The study explains why anti-inflammatory drugs benefit only a few people with severe COVID-19

Reviewed by Emily Henderson, B.Sc.November 16, 2020

The tipping point for people with COVID-19 typically comes in the second week of symptoms. As most people begin to recover, few others find it increasingly difficult to breathe and end up in the hospital. It has been theorized that those whose lungs begin to fail are victims of their own overactive immune systems.

A new study from Washington University School of Medicine in St. Louis and St. Jude Children’s Research Hospital in Memphis, Tennessee, however, suggests that an out-of-control immune response isn’t the primary problem for the vast majority of hospitalized COVIDs. -19 patients.

Only 4% of the patients in the study had very high levels of immune molecules meaning a so-called “cytokine storm”. The rest had inflammation, but not a remarkably high amount for people battling infections. If anything, the COVID-19 patients had less inflammation than a comparable group of flu patients.

The results, published November 13 in Advances in science, help explain why anti-inflammatory drugs such as dexamethasone only benefit a fraction of people with severe COVID-19 and suggest that more research is needed to identify the causes of respiratory failure in COVID-19 patients.

One of the very first published articles on COVID-19 patients in China reported high levels of cytokines in people in intensive care, what we might call a cytokine storm.

We wanted to get a better idea of ​​what this cytokine storm was like, so we started looking for it in our patients and were very surprised when we didn’t find it. We have found that cytokine storm does occur, but is relatively rare, even in COVID-19 patients who continue to have respiratory failure and require a ventilator.

But now this idea has been established that respiratory failure in COVID-19 is driven by the cytokine storm, and many unproven anti-inflammatory treatments are given to critically ill COVID-19 patients in an attempt to suppress the cytokine storm. This worries me because such treatments are unlikely to help most people with COVID-19. “

Philip Mudd, MD, PhD, Studio CoSenior Author and assistant professor of emergency medicine who sees patients at Barnes-Jewish Hospital.

Dr. Mudd sees patients at Barnes-Jewish Hospital.

Before the pandemic, Mudd began investigating the immune response to the flu infection, using blood samples obtained, with consent, from flu patients seeking assistance in the emergency room at Barnes-Jewish Hospital.

In late March, when COVID-19 patients began filling the emergency department, Mudd and senior co-author Ali Ellebedy, PhD, an assistant professor of pathology and immunology and a fellow flu expert, realized they could use the same approach to investigate how the immune response goes awry in severe cases of COVID-19.

The researchers analyzed immune cells and molecules in blood samples from 168 COVID-19 patients, 26 flu patients and 16 healthy people.

Samples were taken from flu patients in 2019 or 2020 and from COVID-19 patients and healthy controls this year. They also gathered information on how each patient performed – whether a patient needed intensive care or mechanical ventilation – and whether he survived.

Along with Mudd and Ellebedy, the research team included senior co-author Paul Thomas, PhD, and co-first author Jeremy Crawford, PhD, both of St. Jude, among others.

The number of inflammatory cells in the blood of COVID-19 and flu patients was roughly the same. Seven of the COVID-19 patients (4%) showed signs of a cytokine storm, with extremely high levels of cytokines even compared to other critically ill patients.

Most COVID-19 patients with acute respiratory failure not only did not have a cytokine storm, but had less inflammation than flu patients who were equally ill.

Clinical studies have shown that some severely ill COVID-19 patients improve on steroid drugs such as dexamethasone that suppress inflammation. A meta-analysis published in September places the percentage of beneficiaries between 2% and 9%. These findings coincide with the findings of this study, Mudd said.

“It could be that 4% of the people who have the cytokine storm are the ones benefiting from steroids in those clinical trials,” Mudd said. “I think our work helps explain why steroids help some people. But from our data, it doesn’t appear that most COVID-19 patients have a steroid deficiency. If you are giving steroids to someone who already has a lot of steroids in the their body may not be good for them. “

The key will be to find a way to identify people at high risk of a cytokine storm when they first arrive at the hospital, so that steroid treatment can be properly targeted to those who are most likely to benefit and least likely to. be damaged.

The researchers ran a panel of routine lab tests – blood cell counts, measurements of common inflammatory markers – but couldn’t find a signature of an impending cytokine storm. They are carrying out more in-depth analyzes to find a way to predict who will develop a cytokine storm.

“The subjects in the cohort with the ‘true’ cytokine storm phenotype are such outliers compared to the others, it seems likely that there are significant differences in the multiple immune pathways that drive this phenotype,” said Thomas. “If we can identify the features of those pathways that can be rapidly assessed in a clinical setting, it could be useful for patient stratification.”

With the cytokine storm largely ruled out, the cause of most cases of respiratory failure in COVID-19 patients remains unknown, Mudd said.

“In the population we studied, 24 percent died, but only 4 percent had a cytokine storm,” Mudd said. “Most of the people who have died from COVID-19 have died without a cytokine storm. Severe influenza is more inflammatory than severe COVID-19. So what’s causing their lungs to fail? We don’t know yet. We are. trying to find out. “