Nitric Oxide (NO) inhalation to treat COVID-19: coupling in-situ NO-generating modules to ventilators

**COVID-19:** in December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral pneumonia of unknown cause. Coronavirus RNA was quickly identified in some of these patients. This novel coronavirus has been designated SARS-CoV-2, and the disease caused by this virus defined as COVID-19\. This disease has now become pandemic, and with well over 1 million confirmed cases, 100,000 deaths and a case fatality rate that exceeds that of influenza by at least an order of magnitude. COVID-19 represents a substantial challenge to healthcare systems and economies worldwide.

**Nitric Oxide (NO) gas:** (not to be confused with Nitrous Oxide, N2O, or Nitrogen Dioxide, NO2) is produced naturally by the body for controlling numerous bodily functions (e.g. blood flow, wound healing, inflammation) and as a potent antimicrobial (including against drug-resistant bacteria, fungi and viruses). NO inhalation therapy, in which NO gas in controlled concentrations is delivered to patients' lungs via ventilators, is an approved treatment for a number of respiratory conditions. Currently approved NO inhalation therapy systems mix NO gas, stored in large compressed gas cylinders, with air flow for breathing. NO inhalation is currently being investigated by several research groups worldwide for treatment and prevention of COVID-19 - the therapy previously showed promise during the 2002 SARS outbreak.

**Problem:** assuming the therapy works in clinical studies, key barriers remain to rapid, widespread and cost-effective deployment. Current systems using compressed NO gas cylinders are prohibitively expensive (£100/hour over several days of continuous treatment) and only available for niche use - scaling up delivery to address COVID-19 would be expensive and logistically impractical.

**Potential solution:** plasma technology (electrically ionised gas, the fourth state of matter after solid, liquid and gas) can produce NO in-situ from air (nitrogen and oxygen). Coupled in-line to existing ventilators, Fourth State's compact, modular and affordable plasma devices could intelligently deliver NO in the flow of air to the lungs, using just electricity as an input. Our devices have previously been independently verified by UK universities to produce NO in controlled quantities, with corresponding known biological effects (antimicrobial action, accelerated wound healing processes).