Human rhinovirus detection in the lower respiratory tract of hematopoietic cell transplant recipients: association with mortality

Seo, Sachiko; Waghmare, Alpana; Scott, Emily M; Xie, Hu; Kuypers, Jane M; Hackman, Robert C.; Campbell, Angela P.; Choi, Su-Mi; Leisenring, Wendy M.; Jerome, Keith R.; Englund, Janet A.; Boeckh, Michael

Our primary comparison was between patients with HRV URI and those with HRV detection in the BAL ( Figure 1A) . While the comparison of mortality after URI and LRI alone is not conclusive evidence for a causative effect of HRV for LRI, the two curves are significantly difhaematologica | 2017; 102(6) A C B ferent, and in addition, look remarkably similar to curves previously documented for other respiratory viruses, such as PIV, in HCT recipients. 15 Second, the fact that mortality in patients with or without co-pathogens is similar could suggest that HRV by itself is a cause of LRI, because otherwise one would expect the outcome to be improved in patients without co-pathogens. Next, factors associated with mortality following HRV BAL positivity were similar to those for other respiratory viruses (RSV, PIV, HMPV, influenza viruses) reported by our group and others, [14] [15] [16] [19] [20] [21] [22] [23] and included oxygen use, cytopenias, and high-dose corti-costeroid use (Tables 2 and 4 ). An important analysis was the comparison of the outcome of HRV LRI with other well-established viral pneumonias. We used 3 previously described cohorts [14] [15] [16] and analyzed overall mortality in a multivariable Cox model that adjusted for key factors that are associated with poor outcome. There was no difference in mortality after LRI between HRV and the other 3 viruses, even after adjusting for several important factors, such as the presence of co-pathogens and oxygen use at the time of diagnosis (Table 6, Figure 2 ), providing strong evidence that HRV detection in the BAL is indeed a clini- cally significant finding. Although the Cox model adjusted for oxygen use, we performed a subset analysis of patients who presented without oxygen use ( Figure 2B ). This group likely had minimal or no acute lung injury at the time of diagnosis and the subsequent outcome in these patients was more likely to be associated with the viral insult rather than the inflammatory changes associated with acute lung injury. Although mortality was, as expected, lower in this group, mortality rates approaching 20% by 3 months after diagnosis were documented, indicating an important negative impact on survival. Importantly, there were no apparent differences in LRI outcomes between HRV and RSV, PIV or influenza virus. We also examined virologic factors to evaluate the role of HRV in lung disease. Tissue documentation of a pathogen is considered a key factor supporting a pathogenic role of an infectious agent. 24, 25 Although we were limited by the small number of tissue samples from lung biopsies and autopsies in our cohort, we were able to culture HRV from lung biopsies in 6 of 22 patients who had S. Seo et al. 1128 haematologica | 2017; 102(6) cultures performed. This is a remarkable result because our culture system is not optimized for HRV recovery (which in general is improved by incubation at lower temperatures and other methods, such as roller flasks, as used in previous papers), 7 and suggests a high viral load may have been present. Since viral culture positivity from biopsy material is generally considered to indicate invasive viral disease for other respiratory viruses and cytomegalovirus (CMV), 24, 26, 27 we consider this finding to be highly significant. We also detected HRV RNA by PCR in archived frozen tissue from lung biopsies and autopsy samples. The HRV PCR Ct values of the BAL samples, which provide a rough estimate of the HRV viral load, were not as