Zinter Matt S, Dvorak Christopher C, Mayday Madeline Y, Reyes Gustavo, Simon Miriam R, Pearce Emma M, Kim Hanna, Shaw Peter J, Rowan Courtney M, Auletta Jeffrey J, Martin Paul L, Godder Kamar, Duncan Christine N, Lalefar Nahal R, Kreml Erin M, Hume Janet R, Abdel-Azim Hisham, Hurley Caitlin, Cuvelier Geoffrey D E, Keating Amy K, Qayed Muna, Killinger James S, Fitzgerald Julie C, Hanna Rabi, Mahadeo Kris M, Quigg Troy C, Satwani Prakash, Castillo Paul, Gertz Shira J, Moore Theodore B, Hanisch Benjamin, Abdel-Mageed Aly, Phelan Rachel, Davis Dereck B, Hudspeth Michelle P, Yanik Greg A, Pulsipher Michael A, Sulaiman Imran, Segal Leopoldo N, Versluys Birgitta A, Lindemans Caroline A, Boelens Jaap J, DeRisi Joseph L
Division of Critical Care Medicine, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Division of Allergy, Immunology, and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
medRxiv. 2023 Nov 29:2023.11.29.23299130. doi: 10.1101/2023.11.29.23299130.
Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.
肺损伤是小儿造血细胞移植（HCT）后生存的主要决定因素。为了改善治疗结果，需要更深入地了解肺部微生物、免疫和肺上皮之间的关系。在这项多中心研究中，我们收集了2014年至2022年间在32家儿童医院接受治疗的229名患者的278份支气管肺泡灌洗（BAL）样本。利用配对的宏转录组和人类基因表达数据，我们确定了4个具有不同BAL组成的患者集群。在采样前需要呼吸支持的患者中，根据集群不同，院内死亡率在22%至60%之间（p = 0.007）。最常见的患者亚型集群1显示共生微生物数量适中且多样性高，具有强大的代谢活性，感染率低，基因表达表明肺泡巨噬细胞占主导，死亡率低。第二常见的集群显示气道微生物负担非常高，基因表达富含中性粒细胞信号，频繁发生细菌感染，死亡率中等。集群3显示共生微生物显著减少，生物多样性丧失，基因表达表明存在纤维增生途径，病毒和真菌病原体增加，死亡率高。最后，集群4显示微生物群严重耗竭，葡萄球菌和病毒富集，基因表达由淋巴细胞激活和细胞损伤驱动，死亡率最高。用随机森林分类器对BAL集群进行建模，并在来自荷兰的57名患者的地理上不同的验证队列中重现，概括了基于集群的类似死亡率差异（p = 0.022）。抗生素暴露程度与BAL微生物的耗竭和真菌的富集密切相关。通过分析每个BAL微生物相对于整体微生物群组成，从所有检测到的微生物中解析出潜在病原体，这提高了对许多先前隐匿病原体的敏感性。这些发现支持对小儿HCT中肺部微环境的个性化解读，这可能有助于进行以生物学为靶点的干预以改善治疗结果。
