection. Hamelin et al. compared intraperitoneal ribavirin and glucocorticoids in hMPV infected mice and found ribavirin significantly decreased both hMPV replication in lungs and pulmonary inflammation on postinfection day five whereas glucocorticoids only reduced alveolar and interstitial inflammation [4].

There is little data on successful treatment of human metapneumovirus with ribavirin in the immunocompromised patients, including multiple myeloma patients. We report a case of human metapneumovirus pneumonia with successful symptom resolution after a five-day course of inhaled ribavirin.

A 56-year-old white female with multiple myeloma presented to outpatient clinic with low grade fever, non-productive cough and chest congestion. She also had progressive dyspnea on exertion with minimal exertion. She denied chest pain, dysuria, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, rash and oral lesions. She had no recent travel or sick contacts. She had a past medical history of lambda light chain multiple myeloma complicated by acute kidney injury, diffuse bone involvement and plasmacytoma of the right iliac crest one year prior to arrival. This was treated with successful autologous bone marrow transplant one year ago, and since then she had been managed on prednisone 20 mg/day. She received levofloxacin at an outside hospital before presentation with slight improvement in her fever curve but not complete resolution. Her temperature was 100.6°F, heart rate was 120 beats per minute, blood pressure was 110/70 mmHg, and oxygen saturation was 93% on 2L nasal cannula. On examination she was in no acute respiratory distress. Fine bibasilar crackles were heard, and her examination was otherwise unremarkable. Her laboratory were significant for absolute neutrophil count of 143. The hemoglobin levels, platelet count, renal and liver function tests were within normal limits. Conventional radiographic findings (Figure 1) and subsequent computed tomography (CT) scan (Figure 2) on admission and hospital day-2, respectively, revealed bilateral patchy lung infiltrates, right lower lobe atelectasis with discrete ground-glass opacification. On admission blood and sputum samples were obtained for routine microscopy and culture, including bacterial, fungal and mycobacterial cultures, and were unrevealing. Nasal washings were also negative for respiratory syncitial virus (RSV), influenza, para-influenza and fungal assay were all negative. She underwent a bronchoscopy with bronchoalveolar lavage (BAL). The BAL fluid was also cultured for bacteria, fungi and mycobacteria and all were negative. Additional diagnostic testing of the BAL fluid for Pneumocystis jirovecii and other respiratory viruses (influenza A and B, RSV, parainfluenza virus, adenovirus, and enterovirus) remained negative but hMPV type B was detected using direct fluorescent antibody testing.

The patient remained symptomatic and febrile even on broad spectrum anti-bacterial agents. Here initial antibiotic regimen included cefepime 2 g IV BID, vancomcyin 1 g IV q18 hours, trimethoprim/sulfamethoxazole 25 mL IV q8 hours and azithromycin 250 mg IV daily. Based on the results of BAL fluid testing a five-day course of inhaled ribavirin, 2 g q8 hours, was initiated. Her neutropenia resolved with administration of filgrastim at a dose of 5 mg/kg/day. With ribavirin treatment, her shortness of breath and respiratory distress gradually improved, and her oxygen was weaned off. She also showed marked improvement in her physical examination within 48 hours. As a result she was discharged home within three days of completion of her inhaled ribavirin treatment. A computed tomography scan of thorax performed two months after her discharge showed complete resolution of ground glass opacities (Figure 3). Incidentally, she was noted to have elevated lambda light chain and beta-2 microglobulin levels, with a low free lambda/kappa light chain concerning for multiple myeloma recurrence. Bone marrow biopsy confirmed a relapse of her multiple myeloma. This, in addition to her acute illness, was a probable reason for her neutropenia at presentation. The patient developed further complications of recurrent multiple myeloma. She presented four months later with acute renal failure and cord compression related to spinal metastases. When she became uremic and obtunded, her family decided to pursue palliative care measures and withdrew aggressive resuscitation. She died five months after metapneumovirus diagnosis.

The development of fever with pulmonary infiltrates is a frequent life-threatening complication in immunocompromised patients, requiring early diagnosis and treatment. Our patient's acute respiratory illness was consistent with hMPV infection based on her clinical presentation, hMPV direct fluorescent antibody testing result, and the absence of alternate explanation for her symptoms. She had an indolent but progressive respiratory illness consistent with hMPV. Her history of multiple myeloma and corticosteroid treatment resulted in immunosurpression and likely contributed to her prolonged course. Respiratory infections due to hMPV, like RSV are more severe in immunocompromised patients [1] . CT scan also showed bilateral ground glass opacities not present on CT scan performed five months prior to presentation consistent with a viral etiology.

An hMPV associated respiratory disease occurs in all age groups. It is found in 3.4% of adult population with respiratory tract infection [1] [5]. The hMPV infections may be more severe and the course more prolonged in immunocompromised patients due to poor clearance of virus.

In a study by William et al., 251 episodes of respiratory tract infections were studied in patients with hematological malignancies [6]. Twenty-two (9%) of these episodes were found to be associated with hMPV infection. Of these, 16 occurred in hematopoietic cell transplant recipients and three of nine patients with lower respiratory tract disease died.

Ribavirin is a synthetic guanosine nucleoside analog with in vitro activity against hMPV [7]. Its mechanism of action involves inhibition of viral RNA polymerase. Data on ribavirin treatment of hMPV in immunocompromised hosts are limited. Englund et al. detected hMPV in bronchoalveolar lavage specimens from 5 of 163 (3.0%) HSCTs patients [8]. Four of the five patients died with acute respiratory failure. The one patient treated with inhaled ribavirin had a fatal outcome. Another case report by Kamble et al. reported successful treatment in a hematopoietic stem cell transplant patient with a four-day course of intravenous ribavirin and immunoglobulins [9]. In another case series by Shahda et al., nine immunocompromised patients with hMPV pneumonia were studied-two were successfully treated with oral and aerosolized ribavirin along with intravenous immunoglobulins (IVIg) [10]. In another case series, Egli et al., described two multiple myeloma patients with hMPV pneumonia [11]. Of these two, one was treated with IVIg and oral ribavirin while the other was treated with IVIg alone.

We report the first case of successful outcome and improved respiratory distress with inhaled ribavirin alone without oral antiviral therapy or IVIg in a multiple myeloma patient. In the absence of data on hMPV treatment outcomes, experience with inhaled ribavirin in immunocompromised RSV patients led us to select inhaled rather than oral or IV administration [12]. Likewise, there are no studies of optimal ribavirin dosing in human metapneumovirus pneumonia. However, randomized controlled multicenter trials of inhaled ribavirin in RSV infection suggested the use of 6 g/24 h of aerosolized ribavirin at a rate of 2 g/8h, the dose selected for our patient [13]. We believe the early recognition of hMPV pneumonia and timely therapy with inhaled ribavirin contributed to the successful outcome. Inhaled ribavirin is an expensive and cumbersome treatment modality but may be appropriate in heavily immunocompromised population like current patient. However, multi-center case series are needed to shed light on the long-term safety and efficacy of inhaled ribavirin. From the time our patient was diagnosed and treated new research has suggested that oral ribavirin may be an option for patients with RSV and moderate to severe immunosuppression, a finding that may hold promise in hMPV [14].

The goals of this case report are:

1. to alert clinicians to the possibility of hMPV as a cause of severe community acquired pneumonia in immunocompromised hosts
2. to highlight the importance of early suspicion of viral infection and rapid diagnostic testing
3. to suggest the use of inhaled ribavirin as a possible treatment modality. Prompt administration of inhaled ribavirin should be considered in immunocompromised patient population with established hMPV infection.

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