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Observational Study
. 2023 Aug 31;228(5):627-636.
doi: 10.1093/infdis/jiad190.

Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Elisa B Margolis  1   2 , Gabriela Maron Alfaro  1   2 , Yilun Sun  3 , Ronald H Dallas  1 , Kim J Allison  1 , Jose Ferrolino  1 , Hailey S Ross  1 , Amy E Davis  1   4 , Qidong Jia  1 , Paige Turner  1 , Victoria Mackay  1 , Cara E Morin  5 , Brandon M Triplett  6 , Eileen J Klein  7 , Janet A Englund  7 , Li Tang  3 , Randall T Hayden  8
Affiliations
Observational Study

Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Elisa B Margolis et al. J Infect Dis. .

Erratum in

Abstract

Background: Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT.

Methods: In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis.

Results: Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96).

Conclusions: Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.

Keywords: immunocompromised hosts; infections; microbiome; transplantation complications.

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Conflict of interest statement

Potential conflicts of interest. G. M. A. receives research support from Astellas Inc and SymBio Pharmaceuticals Inc. R. T. H. has served as a consultant for Abbott Laboratories, Roche Diagnostics, T2 Diagnostics, and MiraVista. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Microbiome indices are age specific and differ in healthy cohort (n = 353) and those in this study undergoing hematopoietic cell transplantation (HCT) (n = 74). Cutoffs for phylogenetic diversity (A; 20th percentile) dominant taxa (B; 90th percentile), stool bacterial load (C; 20th percentile), and butyrogens (D; 50th percentile) is demarcated with dotted lines. Significance (**P ≤ .01; ***P ≤ .001) seen between age categories of healthy and HCT cohorts by Kruskal–Wallis test. Abbreviations: BWPD, balanced weighted phylogenetic diversity; HCT, hematopoietic cell transplantation; rRNA, ribosomal RNA.
Figure 2.
Figure 2.
Particular ratios of bacteria species found in the microbiota of pediatric patients prior to conditioning predict infections that occur in the year after transplant. The phylotypes chosen for ratios showed similar patterns of differing in abundance and distribution in different communities. Outcomes considered included bacterial infections (including bacteremia, pneumonia, urinary tract infection, and Clostridioides difficile infection [CDI]), bacteremia (alone), CDI, viral infections (included reactivation of systemic viruses, viral enterocolitis, and viral lower respiratory tract infections), viral enterocolitis, and acute graft-versus host disease (GVHD) (any grade). Only microbiota ratios (log10 transformed) where the Cox hazard ratios for which the 95% confidence interval (CI) did not include 1, after adjusting for age, sex, and conditioning regimen, were considered predictive for infectious outcomes. Cox regression analysis for all 10 ratios considered is available in Supplementary Table 4 and quantitative differences in these ratios are available in Supplementary Figures 4 and 6.
Figure 3.
Figure 3.
Distinct ratios of bacteria species found in the microbiota of pediatric patients at time of neutrophil recovery predict infections that occur through the first year of transplantation. The phylotypes chosen for ratios showed similar patterns of differing in abundance and distribution in different communities. Outcomes considered included bacterial infections (including bacteremia, pneumonia, urinary tract infection, and Clostridioides difficile infection [CDI]), bacteremia (alone), CDI, viral infections (included reactivation of systemic viruses, viral enterocolitis and viral lower respiratory tract infections), viral enterocolitis, and acute graft-versus-host disease (GVHD) (any grade). Only microbiota ratios (log10 transformed) where the Cox hazard ratios for which the 95% confidence interval (CI) did not include 1, after adjusting for age, sex, and conditioning regimen, were considered predictive for infectious outcomes. Cox regression analysis for all 10 ratios considered is available in Supplementary Table 5 and quantitative differences in these ratios are available in Supplementary Figures 5 and 6.
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