How does COVID-19 kill? Uncertainty over whether it is the virus itself \u2014 or the response by a person\u2019s immune system \u2014 that ultimately overwhelms a patient\u2019s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.<\/p>
Clinical data suggest that the immune system plays a part in the decline and death of people infected with the new coronavirus, and this has spurred a push for treatments such as steroids that rein in that immune response. But some of these treatments act broadly to suppress the immune system, stoking fears that they could actually hamper the body\u2019s ability to keep the viral infection in check.<\/p>
\u201cMy greatest fear is that this gets taken to an extreme, where people are using whatever they can get their hands on to turn off the immune response,\u201d says Daniel Chen, an immunologist and chief medical officer at IGM Biosciences in Mountain View, California. \u201cYou can\u2019t knock down the immune system at a time when it\u2019s battling an infection.\u201d<\/p>
As coronavirus patients flood hospitals worldwide, physicians are wading through streams of incomplete data and preprints that have not been peer-reviewed, struggling to find ways to help their patients and sharing experiences on social media. Some doctors are trying cocktails of unproven therapies in a desperate bid to save lives.<\/p>
\u201cPeople are watching patients deteriorate before their eyes, and there\u2019s a very strong motivation to reach for any therapy that you think could be effective,\u201d says Kenneth Baillie, an intensive-care anaesthetist at the University of Edinburgh, UK. \u201cWhen I feel powerless at the end of a bed, I feel the same.\u201d<\/p>
Some of the earliest analyses of coronavirus patients in China suggested that it might not be only the virus that ravages the lungs and kills; rather, an overactive immune response might also make people severely ill or cause death. Some people who were critically ill with COVID-19 had high blood levels of proteins called cytokines, some of which can ramp up immune responses. These include a small but potent signalling protein called interleukin-6 (IL-6). IL-6 is a call-to-arms for some components of the immune system, including cells called macrophages. Macrophages fuel inflammation and can damage normal lung cells as well. The release of those cytokines, known as a cytokine storm, can also occur with other viruses, such as HIV.<\/p>
The ideal counter, then, would be a drug that blocks IL-6 activity and reduces the flow of macrophages into the lungs. Such drugs, known as IL-6 inhibitors, already exist for the treatment of rheumatoid arthritis and other disorders. One called Actemra (tocilizumab), made by the Swiss pharmaceutical firm Roche, has been approved in China to treat coronavirus patients, and researchers around the world are working furiously to test it and other drugs of this type.<\/p>
But globally there is not enough of the drug to go round, and many clinicians are turning to steroids, which more broadly dampen the immune system, says James Gulley, an immuno-oncologist at the National Cancer Institute in Bethesda, Maryland. IL-6 inhibitors may suppress only those immune responses that are governed by IL-6, allowing other immune responses that might help the body fight COVID-19 to continue. But steroids and some other therapies that act more generally might significantly reduce the body\u2019s ability to fight infection overall. These drugs will not only suppress macrophages, but also immune cells called CD4 T cells, which are crucial for initiating immune responses, and also CD8 T cells, which are the body\u2019s antiviral assassins, capable of destroying infected cells with more precision than macrophages. \u201cWhen things get really bad, they\u2019ll throw on steroids,\u201d says Gulley. \u201cI am a bit worried about where some people are going.\u201d<\/p>
Chen notes that although IL-6 levels are high in some acutely ill patients, viral loads are high as well, suggesting that the body is still fighting off an active viral infection. \u201cYou have to assume that there\u2019s an ongoing antiviral immune response that is important to these patients,\u201d he says. If so, then reducing CD4 and CD8 T cells could undermine that response.<\/p>
Steroids and other immune suppressants are already being tested against coronavirus in clinical trials. In March, UK researchers launched the RECOVERY study, a randomized clinical trial that will evaluate the steroid dexamethasone and other potential treatments for COVID-19. This worries rheumatologist Jessica Manson at University College Hospital in London. Evidence from previous outbreaks caused by related coronaviruses suggests that steroids hold little benefit, and might even delay the time it takes for patients to rid themselves of the virus, she says. And the RECOVERY trial calls for giving the treatments before patients become critically ill and have no other recourse.<\/p>
But Peter Horby, who studies infectious diseases at Oxford University in the UK and leader of the RECOVERY trial, notes that the trial will be using relatively low doses of steroid. \u201cHigher doses are not routinely recommended, but the jury is out on lower doses,\u201d he says. \u201cAnd many authorities, including the World Health Organization, recommend a trial.\u201d<\/p>
A combination of damage from both a virus and the immune response to it is not uncommon, says Rafi Ahmed, a viral immunologist at Emory University in Atlanta, Georgia. The effects of ‘hit-and-run’ viruses such as norovirus, which make people sick almost immediately after infection, are more probably due to the virus itself, he says. By contrast, people infected with viruses such as coronavirus do not show symptoms until several days after infection. By then, collateral damage from the immune response often contributes to the illness.<\/p>
\u201cIt\u2019s very hard to dissect what per cent of it is due to the virus itself, and what per cent is the immune response,\u201d Ahmed says. \u201cBut it\u2019s almost always a combination of the two.\u201d<\/p>
In the absence of an answer, Ahmed is hopeful that researchers will arrive at a combination therapy, such as an IL-6 inhibitor that does not completely suppress the immune system, combined with an antiviral drug that directly targets the virus. Other drugs that target the immune system are also being tested, including one called anakinra, which targets a signalling protein called IL-1, and may provide a way to reduce specific immune responses without hampering CD4 and CD8 T cells, says Chen.<\/p>
But Baillie says that given the widespread use of steroids to treat people with coronavirus already, it is important to collect data on the practice. And although he is also concerned about suppressing immune responses in coronavirus patients, he notes that it is still possible that the practice could hold some benefit. \u201cThe only responsible thing to do is to use them in the context of a randomized clinical trial,\u201d he says. \u201cThere\u2019s no other way to know if a treatment is working.\u201d<\/p>