Effects of the oral microbiome on Adverse Outcomes of Pediatric Hematopoietic Cell Transplantation

ABSTRACT: Dental clearance, to assure the absence of dental caries, is a routine process prior undergoing hematopoietic cell transplant (HCT). Dental caries is one of the most prevalent childhood diseases worldwide, affecting 25-50% of children in the United States, and in preliminary and published studies, we have found a surprising association between the presence of active dental caries prior to transplant, and risk for blood stream infection (BSI) in pediatric hematopoietic cell transplant (HCT) recipients. BSI is a life-threatening condition associated with significantly worse clinical outcomes, and therefore we propose to further understand the association between the cariogenic oral microbiome and translocation of microbes to the blood stream of in pediatric HCT recipients . We propose to test the hypothesis that oral microbes in children undergoing hematopoietic cell transplant, can be translocated to the blood stream, and are associated with adverse outcomes. We will test this hypothesis through 2 specific aims. Aim 1 will determine the relationship between dental treatment and the cariogenic oral microbiome prior to admission, and adverse effects related to the translocation of oral microbes to the blood stream in children undergoing HCT. Aim 2 will identify interkingdom networks in the oral and blood microbiome of pediatric patients over the course of HCT therapy, related to their pre-transplant caries status. To achieve these aims we will recruit pediatric patients from the UCSF pediatric Bone & Marrow Transplant unit at UCSF Benioff Children’s Hospital. Oral samples including supragingival plaque and saliva, will be collected at the time of admission, post-conditioning, and post- transplant. Blood samples will be collected at the time of admission and post-conditioning. Blood microbes will be compared to oral microbes following shotgun metagenomic sequencing, and assessed for their association with adverse treatment outcomes including fever, mucositis, and BSI. Taxonomic and functional modules of the cariogenic microbiome that are altered through the course of HCT will be characterized by shotgun metagenomic sequencing , and compared in pre-HCT caries- active and caries-free subjects. We will expand the current oral microbiome paradigms beyond bacteria to include fungi, viruses and archaea and their relationships in the context of dental caries risk in HCT. We expect that the unique function and location of the cariogenic oral microbiome on tooth surfaces, may enhance survival of these microorganisms from the effects of chemotherapy drugs and antibiotics, to facilitate microbial translocation to the blood stream. Our findings will provide a foundation for the development of rationally designed oral care programs aimed at reducing morbidity in this highly vulnerable population.