Why some people experience long-lasting physical and mental effects from covid-19 could be linked to chronic inflammation, according to new research that experts say could help develop new treatments for the confounding condition that continues to afflict millions.
Some early research on the condition has suggested that long covid’s symptoms linger because the virus persists in people’s bodies. But the new study published Friday in Nature Immunology found that people with long covid had activated immune defenses and heightened inflammatory responses for more than six months after initial infection compared with those who fully recovered.
The latest research “leads to a hypothesis that there might be therapeutic targets related to inflammation that might be worth exploring in clinical studies,” said Dan Barouch, the study’s lead author and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center.
The study’s findings signal progress in understanding a condition that is estimated to affect more than 400 million individuals around the world as the coronavirus continues to infect people every day, said Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis who studies long covid. There are no drugs approved for treatment of long covid, leaving doctors to tackle individual symptoms with various therapies.
“This is one piece of the puzzle,” said Al-Aly, who was not involved in the new study. “It’s eye-opening in the sense that it gives us more information that these pathways seem to be upregulated or activated in people with long covid.”
What does the new research mean?
Anyone, regardless of their age or severity of their original symptoms, can develop long covid, though some people have a higher risk, according to the World Health Organization. People have reported a constellation of symptoms, as many as 200 different ones, including brain fog, fatigue, dizziness, gastrointestinal problems, heart palpitations and issues with sexual desire. The effects can be present four or more weeks after infection with SARS-CoV-2 and can last weeks, months or even years.
Researchers studied people during the early years of the pandemic from 2020 to 2021 as well as another cohort between 2023 and 2024. The 180 participants included people who were healthy, people infected with the coronavirus but recovered fully, and people with long covid. Scientists analyzed protein levels, gene expression levels, immune responses and viral measurements to see if there were differences between people who went on to develop lingering symptoms.
Across both groups, the researchers saw multiple inflammatory pathways — how the body responds when it is injured or fighting infection — were triggered and stayed activated in people with long covid.
“We would speculate that the initial covid infection triggered chronic inflammation in the host and that it’s probably not the only factor, but probably one of the factors that was associated with long covid afterwards,” Barouch said. He noted that while the researchers did not have access to data before patients were infected, they had “no reason to suspect” that those people already had chronic inflammation.
Barouch said the findings of his study were limited, in part, by a small group of participants. While the researchers documented similar observations between both groups, which suggests that the findings could be generalized, he noted the need for larger studies of more diverse populations followed over a period of time.
Based on the study’s data, Barouch said he started a clinical trial to test an anti-inflammatory drug that is typically used to treat eczema which targets one of these pathways. The trial has enrolled 45 participants and is ongoing, he said.
A randomized trial of a drug commonly used to treat gout that reduces inflammation found that the medication did not help people with long covid. This medication targets inflammation in a different way than the anti-inflammatory therapies Barouch said he and his team are studying.
He also cautioned that more research needs to be done. Questions still remain, he said, about whether using a drug on one pathway is enough to treat long covid when multiple pathways are activated.
“But I do think that in the broader sense, identification of chronic inflammation as associated with long covid will lead to therapeutic strategies that include anti-inflammatory drugs,” he added.
What’s the latest on treatments?
Understanding the biological causes of long covid is critical for developing treatments, Barouch and other experts said.
Because some research has suggested that the coronavirus could be lingering in people with long covid, there have been studies of the antiviral Paxlovid, which is used to treat acute covid infections. At least two initial studies using the drug for long covid treatment showed no therapeutic efficacy, but other research is ongoing.
Barouch emphasized that his research doesn’t contradict any existing theories, but adds data that can be used to support more studies of other therapies.
The new study marks a welcome shift toward more investigation of alternative treatments, said Alba Azola, a rehabilitation physician and the co-director of the Long COVID/Chronic Fatigue Syndrome Clinic at Johns Hopkins Medicine.
“For too long in the field of long covid a lot of attention has gone to viral persistence and viral specific kind of interventions,” said Azola, who was not involved in the latest research. “It’s important to look at, but also not the only pathway.”
Long covid could have different biological pathways and responses to treatments.
“If we can get to a place where we can potentially find specific biologics that are going to be effective against the pathways that we’re seeing in common, that may give us a bigger gun to target more of those symptoms that are presenting,” Azola said.
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