A safety evaluation of intermittent high-dose inhaled nitric oxide in viral pneumonia due to COVID-19: a randomised clinical study

Abstract

High-dose inhaled Nitric Oxide (iNO) has been shown to have anti-inflammatory, vasodilator, and antimicrobial properties, resulting in improved arterial oxygenation as well as a beneficial therapeutic effect on lower respiratory tract infections. This study evaluated the safety and efficacy of 150-ppm intermittent iNO administered with a novel iNO-generator, for treating adults hospitalised for viral pneumonia. In this prospective, open-label, multicenter study, subjects aged 18-80, diagnosed with viral pneumonia received either standard supportive treatment alone (Control-Group) or combined with iNO for 40 min, 4 times per day up to 7 days (Treatment-Group). Out of 40 recruited subjects, 35 were included in the intention-to-treat population (34 with COVID-19). Adverse Events rate was similar between the groups (56.3% vs. 42.1%; respectively). No treatment-related adverse events were reported, while 2 serious adverse events were accounted for by underlying pre-existing conditions. Among the Treatment-Group, oxygen support duration was reduced by 2.7 days (Hazard Ratio = 2.8; p = 0.0339), a greater number of subjects reached oxygen saturation ≥ 93% within hospitalisation period (Hazard Ratio = 5.4; p = 0.049), and a trend for earlier discharge was demonstrated. Intermittent 150-ppm iNO-treatment is well-tolerated, safe, and beneficial compared to usual care for spontaneously breathing hospitalised adults diagnosed with COVID-19 viral pneumonia.For over 25 years, inhaled Nitric Oxide (iNO) therapy has been used as a rescue treatment to improve arterial oxygenation in Acute Respiratory Distress Syndrome 1,2 , a major complication of Viral Pneumonia (VP). Nitric Oxide (NO) is a gas produced from arginine in mammalian cells by three NO synthase (NOS) enzymes: neuronal, endothelial, and inducible NO synthase (iNOS) 3 . Endogenous NO is an endothelium-derived relaxing factor that plays key roles in vascular signalling and blood flow regulation, induces vasodilation, and host defence against various microbial pathogens including bacteria, viruses, fungi, and parasites 4-6 . Following infection or cytokine stimulation, pulmonary iNOS expression is upregulated in macrophages and neutrophils, which play an important protective role against infectious organisms 7 .At high doses, NO demonstrates antimicrobial properties against a variety of infectious microorganisms. Pre-clinical and clinical evidence suggests iNO presents favourable clinical applications as a treatment of lung infections, due to multiple therapeutic properties including the potential reduction in microbial load [8][9][10][11][12][13] .VP is a serious threat to global health, especially after the outbreak of the coronavirus disease during 2019 (COVID-19) pandemic. Approximately 6 million cases of community-acquired pneumonia occur annually, with over 20% requiring hospitalisation 15 and a similar percentage presenting severe-critical pneumonia 16 . Along with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), noteworthy causes of VP are respira...