Human Metapneumovirus Infections in Hematopoietic Cell Transplant Recipients: Seasonality and Factors Associated with Progression to Lower Respiratory Tract Disease

Background: Human metapneumovirus (HMPV) is a respiratory virus that was first identified in 2001. In immunocompromised hosts, HMPV upper respiratory tract infection (URI) can progress to lower respiratory tract disease (LRD). The mortality rate after HMPV LRD in hematopoietic cell transplant (HCT) recipients is as high as 40%, similar to that of respiratory syncytial virus, a structurally similar respiratory virus. To date, most studies in HCT recipients are of very small sample size, and minimal data exists on risk factors for LRD. Here we analyzed the seasonality of HMPV infections as well as patient, transplant and viral risk factors for progression to LRD. 

Methods:  This retrospective cohort study included HCT recipients with HMPV documented by RT-PCR transplanted between 2004 and 2014 at FHCRC. To detect HMPV, nasopharyngeal, bronchoalveolar lavage (BAL) or lung biopsy samples were tested by quantitative PCR with or without culture or direct fluorescent antibody staining. LRD was defined as detection of HMPV in a BAL or biopsy sample with new pulmonary infiltrates. Patients diagnosed with LRD ≥ 2 days after URI diagnosis were considered to have progression to LRD. Factors associated with probability of progression to LRD were analyzed using Cox regression models.

Results: HMPV was detected in 118 HCT recipients. Most cases were identified between December and May. The median time to HMPV detection after HCT was 278.5 days (range -5–2773). Among 118 patients, 88 and 30 had URI alone and LRD, respectively. The median viral load in nasal wash samples was 1.2x10⁶copies/ml (range, 3.3x10-1.6x10⁹). Among 30 patients with LRD, 17 patients progressed from URI to LRD after a median of 7 days (range, 2–63). The probability of 40-day progression to LRD was 16%. Progression rates decreased with increasing time between HCT and HMPV infection (Figure; 0-30 vs. >365 days, p=0.009, 31-365 vs. >365 days, p=0.09). Multivariate Cox analysis showed that only steroid use ≥ 1mg/kg within 2 weeks prior to diagnosis was significantly associated with progression to LRD (adjusted HR 4.1, p=0.04), although earlier detection of HMPV after HCT (day 0-30, HR 3.5, p=0.01), low lymphocyte count (< 100 cells/mm³, HR 4.0, p=0.008), and low monocyte count (< 100 cells/mm³, HR 2.9, p=0.04) were also important factors in the univariate analyses. Viral load in nasal wash samples at diagnosis was not a predictor for progression to LRD.

Conclusions: HMPV infections in HCT recipients occurred primarily in the winter and spring. The progression rate from URI to LRD approached 40% in patients who acquired HMPV infection within 30 days after HCT, likely related to low cell counts, while later acquisition was associated with lower risk of progression. The most important risk factor of progression to LRD was steroid use of ≥ 1mg/kg prior to URI. Further studies are needed to define the role of viral load in the pathogenesis of progressive disease.