A well-known scientific journal writes about the doubts that doctors and scientists face when analyzing data on the treatment of coronavirus. Experts agree that the patient's immune response interferes with healing, but they disagree on how to bypass the immune system without harming the patient.
How does COVID-19 kill? Doubts about what exactly infects human organs - the virus itself or the response of the infected person's immune system - prevent doctors from finding optimal ways to treat patients suffering from severe coronavirus.
Clinical evidence suggests that the immune system plays a role in people infected with the new coronavirus weakening and dying. This gave rise to the use of drugs such as steroids, which curb such a powerful immune response. But some drugs suppress the immune system, and this raises concerns that such drugs are actually interfering with the body's ability to cope with viral infections.
“What scares me the most is that it goes to extremes when people grab onto anything in an attempt to turn off the immune response,” said immunologist Daniel Chen, who is the medical director of the biotech company IJ -Em Biosciences "(IGM Biosciences). "You can simply disable the immune system as it fights the infection."
Chasing medicine
Today, with coronavirus cases overwhelming hospitals around the world, doctors are sifting through mountains of incomplete data and peer-reviewed research papers to find ways to help patients and share their experiences on social media. Some doctors, in a desperate attempt to save the lives of patients, resort to combinations of unproven drugs and treatments.
“People see patients fading away before their very eyes, and they have a very strong urge to grab onto any drug they think is effective,” says resuscitation anesthesiologist Kenneth Bailli, who works in Britain at the University of Edinburgh. "I have the same desire when I stand at the patient's bedside and feel powerless."
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The first tests taken from those infected with the coronavirus in China indicate that not only the virus infects the lungs and kills the patient. Rather, the overreaction of the immune system causes severe illness and death. Some people with severe COVID-19 have very high levels of cytokine proteins in their blood, which can enhance the immune response. Among them is the small but powerful signaling protein interleukin-6 (IL-6). IL-6 calls to arms several components of the immune system, including macrophage cells. Macrophages increase inflammation, but can also infect healthy lung cells. The release of cytokines, which is known as a cytokine storm, occurs during other viral infections such as HIV.
Thus, a drug that blocks interleukin-6 activity and reduces the influx of macrophages into the lungs should be the ideal counterbalance. Such drugs, known as IL-6 inhibitors, are already being used to treat rheumatoid arthritis and other conditions. One of them is called Actemra (tocilizumab), and is produced by the Swiss pharmaceutical company Roche. In China, it is approved for the treatment of those infected with the coronavirus, and scientists around the world are hastily testing Actemra and other drugs of this type.
Immunity problems
But in the world, this drug is simply not enough, and many physicians use steroids, which are more active in weakening the immune system, says James Gulle, an immuno-oncologist at the National Cancer Institute in Bethesda, Maryland. IL-6 inhibitors can only suppress the immune responses controlled by IL-6, allowing other immune responses that help the body fight COVID-19 to continue to function. However, steroids and certain other drugs with more general effects can significantly impair the body's ability to fight infection. They suppress not only macrophages, but also immune CD4 T cells, which are very important for triggering the immune response, as well as CD8 T cells, which are antiviral killers in the body.capable of destroying infected cells much more accurately than macrophages. “When things get really bad, they add steroids,” says Galli. "I'm a little worried about the direction some of the doctors are heading."
Chen notes that although the level of IL-6 in some critically ill patients is high, the concentration of the virus in the blood is also very high, which suggests that the body is still fighting an active viral infection. “We have to assume that the antiviral immune response continues, which is very important for these patients,” he says. If this is the case, then decreasing the number of CD4 and CD8 T cells may weaken this response.
Steroids and other drugs to suppress the immune system are already undergoing clinical testing to combat coronavirus. In March, British scientists began a study called RECOVERY, which is a randomized clinical trial of the steroid dexamethasone and other drugs to treat COVID-19. This is alarming for rheumatologist Jessica Manson of University College London Hospital. Data from previous epidemics caused by related coronaviruses suggest that steroids are of little use and may even lengthen the time it takes for a sick person to clear the virus, she notes. The RECOVERY study may lead to the fact that these drugs are given to patients before they become seriously ill, and they have no other choice.
However, Peter Horby, who studies infectious diseases at Oxford University and is leading this study, notes that it uses relatively small doses of steroids. “We generally don't recommend larger doses, but lower doses are not so clear,” he says. "And this test has been recommended by so many reputable bodies, including the World Health Organization."
Complex therapy
Combined damage from the virus and the immune response is common, says viral immunologist Rafi Ahmed, who works in Atlanta at Emory University. Exposure to viruses such as norovirus, which works in a fight-and-flight fashion that causes a person to get sick almost immediately after infection, is most likely caused by the virus itself, he says. However, people who become infected with the coronavirus do not develop symptoms until a few days after infection. By then, the collateral damage from the immune response often aggravates the disease.
“It is very difficult to determine exactly which percentage is caused by the virus itself and which is the immune response,” says Ahmed. "But it's almost always a combined effect."
Ahmed hopes that in the absence of an answer to this question, scientists will conclude that complex therapy is necessary, say, with the use of an IL-6 inhibitor, which does not completely suppress the immune system, in combination with an antiviral drug that directly affects the virus. Other drugs that affect the immune system are also being tested, including Anakinra, which targets the signaling protein IL-1 and can attenuate some immune responses without interfering with CD4 and CD8 T cells, Chen said.
However, Bailey notes that steroids are now widely used in the treatment of people with coronavirus, and therefore it is important to collect data on the results. He is also worried about the suppression of the immune response in patients with COVID-19, but he emphasizes that such a practice can still bring some benefits. “The only responsible way is to use them in randomized clinical trials,” says Bailey. "We just have no other way to know if this treatment works."
By Heidi Ledford