Randomized controlled trial of gut decontamination in pediatric patients undergoing allogeneic hematopoietic cell transplantation

Abstract

ABSTRACTBackgroundGut decontamination (GD) can decrease the incidence and severity of acute graft- versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). Several HCT centers standardly practice GD with different antibiotic regimens. In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.MethodsWe randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).ResultsThe two arms did not differ in Shannon diversity of the gut microbiota at two weeks post- HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T- cell subsets was similar, but absolute CD19+ B-cell counts were higher in the GD arm at 12 months post-HCT (p=0.02). Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including the genus Staphylococcus.ConclusionsWhile GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut microbial pathogens.Key points:–In this phase 2 randomized study of gut decontamination (GD) in 20 pediatric HCT patients, neither two-week post-HCT Shannon diversity of the gut microbiome nor incidence of aGVHD differ between the GD and no-GD arms.–All bloodstream infections (BSIs) caused by pathogens traceable to the gut either temporally or via strain-specific analysis (concomitant gut colonization) occurred in patients in the no-GD arm; this suggests that GD with vancomycin-polymyxin B may decrease the incidence of gut-derived BSI in allo-HCT patients.–In contrast to prior studies, we find that non-mucosal barrier injury (MBI) pathogens, such as Staphylococcus aureus, can be found in the gut microbiome of HCT patients.