Home Nitric Oxide Therapy for COVID-19

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of cardiopulmonary and vascular complications, ranging from upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), as well as shock, acute kidney injury, and thromboembolic complications (1, 2). Although SARS-CoV-2 initially infects the upper respiratory tract epithelia, some of the most serious complications of the disease appear to arise through vascular inflammation and injury. Although further mechanistic and epidemiological studies are needed, case reports, imaging studies, and autopsy series have suggested the possibility that the SARS-CoV-2 virus, once in the lower respiratory tract, may directly infect endothelial cells, leading to a cascade of consequences including vasoplegia, vascular thromboses, pulmonary edema, endothelial sloughing, and abnormal regulation of pulmonary perfusion (2, 3). Regardless of the mechanisms, it is clear that patients often develop severe respiratory failure with hypoxemia that may be refractory to oxygen supplementation and often requires invasive mechanical ventilation. Because of the rapidity with which the virus spread, many healthcare systems were stressed by the sudden increase in coronavirus disease (COVID-19) cases, with the accompanying increased need for hospital beds, ICU beds, ventilators, and even oxygen. A high percentage of mechanically ventilated patients develop multi-organ failure syndrome, characterized by pressor-dependent shock and a high associated mortality. Even those who survive with the assistance of mechanical ventilation may require prolonged hospitalizations (4). These concerted adverse sequalae of SARS-CoV-2 infection create major strains on health care system resources.

It is with this backdrop that, in this issue of the Journal, Zamanian and colleagues (pp. 130–132) present an interesting and compelling case of a patient with pulmonary arterial hypertension (PAH) who was treated remotely in an ambulatory setting with inhaled nitric oxide (iNO) (5). This patient with well-controlled vasoreactive PAH lived in a remote area more than 300 miles away from their center and experienced symptoms of worsening breathlessness after being diagnosed with COVID-19. Considering her concerns about traveling the long distance to their center to receive care, and with recognition of her prior confirmed responsiveness to iNO, they established a plan to support her with an ambulatory iNO system while monitoring her symptoms, vital signs, and functional capacity remotely. The patient had rapid and sustained improvement in her 6-minute-walk distance, as assessed by her caregiver, and symptom score, and she recovered over several days without having to engage emergency department or hospital care.

This case report raises many questions. How might iNO have benefited this patient? Would we expect the benefit to be unique to iNO, or could other therapies that increase signaling along the NO axis also be helpful, such as NO donors, NO precursors, or phosphodiesterase 5 inhibitors? Can NO be safely administered to a patient in their own home, potentially helping to unburden overwhelmed healthcare systems?

NO is a free radial gas that functions as an important signaling molecule in human physiology. Its canonical receptor, guanylate cyclase, is highly expressed vascular smooth muscle cells, where it becomes activated once NO binds to its heme moiety, significantly increasing its enzymatic conversion of guanosine-5′-triphosphate to cyclic guanosine monophosphate, which subsequently promotes vasorelaxation. As a gas, it has unique pharmacological properties including its delivery into well-ventilated lung units where it promotes local vasodilatation. When NO enters the blood stream, it rapidly reacts with intraerythrocytic Hb, thus inactivating the NO, resulting in an extremely short half-life, which limits its systemic effects. By preferentially vasodilating pulmonary arterioles in well-ventilated lung units, it decreases the relative blood flow to poorly ventilated lung units and enhances $\stackrel{.}{\mathrm{V}}/\stackrel{.}{\mathrm{Q}}$ matching, increasing oxygenation (6). NO also induces mild bronchodilation, and inhibits neutrophil-mediated oxidative burst (6). These properties have been well known for decades and have led to U.S. Food and Drug Administration approval for the treatment of persistent pulmonary hypertension of the newborn, as well as various trials of iNO for patients with myriad conditions including ARDS, right ventricular failure after cardiac surgery, acute pulmonary embolism, and more recently pulmonary fibrosis in patients requiring long-term oxygen therapy (6–10). In patients with SARS, iNO was associated with improvements in oxygenation in a severity-matched observational cohort (11). Both endogenous and exogenous NO were shown to inhibit SARS-CoV viral replication (12). While iNO has not been shown to reduce the time on mechanical ventilation or mortality in adults with ARDS, iNO does significantly improve oxygenation in ARDS patients and leads to reduction in pulmonary vascular resistance (6) (Figure 1). These therapeutic responses suggest that iNO could be used early in the course of COVID-19 infection to reduce the need for invasive mechanical ventilation. Studies of prone positioning and neuromuscular blockers in ARDS both provide a historical reminder of that potential, as clinical trials of early delivery of those therapies demonstrated benefits where prior studies had not (13, 14).

Figure 1.

Summary of major therapeutic properties of inhaled nitric oxide gas (NO). From top left: inhaled NO gas is known to be a selective pulmonary vasodilator. NO can improve right heart function and decrease pulmonary vasoconstriction in subjects with acute and chronic pulmonary hypertension. Middle left vignette: breathing NO gas is shown to improve ventilation and provide bronchodilation in mild asthmatic subjects. Bottom left vignette: NO gas in the alveolar space improves oxygenation by increasing blood flow to ventilated lung units (i.e., improvement of ventilation perfusion matching). Top and middle right vignettes: in vitro and in vivo data showed that NO gas can act as an antiinflammatory and antithrombotic agent. Bottom right vignette: NO donors and NO gas showed antibacterial and antiviral properties in in vitro studies and early clinical investigations. The extent of benefits of these six therapeutic pathways of NO gas in coronavirus disease (COVID-19) infection are now under investigation. Some of those studies testing NO therapeutic properties are highlighted in Table 1.

Zamanian’s case also highlights the feasibility of portable iNO delivery systems to treat patients at home, an option not previously available. While GENOSYL DS (VERO Biotech) is designed for the hospital intensive care setting, it has features, such as a tankless delivery system, that make it feasible to deliver at home, as demonstrated in this case. Other systems, such as INOpulse (Bellerophon Therapeutics), Nu-Med Plus (UT), and an iridium electric NO generator (Third Pole Therapeutics), have been designed with at least some degree of portability. Although there would be concerns in treating patients with a therapy like iNO at home, there is precedent. In a randomized and placebo-controlled trial of ambulatory patients with fibrotic lung disease requiring long-term oxygen, INOpulse therapy was associated with greater physical activity than placebo, and in an acute dose escalation study of patients with pulmonary hypertension associated with pulmonary fibrosis, iNO delivered through the INOpulse system lead to a 30% reduction in pulmonary vascular resistance, with improvements in $\dot{\mathrm{Q}}$ and pulmonary artery compliance (15).

It is important to recognize that the experience of Dr. Zamanian’s patient is unlikely to be representative of all patients with COVID-19, or even those with PAH complicated by COVID-19. This patient had an established diagnosis of vasoreactive PAH, and as a physician herself, was uniquely qualified to engage in a complex treatment regimen. But the example serves as an interesting proof-of-concept study that supports the rationale of studying iNO therapy in patients with COVID-19 to establish if this intervention can improve oxygenation and reduce need for mechanical ventilation. In Table 1, we have summarized planned and ongoing clinical trials available that are testing NO gas therapy in COVID-19 patients. Dr. Zamanian and colleagues are to be commended for their innovative approach and important contribution to this field.

Table 1.

Ongoing Clinical Trials Registered on clinicaltrials.gov Testing NO Gas in COVID-19 Infection

Short Title	PI	Coordinating Center	Study Design	Drug	Dose (ppm)	Duration	Subjects (n)	Study Status	Follow-up (d)	Detailed Protocol	Primary Endpoint	Secondary Endpoint	NCT Number
NO Therapy: Healthcare Providers	Lorenzo Berra	MGH, Boston	Multicenter, open-label RCT	NO gas	160	15 min twice daily	470	Recruiting	14	https://www.medrxiv.org/content/10.1101/2020.04.05.20054544v1	Prevention of COVID-19 in healthcare providers	(I) Prevention to become positive	NCT04312243
												(II) Number of quarantine days
NO Therapy: COVID-19 Infection in ED	Stuart Harris	MGH, Boston	RCT	NO gas	250	30 min, single dose	260	Recruiting	28	Not available	Rates of return visits to the ED	(I) Inpatient hospitalization	NCT04338828
												(II) Rates of intubation
												(III) Mortality
NO Therapy: Spontaneous Breathing COVID-19 Infection	Lorenzo Berra	MGH, Boston	Multicenter, open-label RCT	NO gas	160	30 min twice daily	240	Recruiting	28	https://www.medrxiv.org/content/10.1101/2020.03.10.20033522v1	Prevention of progression of the disease	(I) Antimicrobial effect	NCT04305457
												(II) Other clinical outcomes
NO Therapy: Ventilated Patients with COVID-19	Lorenzo Berra	MGH, Boston	Multicenter, open-label RCT	NO gas	Initial dose 80	Continuous until extubation	200	Recruiting	90	https://www.medrxiv.org/content/10.1101/2020.03.09.20033530v1	Sustained improved oxygenation	(I) Time to reach normoxia	NCT04306393
												(II) Other clinical outcome
High-Dose NO for COVID-19 (ICU Patients)	Jennifer Lister	University Health Network, Toronto	Multicenter, open-label RCT	NO gas	160	6 h for 2 d	20	Not yet recruiting	3	Not available	Rate of PCR positivity	Not available	NCT04383002
The NO-COVID-19 Study	Marvin Kostam	Tufts Medical Center, Boston	Open-label RCT	NO gas	20	Not available	42	Not yet recruiting	28	Not available	Prevention of progression of the disease	(I) Prevention of progression	NCT04388683
												(II) Clinical improvement
Pulsed NO in Mild or Moderate COVID-19	Hunter Gilles	Not available	Expanded access	NO gas	20	14 d	Not available	Recruiting	28	Not available	Prevention of progression of the disease	Not available	NCT04358588
Randomized Trial of INOpulse for COVID-19	Roger Alvarez	Miller School of Medicine, Miami	Placebo- controlled RCT	NO gas	40	To resolution of acute hypoxemia	30	Not yet recruiting	2	Not available	Safety and tolerability	(I) Prevention of progression	NCT04398290
												(II) Clinical improvement
NO Releasing Solutions to Prevent and Treat COVID-19	Jeremy Road	BC Diabetes Vancouver	Multicenter RCT	NORS	Not available	14	200	Recruiting	21	Not available	Prevention of COVID-19 and progression of the disease	(I) Prevention of progression	NCT04337918
												(II) Antimicrobial effect
NO Treatment for Lung Infections	Jeremy Road	Diamond Centre Vancouver	Sequential assignment	NO gas	160	Not available	20	Active, not recruiting	26	Not available	Safety	(I) Lung function	NCT03331445
												(II) Antimicrobial effect
												(III) Quality of life

Definition of abbreviations: BC = British Columbia; COVID-19 = coronavirus disease; ED = emergency department; MGH = Massachusetts General Hospital; NO = nitric oxide; NORS = NO-releasing solution; PI = principal investigator; RCT = randomized controlled trial.