Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality

Brabander, Justin de; Boers, Leonoor S.; Kullberg, Robert F. J.; Zhang, Shiqi; Nossent, Esther J.; Heunks, Leo; Vlaar, Alexander P.J.; Bonta, Peter I.; Schultz, Marcus J.; Poll, Tom van der; Duitman, JanWillem; Bos, Lieuwe D. J.

doi:10.1136/thorax-2023-219989

Cited by 21 publications

(7 citation statements)

References 51 publications

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“…Steroids were associated with decreased BAL neutrophils in a case series of 12 patients with COVID-19 ARDS who required ECMO 39 . In patients with non-resolving ARDS, steroid treatment was associated with decreased BAL concentrations of the neutrophil chemoattractants CXCL1 and CCL20 40 . Two observational studies have described the effects of dexamethasone on gene expression in patients with COVID-19 ARDS.…”

Section: Discussionmentioning

confidence: 95%

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

Fragiadakis,

Neyton,

Patel

et al. 2023

Preprint

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Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. We performed bulk and single-cell RNA sequencing of the lower respiratory tract and blood, and plasma cytokine profiling to study the effect of dexamethasone on systemic and pulmonary immune cells. We find decreased signatures of antigen presentation, T cell recruitment, and viral injury in patients treated with dexamethasone. We identify compartment- and cell- specific differences in the effect of dexamethasone in patients with severe COVID-19 that are reproducible in publicly available datasets. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

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Section: Discussionmentioning

confidence: 95%

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

Fragiadakis,

Neyton,

Patel

et al. 2023

Preprint

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“…It also recruits Th17 cells and regulatory T cells to inflammatory sites since CCR6 is present on these cell types. Patients with COVID-19 were found to have elevated levels of CCL20 in both bronchoalveolar lavage (BAL) fluid and plasma samples 46 . Pulmonary arterial hypertension in individuals with SSc is associated with elevated serum CCL20 levels 44 .…”

Section: Discussionmentioning

confidence: 99%

Potential therapeutic targets for COVID-19 complicated with pulmonary hypertension: a bioinformatics and early validation study

Hou,

Jiang,

et al. 2024

Sci Rep

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Coronavirus disease (COVID-19) and pulmonary hypertension (PH) are closely correlated. However, the mechanism is still poorly understood. In this article, we analyzed the molecular action network driving the emergence of this event. Two datasets (GSE113439 and GSE147507) from the GEO database were used for the identification of differentially expressed genes (DEGs).Common DEGs were selected by VennDiagram and their enrichment in biological pathways was analyzed. Candidate gene biomarkers were selected using three different machine-learning algorithms (SVM-RFE, LASSO, RF).The diagnostic efficacy of these foundational genes was validated using independent datasets. Eventually, we validated molecular docking and medication prediction. We found 62 common DEGs, including several ones that could be enriched for Immune Response and Inflammation. Two DEGs (SELE and CCL20) could be identified by machine-learning algorithms. They performed well in diagnostic tests on independent datasets. In particular, we observed an upregulation of functions associated with the adaptive immune response, the leukocyte-lymphocyte-driven immunological response, and the proinflammatory response. Moreover, by ssGSEA, natural killer T cells, activated dendritic cells, activated CD4 T cells, neutrophils, and plasmacytoid dendritic cells were correlated with COVID-19 and PH, with SELE and CCL20 showing the strongest correlation with dendritic cells. Potential therapeutic compounds like FENRETI-NIDE, AFLATOXIN B1 and 1-nitropyrene were predicted. Further molecular docking and molecular dynamics simulations showed that 1-nitropyrene had the most stable binding with SELE and CCL20.The findings indicated that SELE and CCL20 were identified as novel diagnostic biomarkers for COVID-19 complicated with PH, and the target of these two key genes, FENRETI-NIDE and 1-nitropyrene, was predicted to be a potential therapeutic target, thus providing new insights into the prediction and treatment of COVID-19 complicated with PH in clinical practice.

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“…Joint modeling is a flexible approach that can mitigate some of the effects of informative censoring 28 . The latter is particularly relevant for translational studies in the ICU because patients who experienced early mortality or those who improved quickly and were discharged from the ICU could not contribute later follow-up samples 46 . Our joint models revealed that baseline features in the lung compartment (Shannon index and anaerobe or pathogen abundance) were predictive of survival, whereas their longitudinal changes were not, except for marginal effects of anaerobe abundance.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure

Kitsios,

Sayed,

Fitch

et al. 2024

Nat Commun

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Critical illness can significantly alter the composition and function of the human microbiome, but few studies have examined these changes over time. Here, we conduct a comprehensive analysis of the oral, lung, and gut microbiota in 479 mechanically ventilated patients (223 females, 256 males) with acute respiratory failure. We use advanced DNA sequencing technologies, including Illumina amplicon sequencing (utilizing 16S and ITS rRNA genes for bacteria and fungi, respectively, in all sample types) and Nanopore metagenomics for lung microbiota. Our results reveal a progressive dysbiosis in all three body compartments, characterized by a reduction in microbial diversity, a decrease in beneficial anaerobes, and an increase in pathogens. We find that clinical factors, such as chronic obstructive pulmonary disease, immunosuppression, and antibiotic exposure, are associated with specific patterns of dysbiosis. Interestingly, unsupervised clustering of lung microbiota diversity and composition by 16S independently predicted survival and performed better than traditional clinical and host-response predictors. These observations are validated in two separate cohorts of COVID-19 patients, highlighting the potential of lung microbiota as valuable prognostic biomarkers in critical care. Understanding these microbiome changes during critical illness points to new opportunities for microbiota-targeted precision medicine interventions.

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Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality

Cited by 21 publications

References 51 publications

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19

Potential therapeutic targets for COVID-19 complicated with pulmonary hypertension: a bioinformatics and early validation study

Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure

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