Corticosteroid use in ARDS and its application to evolving therapeutics for coronavirus disease 2019 (COVID‐19): A systematic review

Abstract

Data regarding the use of corticosteroids for treatment of acute respiratory distress syndrome (ARDS) are conflicting. As the coronavirus disease 2019 (COVID-19) pandemic progresses, more literature supporting the use of corticosteroids for COVID-19 and non-COVID-19 ARDS have emerged. Glucocorticoids are proposed to attenuate the inflammatory response and prevent progression to the fibroproliferative phase of ARDS through their multiple mechanisms and anti-inflammatory properties. The purpose of this systematic review was to comprehensively evaluate the literature surrounding corticosteroid use in ARDS (non-COVID-19 and COVID-19) in addition to a narrative review of clinical considerations of corticosteroid use in these patient populations. OVID Medline and EMBASE were searched. Randomized controlled trials evaluating the use of corticosteroids for COVID-19 and non-COVID-19 ARDS in adult patients on mortality outcomes were included. Risk of bias was assessed withthe Risk of Bias 2.0 tool. There were 388 studies identified, 15 of which met the inclusion criteria that included a total of 8877 patients. The studies included in our review reported a mortality benefit in 6/15 (40%) studies with benefit being seen at varying time points of mortality follow-up (ICU survival, hospital, and 28 and 60 days) in the COVID-19 and non-COVID-19 ARDS studies. The two non-COVID19 trials assessing lung injury score improvements found that corticosteroids led to significant improvements with corticosteroid use. The number of mechanical ventilation-free days significantly were found to be increased with the use of corticosteroids in all four studies that assessed this outcome. Corticosteroids are associated with improvements in mortality and ventilator-free days in critically ill patients with both COVID-19 and non-COVID-19 ARDS, and evidence suggests their use should be encouraged in these settings. However, due to substantial differences in the corticosteroid regimens utilized in these trials, questions still remain regarding the optimal corticosteroid agent, dose, and duration in patients with ARDS.

The Relationship between COVID-19 and Hypothalamic–Pituitary–Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess—The CAPISCO International Expert Panel

“…Glucocorticoids have been widely used in the previous severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) epidemics and ARDS in general; however, the data regarding their efficacy were contradictory and generally of low quality [6]. They exert potent antiinflammatory effects across both innate and adaptive immune systems through the DNA-dependent regulation of antiinflammatory proteins, non-genomic modulation of inflammation, and direct protein interference of transcription factors such as nuclear factor kappa B [7][8][9]. In early 2020, a retrospective study of 201 patients admitted with confirmed COVID-19 pneumonia in Wuhan, China, provided the first evidence supporting their usage by demonstrating that treatment with methylprednisolone was associated with a reduced risk of death among patients with ARDS [10].…”

Lung targeted liposomes for treating ARDS

“…Glucocorticoids diffuse through cell membranes leveraging amphipathic properties and cellular receptors. In the cytoplasm glucocorticoids bind glucocorticoid receptors reducing proinflammatory cytokine synthesis and inhibiting fibroblast proliferation and collagen synthesis via non-genomic and genomic pathways [ 20 , 21 ]. In addition, steroids decrease NO synthase in macrophages, leading to decreased NO secretion [ 22 ].…”

“…MPS was evaluated for treating early ARDS and showed positive therapeutic outcomes and improved survival [ 17 , 18 ] Methylprednisolone treatment of COVID-19 patients resulted in higher oxygenation index [ 19 ], with doses ranging from 1 mg/kg-body-weight per day to single doses of 40–500 mg [ 20 ]. However, systemic and prolonged administration of glucocorticoids is associated with severe side effects, such as interference with wound healing process, inhibition of effector cells in fighting active infections and other myopathic, cardiovascular and dermatologic side effects [ 23 , 24 ].…”

Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans

“…Glucocorticoids (GCs) are steroid hormones that regulate multiple physiological functions in all mammalian tissues, including development, immunomodulation, maintenance of circadian rhythm, and the response to stress [ 1 , 2 ]; connect external environmental stress signals with the function of many cell types, which produces profound changes in immune cells, including macrophages [ 3 ]; maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, as well as white and brown adipose tissues [ 4 ]; maintain tissue homeostasis; and regulate metabolism, cardiovascular and neural function, reproduction, and immune activity [ 5 ]. GCs are used to treat a variety of pathologies, such as inflammatory diseases [ 6 ], multiple sclerosis [ 7 ], systemic lupus erythematosus [ 8 ], lupus nephritis [ 9 ], Duchenne muscular dystrophy [ 10 ], rheumatoid arthritis [ 11 , 12 ], multiple myeloma [ 13 ], pediatric acute lymphoblastic leukemia [ 14 ], and respiratory pathologies [ 15 ], or as a part of complex therapy to treat SARS-CoV-2 infection [ 16 , 17 ] and various cancers including glioblastoma multiforme (GBM) [ 18 , 19 ]. The above demonstrates the usefulness and importance of GCs in the treatment of various pathologies, which is described in detail in numerous reviews devoted to various aspects of the therapeutic use of GCs and the molecular mechanisms of their action.…”