UniteToFight—a virtual conference on Long Covid and ME/CFS—took place on May 15 and 16, 2024. Organized by five patients with Long Covid and attended by over 10,000 people from all over the world, the conference focused on discussing progress and challenges with Long Covid and ME/CFS research; emphasizing the social impact of these diseases; and sharing ideas about how best to help researchers and patients moving forward. Among the dozens of researchers presenting were these eight experts funded by Solve M.E. or collaborating with Solve on key research projects:

• Dr. Akiko Iwasaki, renowned Long Covid expert from Yale University (Connecticut)
• Ms. Amy Mooney, community activist and occupational therapist specializing in helping people with complex chronic illnesses (Illinois)
• Dr. Amy Proal, president of PolyBio Research Foundation (Massachusetts)
• Dr. Bhupesh K. Prusty, professor at Riga Stradins University (Latvia) and Solve Ramsay Research Grant winner (Class of 2016)
• Dr. David Putrino, director of Long Covid and ME/CFS research at Icahn School of Medicine at Mount Sinai (New York)
• Dr. Carmen Scheibenbogen, head of the Immunodeficiency Outpatient Clinic at Chari-té Berlin (Germany) and Solve Ramsay Research Grant winner (Classes of 2016 and 2017)
• Mr. David Tuller, senior fellow in public health and journalism at the University of California, Berkeley (California)
• Dr. Rob Wüst, Long Covid and ME/CFS expert from Vrije University Amsterdam (Netherlands) and Solve Ramsay Research Grant winner (Class of 2022)

As the conference organizers post recordings of the conference over the next few weeks, we will summarize presentations by some of the above-listed names below.

Dr. Bhupesh K. Prusty

Bhupesh Prusty is an associate professor at Rīga Stradiņš University in Latvia. A highly accomplished molecular virologist, Professor Prusty won a Ramsay Award in 2016 to study how human herpesvirus 6 damages mitochondria to drive ME/CFS. Since then, he has published half a dozen papers on ME/CFS and related diseases, focusing on inflammation, mitochondria, and viral reactivation in ME/CFS. In his UniteToFight presentation, Dr. Prusty explored a new topic—his intriguing and elegant results on how a protein called fibronectin and a type of antibody called immunoglobulin M relate to ME/CFS and Long Covid.

Fibronectin has several functions. In spaces around cells, fibronectin solidifies the matrix and fixes the position of cells in tissues. In the blood, fibronectin binds immune complexes and pathogens (like viruses and bacteria). On the one hand, if fibronectin levels are too low then patients may have trouble dealing with pathogens. On the other hand, if fibronectin levels are too high then the protein may accumulate and impact the blood–brain barrier. So fibronectin levels—which rise and fall as infections come and go—are closely regulated.

Immunoglobulin M antibody (specifically, immunoglobulin M antibody called IgM-Fn1) binds and regulates fibronectin. Unlike some antibodies whose levels rise only during infection, immunoglobulin M is there even without infection. The levels of IgM-Fn1 and fibronectin are usually opposite: when IgM-Fn1 levels are low, fibronectin levels are high; and when IgM-Fn1 levels are high, fibronectin levels are low. Levels of both these proteins change during infection. For example, when some pathogens infect mice, fibronectin levels drop and IgM-Fn1 levels rise. Then, when the mice recover from infection, fibronectin and IgM-Fn1 levels return to normal.

Dr. Prusty’s team found that patients with Long Covid or ME/CFS have exceedingly high levels of fibronectin. Patients with the most severe symptoms usually have the highest levels. In fact, on the basis of fibronectin levels alone, the researchers could generally tell whether a person was healthy, had Long Covid, or had ME/CFS. And as would be expected, levels of IgM-Fn1 in patients with Long Covid or ME/CFS are very low, and patients with the most severe symptoms usually have the lowest IgM-Fn1 levels.

For two years, the team tracked severity of symptoms, fibonectin levels, and IgM-Fn1 levels in patients with Long Covid. On the basis of IgM-Fn1–fibronectin ratios at the start of the study, they divided patients into four groups: group 1 (highest fibronectin, lowest IgM-Fn1, most severe symptoms) through group 4 (lowest fibronectin, highest IgM-Fn1, mildest symptoms). For the patients who started in group 1, symptoms usually remained just as severe over the next two years, or improved only a bit. But for patients who started in other groups, symptoms generally got better. Patients who started in group 4 had the highest rates of recovery. These results show that the IgM-Fn1–fibronectin ratio may be an effective way to predict which patients with Long Covid will recover, and which will not.

Unfortunately, IgM-Fn1–fibronectin ratios were not as useful for predicting recovery for patients with ME/CFS. Dr. Prusty’s team thinks this is because while patients with Long Covid are but a few years removed from their infections with SARS-CoV-2, most patients with ME/CFS have had this disease for many years, long after their initial infections. IgM-Fn1–fibronectin ratios seem to best predict recovery for patients in the initial years of disease, but not for patients with more prolonged disease.

Still, Dr. Prusty’s results are important because they suggest that measuring fibronectin and IgM-Fn1 levels can predict which patients with Long Covid will probably recover, and which will struggle to recover. His results also suggest that we use immunoglobulin-based therapy (for example, intravenous immunoglobulins) to treat patients with ME/CFS or Long Covid. The team will test these possibilities in future work.

One of the goals of the Solve Ramsay Research Program is to attract and maintain new researchers to study ME/CFS and Long Covid. In this regard, Dr. Prusty is a real success story, since he has continued to innovate and evolve since finishing his Ramsay project almost eight years ago.

Watch the recording of Dr. Prusty’s presentation here.

Dr. Amy Proal

Dr. Amy Proal is the president and chief scientific officer at the PolyBio Research Foundation, a 501(c)(3) nonprofit organization focused on infection-associated chronic illnesses. In 2019, she coordinated the study by a Solve Ramsay Research Grant-winning team to analyze blood, cerebrospinal fluids, and gut microbiomes from patients with ME/CFS, publishing key papers on how ME/CFS activates platelets and microclots. She also published papers on how to analyze blood and saliva from patients with Long Covid to detect problems with the immune system and with clotting. She is a key member of the Long Covid Research Consortium, a group of leading scientists who meet every two weeks to share ideas and resources about Long Covid, ME/CFS, and related diseases.

In her UniteToFight presentation, Dr. Proal described one of the central hypotheses of the Long Covid Research Consortium—that for a substantial fraction of patients with Long Covid, symptoms are caused by SARS-CoV-2 reservoirs that stealthily persist for months or years after first infections, continuing to provoke the immune system and to cause long-term problems. So, she explained, we must detect these hidden pockets of virus and eradicate them from the body.

Dr. Proal’s team and other Consortium teams found SARS-CoV-2 not only in blood and saliva of patients, but also hiding in diverse tissues and cells, like the gut, brain, lymph node, bone marrow, and platelets. But researchers rarely ask patients for samples from these tissues, focusing more on more conveniently accessible blood and saliva. So, one of her key points was that we must also obtain these other important samples. Especially important are samples from gut tissues because SARS-CoV-2 often hides in the guts of patients. (Gut tissue expresses much ACE2, the receptor SARS-CoV-2 uses to enter cells.)

Dr. Proal described the big picture of what may happen when SARS-CoV-2 hides in the gut. The gut connects with the vagus nerve, which connects with a part of the brain that controls how we respond to sickness (bringing about flu-like symptoms, nausea, pain, trouble with breathing and with heart rates). So, if the vagus nerve thinks our gut is always infected with SARS-CoV-2, then it may continually activate these symptoms. (This is also true for ME/CFS. Over 8 in 10 patients with ME/CFS have evidence for long-term enterovirus reservoirs in their stomach tissues. And these vagus nerve–stimulated symptoms are common also for patients with ME/CFS.) Hidden SARS-CoV-2 infection may wear down the gut lining over time, so viral proteins (most important, the spike protein) may leak from the gut into the blood. Up to 6 in 10 patients with Long Covid have spike protein in their blood. However, we cannot always detect the leaky spike protein because these levels rise and fall. During stressful times, a lot of protein may leak into the blood; during less stressful times, less may leak. Thus, another key point was that we cannot rely on available blood tests to tell whether patients have viral reservoirs, which may cause Long Covid.

Dr. Proal emphasized these key points:

We need better tests to better detect hidden viral reservoirs, and we must find drugs to clear the body of SARS-CoV-2 reservoirs. Doctors have limited options for searching for signs of hidden virus. For example, they may order a blood test to measure spike protein in blood. But this test won’t detect trace levels of protein, and spike protein in patient blood can fall to vanishingly small levels. Also, we must better explore immunotherapies (like those that activate T cells or natural killer cells) to help clear viral reservoirs from patients with LC or ME/CFS.

We need the NIH to quickly fund research and clinical trials on the most promising leads. This may require a visionary person, who can see the big picture and who can quickly redirect NIH funding as we learn more about what is going on.

We must realize we have the power to figure this out. We have immense experience finding and attacking other hidden viral reservoirs (for example, detecting and attacking the HIV virus). The smartest and most motivated scientists are working nonstop to use these strategies—and new ones—to eradicate SARS-CoV-2. We know what to test in clinical trials, but we need the government’s help to quicken our progress in helping millions of people suffering from these diseases.

Watch the recording of Dr. Proal’s presentation here.

Dr. Carmen Scheibenbogen

Dr. Carmen Scheibenbogen is head of the immunodeficiency outpatient clinic at Charite Universitatsmedizin (Berlin, Germany) and specializes in ME/CFS. Solve M.E. awarded her a Ramsay grant in 2016 to study autoimmune signatures in patients with ME/CFS. Since then, she has published close to a hundred papers about her research.

In this presentation, Dr. Scheibenbogen discussed the factors that may determine whether a person with Long Covid develops ME/CFS; how patients with both Long Covid and ME/CFS differ from patients with only Long Covid; and the importance of clinical trials to advance new treatments for these patients. She noted that about half of patients with Long Covid will develop ME/CFS. The patients who develop ME/CFS have more post-exertional malaise, more brain fog, and more light sensitivity than patients who do not develop ME/CFS. Dr. Scheibenbogen’s team believes that lower perfusion of capillaries causes these symptoms. Patients with Long Covid have inflamed capillaries, so their muscles get too little oxygen. With too little oxygen, mitochondria supply too little usable energy to muscle cells and dangerous elements build up (like protons, calcium, nitrogen), which damage the muscle. In about half of patients with Long Covid, the capillaries improve. But in the other half, the capillaries stay inflamed and the mitochondrial and muscle problems get worse—these people eventually develop ME/CFS.

Dr. Scheibenbogen ended by summarizing promising results of clinical trials to find biomarkers of patients with Long Covid who would probably also develop ME/CFS; to diagnose disease in these patients; and to treat these patients (for example, by using methods to remove dangerous autoantibodies, which induce ME/CFS; or by using steroids or hyperbaric oxygen therapy to treat inflammation). But her take-home point was that we urgently need more rapid trials to test these treatments to help patients.

Watch the recording of Dr. Scheibenbogen’s presentation here.

Dr. Rob Wüst

Dr. Rob Wüst is an exercise physiologist at the Vrije de Universiteit (Amsterdam, Netherlands) who specializes in symptoms of Long Covid and ME/CFS that affect physical exertion (as distinguished from those that affect cognitive or mental exertion). He received a Ramsay grant from Solve M.E. in 2022 to study muscle pain, post-exertional malaise, and treatments for pain and malaise in patients with Long Covid. In the past two years, he published seven papers on this topic.

Dr. Wüst has been studying the two most prominent symptoms of Long Covid—post-exertional malaise and general fatigue. Specifically, he has been finding ways post-exertional malaise differs from general fatigue and has found significant differences at the physiological and molecular levels.

Collecting muscle samples and questionnaire answers from people before they took an exercise-bike test and after, Dr. Wüst found patients with Long Covid differed from healthy participants in several ways. Some of these differences contribute to general fatigue; these usually involve structural changes in the body (for example, poorer mitochondrial respiration in muscles; less power output from muscle; more fast-fatiguing type 2 muscle fibers and less long-lasting type 1 muscle fibers; more fatigue-related metabolites). Other differences contribute to post-exertional malaise; these were quickly triggered by the exercise bike (for example, rapid changes to metabolites, infiltration of immune cells and microclots into skeletal muscles, and increased molecular markers for muscle damage).

These results are important because exercise does not help some patients with Long Covid or ME/CFS—it actually worsens their health. This distinguishes Long Covid and ME/CFS from other chronic diseases (like diabetes, heart failure, or depression), for which exercise generally helps patients. By understanding why patients with Long Covid or ME/CFS experience these symptoms, Dr. Wüst’s team is developing ways to treat both general fatigue and post-exertional malaise and guidelines for patients to reduce symptoms. For example, he explained how physical therapy may be helpful for some patients with Long Covid if they have no symptoms of post-exertional malaise (but only of general fatigue). Also, he stressed that patients must know their limits for physical activity and must pace themselves to avoid exceeding these limits.

Watch the recording of Dr. Wüst’s presentation here.