Doubts about immune “storm” that kills some patients

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The mystery of what ultimately causes certain deaths from Covid-19 and how they can be prevented unfortunately remains

Scientists are now raising serious doubts about what causes the so-called “cytokine storm”, a self-destructive immune system reaction that severely worsens the condition of several patients with Covid-19.

The doubt focuses on a cytokine, interleukin-6 (IL-6), which has been held primarily responsible for the boomerang reaction of the body’s defenses against SARS-CoV-2 coronavirus, but this is not confirmed by the latest research. This, according to the New York Times, inevitably also casts doubt on the effectiveness of coronavirus treatments, which focus on interleukin-6, in order to catalyze the “storm”. It also preserves the mystery of what ultimately causes certain deaths from Covid-19 and how these can be prevented.

The “cytokine storm”, as an explanation for some of the deaths of coronavirus patients, began with early reports from China, where IL-6-blocking drugs were first tested, followed by similar reports from Italy. This immune overreaction is sometimes seen in severe infections, even if patients show a small to a negligible amount of coronavirus, which indicates that their body has “got rid” of it.  But – according to the “storm” theory – the body’s defenses can become uncontrollable, releasing massive cytokines, which cause serious damage to tissues and organs.

Some medicines that block interleukin-6 and are already in use (e.g. for the treatment of rheumatoid arthritis), were used in many hospitals around the world in the treatment of patients with Covid-19. But newer studies, some scientists argue (not everyone agrees), show that IL-6 is not the main culprit of “storms”, nor do the latter always occur with same way. New research has failed to show that anti-interleukin-6 drugs are effective in Covid-19, while in some cases IL-6 levels are not even more elevated in patients with coronavirus than in other patients who are in a serious condition for another reason.

Three studies in American medical journals (two in the JAMA Internal Medicine and one in the New England Journal of Medicine) found no evidence that a common IL-6 drug, tocilizumab for rheumatoid arthritis, reduces the risk of death in patients with Covid -19 in critical condition. The drug company Roche itself made its own tests and found that this does not really help in the case of Covid-19.

Some scientists, such as Dr Carolyn Calfeean intensive care medicine expert at the University of California, have a problem with the very term “cytokine storm,” which she says “has no specific definition.” The term may be imaginative and has caught the attention of the media and the public, but “without definition, there are no diagnostic criteria to show that there really is such a thing.”

But even if there is a “storm”, interleukin-6 is more of a passenger than a driver, as hundreds of cytokines are released when the immune system is activated and interacts with each other through complex processes. “You take this thing like spaghetti that is connected in so many different ways.” It’s very optimistic that IL-6 “will be the answer to everything,” said Dr Bruce Walker, director of immunology at the Ragon Institute of Massachusetts General Hospital and MIT and Harvard Hospitals.

Until recently, there were no systematic studies evaluating whether IL-6 levels were abnormally elevated in patients with Covid-19. But a new study, led by infectious disease specialist Jonathan Parr of the University of North Carolina, shows that it is not and it is often lower than in other serious cases (e.g. sepsis). A second study, led by Calfee, which evaluated five studies in more than 900 patients with severe Covid-19, found that interleukin-6 levels ranged from normal to only slightly elevated.

Pulmonologist-critical care physician Dr. William Fischer from the University of North Virginia pointed out that the idea of a cytokine storm ‘appears in the spotlight in any serious virus infection such as AIDS, Ebola, flu, Lassa fever, SARS and MERS’. But, as he said, “it can be difficult to tease apart what drives pathology — whether it’s just the virus or both the virus and the very immune response that is needed to clear the virus.”

In addition to IL-6, other factors, such as ferritin and CRP proteins, may be involved in the self-destructive defensive response. In any case, Calfee stressed, the new findings, on the role of IL-6 and the usefulness of the drugs against it, teach a lesson to doctors: “We have to be really humble about biologic complexity.”