Doctors must optimize treatments for deadly inflammation in Covid-19 patients to save more lives.
The Covid-19 pandemic has infected more than 68 million individuals worldwide and killed 1.5 million people, including more than 285,000 Americans. And many hospitals are now running short on beds for the sickest patients.
Approximately one in 25 people with Covid-19 need hospitalization, and about 9 percent of hospitalized Covid-19 patients end up having acute respiratory distress syndrome (ARDS). Hospital care does not guarantee survival, with Covid-19 killing about 2.1 percent of people who get it in the US.
We don’t always know why the SARS-CoV-2 virus that causes Covid-19 ravages some people so much more horribly than others. But one thing many of these severe patients have in common is an overly active immune response.
This intense immune reaction to the virus often has features of cytokine storm syndrome (CSS). And, fortunately, we have drugs to treat this sort of immune response generally, including one President Trump took while he was sick with Covid-19, dexamethasone.
But these drugs must be given at the right time to Covid-19 patients specifically experiencing CSS, not simply all patients with severe Covid-19, to get the best outcomes. In short, we must optimize the drugs we already have. And there is still a lot we need to learn about how these sorts of treatments work in the case of Covid-19.
What we know about cytokine storms in Covid-19
Cytokine storm syndrome is an umbrella term for a variety of hyper-inflammatory reactions to various insults and triggers. It can be brought on by other viruses, such as influenza and Epstein-Barr virus, as well as blood cell-related malignancies such as lymphoma and leukemia.
The diagnosis of CSS is complicated. There is no single agreed-upon set of criteria for deciding if someone has CSS without their already having another related underlying condition.
Pinpointing it in people with Covid-19 is even trickier, in part because levels of key blood markers are not as high as the levels seen in patients with CSS in other contexts. Additionally, severe lung inflammation is generally a late development in CSS, but it’s early in Covid-19.
Nevertheless, like other CSS patients, those with severe Covid-19 often develop multi-organ dysfunction syndrome in which organ damage appears to be caused primarily by excessive immune system activation and/or blood clotting, rather than by the virus itself.
These patients also have other overlaps with general CSS cases, including fever, liver dysfunction, low blood counts (particularly low lymphocyte counts), and very elevated markers of inflammation.
We still don’t know, however, exactly how Covid-19 triggers this hyper-inflammation. It only occurs in a subset of infected individuals, and there may be genetic risk factors. For other cytokine storm syndromes, 30-40 percent of patients do harbor mutations in genes that alter the immune response to infection. Time and further research will tell if something similar occurs with Covid-19.
Since the pandemic began, we have also learned more about the timeline of how these severe cases often go. And this can help determine how best to treat people.
For symptomatic individuals, infection with Covid-19 comes in phases, with the early days (the first week) dominated by viral replication leading into features of a flu-like illness (such as fever, cough, diarrhea). In up to 20 percent of adults with symptomatic infection, shortness of breath with low blood oxygen levels may develop five to 10 days after the onset of symptoms.
And things can deteriorate rapidly from there. Hospitalized patients requiring oxygen support can quickly (often within hours) progress to requiring ICU management for ARDS, low blood pressure, and subsequent multi-organ dysfunction.
Confirmed predictors of patients at risk of developing more severe complications include being older than 60, obesity, underlying cardiovascular disease, and/or a history of asthma or other chronic respiratory disease. Recent studies have also identified several blood test abnormalities at the time of early symptom onset that are predictive of a patient developing more severe complications later.
But these sorts of tests are not routinely done. And it still doesn’t tell doctors exactly how best to treat these individuals who end up getting life-threateningly ill.
Antiviral drugs don’t help cytokine storms, but we are learning how some other drugs can
We do have some ways to attack the virus itself. Antiviral approaches are likely to be most beneficial early in the disease course when symptoms are first present and the virus is still infectious. But even then they haven’t by any means been a cure-all.
At present, remdesivir, a nucleotide analog that has received emergency use authorization from the FDA, has been demonstrated to somewhat shorten hospital stays but has not been shown to improve survival. Other treatments hyped by the current administration, including hydroxychloroquine, have not proven to be effective.
Because none of the antiviral approaches have thus far been proven to increase survival rates or prevent the development of ARDS or multi-organ dysfunction syndrome, we need treatments for patients fighting CCS in order to save more lives.
The most accessible and comprehensive anti-inflammatory approach to treating Covid-19 associated CSS involves the use of glucocorticoids (anti-inflammatory steroids). These include prednisone, methylprednisolone, and dexamethasone, the steroid given to President Trump. Many hospitals have adopted dexamethasone as the standard of care for hospitalized patients with Covid-19 pneumonia.
These steroids not only inhibit cytokine production but also broadly tamp down many other aspects of the immune response, which makes them helpful in reducing harmful inflammation, but also tricky to use — especially in the case of an infection.
As immunosuppressants, these drugs are associated with a vast array of side effects, including secondary infections. The use of glucocorticoids to treat previous fatal coronavirus epidemics, SARS and MERS, reported mixed results. There was even concern that the use of glucocorticoids may increase mortality, so the World Health Organization strongly discouraged their use early on during the SARS-CoV-2 pandemic.
Nevertheless, out of desperation, clinicians overwhelmed by the pandemic resorted to these drugs to lower the massive numbers of Covid-19 deaths.
So far, several retrospective analyses have reported lower Covid-19 mortality in glucocorticoid-treated patients compared to control groups. A September meta-analysis done by the World Health Organization also concluded that glucocorticoids do save lives for some hospitalized Covid-19 patients, reducing all-cause mortality over four weeks from 40 percent to 32 percent.
A randomized placebo-controlled trial of 2,104 hospitalized Covid-19 patients, published in July, reported a statistically significant decrease in mortality with modest doses of dexamethasone for those on ventilators, from about 41 percent in the control group to about 29 percent in those receiving the steroid.
Those not requiring oxygen, and perhaps not experiencing CSS, trended toward worse outcomes (14 percent in the control group died versus almost 18 percent of those receiving the treatment). Similarly, a recent study reported that patients with notable markers of inflammation improved with glucocorticoids, but those with lower levels fared worse.
These studies underscore the importance of careful patient selection for these treatments, namely that they should be used specifically to treat CSS in Covid-19 patients, not simply all patients with severe Covid-19. Initiating glucocorticoids as early as possible in CSS patients who will benefit, but avoiding needlessly immunosuppressing other patients who will not benefit from (and may be harmed by) them is a challenging needle to thread. Looking for biomarkers for hyper-inflammation during hospitalization could help clinicians determine which patients are the best candidates for treatment with these potentially life-saving drugs.
Ideally, more targeted anti-inflammatories would be best to deploy in an effort to further lower Covid-19 mortality rates. We have a few leads, documented in high-quality studies of specifically anti-cytokine treatments in Covid-19 CSS patients, but the research is ongoing.
More recent — but lower quality — studies suggest that we might have luck using less risky, targeted immunomodulatory and immunosuppressive therapies, which have documented success treating non-Covid-19 CSS. Many of these treatments — including Tocilizumab (IL-6 blockade), IL-1 blockade, and emapalumab — have had mixed results and are still under investigation. Currently, for example, IL-6 blockade is not looking promising.
While we all eagerly await the availability of safe and effective vaccines to prevent infection with SARS-CoV-2 and subsequent Covid-19, we need to optimize antiviral treatments and therapies directed against the associated CSS when it develops. New iterations of antiviral approaches will hopefully decrease the development of hyper-inflammation.
But until these arrive, glucocorticoids and/or anti-cytokine approaches will likely be necessary to save lives. With glucocorticoids already being readily available globally and relatively inexpensive, they may be our best therapeutic option for treating Covid-19 CSS worldwide for now.
Randy Q. Cron, MD, PhD, is a professor of pediatrics and medicine and director of the Division of Pediatric Rheumatology at the University of Alabama at Birmingham. In November 2019, he published Cytokine Storm Syndrome, the first dedicated textbook on cytokine storms.
W. Winn Chatham, MD, is a professor of medicine, clinical immunology, and rheumatology; senior scientist at the Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center (CAMBAC); and director of Rheumatology Clinical Services at the University of Alabama at Birmingham.
Scott W. Canna, MD, is an assistant professor of pediatrics and immunology at the University of Pittsburgh. He is a scholar of the Richard King Mellon Foundation Institute for Pediatric Research with expertise on auto-inflammation and cytokine storm disorders.
Author: Randy Cron