What Types of Antibiotic Exposure Associates with Increased Risk of Respiratory Viral Disease Progression in Allogeneic Hematopoietic Cell Transplant Recipients

Introduction Recent animal and human data suggest that antibiotic exposure prior to respiratory viral infection (RVI) increases risk of respiratory disease progression, presumably due to immunomodulatory effects of changes in the microbiota. However, few studies have identified the specific antibiotics that may be linked to respiratory viral disease progression. Objectives To investigate the associations between antibiotic exposure and disease progression of select RVIs after allogeneic hematopoietic cell transplantation (HCT). Methods We analyzed patients who underwent allogeneic HCT (4/2008-9/2018) and had their first RVI due to parainfluenza virus (PIV), respiratory syncytial virus (RSV), human metapneumovirus (MPV) or human rhinovirus (HRV) during the first 100 days after HCT. Antibiotic exposure in the 21 days before RVI onset was defined as A) any versus no use of specific antibiotics, and B) total antibiotic-days. Antibiotic-days was defined as cumulative sum of antibiotics received during each day in the specified time window. The probability of disease progression was estimated by cumulative incidence curves, treating death as a competing risk. We used Cox proportional hazard models to examine associations between antibiotic exposure and risk of disease progression to LRTD, adjusting for type of RVI, age at transplant, steroid use, lymphopenia and neutropenia before RVI onset. Data were censored at death, discharge, or 30 days post-RVI onset, whichever came first. Results We identified 469 HCT recipients (379 adults, 90 children) with first RVI (PIV 93, RSV 54, MPV 27, HRV 295), of which, 124 progressed to LRTD. Cumulative incidence of LRTD by tertiles of the total antibiotic-days (median 11, range 0-56) during the 21 days before onset of RVI is shown in Figure 1. In separate models, higher total antibiotic-days, use of antibiotics with broad anaerobic activity and use of cephalosporins with limited anaerobic activity were significantly associated with progression to LRTD. Figure 2 shows a forest plot of the adjusted hazard ratios between type of antibiotic exposure and progression to LRTD. Conclusion This study suggests that cumulative exposure to antibiotics prior to RVI is a risk factor for respiratory viral disease progression. Despite complex antibiotic use patterns in HCT recipients, our findings also suggest antibiotics of varying spectra may be associated with respiratory viral disease progression.