Could a drug used in cancer treatment spare hospital patients from the ravages of severe COVID19?
Yale doctors think it can after giving the medication, known as tocilizumab, to severely ill patients back in March.
How does tocilizumab work? It has a long history of dampening the life-threatening immune system reactions cancer patients often experience while undergoing treatment. Since the same kind of dangerous response develops in many COVID19 cases, the researchers thought the drug might make a difference for the sickest patients.
The result -- while preliminary -- appears to be a dramatically lower death rate among patients placed on mechanical ventilators.
How much lower? Among the first 239 COVID19 patients treated at Yale New Haven Hospital, in Connecticut, during the early weeks of the pandemic, 153 were treated with tocilizumab, including all 48 patients who had been placed on ventilators. "Instead of survival rates of 10% to 50% reported elsewhere, it was 75% in [ventilated] patients treated with tocilizumab," said study author Dr. Christina Price, Yale's chief of clinical allergy and clinical immunology.
In addition, among those seriously ill patients who ultimately survived COVID19, tocilizumab appears to have significantly shortened overall ventilation time. While hospitals around the country were having to keep patients hooked up for between 12 to 14 days, ventilations at Yale typically lasted only about five days.
How tocilizumab works against COVID19?
What accounts for its apparent success against COVID19?
It all originates in the threat posed by a deadly immune system phenomenon known as "cytokine release syndrome" (CRS), an out-of-control inflammatory response that the virus triggers in some patients.
CRS is "when the body's response to fighting the virus goes so unchecked it ends up being harmful, damaging the liver, the kidney, the lungs. You need an immune response. You can't totally shut it down completely. But you can't let it get out of control, which is what can happen to cancer patients undergoing treatment. And to COVID patients," Price said.
The problem? "There were no [U.S. Food and Drug Administration]-approved medications for COVID in March," she stressed.
"Of course any time you try a new treatment, you want to do it in a controlled clinical trial setting. You obviously need to be very careful," Price explained. "But the reality was that we were seeing that a pandemic is about to hit and we just had to wade through this data-free zone to figure out what we were going to do, because if your grandmother comes in sick, you're going to try to do something. You're not going to do nothing."
Fortunately, Price said, "Yale has been a pioneer in immunotherapy in cancer. So most of us have a lot of expertise in clinical immunology. And we knew tocilizumab," a biologic therapy approved for the treatment of rheumatoid arthritis, a number of autoimmune diseases and CRS itself. "So, we know it can be a targeted immune system suppressant with surgical precision," she explained.
In addition, "there were some preliminary reports coming out of Spain, Italy and China, where some doctors had been using it and saying they were getting a good response," Price noted.
"So, we designed a very rigorous protocol for how and when to administer it," Price said. "And we went in big."
After seeing significant success among very sick COVID19 patients, Price and her team decided to expand their tocilizumab protocol, offering the drug to less ill patients, to tamp down or prevent CRS altogether.
Again, tocilizumab appeared to be effective, keeping patients with early signs of CRS from progressing to severe or critical disease. It also was good at "markedly blunting the need for mechanical ventilation in the intensive care unit," she added. In fact, when taking into account all patients given the drug, Yale's two-week COVID19 survival rate hit 87%, the researchers reported.
Another unexpected development: much lower rates of death among patients of color.
Black, Hispanic patients saw even better results
"More than 50% of our patients were Black and Hispanic," Price noted. "And those patients, after we adjusted for age, actually did better than our white patients, which is very different from what's happening everywhere else in the country."
As to why, Price said the jury is still out. "Our patients were not healthier. They had the same co-morbidities as everywhere else in the country. But I think it's because we developed a totally unbiased protocol. We based our judgment calls on who and when to give the drug based on specific threshold criteria, and nothing else," she said.
Still, Price acknowledged that it is premature to draw definitive conclusions about tocilizumab's promise. "We clearly have to wait for the rigorous randomized double-blind studies, which are being done now. They're ongoing," she added.
That caution was echoed by Dr. Albert Rizzo, chief medical officer of the American Lung Association.
"There's always a risk-benefit calculation that the frontline staff has to make in this kind of situation," he noted.
"They have to decide if a treatment is probably going to be of more benefit than harm when trying to save somebody, based on past experience and new information they're getting from other facilities. And so I do think it made good sense to use this drug in a protocol as they did at Yale," Rizzo said.
"But we'll know much better how to treat COVID19 patients six months from now, once all of the studies that are coming out are thoroughly vetted," he stressed.
"We'll find that some drugs work better with some patients than others. Or that some may do better with a combination of drugs. And until a vaccine is available, we will certainly have to continue to look for better drugs, and better cocktails. Because while this drug appears to improve survival, it isn't a cure," Rizzo said.
Price and her colleagues published their findings in the June 15 issue of Chest.
Another drug, an inexpensive steroid known as dexamethasone, has also shown promise in treating COVID19. Among 2,100 people with severe infections, it cut the odds of death in ventilated patients by one-third, British researchers reported last week. But Price noted some key differences between the two medications.
"As for dexamethasone, I'm super excited that something cheap and readily available could be game changer," said Price. "But my only caution is we only gave one dose of tocilizumab and we're getting these results. For dexamethasone, it's about 10 days of steroid, which is not trivial. And Black and brown people disproportionately have diabetes. And for someone with diabetes, the side effects associated with steroid use is not insignificant, as it shoots glucose levels sky-high."