Dataset Information

The pulmonary metatranscriptome prior to pediatric HCT identifies post-HCT lung injury.

ABSTRACT: Lung injury after pediatric allogeneic hematopoietic cell transplantation (HCT) is a common and disastrous complication that threatens long-term survival. To develop strategies to prevent lung injury, novel tools are needed to comprehensively assess lung health in HCT candidates. Therefore, this study analyzed biospecimens from 181 pediatric HCT candidates who underwent routine pre-HCT bronchoalveolar lavage (BAL) at the University Medical Center Utrecht between 2005 and 2016. BAL fluid underwent metatranscriptomic sequencing of microbial and human RNA, and unsupervised clustering and generalized linear models were used to associate microbiome gene expression data with the development of post-HCT lung injury. Microbe-gene correlations were validated using a geographically distinct cohort of 18 pediatric HCT candidates. The cumulative incidence of post-HCT lung injury varied significantly according to 4 pre-HCT pulmonary metatranscriptome clusters, with the highest incidence observed in children with pre-HCT viral enrichment and innate immune activation, as well as in children with profound microbial depletion and concomitant natural killer/T-cell activation (P < .001). In contrast, children with pre-HCT pulmonary metatranscriptomes containing diverse oropharyngeal taxa and lacking inflammation rarely developed post-HCT lung injury. In addition, activation of epithelial-epidermal differentiation, mucus production, and cellular adhesion were associated with fatal post-HCT lung injury. In a separate validation cohort, associations among pulmonary respiratory viral load, oropharyngeal taxa, and pulmonary gene expression were recapitulated; the association with post-HCT lung injury needs to be validated in an independent cohort. This analysis suggests that assessment of the pre-HCT BAL fluid may identify high-risk pediatric HCT candidates who may benefit from pathobiology-targeted interventions.

SUBMITTER: Zinter MS

PROVIDER: S-EPMC7995292 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Mortality associated with acute lung injury remains high. Early identification of acute lung injury prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score identifies patients at risk for acute lung injury but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of early acute lung injury to identify patients with lung injury prior to the need for positive pressure ventilation.Prospective observational cohort study.Stanford University Hospital.We prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.None.Of the 256 patients enrolled, 62 patients (25%) progressed to acute lung injury requiring positive pressure ventilation. Clinical variables (through first 72 hr or up to 6 hr prior to acute lung injury) associated with progression to acute lung injury were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to acute lung injury. A simple three-component early acute lung injury score (1 point for oxygen requirement > 2-6 L/min or 2 points for > 6 L/min; 1 point each for a respiratory rate ? 30 and immune suppression) accurately identified patients who progressed to acute lung injury requiring positive pressure ventilation (area under the receiver-operator characteristic curve, 0.86) and performed similarly to the Lung Injury Prediction Score. An early acute lung injury score greater than or equal to 2 identified patients who progressed to acute lung injury with 89% sensitivity and 75% specificity. Median time of progression from early acute lung injury criteria to acute lung injury requiring positive pressure ventilation was 20 hours.This pragmatic definition of early acute lung injury accurately identified patients who progressed to acute lung injury prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of acute lung injury.

Project description:IntroductionVariability in rehabilitation disposition has been proposed as a trauma center quality metric. Benchmarking rehabilitation disposition is limited by a lack of objective measures of functional impairment at discharge. The primary aim of this study was to determine the relative contribution of patient characteristics and hospitalization factors associated with inpatient and outpatient rehabilitation after discharge. The secondary aims were to evaluate the sensitivity of the Functional Status Scale (FSS) score for identifying functional impairments at hospital discharge and track post-discharge recovery.Patients and methodsWe report a planned secondary analysis of a prospective observational study of seriously injured children (<15 years old) enrolled at seven pediatric trauma centers. Functional Status Scale (FSS) score was measured for pre-injury, hospital discharge, and 6-month follow-up timepoints. Multinomial logistic regression identified factors associated with three dispositions: home without rehabilitation services, home with outpatient rehabilitation, and inpatient rehabilitation. Relative weight analysis was used to identify the impact of individual factors associated with inpatient or outpatient rehabilitation disposition.ResultsWe analyzed 427 children with serious injuries. Functional impairment at discharge was present in 103 (24.1%) children, including 43/337 (12.8%) discharged without services, 12/38 (31.6%) discharged with outpatient rehabilitation, and 44/47 (93.6%) discharged to inpatient rehabilitation. In multivariable modeling, variables most contributing to prediction of inpatient rehabilitation were severe initial Glasgow coma scale (GCS), injured body region, and functional impairment at discharge. Severe initial GCS, private insurance, and extremity injury were independently associated with disposition with outpatient rehabilitation. Patients discharged without services or with outpatient rehabilitation most frequently had motor impairments that improved during the next 6 months. Patients discharged to inpatient rehabilitation had impairments in all domains, with many improving within 6 months. A higher proportion of patients discharged to inpatient rehabilitation had residual impairments at follow-up.ConclusionInjury characteristics and discharge impairment were associated with discharge to inpatient rehabilitation. The FSS score identified impairments needing inpatient rehabilitation and characterized improvements after discharge. Less severe impairments needing outpatient rehabilitation were not identified by the FSS score.

Project description:BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.MethodsUsing Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining.ResultsWe reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1-/- mice, Ism1-/- lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages.ConclusionTogether with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.

Dataset Information

The pulmonary metatranscriptome prior to pediatric HCT identifies post-HCT lung injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets