By Richard Sima The Washington Post<\/p>\n\n\n\n
Five years since the pandemic began, millions of people are still grappling with long COVID, even as new patients are joining their ranks.<\/p>\n\n\n\n
\u201cConsidering how far along we are and how tens of millions of people are suffering, we\u2019ve done very little,\u201d said Eric Topol, a professor of translational medicine and the executive vice president of Scripps Research.<\/p>\n\n\n\n
But researchers are pressing ahead with new clinical trials for more targeted treatments built on advances in our understanding of long COVID. There\u2019s now a large body of research on the condition. \u201cIt is absolutely not mysterious,\u201d said Hannah Davis, co-founder of the Patient-Led Research Collaborative.<\/p>\n\n\n\n
\u201cThis is a campaign of human service and scientific discovery,\u201d said Wes Ely, professor of medicine and co-director of the Center for Critical Illness, Brain Dysfunction, and Survivorship at Vanderbilt University Medical Center.<\/p>\n\n\n\n
Long COVID is an umbrella term, and treating it as one disease is, in a way, equivalent to thinking cancer is one entity as opposed to the hundreds of types, each with different diagnostics, prognosis and treatments, said Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis.<\/p>\n\n\n\n
Long COVID potentially has many subtypes with different biological pathways and responses to different treatments, researchers said.<\/p>\n\n\n\n
\u201cIt is a constellation of many things, and dissecting out those things is going to be the biggest challenge,\u201d said Janna Moen, a neuroscientist at the Howard Hughes Medical Institute, who recently wrote a review about how the immune system affects the brain and spinal cord in people with long COVID, which is awaiting peer review.<\/p>\n\n\n\n
\u201cIt\u2019s going to mean that everybody is going to need a different treatment. Personalized medicine is going to become very necessary,\u201d she added.<\/p>\n\n\n\n
One pathway to long COVID may be through immune system dysfunction, where the \u201cimmune system goes haywire,\u201d Topol said.<\/p>\n\n\n\n
People have a 20 to 40% increased risk of developing different autoimmune issues following a coronavirus infection, four large datasets of millions of patients show.<\/p>\n\n\n\n
Some people with long COVID also have persistently elevated autoantibodies, where the immune system mistakenly produces antibodies that attack healthy tissue \u2014 particularly in the nervous system \u2014 which may play a role in the condition, said Akiko Iwasaki, professor of immunobiology at Yale University School of Medicine.<\/p>\n\n\n\n
In addition, coronavirus infection can reactivate latent viruses, which may contribute to autoimmunity. The Epstein-Barr virus \u2014 known for its role in infectious mononucleosis and present in over 95% of adults \u2014 gets reactivated in a subset of people, which may be linked to developing long COVID, Iwasaki said.<\/p>\n\n\n\n
Another pathway to long COVID may be viral persistence, where bits of the coronavirus linger long after the acute infection.<\/p>\n\n\n\n
Viral persistence could chronically activate the immune system into producing a smoldering inflammation that can weaken the blood-brain barrier, which typically shields the brain. Inflammatory molecules could cross into the brain and trigger neuroinflammation.<\/p>\n\n\n\n
Many researchers were surprised to learn that viral particles can linger in the body even after the acute infection is over.<\/p>\n\n\n\n
\u201cWe just didn\u2019t think of coronaviruses having the capability of lasting more than a couple of weeks,\u201d said Michael Peluso, an assistant professor and infectious-disease clinician at the University of California at San Francisco.<\/p>\n\n\n\n
But fragments of the virus can stay in our bodies for far longer \u2014 14 months after infection in some patients, and almost two years in some others.<\/p>\n\n\n\n
Coronavirus spike protein may be particularly disruptive and inflammation-inducing, lingering in the skull, meninges \u2014 the protective tissue around the brain \u2014 and the brain itself. It is also associated with inflammation and damage in the nervous system, according to a 2024 study.<\/p>\n\n\n\n
Yet another route to long COVID may be through the inflammation of the endothelial cells that line blood vessels throughout the body, including the brain.<\/p>\n\n\n\n
The coronavirus spike protein also binds to clotting proteins in the blood, creating microclots that are themselves pro-inflammatory and alter immune cell activity, a 2024 study reported.<\/p>\n\n\n\n
Research has consistently found that people with long COVID have reduced blood flow in the brain.<\/p>\n\n\n\n
All these different likely biological pathways of long COVID are \u201call kind of related unfortunately in a way that makes it very hard to parse out exactly what the problem is,\u201d Moen said.<\/p>\n\n\n\n
Despite progress in basic research, there are no validated diagnostic tests for long COVID.<\/p>\n\n\n\n
\u201cIt is a patient-reported syndrome,\u201d Peluso said. Though many other medical conditions are diagnosed wholly based on how people feel, such as pain disorders and depression, \u201ca lot of people use that to discount it or express skepticism or disparage the condition,\u201d he said.<\/p>\n\n\n\n
As a result, long COVID patients face challenges in getting adequate access to care. Though long COVID is now more recognized in the medical fields, the onus is still on the patient to find doctors who will listen.<\/p>\n\n\n\n
\u201cWe tend to stay the same or get worse. And we\u2019re very needy. We need a lot of medications. We need a lot of paperwork filled out,\u201d said Moen, who as a long COVID patient has seen dozens of doctors. \u201cA lot of them just don\u2019t like taking us as patients.\u201d<\/p>\n\n\n\n
The lack of a biomarker has also stymied clinical trials looking for evidence of improvements, researchers said.<\/p>\n\n\n\n
\u201cThere really needs to be a concerted, organized and well-funded biomarker discovery effort for this problem so that we can find a diagnostic test,\u201d Peluso said.<\/p>\n\n\n\n
There are also no approved treatments for long COVID.<\/p>\n\n\n\n
\u201cWhat\u2019s so sad here is people are so desperate, and we don\u2019t have anything validated,\u201d Topol said.<\/p>\n\n\n\n
During an infection, the \u201cpreponderance of evidence\u201d shows that taking antivirals, such as Paxlovid, does decrease the risk of developing long COVID later \u2014 though it\u2019s not unanimous, Al-Aly said. A 2025 clinical trial of over 20,000 participants found that people treated with another antiviral, molnupiravir, felt better, had fewer and milder symptoms, and took less time off work six months after infection.<\/p>\n\n\n\n
However, once long COVID has developed, antivirals have not been effective, with two recent large randomized clinical trials finding no differences in outcomes compared with placebos.<\/p>\n\n\n\n
Instead, the strategy is to manage the symptoms \u2014 variable as they are \u2014 in each patient.<\/p>\n\n\n\n
There is no \u201ccookie-cutter protocol\u201d for treating long COVID, Ely said. \u201cThe best clinicians evaluate them head to toe and see what their story is and how they\u2019re suffering. And they tailor their therapy accordingly,\u201d he said.<\/p>\n\n\n\n
Davis, who has long COVID, has tried blood thinners, antivirals and other repurposed drugs for her symptoms to varying degrees of success.<\/p>\n\n\n\n
Other patients have tried treatments such as hyperbaric oxygen chambers and plasmapheresis, which filters out and then replaces their blood, but studies on these interventions tend to be small and without a placebo control, Topol said.<\/p>\n\n\n\n
Like the virus they study, researchers and clinicians have evolved in how they tackle long COVID.<\/p>\n\n\n\n
Earlier clinical trials lumped together people with all kinds of long COVID symptoms; now, researchers are increasingly stratifying patients by symptoms in hopes of targeting specific biological pathways with their treatments.<\/p>\n\n\n\n
This approach would also make it more likely to spot therapeutic benefits that could otherwise be missed if given to a broader patient population.<\/p>\n\n\n\n
The treatment strategy has also shifted.<\/p>\n\n\n\n
\u201cAll of the initial trials were really focused on targeting the virus, and now we\u2019re starting to see trials that are focusing on targeting the immune system,\u201d Peluso said.<\/p>\n\n\n\n
Peluso, Ely and their collaborators are running a large double-blind, randomized clinical trial on a treatment seeking to turn off the immune \u201clight switch that is creating this disease state, creating so much human suffering,\u201d Ely said.<\/p>\n\n\n\n
The trial, REVERSE-LC, will give patients baricitinib, which is an FDA-approved immunotherapeutic drug for treating other immune disorders such as rheumatoid arthritis and alopecia areata.<\/p>\n\n\n\n
Another ongoing double-blind, randomized clinical trial, called ADDRESS-LC, will test a different, more specific immunomodulator called bezisterim for neurocognitive long COVID.<\/p>\n\n\n\n
Bezisterim is a novel anti-inflammatory agent that has been shown to selectively inhibit specific inflammatory pathways while not suppressing the immune system, said Penelope Markham, senior vice president at BioVie, a pharmaceutical company sponsoring the study.<\/p>\n\n\n\n
Importantly, it can cross the blood-brain barrier, meaning it may potentially treat neuroinflammation at its source, and is being developed to treat\u00a0other\u00a0inflammatory neurological conditions such as Parkinson\u2019s disease.<\/p>\n\n\n\n
Still, researchers say what is coming down the pipeline is not enough compared with all the treatments that have been identified as promising.<\/p>\n\n\n\n
\u201cThere\u2019s a lot of potential shots on goal. And you have to run through this, but you can\u2019t know until you\u2019ve done the rigorous test,\u201d Topol said.<\/p>\n\n\n\n
The goal of these clinical trials is to \u201cprovide mercy, and mercy out of love \u2026 And my definition of mercy is my willingness to dive into their chaos and provide lifting and healing,\u201d Ely said.<\/p>\n","protected":false},"excerpt":{"rendered":"
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