Janelle Ayres, a physiologist specializing in infectious diseases at the Salk Institute for Biological Studies, describes this concept as a “disease tolerance mechanism” — the ability, sometimes hard-wired, sometimes induced by environmental factors, to survive infections without falling ill. “Our traditional view has been: To survive an infection, you have to kill it,” she told me. “We have a very disease-centric approach to biology.” But infection doesn’t always equate to disease. Many of the most frightening pathogens — tuberculosis, cholera, polio and now the coronavirus — don’t cause illness in everyone they infect. Some people experience these infections with few if any symptoms. Their immune systems evidently handle the invasion with the perfect balance of aggression, restraint and repair — or tolerance — to stave off disease. The drugs of the future, Ayres hopes, will enable these native tolerance mechanisms that help some shrug off, with few ill effects, the diseases that sicken and kill others.
The Covid-19 pandemic has already prompted many physicians to bend in this direction. So few tools exist to reliably eliminate the virus from our bodies that they have, out of necessity, turned to the idea of prodding the immune system in various ways. They have shifted their focus in a manner that Ayres has long argued is necessary: from eradicating the pathogen to helping the patient survive the pathogen. They are, in a way, pinning their hopes on innate tolerance mechanisms.
Dozens of trials are currently underway that focus on the immune system. These involve everything from cheap, over-the-counter pain medication to expensive antibodies manufactured in living cells. The drugs they are testing include anakinra, used by Navarro-Millán; leronlimab, a drug with anti-inflammatory properties originally developed to treat H.I.V.; and drugs that block IL-6 (full disclosure: My wife works for Genentech, owned by Roche, which manufactures tocilizumab, one of the IL-6 blockers). One study in Britain is testing high doses of a stomach-friendly formulation of the nonsteroidal anti-inflammatory ibuprofen, better known in the United States as Advil. (Don’t try this at home.) Researchers are even looking into low-dose X-ray radiation as a way to calm the immune system, a method that was used in the early 20th century to treat pneumonia but has since fallen out of use.
There’s an intriguing trial on an old drug originally developed to treat gout, a painful inflammatory condition of the joints, called colchicine. The drug, which was recently shown to offer protection against heart attacks, targets the very pathway — called NLRP3 inflammasome — that some scientists believe is naturally dampened in bats. Unlike biologics, which are given intravenously, colchicine can be taken in pill form. And while biologics can cost hundreds of dollars per dose, colchicine is dirt cheap. “We think that in the setting of this viral infection, NLRP3 gets activated aberrantly,” says Priscilla Hsue, a professor of medicine at U.C.S.F. and one of the physicians overseeing the trials. “And that leads to downstream badness.” The drug, it’s hoped, will prevent the immune system from ever getting to the point where it becomes overly activated. The study aims to start treatment early by sending pills to the homes of patients who have tested positive for Covid-19. “The thought is, If we can intervene early with an anti-inflammatory agent, we can have an impact on slowing down progression and keeping patients off ventilators,” Hsue says.
It remains to be seen which, if any, drug will work best, and what might be the unforeseen consequences of suppressing the immune system in the midst of its battle with the coronavirus. Some trials are already showing failures. Despite promising results from early, weak studies, two of the strongest trials to date on the IL-6 blockers tocilizumab and sarilumab suggest no benefit. (The pharmaceutical companies running the studies, Roche and Regeneron, are continuing with other trials testing their IL-6 blockers.)
Or maybe the studies would have produced better results had they been designed differently. Thomas Yadegar, who thinks tocilizumab can be a lifesaver, if used in the right way, surmises that one study didn’t employ stringent-enough criteria for choosing its study patients. Navarro-Millán thinks the trials tried to treat patients too late in the course of the disease. She likened these efforts to trying to cure Stage 4 metastatic cancer — probably doomed from the start.
Other researchers also raise this issue of timing — when doctors should administer drugs to curb immune responses — in a more general sense. Suppressing the immune system too soon after infection could be counterproductive because it might squelch the initial antiviral response and allow the coronavirus to proliferate, says Dawn Wahezi, a pediatric rheumatologist at Children’s Hospital at Montefiore. Yet treating too late may make it impossible to quell the eventual immune overreaction. “Knowing when is the right time — I think that’s one of the key components,” Wahezi told me. “There’s a very delicate window where immunomodulators can help.”