Assessing Risk of Infectious Episodes in Patients Post Hematopoietic Stem Cell Transplantation Using Pre-Transplant Baseline Colonization Screening
Authors: Leite Tamara , Janusz Nicole , Mortimer Leanne , Carroll Amanda , Kekre Natasha K. , Kennah Michael , Sant Nadia , Yan Austin , Senechal Jaxon , MacFadden Derek , Buchan C. Arianne 
Published: December 2024

INTRODUCTION
Infection is a major cause of mortality following hematopoietic stem cell transplant (HCT). The primary source of bacterial infections are gut-derived bacteria from the patient's own microbial flora. Understanding patient specific colonizing organisms may inform downstream infections.
This study aims to establish feasibility of identifying baseline colonization of antimicrobial resistant organisms (AROs), such as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum beta-lactamase (ESBL), and fluoroquinolone-resistant (FQR) enterobacterales and Clostridioides difficile (C. difficile), to assess the association between pre-transplant colonization and subsequent post-transplant infection.

METHODS
This prospective cohort study followed 60 HCT patients (34 autologous and 26 allogenic) for 6 months. Primary hematologic diagnoses were multiple myeloma (30%), leukemia (AML, ALL; 27%) and myelodysplastic syndrome (15%). Stool samples were collected pre-transplant and twice weekly for 3 weeks post-transplant. Culture-based stool samples were processed using selective media to detect colonization with AROs harbouring resistance mechanisms and antibiotic class resistance in Gram-negative organisms. C. difficile colonization was assessed using routine glutamine dehydrogenase (GDH) assay and toxin B gene PCR. Clinical data collected included infectious complications, neutropenia, disease relapse, and mortality. Infectious episodes were identified using positive culture results and patients' clinical history, classified by pathogen and ARO type.

RESULTS
Baseline colonization with C. difficile and/or AROs was identified in 27% (16/60) of patients. The median length of neutropenia was 11 (IQR 7-32) days, with 72% (43/60) of patients developing febrile neutropenia.
C. difficile colonization was identified in 10% (6/60) of patients. All colonized patients were asymptomatic at baseline. Ten (17%) patients developed a C. difficile infection (CDI) within 6 months of transplant, with 3 individuals having recurrent CDIs. Of these 10 patients, 50% were amongst those colonized at baseline. Of all colonized patients, 83% (5/6) developed CDI over the course of their follow up period.
ARO colonization was found in 18% (11/60) of patients, including VRE (4/11), ESBL and FQRE (4/11), and FQRE alone (3/11). Of the 7 patients colonized with ESBL or FQRE, 1 (14%) patient developed a bloodstream infection with an ESBL K. pneumonaie. An additional 16 (27%) patients were found to be colonized with other Gram-negative organisms, the majority of which harboured inducible beta-lactamases (AMP-C).
In the overall cohort, 50% of patients experienced at least 1 culture-positive infection within the first 6 months post-HCT. The majority (45%) of infections were viral in nature. Bloodstream infections accounted for 23% (16/71) of all infections, of which there were 13 episodes of bacteremia amongst 10 participants. Of these, 4/10 participants were diagnosed with resistant Gram-negative bacteremia including 3 with ESBL K. pneumonaie. Furthermore, 2/10 participants were diagnosed with VRE bacteremia.
Of the 26 individuals who underwent an allogenic HCT, data pertaining to graft-vs-host disease (GVHD) was available for 23 participants at the 6-month follow-up. Nine (39%) individuals developed GVHD, with most cases presenting as skin GVHD. Among these, there was 1 severe case of gastrointestinal GVHD which resulted in death.
Complete 6-month follow-up data regarding disease relapse and mortality was available for 47 of the 60 participants. Six (13%) individuals relapsed within the follow-up period and 4 of the patients underwent further treatment (e.g., chimeric antigen receptor T-cell (CART) therapy, subsequent allogenic HCT). The remaining 2 individuals' relapse resulted in death. In total, there were 6/47 (13%) reported deaths by the 6-month follow-up, including 2 secondary to infection.

CONCLUSION
This study highlights the significant burden of infections post-HCT and demonstrates the feasibility of establishing pre-transplant baseline colonization to identify resistant organisms that may inform downstream infection risk. Future studies are needed to evaluate use of colonization data for predicting post-transplant infection and assess the role of targeted prophylaxis or treatment based on patient's flora.