RESUMO
BACKGROUND: Glucocorticoids are commonly used in patients with or at-risk for acute respiratory distress syndrome (ARDS), but optimal use remains unclear despite well-conducted clinical trials. We performed a secondary analysis in patients previously enrolled in the Acute Lung Injury and Biospecimen Repository at the University of Pittsburgh. The primary aim of our study was to investigate early changes in host response biomarkers in response to real-world use of glucocorticoids in patients with acute respiratory failure due to ARDS or at-risk due to a pulmonary insult. Participants had baseline plasma samples obtained on study enrollment and on follow-up 3 to 5 days later to measure markers of innate immunity (IL-6, IL-8, IL-10, TNFr1, ST2, fractalkine), epithelial injury (sRAGE), endothelial injury (angiopoietin-2), and host response to bacterial infections (procalcitonin, pentraxin-3). In our primary analyses, we investigated the effect of receiving glucocorticoids between baseline and follow-up samples on host response biomarkers measured at follow-up by doubly robust inverse probability weighting analysis. In exploratory analyses, we examined associations between glucocorticoid use and previously characterized host response subphenotypes (hyperinflammatory and hypoinflammatory). RESULTS: 67 of 148 participants (45%) received glucocorticoids between baseline and follow-up samples. Dose and type of glucocorticoids varied. Regimens that used hydrocortisone alone were most common (37%), and median daily dose was equivalent to 40 mg methylprednisolone (interquartile range: 21, 67). Participants who received glucocorticoids were more likely to be female, to be on immunosuppressive therapy at baseline, and to have higher baseline levels of ST-2, fractalkine, IL-10, pentraxin-3, sRAGE, and TNFr1. Glucocorticoid use was associated with decreases in IL-6 and increases in fractalkine. In exploratory analyses, glucocorticoid use was more frequent in participants in the hyperinflammatory subphenotype (58% vs 40%, p = 0.05), and was not associated with subphenotype classification at the follow-up time point (p = 0.16). CONCLUSIONS: Glucocorticoid use varied in a cohort of patients with or at-risk for ARDS and was associated with early changes in the systemic host immune response.
RESUMO
GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reanalyzed. We used mouse models of hemorrhagic acute lung injury mediated by Pseudomonas aeruginosa exoproducts in wild-type mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral. In critically ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in nonsurvivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, and lower respiratory tract GDF15 levels were higher in coronavirus disease (COVID-19) nonsurvivors. In mice, intratracheal P. aeruginosa type II secretion system exoproducts were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and an altered lung transcriptional profile during injury induced by P. aeruginosa type II secretion system exoproducts, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which is associated with plasma levels in humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway.