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New research from the Allen Institute and the Fred Hutchinson Cancer Center provides evidence that an overactive inflammatory response could be a root cause of many cases of long COVID. The study, published today in the journal Nature Communications, details the discovery of a set of molecules associated with inflammation that were present in a subset of patients with long COVID and were not detected in those patients who had recovered from the virus.

While previous research has shown links between inflammation and long COVID, the new research is the first to trace the persistence of markers of inflammation in patients over time.

The patients for the new analysis are part of a larger research project, the Seattle COVID Cohort Study, led by Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division, and Julie Czartoski, ARNP, research clinician at Fred Hutch.

Of the 55 patients with long COVID, the study found that about two-thirds of them has persistently high levels of certain signals of inflammation in their blood. The study also examined blood samples from 25 people who had recovered from COVID and another 25 who had never had it to their knowledge. Those who didn’t have long COVID showed no signs of the inflammatory markers in their blood.

The findings indicate that there could be treatment approaches using anti-inflammatory drugs to treat these sufferers of long COVID, but clinicians will need to be able to determine which patients have these markers, and which treatments might be most effective to treat this lingering condition.

“The big question was, can we define which long COVID patients have persistent inflammation versus those that don’t? That would be useful in terms of clinical trial planning and in terms of helping clinicians figure out targeted treatments for their patients,” said study leader Troy Torgerson, MD, PhD, director of Experimental Immunology at the Allen Institute for Immunology.

In their research, the investigators determined that the biomarkers uncovered in this subset of long COVID patients are similar to those also seen in inflammation related to autoimmune diseases such as rheumatoid arthritis. An existing class of drugs called Janus Kinase (JAK) inhibitors, that interfere with the JAK-STAT signaling pathway in lymphocytes, have been approved for the treatment of RA, though they have not been tested in patients with long COVID.

The new findings can trace their way back to one of the earliest studies of immune responses in patients who had contracted COVID, which followed the patients over time in an effort to characterize information about so-called “successful” immune response, defined as patients that didn’t get very sick, didn’t require hospitalization, and recovered fully.

The Seattle COVID Cohort Study, launched in spring of 2020 by Fred Hutch, initially traced the immune response in 18 people with COVID, and soon found that a small group of these patients had symptoms that persisted—what eventually became known as long COVID. One common factor among these patients was the persistence of certain immune responses, with inflammatory response noted as consistently high.

This led the investigators to broaden their research to include the subset of long COVID patients. Central to this study was a panel of roughly 1,500 proteins that circulate in the blood. Analysis of these tests showed different molecular profiles of long COVID, one that is an inflammatory form of the disease, and a second that is non-inflammatory. From this information, the researchers hope to zero in on appropriate treatments.

“The ultimate goal is to treat patients,” note study co-author Aarthi Talla, senior bioinformatician at the Allen Institute for Immunology. “Although we call everything long COVID, what’s come out of this work shows us that we might not be able to give everyone the same kinds of therapies and we shouldn’t put everyone into one group for treatment purposes.”

Those patients with non-inflammatory long COVID might be living with permanent organ or tissue damage from their disease, Torgerson noted, which would point to different treatments than for those with high levels of inflammation. The scientists also saw that these groups can’t be distinguished based on symptoms alone. If anti-inflammatory drugs prove effective in treating inflammatory long COVID, patients would first need to be screened to determine which form of long COVID they have.

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