One of the most challenging clinical encounters in infectious diseases is the patient with persistent fatigue and other disabling symptoms after an infection. Some of these patients meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but whatever label we use, the story is often strikingly similar: They were living their healthy lives, doing just fine, until they came down with an infection. Ever since, they have struggled with a wide range of disabling symptoms, dominated by fatigue, cognitive struggles (often called “brain fog”), post-exertional malaise, and other ailments.

The most common trigger in the last half-decade has undoubtedly been Covid-19 — hence long Covid — but now that I’ve been at this infectious diseases job for some time, I can assure you that it happens after other infections as well. Here in New England, the most notorious culprit is Lyme disease. Epstein-Barr virus is another well-described trigger, and I’ve seen similar syndromes after influenza, toxic shock syndrome, *Staph.* sepsis, endocarditis, even acute HIV.

The community of people living with these conditions is enormously frustrated by the slow progress we’ve made in helping them recover. That’s why three recent randomized trials for long Covid caught my eye, and two even have positive signals. What makes them especially interesting is that they approach the problem from three very different directions.

# First approach: What if the issue is persistent infection?

That’s the hypothesis behind [RECOVER-VITAL](https://www.sciencedirect.com/science/article/pii/S1473309926004068), recently published in *Lancet Infectious Diseases*. Led by my colleague Dr. Lindsey Baden, the trial enrolled 959 people with long Covid and randomized them to 15 or 25 days of nirmatrelvir-ritonavir or placebo.

The results were straightforward too: it didn’t work.

Neither duration of nirmatrelvir-ritonavir improved the primary outcome, and there were no meaningful differences in the secondary outcomes either.

Does this prove that persistent SARS-CoV-2 plays no role in long Covid? Of course not. Maybe the wrong people were treated, or treatment started too late, or the drug doesn’t adequately reach whatever reservoir the virus lurks, or even 25 days isn’t long enough.

But I’m skeptical that any of our antivirals will help this condition, just as long-term antibiotics don’t help people with post-Lyme disease syndromes.

# Second approach: What if the problem is persistent inflammation, particularly neuroinflammation?

Enter bezisterim, an investigational oral drug that crosses the blood-brain barrier and is proposed to reduce inflammation and improve insulin sensitivity. In the [ADDRESS-LC trial](https://investors.bioviepharma.com/news/news-details/2026/BioVie-Announces-Topline-Results-from-Phase-2-ADDRESSLC-Trial-Evaluating-Bezisterim-for-the-Treatment-of-Neurological-Symptoms-Associated-with-Long-COVID/default.aspx), 203 participants with long Covid were randomized to bezisterim 20 mg twice daily or placebo. The investigators measured 22 clinical outcomes including fatigue, cognition, sleep, quality of life, and post-exertional malaise.

Here the results are much more interesting than in the RECOVER-VITAL trial, but still not definitive. Although none of the 22 study endpoints reached statistical significance, 21 of 22 numerically favored bezisterim.

Even better, in a prespecified analysis of people who entered the study with the worst fatigue, post-exertional malaise, or objective cognitive impairment, several outcomes significantly favored treatment. The investigators appropriately call these subgroup findings exploratory, but to improve the most severe cases is a highly favorable signal in a phase 2 trial.

I confess these results look more promising than practically anything I’ve seen. But proof that bezisterim works? Not quite yet. These are topline company-reported results in a press release from a phase 2 trial, not a peer-reviewed efficacy trial, and the overall population was negative. Still, there’s plenty there to justify the next study, especially given the long trail of negative results from other interventions.

# Now for the third approach, which is about as far from the Paxlovid trial as you could be, but again with encouraging results

Psychophysiologic symptom relief therapy, or PSRT, starts with a very different hypothesis. The premise is that in at least some people with long Covid without persistent organ injury, an infection can initiate symptoms that are subsequently perpetuated by altered brain processing — including conditioned responses, fear of symptoms, stress, and avoidance behaviors.

The treatment combines education, desensitization, emotional-awareness exercises, and other mind-body techniques. I confess to never having heard about this approach previously, but an [earlier uncontrolled study](https://pmc.ncbi.nlm.nih.gov/articles/PMC10196153/) of just 23 patients produced large improvements, with the acknowledgment that uncontrolled studies of symptom-based illnesses are notoriously difficult to interpret. So investigators, led by Dr. Michael Donnino, did what they needed to do next: a randomized trial.

The new study enrolled 126 people with long COVID and compared PSRT with both usual care and an active control, mindfulness-based stress reduction. That active control is key here: PSRT wasn’t just being compared with putting people on a waiting list and giving the intervention group lots of attention.

According to results [presented in abstract form](https://x.com/mdonnino/status/2093050342149603656?s=20), PSRT produced a large improvement in the primary end point, the Somatic Symptom Scale-8, with separation from both control groups evident by week 4 and persisting through week 13. Fatigue, physical function, cognitive symptoms, pain, and shortness of breath also improved.

As with bezisterim, we don’t have a full paper yet, or all the details of the trial, though it is [registered on ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT06045338). Until we see the full study — methods, screen failures, attrition, effect sizes, individual outcomes, and all the rest — enthusiasm should be tempered accordingly.

There’s another reason to tread carefully. To some people with long Covid — understandably — a treatment directed at the brain sounds perilously close to being told, once again, *it’s all in your head. You’re making it up.*

Just how fraught this subject has become was illustrated by a [recent *WIRED* article](https://www.wired.com/story/the-painful-truth-about-long-covid/?utm_source=partner&utm_campaign=whatfinger&src_src=partner&src_cmp=whatfinger) by Alan Levinovitz, “The Painful Truth About Long Covid,” which argued that potentially useful nonpharmacologic approaches have become extraordinarily difficult even to discuss. The article itself then generated [intense criticism from the long Covid and ME/CFS communities](https://www.meaction.net/post/meaction-community-responds-to-harmful-wired-article), including a petition calling for its retraction and a formal complaint alleging breaches of journalistic ethics.

I can’t pretend to adjudicate all the issues raised by that controversy. But the intensity of the response illustrates the difficult territory we’re entering here. There are good historical reasons patients recoil at suggestions that their disabling physical symptoms are psychological. At the same time, we shouldn’t reject a potentially effective treatment simply because its proposed mechanism involves the brain.

Which brings us back to the randomized trial. If PSRT really does produce the large benefits reported in this study, the appropriate response isn’t to argue about whether the symptoms are “real.” It’s to scrutinize the data, replicate the results, and try to understand why the treatment works.

So three studies, three vastly different approaches to treatment. One targeted the pathogen, SARS-CoV-2; one targeted inflammation and metabolism in the brain; and one tried to change the way the central nervous system processes and perpetuates symptoms. The first approach didn’t work. But the other two produced some of the most encouraging signals I’ve seen yet — with the very important caveat that neither has given us a peer-reviewed, randomized trial to read.

Let’s hope they hold up. Because after decades of seeing people suffer with these postinfectious syndromes, with frustratingly little we can do to help them, I’m all for casting a wide net in the search for effective treatments.

I’d also welcome thoughts in the comments section about how you handle long Covid and other post-infectious ME/CFS conditions. What has worked for you?

Three Very Different Ways to Treat Long Covid [NEJM blog entry]