Progression, Shedding Patterns, and Clinical Disease Associated With Respiratory Virus Infections After Allogeneic Hematopoietic Cell Transplantation (HCT)

Multiplex PCR assays now allow the concomitant testing of multiple respiratory viral pathogens, including viruses previously difficult to detect with traditional diagnostic methods. We present a systematic assessment of respiratory viral shedding patterns, rates of progression from upper (URI) to lower respiratory tract disease (LRD) and association of viruses with clinical disease in a large prospective cohort of allogeneic HCT recipients.

Between 2005 and 2011, 471 allogeneic HCT recipients were followed prospectively with PCR testing of serial nasal wash and throat swab samples and a standardized symptom survey (12 respiratory and 4 systemic symptom questions) for 1 year after HCT (day 0-100: weekly symptom survey and PCR; day 101-365, weekly symptom survey and PCR every 3 months and whenever URI symptoms occurred). Bronchoalveolar lavage testing was done when lower respiratory symptoms and/or radiographic changes occurred. PCR testing for RSV, human metapneumovirus (HMPV), parainfluenza virus (PIV) 1-4, influenza (A, B), adenovirus (ADV), human bocavirus (HBoV), human coronaviruses (HCoV, OC43, 229E, NL63, HKU1), and human rhinoviruses (HRhV) were performed in real time on all upper and lower respiratory tract samples. Viral load was quantified when possible.

From 471 patients, a total of 7,091 samples (median 15, range 1-50 per patient) were tested and 12,709 symptom surveys (median 22, range 1-57 per patient) were collected. Overall, 70% of patients had at least one respiratory virus infection documented during follow-up. 48% of the infections resolved within one week, mostly without treatment (exceptions: all patients with influenza virus and some with RSV received treatment according accepted treatment guidelines). The most common viruses detected were HRhV (32.7%) and HCoV (19.7%), followed by PIV, ADV, RSV, influenza, HMPV and HBoV (Table). Most infectious episodes detected by PCR were associated with respiratory symptoms but completely asymptomatic episodes occurred with HRhV, HCoV, ADV and occasionally with influenza and PIV (Table). Only one patient with RSV infection was completely asymptomatic. Rates of progression from URI to LRD varied from 36% (HMPV) to 5.9% (HBoV) (Table). The time to progression to lower tract disease also varied widely, with the shortest median time observed with RSV and influenza (Table). Only 13% of patients presented initially with LRD (no prior upper respiratory tract viral detection).

In this prospective surveillance study of HCT recipients, we found that (1) asymptomatic infection may occur with HRhV, HCoV, ADV and occasionally with influenza and PIV, but is otherwise rare; (2) progression rates from URI to LRD differ substantially among viruses, with highest rates observed with HMPV and RSV; (3) the proportion of patients presenting initially with LRD was very rare in this surveillance study; and (4), viral shedding may be prolonged, especially for HRhV, HCoV, PIV-3 and influenza A. These results suggest that close monitoring of respiratory viruses in HCT patients may identify patients at risk for experiencing progression to LRD.

Boeckh:Gilead: Consultancy; GSK: Consultancy, Research Funding; Chimeix Inc.: Consultancy, Research Funding; Genentech: Consultancy; Ansun: Research Funding. Chien:Gilead Sciences: Employment. Englund:GSK: Consultancy; Chimerix Inc.: Research Funding; Gilead: Research Funding.