New Method for Lung Microbiomes Analysis Predicts Mortality in Children after Bone Marrow Transplant

Bone marrow transplant, also referred to as hematopoietic cell transplantation (HCT), serves as a critical treatment for children with leukemia, bone marrow failure, and various genetic disorders, including inborn immunodeficiencies and sickle-cell disease. However, the procedure is intense, involving high doses of chemotherapy to eradicate diseased cells in the bone marrow. This treatment suppresses the immune system to allow healthy stem cells to grow, which are then transplanted into the patients. Due to this immune suppression, patients become highly susceptible to viruses, bacteria, and other pathogens during the critical phase when their immune system is "rebooting." Lung infections are especially prevalent among these patients, affecting up to 40% of pediatric HCT recipients. When these infections require ventilator support, the mortality rate can be as high as 50%. Identifying the specific pathogens involved is challenging because doctors using conventional diagnostic tests may not be able to target the correct ones, given the multitude of possible pathogens that could be affecting the lungs.

A groundbreaking approach developed by an international team, which included researchers from UC San Francisco (UCSF, San Francisco, CA, USA) and Chan Zuckerberg Biohub San Francisco (CZ Biohub SF, San Francisco, CA, USA), utilizes a sophisticated method that rapidly and comprehensively detects all potentially pathogenic organisms in the lungs. This technique has revealed associations between specific microbial communities and increased mortality risks, paving the way for more accurate diagnostics and, potentially, more effective treatments to boost survival rates post-transplant. Moving away from traditional diagnostics like culturing, which targets specific pathogens, the team employed metagenomic next-generation sequencing (mNGS) to analyze lung fluid samples from a wide range of pediatric patients. They sequenced the total RNA from each sample, identifying every type of microorganism present, without limiting the analysis to known pathogens.

Upon analyzing the sequencing data on Chan Zuckerberg ID, a free, cloud-based metagenomic platform, the researchers were surprised to find not only bacteria and viruses but also other organisms such as Toxoplasma gondii, a parasite from cat feces; Acanthamoeba, an amoeba from soil; and fungi like Cryptococcus and Pneumocystis. After assessing the microbiome composition of the patients' lungs, the researchers grouped the participants into four clusters and examined the clinical outcomes for each. The cluster with the highest mortality displayed significant lung inflammation and cellular damage, with a marked depletion of microbial species in their lung microbiome, but notable populations of Staphylococcus and viruses were present. The study found that the more altered the immune environment in the lungs, the more distorted the lung microbiomes and the higher the rate of infections observed. The researchers also noted a strong correlation between antibiotic treatment and the reduction of bacterial populations, which was countered by an increase in viral and fungal communities. They pointed out that because the most severely ill patients receive more antibiotics, distinguishing the microbial causes of mortality remains a complex task.

“We took samples from 229 pediatric bone marrow transplant patients across 32 hospitals,” said first author Matt Zinter, assistant professor of pediatrics at UCSF. “Our results, which we validated in an entirely separate cohort, indicate that lung microenvironments are predictive, or prognostic, for the risk of mortality. Our ultimate goal is to figure out how to modulate pulmonary biology for the benefit of our patients.”

“Pulmonary infections in HCT patients are complex — there might be common microbes causing them, but also very rare and uncommon microbes,” added Zinter. “We’ve found organisms that physicians treating these patients likely aren’t even aware of because there is not currently a good clinical test available for them.”

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