JAK Inhibitors and Corticosteroids for COVID-19 Cytokine Storm Treatment

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• JAK Inhibitors Mechanism
• Corticosteroids Efficacy
• Patient Selection and Timing
• Clinical Markers of Inflammation
• Antiviral Therapies Role
• Full Transcript

JAK Inhibitors Mechanism

Dr. Randy Cron, MD, describes Janus kinase (JAK) inhibitors as small molecule medications. These drugs inhibit intracellular kinases, which are proteins that signal inside cells. JAK inhibitors target receptors for multiple pro-inflammatory cytokines, including interleukin-6 and interferon-gamma. This mechanism allows them to block signaling for several cytokines simultaneously.

Dr. Randy Cron, MD, notes that JAK inhibitors offer a middle ground in immunosuppression. They are not as broadly suppressive as glucocorticoids but target more than a single cytokine. Some studies have shown a survival benefit with these agents in severe COVID-19, while others have not demonstrated the same results.

Corticosteroids Efficacy

Dr. Randy Cron, MD, explains a significant shift in treatment paradigms. Despite World Health Organization guidance from prior coronavirus outbreaks (SARS, MERS) advising against steroids, they have proven highly effective for COVID-19. Glucocorticoids are now considered one of the best available treatments for the cytokine storm syndrome associated with this disease.

Dr. Randy Cron, MD, states that steroids are broadly immunosuppressive. While not a complete "home run," they are definitely helpful in modulating the hyperinflammatory response. Their widespread global availability also makes them a critical tool in managing severe cases.

Patient Selection and Timing

Dr. Randy Cron, MD, emphasizes that patient selection and timing are paramount for corticosteroid use. He explains the natural progression of COVID-19 infection. Up to 40% of infected individuals may be asymptomatic, while another 40-50% experience a cold or flu-like illness. The critical 10-20% require hospitalization due to respiratory distress and oxygen needs.

Dr. Cron advises against giving steroids within the first five days of symptoms. This is when the virus is actively replicating, and the immune system needs to fight the infection. The optimal time for steroid administration is when a patient develops an oxygen requirement and requires hospitalization, balancing immune support with inflammation control.

Clinical Markers of Inflammation

Identifying the right patients for immunomodulatory therapy requires monitoring specific clinical markers. Dr. Randy Cron, MD, notes that traditional cytokine storm syndrome criteria do not perform perfectly for COVID-19. Clinicians have developed COVID-specific criteria to better identify hyperinflammation.

Key indicators for treatment include fever, an oxygen requirement, confirmed infection by PCR, and evidence of lung disease on imaging (chest X-ray or CT). Dr. Randy Cron, MD, highlights that elevated markers of inflammation, such as C-reactive protein (CRP) or ferritin, further help identify patients who will benefit from steroids. This combination of clinical and laboratory findings guides treatment decisions.

Antiviral Therapies Role

Dr. Randy Cron, MD, underscores the importance of combining antiviral therapies with immunomodulators. Antivirals like remdesivir for hospitalized patients or oral protease inhibitors for outpatients work by preventing viral replication. Administering these agents early in the disease course is crucial.

Dr. Randy Cron, MD, explains that controlling the underlying viral trigger can prevent or lessen the severity of the subsequent cytokine storm. This principle applies to all cytokine storm syndromes: treating the inciting cause is a fundamental part of management. The interview with Dr. Anton Titov, MD, clarifies that a multi-pronged approach targeting both the virus and the hyperinflammatory response offers the best outcomes for patients.

Full Transcript

Dr. Randy Cron, MD: There are a group of medicines called Janus kinase inhibitors. These are small molecules that inhibit kinases, which are proteins inside the cell that signal. These kinases are associated with cytokine receptors for various pro-inflammatory cytokines like interleukin-6 or interferon-gamma. They not only inhibit the signaling of one cytokine but multiple cytokines that share these receptors and kinases. Nevertheless, they are not as broadly immunosuppressive as something like glucocorticoids. They are somewhere in between an individually targeted cytokine. Some studies have shown that they have benefit in terms of survival for patients with severe COVID-19, whereas others have not.

I think I mentioned this when we first spoke: one of the thoughts is that glucocorticoids, which are broadly available worldwide as anti-inflammatory steroids, despite the fact that prior coronavirus pandemics like SARS and MERS suggested to the World Health Organization and others that you should not give steroids for these conditions because they may actually make things worse by dampening your immune response to the virus. It turns out that steroids are probably the best treatment we have for the cytokine storm syndrome feature of this disease. That is because they are very broadly immunosuppressive. Again, not a home run like we see with other cytokine storm syndromes, but definitely helpful.

Dr. Randy Cron, MD: But it is complicated in terms of patient selection, like which patients with COVID you give these to. Probably just as important, if not more importantly, the timing of administration is really important. This virus may infect up to 40% of people who get infected, whether it is Delta, Omicron, or the original Alpha strains.

A lot of people are asymptomatic. Then there are a bunch of people, maybe up to 40–50%, who have a cold or flu-like illness for a week or two. It is not fun, but they are not hospitalized. Then there are the 10 to 20% who do require hospitalization with this virus. It is usually because the virus sets up shop in the lung, and they have respiratory distress and require oxygen.

With steroids, you probably are not going to want to give steroids within the first five days of symptoms like fever and cough, and sometimes GI symptoms, or whatever comes with the original infection. That is the time when the virus is really replicating and expanding, and there you want your immune system to be fighting the virus. Steroids will help prevent that during the early part of infection, but you do not want to wait until it is too late. Then when you develop an oxygen requirement and require hospitalization, people have looked at this from a variety of different ways in terms of looking at one of the markers of cytokine storm syndrome or hyperinflammation that we should be looking for.

Different people have looked at different things. Again, the criteria that we have used for other cytokine storms in the past do not perform that well in trying to identify those patients. So people have tried to even come up with their own criteria that are specific for COVID. They were okay, but they are not ideal either.

Dr. Randy Cron, MD: But nevertheless, if you have, in addition to fever and oxygen requirement, evidence of infection usually by PCR, evidence of lung disease usually by imaging whether it is chest X-ray or CT, for example, and you have one or two markers of inflammation that are elevated like C-reactive protein or elevated ferritin, then maybe these are the people who will benefit from steroids at that time. That has more or less been true. So steroids for most hospitalized patients have become standard of care.

This does not bespeak at all the use of antivirals, which you also want to give early, whether you are hospitalized and you would get remdesivir or outpatient there is some oral combination of protease inhibitors, for example, that have shown benefit at preventing the virus from replicating. If you can prevent the virus, the cytokine storm aspect of it may be less severe. That is something that is true of all our cytokine storms: if you know the underlying trigger, which oftentimes we do not, you definitely want to treat that as well.