Glucocorticoid use in acute respiratory failure from pulmonary causes and association with early changes in the systemic host immune response

Abstract

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.

Keywords: ARDS; Cytokines; Glucocorticoids; Immune responses; Inflammation; Phenotypes; Pneumonia.

Fig. 1

Patient flow diagram. ALIR—Acute Lung Injury Registry and Biospecimen Repository; ARDS—acute respiratory distress syndrome

Fig. 2

Proportion of study participants receiving glucocorticoids with distribution of type and average daily dose. A Illustrates the distribution of glucocorticoids administered to participants between baseline and follow-up samples in the study cohort. Hydrocortisone alone (37%) was the most commonly prescribed glucocorticoid regimen. B Illustrates the average dose of glucocorticoids administered per study day grouped by type of glucocorticoid regimen. Data represent median and upper limits of the interquartile range

Fig. 3

Association of glucocorticoid use with early changes in markers of the systemic host immune response. p-values represent results from doubly robust inverse probability of treatment weighting analysis with each host response biomarker at follow-up as the outcome and with receipt of at least one dose of glucocorticoids between baseline and follow-up samples as the intervention. Unadjusted p-values are reported. *Denotes significance after adjusting for multiple comparisons by the method of Simes with a false discovery rate of 0.1. CI, confidence interval; Ang-2, angiopoietin-2; IL, Interleukin; ST-2, suppressor of tumorigenicity-2; sRAGE, soluble receptor of advanced glycation end-products; sTNFr1, soluble tumor necrosis factor receptor 1

Fig. 4

Transition of host response subphenotypes between baseline and follow-up time points. 103 participants (70%) were in the hypoinflammatory subphenotype at baseline. 91% remained hypoinflammatory at follow-up (39% received glucocorticoids) and 9% became hyperinflammatory (44% received glucocorticoids). 45 participants were hyperinflammatory at baseline of whom 53% remained hyperinflammatory (57% received glucocorticoids) and 47% became hypoinflammatory (58% received glucocorticoids). GCs, glucocorticoids; hypo, hypoinflammatory subphenotype; hyper, hyperinflammatory subphenotype

Fig. 5

Transition of host response subphenotypes at baseline and follow-up time points stratified by receipt of glucocorticoids. A Illustrates the transition of host response subphenotypes in the participants that did not receive glucocorticoids between baseline and follow-up time points. B Illustrates the transition of host response subphenotypes in the participants that received at least one dose of glucocorticoids between baseline and follow-up samples. Hypo—hypoinflammatory subphenotype; hyper—hyperinflammatory subphenotype