Lack of Clinical Benefit of Interferon β-1a Among Patients With Severe Acute Respiratory Distress Syndrome

Abstract

In acute respiratory distress syndrome (ARDS), the alveolarcapillary units are disrupted, with lung endothelial and epithelial injury resulting in exudative pulmonary edema containing inflammatory mediators, solutes, proteins, and leukocytes. 1 Treating pulmonary endothelial injury in ARDS may improve patient outcomes. Interferon β-1a (IFN-β-1a), a type 1 IFN, is one such treatment that may improve pulmonary endothelial barrier function. In addition to its myriad immunologic effects, IFN-β-1a upregulates cluster of differentiation 73 (CD73) on pulmonary endothelial cells, thereby increasing extracellular adenosine concentrations, which acting via adenosine receptors improves pulmonary endothelial barrier function through junctional reorganization, cytoskeleton rearrangement, and further transcriptional upregulation of CD73. [2][3][4] Based on these preclinical experimental observations, the clinical utility of IFN-β-1a for ARDS was previously tested by Bellingan and colleagues 5 in an open-label, phase 1/2 dosefinding study in adult patients with ARDS, with 28-day mortality as the primary end point. In this nonrandomized study, IFN-β-1a was administered in escalating doses, with an optimum tolerated dose of 10 μg. Among the 37 patients who received IFN-β-1a, mortality was 8% compared with a higher mortality rate of 32.2% among 59 control patients (recruited contemporaneously but not randomized). This mortality difference, albeit in a nonrandomized sample, prompted the authors to design an efficacy trial.In this issue of JAMA, Ranieri and colleagues 6 report the results of a clinical trial in which 301 adults admitted with moderate or severe ARDS based on the Berlin definition 7 were randomized to receive intravenous IFN-β-1a (10 μg) or placebo once daily for 6 days. The trial enrolled patients from 74 intensive care units in 8 European countries between December 2015 and December 2017. A novel approach was used to con-

Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review

“… 54 However, it is worth remembering that there is yet no evidence that suppressing the physiological inflammatory response to the virus is indeed beneficial. Previous experience with pharmaceutic inflammatory response modulation in patients with ARDS 55 and sepsis 56 have been notoriously unsuccessful.…”

Acute respiratory distress syndrome

“…163,164 The increasing interest in the use of enrichment strategies, either prognostic (enrolling patients at high risk for ARDS-related poor clinical outcomes) or predictive (enrolling patients with a biological phenotype well matched to the drug's mechanism) approaches, might improve the success rate of future studies. 165,166…”