Pulmonary microbiome and gene expression signatures differentiate lung function in pediatric hematopoietic cell transplant candidates

Abstract

Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pretransplant lung function has hindered the development of lung-targeted interventions. In this study, we quantified the association between bronchoalveolar lavage (BAL) metatranscriptomes and paired pulmonary function tests performed a median of 1 to 2 weeks before allogeneic HCT in 104 children in The Netherlands. Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung injury–related mortality after HCT. Depletion of commensal supraglottic taxa, such as Haemophilus , and enrichment of nasal and skin taxa, such as Staphylococcus , in the BAL microbiome were associated with worse measures of lung capacity and gas diffusion. In addition, BAL gene expression signatures of alveolar epithelial activation, epithelial-mesenchymal transition, and down-regulated immunity were associated with impaired lung capacity and diffusion, suggesting a postinjury profibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality. These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.

Novel approaches to the prediction and diagnosis of pulmonary complications in the paediatric haematopoietic stem cell transplant patient

“…Staphylococcus spp.) had higher post-HSCT mortality compared to those children with diverse oropharyngeal microbiomes and lacking inflammation [23]. This dysbiosis was shown to be associated with pre-HSCT reduction in lung function (reduced forced vital capacity <60% predicted) and post-HSCT lung injury, specifically reduced airway epithelial cell integrity.…”

“…This dysbiosis was shown to be associated with pre-HSCT reduction in lung function (reduced forced vital capacity <60% predicted) and post-HSCT lung injury, specifically reduced airway epithelial cell integrity. The hypothesis that microbiome depletion in combination with alveolar injury during HSCT due to chemotherapy, radiation or infection, promotes a pro-fibrotic response [23]. Post-HSCT pulmonary fibrosis is exceedingly difficult to treat and is often fatal.…”

“…The pulmonary microbiome and gene expression signatures of a large cohort of children ( n = 104) were evaluated prior to HSCT [23]. Patients who had depletion of the normal commensal supraglottic taxa (e.g.…”

The Microbiome and Its Impact on Allogeneic Hematopoietic Cell Transplantation

“…Studies of the skin microbiome 30,31 found that cutaneous aGVHD was associated with increased abundances of Staphylococcus , a finding highly reminiscent of that seen in children with atopic dermatitis 32 . Pulmonary toxicities and changes in the pulmonary microbiome have also been found to be coassociated in pediatric alloHCT patients 33,34 . Changes in the ocular microbiota have also been observed in patients with ocular cGVHD, including in composition of bacteria as well as viruses 35 .…”

“…32 Pulmonary toxicities and changes in the pulmonary microbiome have also been found to be coassociated in pediatric alloHCT patients. 33,34 Changes in the ocular microbiota have also been observed in patients with ocular cGVHD, including in composition of bacteria as well as viruses. 35 Whether the microbiome of the oral cavity or upper gut could be similarly associated with upper GI aGVHD has not yet been well studied, although the dental biofilm microbiome has been reported to be associated with aGVHD.…”