Nitric oxide helps your cells work. It’s a colorless, odorless gas that plays an important role in the function of the body, especially in the respiratory system. It encourages normal vascular function. It helps regulate inflammation. And it has antimicrobial qualities, which is to say it attacks invading organisms.
But there’s a problem: A serious novel coronavirus infection seems to result in or at least overlap with a loss of nitric oxide. That might be a factor in some of the more dangerous aspects of the disease—one scientists think could potentially be helped with something as simple as an inhaler.
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A team of scientists at Washington, D.C.’s George Washington University and Albert Einstein College of Medicine in the Bronx suspect they’ve connected the dots. If COVID-19 patients suffer from a lack of nitric oxide, the scientists’ reasoning goes, why not just hand them a machine full of the stuff?
The idea is elegant in its simplicity. But that simplicity could be deceiving, outside experts cautioned.
The feds have approved a few companies to provide pricey nitric-oxide devices for use by COVID-19 patients on an emergency basis. But that won’t cut it when more than 1,000 people per day are dying with COVID-19 in the United States. Doctors need effective therapies they can safely administer widely and routinely, in hospitals and at home, at reasonable cost.
Also known by its chemical shorthand “NO,” nitric oxide has a long history in medicine. For decades, doctors have administered it to treat a variety of pulmonary diseases, including older types of coronavirus infections.
Normally, our blood vessels produce their own NO, using it to ward off viruses and control inflammation, among other functions. When you’re sick with a respiratory virus or some other disease and your body can’t make its own NO, doctors can add it to your system by way of an inhaler or a tank.
Besides a range of viral infections, research indicates NO also works on hemorrhagic shock, type 2 diabetes, hypoxia-reoxygenation injury, and hypoxia-induced sickle cell crises.
If NO helps treat those diseases, it could work on COVID-19, medical researchers Nagasai Adusumilli, David Zhang, Joel Friedman, and Adam Friedman concluded. “Exogenous NO for targeted patient populations may be a treatment that can reduce viral load in the lungs [and] prevent the chain of events that rapidly destabilizes patients,” they recently wrote in the science journal Nitric Oxide.
Working with Pedro Cabrales, a University of California, San Diego bioengineer, the GWU-Albert Einstein team conducted experiments on mice, hamsters, rats and pigs, administering NO and studying the results.
They determined that dosing COVID patients with NO might, among other benefits, help to calm the overactive immune response—the so-called “cytokine storm”—that has proved so dangerous in some severe novel coronavirus cases.
The tests “clearly show that in both acute and chronic inflammatory conditions, systemic enhancement of NO levels in the circulation prevent and reverse cytokine-storm symptoms,” Joel Friedman told The Daily Beast.
There are other benefits, Friedman added. Giving a COVID-19 patient NO could “reduce pro-inflammatory cytokine profiles, deactivate the activated killer macrophages, restore tissue perfusion, reduce vascular leakage, inhibit the sticking of cells on the lining of blood vessels, reverse blood flow stagnation, and reduce oxidative damage.”
In short, Friedman concluded, “inhalation of gaseous NO is anticipated to reduce the viral load and thereby limit the inflammatory response.”
Friedman and his colleagues might be on to something, Ankit Desai, a professor of medicine at Indiana University, told The Daily Beast. After all, inhaled NO —“iNO,” in medical parlance—has a history of success.
“Best part of inhaled NO is we’ve got decades of experience with it,” Desai explained.
And the need is clear. There aren’t a lot of highly effective therapies for early treatment of potentially severe COVID-19 cases, Desai said. “We have Remdesivir that might have some effect in some patients.” Other than that, “we have nothing.”
He’s exaggerating, but only slightly. There are other COVID-19 therapies besides Remdesivir, an antiviral that doctors administer via injection and seems to shorten hospital stays. The widely available steroid dexamethasone seems to help reduce mortality, and there’s still promise in plasma drawn from recovered COVID-19 patients.
But what Desai wants is a simple, widely available therapy that is broadly effective.
Before we can add inhaled nitric oxide to the therapeutic toolkit for COVID-19, we first need to know for sure that it’s safe and it works. Right now, there isn’t a lot of human data.
NO has proved to be reasonably safe in the treatment of non-COVID diseases, Desai said. But he stressed that where doctors administer the gas in non-COVID cases, they usually do so in what he described as a “monitored setting,” with doctors and nurses directly overseeing treatment.
It could be riskier sending patients home, unsupervised, with an NO device of their own.
The FDA has approved several companies, including VERO Biotech in Atlanta, to sell NO-dosing machine to COVID-19 patients for home use. VERO Biotech did not respond to a request for comment.
Last month, in the American Journal of Respiratory and Critical Care Medicine, a trio of researchers examined one case where a doctor sent a COVID-19 patient home with VERO Biotech’s device. “The patient had rapid and sustained improvement,” they wrote.
But there were caveats, especially when it came to safety. The patient herself was a doctor and was familiar with the NO system. She “was uniquely qualified to engage in a complex treatment regimen,” as the researchers wrote.
A few isolated cases like that aren’t enough to satisfy most scientists or the FDA. Adusumilli, Zhang, Friedman and Friedman admitted there wasn’t enough data on home-use of NO devices. “As groups continue to publish more results with their respective NO platforms, dosing and protocol variations should be examined in evaluating the studies,” they wrote.
Even if it’s safe, it’s not clear that NO would do for novel coronavirus-infected humans what early tests indicate it does in hamsters and pigs.
“It is important to remember that there are no compelling human data supporting a mortality benefit with use of iNO for COVID-19 or other forms of respiratory failure,” Kathleen Chiotos, a pediatrician and researcher at The Children’s Hospital of Philadelphia, told The Daily Beast. “Well-designed clinical trials are therefore critical to establish the effectiveness of iNO before recommending widespread use of this therapy for COVID-19 patients.”
There’s another problem, Desai pointed out. “Currently, inhaled NO is not considered one of the cheapest drugs.” It costs around $150 per hour per patient to administer NO at a hospital. A whole course of treatment could cost $15,000.
It doesn’t matter if NO works on COVID-19 if people can’t afford to pay for it.
“Implementing is just as challenging as the discovery of disease sometimes,” Desai said.
