Emerging pharmacological therapies for ARDS: COVID-19 and beyond

Abstract

ARDS, first described in 1967, is the commonest form of acute severe hypoxemic respiratory failure. Despite considerable advances in our knowledge regarding the pathophysiology of ARDS, insights into the biologic mechanisms of lung injury and repair, and advances in supportive care, particularly ventilatory management, there remains no effective pharmacological therapy for this syndrome. Hospital mortality at 40% remains unacceptably high underlining the need to continue to develop and test therapies for this devastating clinical condition. The purpose of the review is to critically appraise the current status of promising emerging pharmacological therapies for patients with ARDS and potential impact of these and other emerging therapies for COVID-19-induced ARDS. We focus on drugs that: (1) modulate the immune response, both via pleiotropic mechanisms and via specific pathway blockade effects, (2) modify epithelial and channel function, (3) target endothelial and vascular dysfunction, (4) have anticoagulant effects, and (5) enhance ARDS resolution. We also critically assess drugs that demonstrate potential in emerging reports from clinical studies in patients with COVID-19-induced ARDS. Several therapies show promise in earlier and later phase clinical testing, while a growing pipeline of therapies is in preclinical testing. The history of unsuccessful clinical trials of promising therapies underlines the challenges to successful translation. Given this, attention has been focused on the potential to identify biologically homogenous subtypes within ARDS, to enable us to target more specific therapies ‘precision medicines.’ It is hoped that the substantial number of studies globally investigating potential therapies for COVID-19 will lead to the rapid identification of effective therapies to reduce the mortality and morbidity of this devastating form of ARDS.

Is severe COVID-19 pneumonia a typical or atypical form of ARDS? And does it matter?

“…even if COVID-19 ARDS were an atypical subset of ARDS (and it's not clear that this is indeed the case), should this prompt any changes to management? The "vasocentric" pathophysiology demonstrated in this and many other studies suggests a potential role for vascular interventions such as therapeutic anticoagulation [13]; relevant clinical trials are ongoing. An important question is whether the findings of this study suggest any changes in ventilatory management.…”

Protective function of DJ-1/PARK7 in lipopolysaccharide and ventilator-induced acute lung injury

“…Protective mechanical ventilation strategies can lead to further exacerbation of lung injury caused by over-distention and repetitive mechanical stretch stress associated with ventilator-induced lung injury (VILI) [ [12] , [13] , [14] ]. Pharmacological approaches to alleviate ARDS/VILI do not currently exist but may be rapidly emerging [ 15 ].…”

Antiviral Dosing Modification for Coronavirus Disease 2019–Infected Patients Receiving Extracorporeal Therapy

“…Several investigational agents including chloroquine/hydroxychloroquine, azithromycin, dexamethasone, darunavir/ritonavir, lopinavir/ritonavir, favipiravir, and remdesivir are used clinically based on early published evidence of clinical efficacy. In addition, a list of potential drug therapies for acute respiratory distress syndrome (ARDS) in COVID-19–infected patients has been intensively reviewed by Horie et al ( 1 ). A recent results reported by Randomised Evaluation of COVID-19 Therapy (RECOVERY) Collaborative group showed that dexamethasone use in patients with COVID-19 infection receiving respiratory support significantly reduced the 28-day mortality ( 2 ).…”