Cytokine Storm and COVID-19 Mortality: Have We Been Barking Up the Wrong Tree?

“It doesn't make any difference how smart you are, who made the guess, or what his name is. If it disagrees with experiment, it's wrong. That's all there is to it."

- Richard P. Fenyman, American theoretical physicist, Nobel laureate in Physics

"The great tragedy of Science, is the slaying of a beautiful hypothesis by an ugly fact."

- Thomas Henry Huxley, English biologist and anthropologist

Cytokines play a key role in host defense against many microbes, including viruses. But when they’re unregulated, cytokines can cause tissue destruction culminating in death. Recently, interferons (IFNs), a group of cytokines, have been implicated in COVID-19-related mortality. The goal of this Germ Gem post is to provide some background on cytokines in general and to highlight IFNs in particular.

The cytokine storm hypothesis. The first step in the scientific method is to formulate a hypothesis (usually based upon observation) that could explain a given phenomenon. From the earliest days of the COVID-19 pandemic, clinical observations by Chinese doctors suggested that severe and fatal disease, involving damage of many organs, such as the lungs, heart, and kidneys, was caused by a cytokine storm. Treatment with corticosteroids, potent inhibitors of cytokine production, supported this hypothesis and set the stage for a sustained belief that unregulated cytokine release was killing patients. As is often the case in medicine, as more evidence accumulated the popularity of the cytokine hypothesis waned. But then it was resurrected by a large international study published in Science in October, “Autoantibodies against type I IFNs in patients with life-threatening COVID-19.” The findings in this study suggest that the cytokine hypothesis should be narrowed to the class of cytokines called IFNs.

What are cytokines and what is a ‘cytokine storm’? The term ‘cytokine’ is derived from two Greek words, “cyto” meaning cell and “kinos” meaning movement. Cytokines are proteins produced by cells of the immune system that function as signaling molecules. They trigger an array of cellular responses, such as movement (“calling in the troops”) to sites of inflammation, infection, or trauma. There are many types of cytokines, including interleukins, interferons, tumor necrosis factors, growth factors, and others. (I was just getting started in my research career in 1977 when the first interleukin [IL-1] was discovered; now we have IL-1 to IL-38!) In an excellent review on “Cytokine Storm” in the New England Journal of Medicine in December, cytokine storm is defined as “life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.”

If that sounds terribly complicated—it is. Nevertheless, it is very important because as we’ve seen in the case of life-threatening COVID-19, the hypothetical role of cytokines (and of a cytokine storm) has directed treatment approaches from the very start of this pandemic. In fact, the early experience of the Chinese with using corticosteroids to treat severe COVID-19 led to a large randomized clinical trial (RCT) coordinated by Oxford University of the corticosteroid dexamethasone that demonstrated the benefits of treating life-threatening COVID-19 with this corticosteroid. In this case, the hypothesis was borne out. The drug worked. To this day, dexamethasone remains the only therapeutic agent we have in our arsenal for treating severe COVID-19. (Surprisingly, however, RCTs of two other drugs that suppress cytokine-mediated injury in rheumatic diseases [systemic lupus erythematosus and rheumatoid arthritis], namely hydroxychloroquine and tocilizumab, which selectively targets IL-6, showed that these agents are ineffective in the treatment of severe COVID-19.)

What’s the story on IFNs? Like other cytokines, IFNs are cell-signaling proteins that are released in response to pathogens, such as viruses and bacteria, that trigger defenses of the immune system. They are named after their ability to “interfere” with virus replication inside host cells. They also activate immune cells, such as natural killer cells and macrophages, and they increase the ability of uninfected host cells to resist new infection by viruses. The IFN family consists of three main classes of cytokines: type I IFNs, type II IFN, and type III IFN. Seven IFNs have been identified in humans; all are very important for fighting viral infections.

In the October Science article mentioned above, the researchers found that 10% of COVID-19 patients who developed life-threatening pneumonia had antibodies that disable IFNs. (This finding has excited many immunologists and virologists.) These antibodies—known as autoantibodies because they attack proteins of the body itself—were not found in any people with mild or asymptomatic COVID-19 infections. Another unexpected finding was that 94% of patients with these autoantibodies were men, possibly explaining, in part, why men are at greater risk of severe COVID-19.

So where do we go from here with IFNs? The recent evidence shows that IFNs play a critical role in preventing SARS-CoV-2-mediated death. But what’s next? As was reported by Liz Szabo in an article in Kaiser Health News in November (“’Breakthrough Finding’ Reveals Why Certain COVID Patients Die”), “doctors should be cautious about interferon for now, because a study led by the World Health Organization found no benefit from an injected form of the drug in COVID patients.” Nonetheless, researchers have launched more than 100 clinical trials of IFNs that are registered in the National Institutes of Health’s research database (clinicaltrials.gov). While no one knows where these early studies will lead, the hypothesis that IFNs play a key role in preventing severe COVID-19 is supported by evidence. Thus, these cytokines are going to be in the limelight for some time to come.