In recent years, doctors and scientists are increasingly studying long-lasting illnesses that begin after someone recovers from an infection. Two of the most well-known examples are long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
It has been estimated that 400 million people, globally, may have Long COVID, and nearly half of them meet criteria for ME/CFS.
These conditions were often misunderstood or overlooked in the past, but that is starting to change. Researchers are now studying them as part of a larger group of illnesses called post-acute infection syndromes, or PAISs.
A new review by Mass General Brigham investigator Anthony L Komaroff, MD, and Robert Dantzer, MD, of the MD Anderson Cancer Center in Houston, published in Cell Reports Medicine, and a new review by Dr. Komaroff in the Proceedings of the National Academy of Sciences (PNAS), brings together decades of research and new discoveries to help explain what causes these illnesses and how they might be treated. Dr. Dantzer is one of the world's experts on how animals respond to infection.
Their review highlights that long COVID and ME/CFS share many of the same biological problems such as inflammation in the brain, issues with how cells produce energy, and problems with the immune system.
They also introduce the idea that certain brain circuits that evolved to help the body respond to serious illness, may be stuck in the "on" position after the body has cleared the infection and could be causing many of the ongoing symptoms people experience.
In this Q&A, Dr. Komaroff shares what motivated this research and what it could mean for how we understand, diagnose, and treat these complex conditions.
Q: What Inspired You to Study the Field of Long Covid and other Post-Acute Infection Syndromes?
My interest in ME/CFS began more than 40 years ago, when I met patients who never fully recovered from what seemed like a routine viral illness.
At the time, their symptoms couldn't be explained by standard medical tests, which all came back normal. That led some to conclude the symptoms were psychologically based.
A small group of us around the world began to study if there were, in fact, underlying objective biological abnormalities that might be causing the long-lasting symptoms, perhaps in people with a genetic vulnerability.
Over the past 40 years, it became clear that this is the case. The symptoms are associated with multiple underlying abnormalities, involving multiple body systems.
In both reviews, we postulate that Long COVID and ME/CFS fall under a broader category called post-acute infection syndromes.
This helps highlight the biological similarities between them and opens the door to more targeted treatments.
Q: What Did You Find in this Review?
In the review we asked two questions: what causes the symptoms, and why do the symptoms persist for years?
What causes the symptoms?
We identified a range of biological abnormalities common to both ME/CFS and long COVID that can directly cause symptoms.
These include:
Neuroinflammation: Activation of the brain's immune system
Mitochondrial dysfunction: A reduced capacity to generate adenosine triphosphate (ATP), the primary energy source for cells, leading to a decrease in body- and brain-based metabolism.
Immune dysregulation: This can include persistent inflammation, reactivation of latent viruses (like Epstein-Barr virus), and the presence of autoantibodies targeting neural tissues.
Endothelial dysfunction: Disruption of blood flow and the blood-brain barrier, contributing to cognitive and cardiovascular symptoms.
Gut dysbiosis: An imbalance in the gut microbiome that may perpetuate system inflammation
Oxidative stress: An imbalance between the production of free radicals and the body's ability to neutralize them, leading to cellular damage and disease
Could "sickness behavior" be underlying these symptoms?
Our review focuses on another possible cause of the symptoms that has not previously been considered.
We think it is likely that these symptoms may be driven by evolutionarily-conserved responses to vital threats that are seen in all animals that have been studied.
Infection leads to symptoms, and the symptoms lead to behavior changes called sickness behavior. Infection also leads to changes in metabolism. Together, the behavioral and metabolic changes help preserve the body's energy supply, its ATP, for the fight against the infection.
We suspect these behavioral and metabolic changes may be caused by recently discovered groups of dedicated brain cells (neurons) when they are stimulated by an infection or other cause of brain inflammation.
We present evidence that many of the underlying abnormalities that produce symptoms persist in some people, including the infectious agent or pieces of the infectious agent.
In addition, we point out that many of the different underlying abnormalities can reinforce each other, leading to ongoing vicious cycles that maintain the symptoms.
Q: How has the COVID-19 pandemic and Long COVID changed the scientific and public perception of ME/CFS?
The pandemic has been a turning point. In 2020, we published a paper predicting that COVID-19 would lead to a surge in ME/CFS-like conditions, and that has happened.
Long COVID has brought visibility to post-infectious syndromes, because its cause is a specific infectious agent.
This has given credibility to the claim of many ME/CFS patients that their illness began following an acute infection—one in which no infectious agent was tested for.
It also gives credibility to similar syndromes following well-documented acute infections like Lyme disease and West Nile virus.
The scale of long COVID's impact—both in terms of affected individuals and societal costs—has accelerated research and shifted the public discourse.
Q: What are the most interesting biological similarities between ME/CFS and long COVID?
The symptom overlap between ME/CFS and long COVID is well recognized. What our publications have cataloged is the many striking parallels in the underlying abnormalities.
These biological parallels include:
- Brain abnormalities, as seen by various types of brain imaging.
- Autonomic nervous system dysfunction affecting heart rate, breathing, and digestion.
- Immune system dysregulation and autoantibodies
- Impaired energy metabolism leading to fatigue and exercise intolerance.
- Cardiovascular issues, especially involving the lining of blood vessels (the endothelium).
These similarities suggest a shared pathophysiological foundation, reinforcing the case for unified research and treatment strategies.
Q: What are the current treatments for post-acute infection syndrome, and why have some failed to be effective?
Currently, there are no FDA-approved treatments for ME/CFS or long COVID. However, evidence shows that early antiviral treatment and vaccination against SARS-CoV-2 can reduce the risk of developing long COVID.
Our review proposes that neuroinflammation—immune activation within the brain—is one key driver of symptoms. It stimulates the specific neural circuits that produce sickness behavior and metabolic changes.
Therefore, targeting neuroinflammation and the molecules by which it stimulates the neural circuits could lead to more effective therapies. Multiple novel therapies that target neuroinflammation are under investigation.
While promising, these treatments are still in experimental stages and not yet available to clinicians
Q: What are the most important research questions that need to be addressed to better understand and treat ME/CFS and long COVID?
Two major questions stand out:
Cross-condition biological parallels: Do other post-infection syndromes—like post-Lyme disease, post-Ebola, and post-West Nile virus—share the same biological abnormalities as ME/CFS and long COVID? Systematic studies are needed to confirm this.
Therapeutic targeting of neuroinflammation: There are 10–20 experimental approaches currently being tested in lab models to reduce neuroinflammation. Determining which, if any, are effective in humans is a critical next step.
These questions are central to advancing treatment and understanding the broader category of post-acute infection syndromes
Finally, it's important to raise awareness.
The idea of post-acute infection syndromes is still relatively new and not yet widely recognized in medical practice. Promoting this framework can help improve how we diagnose, study, and treat these long-lasting illnesses.
