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Clinical Trial
. 2018 Aug 1;67(4):541-548.
doi: 10.1093/cid/ciy153.

Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia

Hana Hakim  1 , Ronald Dallas  1 , Joshua Wolf  1 , Li Tang  2 , Stacey Schultz-Cherry  1 , Victoria Darling  1 , Cydney Johnson  1 , Erik A Karlsson  1 , Ti-Cheng Chang  3 , Sima Jeha  4 , Ching-Hon Pui  4 , Yilun Sun  2 , Stanley Pounds  2 , Randall T Hayden  5 , Elaine Tuomanen  1 , Jason W Rosch  1
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Clinical Trial

V体育ios版 - Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia

Hana Hakim et al. Clin Infect Dis. .

Abstract

Background: Myelosuppression-related infections remain important causes of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). VSports手机版.

Methods: By analyzing fecal samples collected at diagnosis and after each of the initial 3 phases of chemotherapy, we evaluated the role of gut microbiota in predicting infections in 199 children with newly diagnosed ALL V体育安卓版. The bacterial 16S rRNA gene was analyzed by high-depth sequencing to determine the diversity and composition of the microbiome. .

Results: After the induction and reinduction I phases of chemotherapy, microbial diversity decreased significantly relative to the prechemotherapy value. After chemotherapy, the relative abundance of certain bacterial taxa (eg, Bacteroidetes) decreased significantly, whereas that of other taxa (eg, Clostridiaceae and Streptococcaceae) increased. A baseline gut microbiome characterized by Proteobacteria predicted febrile neutropenia. Adjusting for the chemotherapy phase and ALL risk level, Enterococcaceae dominance (relative abundance ≥30%) predicted significantly greater risk of subsequent febrile neutropenia and diarrheal illness, whereas Streptococcaceae dominance predicted significantly greater risk of subsequent diarrheal illness V体育ios版. .

Conclusions: In children undergoing therapy for newly diagnosed ALL, the relative abundance of Proteobacteria before chemotherapy initiation predicts development of febrile neutropenia, and domination of the gut microbiota by Enterococcaceae or Streptococcaceae at any time during chemotherapy predicts infection in subsequent phases of chemotherapy. VSports最新版本.

Clinical trial registration: NCT00549848. V体育平台登录.

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Figures

Figure 1.
Figure 1.
Change in gut microbiota diversity in 199 children during chemotherapy for acute lymphoblastic leukemia. Fecal samples were obtained at 4 time points (baseline, n = 112; postinduction, n = 97; postconsolidation, n = 107; and postreinduction, n = 90). A mixed-effects linear model was used to examine the change in Shannon indices over time. Patients were included as a random effect. **P < .01; ***P < .001. Abbreviation: NS, not significant.
Figure 2.
Figure 2.
Change in gut microbiota composition during chemotherapy at the same time points as in Figure 1. *Significant change.
Figure 3.
Figure 3.
The relative abundance (RA) of Proteobacteria in the baseline gut microbiota at acute lymphoblastic leukemia diagnosis is associated with increased cumulative incidence of first episodes of febrile neutropenia. The estimated hazard ratio was 2.12 (95% confidence interval, 1.22–3.69; P = .008) for a Proteobacteria RA of ≥0.01 vs an RA of <0.01%, adjusting for gender.
Figure 4.
Figure 4.
Heat map of taxa relative abundance in microbiota of all 406 fecal samples collected at any of the 4 time points. Five clusters (types 1–5) were identified using unsupervised hierarchical clustering of the Jensen-Shannon divergence matrix and ward linkage. Type 1 is dominated by Bacteroidetes; type 2 by other Firmicutes or Clostridiaceae; type 3 by Enterococcaceae, Streptococcaceae, Lactobacillaceae, or Proteobacteria; and type 4 by Blautia species. Type 5 has evenly distributed relative abundances of taxa.
Figure 5.
Figure 5.
Forest plot of hazard ratios (HRs) with 95% confidence intervals (CIs) for febrile neutropenia (A) and diarrheal illness (B) associated with gut microbiome composition and diversity at any of the 4 time points. The Anderson-Gill model was used to compare the risk of each outcome among the microbiome Shannon indices and composition types over time. The reported HRs were adjusted for subsequent chemotherapy phase and acute lymphoblastic leukemia risk level, and the 95% CI and P values were estimated using the robust sandwich estimator.
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