Answers to ‘long COVID’ may lie in Chronic Fatigue Syndrome research

Organisation: Position: Deadline Date: Location:

Between 35%- 70% of post-COVID-19 patients struggle to recover their usual health, writes MedicalBrief. Some answers may be found in data and biological material collected during a four-year study of healthy college students who contracted mononucleosis and subsequently developed Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS).

From 2014 to 2018, DePaul University psychologist Leonard Jason and colleagues at the Northwestern University Feinberg School of Medicine and the Ann & Robert H Lurie Children’s Hospital of Chicago collected personal information and blood samples from more than 4,500 healthy college students. They followed the group as some students contracted mononucleosis and a small proportion of those subsequently developed chronic fatigue syndrome – the debilitating disease also called myalgic encephalomyelitis, or ME/CFS, that is frequently triggered by an acute viral illness.

As Jason and his team were analysing data earlier this year – seeking patterns that might explain why some students remained healthy and others got sick and stayed sick – reports began emerging of troubling medical complaints lasting for weeks and months following cases of COVID-19. Some of these post-COVID symptoms, including profound exhaustion after exertion and deficits in memory and concentration, resembled those experienced by ME/CFS patients.

The researchers came to a quick realisation: The extensive baseline data and biological materials they had gathered from thousands of students created a unique opportunity to investigate risk factors for developing acute and prolonged illness after infection with the novel coronavirus.

“We will be able to compare the biological and behavioural data of young adults’ experiences prior to the COVID-19 epidemic and during the COVID-19 epidemic,” noted Jason during a recent conference presentation about the research.

This kind of prospective research design, in which people are enrolled before falling ill, allows researchers to make robust comparisons between those who return to health and those who never recover. But such studies are expensive and can take years, and they are especially challenging to put together amid a fast-moving pandemic – which helps explain why so little is known about the reasons some people develop long-lasting health problems after a viral illness.

Despite this knowledge gap, post-viral symptoms, such as persistent aches and fatigue after a bout of influenza, are a common phenomenon. These symptoms usually – but not always – resolve on their own over weeks or months. Researchers studying other viral illnesses that emerged over the last two decades – SARS, West Nile virus, Ebola, the H1N1 flu pandemic of 2009 – have also reported that some patients suffered negative long-term health consequences.

“Chronic post-SARS is characterised by persistent fatigue, diffuse myalgia, weakness, depression, and nonrestorative sleep,” concluded the authors of a 2011 study that followed up SARS patients after the 2003 epidemic, which was caused by an earlier coronavirus.

When it comes to COVID-19, people with both severe and milder cases have reported continuing symptoms. Some studies of patients who had been hospitalised found that more than 70% reported continuing problems after the acute episode. In a survey of COVID-19 patients who did not require hospitalisation, the US Centres for Disease Control and Prevention reported that 35% had not returned to their “usual state of health” two to three weeks after a positive viral test.

In the US and elsewhere, major research centres and medical organisations are now launching studies and registries of patients who have not recovered from COVID-19. To date, much of what is known about what has been called “long-COVID” comes from research led by patients themselves, often called “long-haulers.” In May, a research team from Body Politic, an online patient support community, released the results of a survey of 640 long-haulers, documenting a surprising array of symptoms.

Unlike prospective studies, which can follow participants for years, surveys provide a snapshot of information from a single slice of time. A major advantage is that they can incorporate recent developments and be conducted quickly, said Brooklyn, New York, artist Hannah Davis, who has a background in artificial intelligence and is a member of Body Politic’s research team. “We have the benefit of speed,” she said of the group, which disseminated a second and more expansive survey this week.

The new Body Politic survey includes questions about antibody tests, neurological symptoms, and mental health impacts, among other topics that long-haulers have been discussing and debating in online forums. “We just kind of observe what’s happening around us and ask questions based on the trends we start seeing,” said Davis.

Eric Rubenstein, an epidemiology professor at Boston University, is consulting with Body Politic on a proposed survey related to the disability needs of long-COVID patients. Surveys can be especially useful for generating hypotheses for further research and understanding patients’ concerns and priorities, he said. In contrast, prospective research like the DePaul study can provide valuable insights into potential disease mechanisms.

Rubenstein expects more studies of COVID-19 and long-COVID to piggyback on existing research cohorts that were established for other purposes. But the college student study is noteworthy, he said, because the researchers were already investigating another post-viral illness with potentially overlapping features. Given the parallels, he said, “they’ll have some measures that are useful for this topic.”

The similarities between symptoms experienced by ME/CFS patients and some long-haulers suggest that research into the processes driving one disease might provide insights into the other, say researchers. Other post-COVID symptoms appear related specifically to the lung scarring, cardiovascular damage, and other impacts of this particular viral infection.

Jason is among the country’s most respected and prolific ME/CFS researchers, having authored or co-authored dozens of papers on the issue. In the college student study, funded with $3m from the National Institutes of Health, about 5% of the sample developed mononucleosis and 8% of those patients met diagnostic criteria for ME/CFS after six months, said Jason, although the findings are still unpublished. Some immunological markers were associated with developing ME/CFS, he noted, while psychological factors were not.

The students were recruited from Northwestern University, where Jason’s co-investigator, Ben Katz, is a paediatrics professor.

Before the pandemic began, Jason and his colleagues had already received additional funding to conduct follow-up research on their thousands of study participants. Given the new circumstances, they have added questions about coronavirus infection, COVID-19, and post-COVID symptoms, and outreach has already begun. The research has a multiyear timeframe, but some of the data could be released in stages, he said.

“The bottom line is there might be characteristics of individuals that might be genetic or physiological or behavioural that in some ways predispose some people toward both getting an illness and then maybe not recovering from the illness,” said Jason.

Abstract 1
Background: The present study aims to prospectively investigate possible biological and psychological factors present in college students who will go on to develop chronic fatigue syndrome (CFS) following Infectious Mononucleosis (IM). Identification of risk factors predisposing patients towards developing CFS may help to understand the underlying mechanisms and ultimately prevent its occurrence. Our study is enrolling healthy college students over the age of 18. Enrolment began in March of 2013 and is ongoing.
Methods: Biological and psychological data are collected when students are well (Stage 1), when they develop IM (Stage 2), and approximately 6 months after IM diagnosis (Stage 3).
Results: Two case studies demonstrate the progression of student symptomology across all three stages.
Conclusion: The Case Studies presented illustrate the usefulness of a prospective research design that tracks healthy students, following their trajectory of IM illness to either a) full recovery or b) diagnosis with CFS.

Leonard A Jason, Ben Katz, Kristen Gleason, Stephanie McManimen, Madison Sunnquist, Taylor Thorpe

Abstract 2
Background: The long term adverse effects of Severe Acute Respiratory Syndrome (SARS), a viral disease, are poorly understood.
Methods: Sleep physiology, somatic and mood symptoms of 22 Toronto subjects, 21 of whom were healthcare workers, (19 females, 3 males, mean age 46.29 yrs.+/- 11.02) who remained unable to return to their former occupation (mean 19.8 months, range: 13 to 36 months following SARS) were compared to 7 healthy female subjects. Because of their clinical similarities to patients with fibromyalgia syndrome (FMS) these post-SARS subjects were similarly compared to 21 drug free female patients, (mean age 42.4 +/- 11.8 yrs.) who fulfilled criteria for fibromyalgia.
Results: Chronic post-SARS is characterized by persistent fatigue, diffuse myalgia, weakness, depression, and nonrestorative sleep with associated REM-related apneas/hypopneas, an elevated sleep EEG cyclical alternating pattern, and alpha EEG sleep anomaly. Post- SARS patients had symptoms of pre and post-sleep fatigue and post sleep sleepiness that were similar to the symptoms of patients with FMS, and similar to symptoms of patients with chronic fatigue syndrome. Both post-SARS and FMS groups had sleep instability as indicated by the high sleep EEG cyclical alternating pattern rate. The post-SARS group had a lower rating of the alpha EEG sleep anomaly as compared to the FMS patients. The post-SARS group also reported less pre-sleep and post-sleep musculoskeletal pain symptoms.
Conclusions: The clinical and sleep features of chronic post-SARS form a syndrome of chronic fatigue, pain, weakness, depression and sleep disturbance, which overlaps with the clinical and sleep features of FMS and chronic fatigue syndrome.

Harvey Moldofsky, John Patcai

Abstract 3
What is already known about this topic? Relatively little is known about the clinical course of COVID-19 and return to baseline health for persons with milder, outpatient illness.
What is added by this report? In a multistate telephone survey of symptomatic adults who had a positive outpatient test result for SARS-CoV-2 infection, 35% had not returned to their usual state of health when interviewed 2–3 weeks after testing. Among persons aged 18–34 years with no chronic medical conditions, one in five had not returned to their usual state of health.
What are the implications for public health practice? COVID-19 can result in prolonged illness, even among young adults without underlying chronic medical conditions. Effective public health messaging targeting these groups is warranted.

Mark W Tenforde; Sara S Kim; Christopher J Lindsell; Erica Billig Rose; Nathan I Shapiro; D Clark Files; Kevin W Gibbs; Heidi L Erickson; Jay S Steingrub; Howard A Smithline; Michelle N Gong; Michael S Aboodi; Matthew C Exline; Daniel J Henning; Jennifer G Wilson; Akram Khan; Nida Qadir; Samuel M Brown; Ithan D Peltan; Todd W Rice; David N Hager; Adit A Ginde; William B Stubblefield; Manish M Patel; Wesley H Self; Leora R Feldstein; IVY Network Investigators; CDC COVID-19 Response Team



Meanwhile, a hospital in one of COVID-19 first epicentres is now calling back survivors measuring what the coronavirus has left in its wake, says a LMT Online report. The Pope John XXIII Hospital in Bergamo, Italy is drawing COVID-19 survivors’ blood, examining their hearts, scanning their lungs, asking them about their lives.

“How are you feeling?” a doctor recently asked the next patient to walk in, a 54-year-old who still can’t ascend a flight of steps without losing her breath. “I feel like I’m 80 years old,” the woman said.

Six months ago, Bergamo was a startling warning sign of the virus’s fury, a city where sirens rang through the night and military trucks lined up outside the public hospital to ferry away the dead. Bergamo has dramatically curtailed the virus’s spread, but it is now offering another kind of warning, this one about the long aftermath, where recoveries are proving incomplete and sometimes excruciating.

Those who survived the peak of the outbreak in March and April are now negative. The virus is officially gone from their systems.

“But we are asking: Are you feeling cured? Almost half the patients say no,” said Serena Venturelli, an infectious-disease specialist at the hospital.

The follow-ups are the basis for medical research: Data on the patients now fills 17 bankers’ boxes, and scientific reports are on the way. Bergamo doctors say the disease clearly has full-body ramifications but leaves wildly differing marks from one patient to the next, and in some cases few marks at all. Among the first 750 patients screened, some 30% still have lung scarring and breathing trouble. The virus has left another 30% with problems linked to inflammation and clotting, such as heart abnormalities and artery blockages. A few are at risk of organ failure.

Beyond that, according to interviews with eight Pope John XXIII Hospital doctors involved in the work, many patients months later are dealing with a galaxy of daily conditions and have no clear answer on when it will all subside: leg pain, tingling in the extremities, hair loss, depression, severe fatigue.

Some patients had pre-existing conditions, but doctors say survivors are not simply experiencing a version of old problems.

“We are talking about something new,” said Marco Rizzi, the head of the hospital’s infectious-disease unit.


And Deborah Copaken, a contributing writer at The Atlantic writes on her continual battle with symptoms after surviving COVID-19:
“The stairs have become my daily Everest. Just six months ago, the steep climb to my fourth-floor walk-up in Brooklyn was a nuisance only when I was carrying bags of groceries. Now, every time I mount those 53 steps, no matter how slowly, even if I’m empty-handed, my heart rate shoots up to marathon-level. I can actually feel the thud-thud in my throat. Sometimes I have to pause between landings to lie on the floor and stick my feet up in the air to avoid passing out.”

Copaken writes that this unusually rapid beating can also be triggered seemingly by nothing – sitting up in bed, standing up from the toilet. “I first noticed it in March, when I came down with COVID-19. Or at least, it seems clear that I came down with COVID-19. My whole household got sick just before the peak of New York City’s outbreak. Like most Americans in the early weeks of the pandemic, we were unable to get tested, so my primary-care physician diagnosed my illness based on symptoms: endless days of fever, loss of taste and smell, sore throat, nausea, exhaustion, body aches, a hacking dry cough, and an intense struggle to breathe.

“Most of these symptoms subsided in mid-April, but some have lingered. For months, I needed a twice-daily dose of a steroid inhaler to breathe normally. I’m more tired and brain-fogged than usual. And I’m still dealing with my racing heart. I’ve always been a bit of a fainter: Years ago, I was diagnosed with orthostatic hypotension, a sudden, rapid decrease in blood pressure that sometimes strikes when I stand up too quickly. But now, instead of fainting once or twice a year, I feel that woozy fade from light to dark daily, sometimes even hourly. A few weeks ago, I stood up to make a smoothie and my heart rate zoomed from lying-in-a-hammock to booming-bass-drum.

“The official name for my new heart troubles, as I’ve recently been diagnosed, is postural orthostatic tachycardia syndrome (POTS). The condition, a puzzling dysfunction of both the heart and the nervous system, messes with how the body regulates involuntary functions, including pulse. POTS is known to affect approximately 500,000 people in the US, typically young women in their late teens or early 20s. But now, several cardiologists with whom I’ve spoken say they’re noticing an unsettling trend. Previously fit and healthy women of all ages who have had COVID-19 are showing up at their offices, complaining of inexplicably racing hearts.

“The more we learn about COVID-19, the stranger its effects appear to be. Beyond its tell-tale fever and cough, troubling early evidence has been mounting that the disease can damage many organs in the body, including the lungs, the brain, and – yes, you guessed it – the heart. An array of cardiac dysfunctions has cropped up, confounding researchers and revealing that COVID-19 is a far more complicated and potentially long-lasting disease than people initially expected. These heart ailments have especially gained attention from sports: Some college football players who have had COVID-19 are sitting out this season with myocarditis, a rare condition that can be fatal if untreated. The Red Sox pitcher Eduardo Rodriguez is doing the same.

“In a strange way, I feel lucky. POTS is not life-threatening – at least, aside from the risk of head trauma from blacking out. But it is destabilising, both physically and mentally, to wander around not knowing what my body has in store for me from one minute to the next. Like so many other aspects of this pandemic, this latest syndrome in my parade of illness is mysterious, disruptive, and scarily indefinite.

“POTS has been recognised under different names by doctors for more than 160 years, but the syndrome’s root cause is still poorly understood. Its apparent link to COVID-19 is even more of a mystery, in the most nascent stage of research.”

Copaken quotes Matthew Tomey, the director of the cardiac intensive-care unit at Mount Sinai Morningside and one of a growing number of cardiologists who have begun studying the lingering effects of COVID-19 on the heart as saying: “We know much more about POTS in general than we do about post-COVID POTS. In a series of patients who do have POTS, over 40% describe symptoms of a preceding viral illness. And so, while we’re still learning more and more about COVID-19 specifically, we have good reason to believe that it is yet another viral illness that could precede the onset of POTS.”

Copaken writes that Tomey is in the middle of gathering data on COVID-19 survivors stricken with all manner of symptoms, so he wasn’t able to share any specific numbers on those with POTS that might hint at exactly how widespread the overlapping conditions are. For now, the evidence is anecdotal. But Tomey and the other cardiologists with whom I spoke all are alarmed by the uptick in POTS and other forms of dysautonomia – the dysfunction of the nerves regulating involuntary body functions – in their practices. This is frustrating for everyone involved. POTS’s unclear origins and wide range of symptoms vex doctors. And they make it easy for patients to be dismissed.

Copaken writes: “For the sake of furthering post-COVID science, I’ve volunteered my own female body to join Tomey’s study sometime this fall. This will require extra trips up and down my stairs. I asked Tomey if I should change apartments. ‘No,’ he said. ‘As difficult as those stairs are for you right now, they may be the salvation to the problem.’ Such is the damning catch-22 of POTS. A racing heart limits physical activity. But to recuperate, I must be active.”


Full STAT News report


Mononucleosis study


Post SARS study


US CDC study


Body Politic Survey 1


Body Politic Survey 2


Full LMT Online report


Full report in The Atlantic

Receive Medical Brief's free weekly e-newsletter

Related Posts

Thank you for subscribing to MedicalBrief

MedicalBrief is Africa’s premier medical news and research weekly newsletter. MedicalBrief is published every Thursday and delivered free of charge by email to over 33 000 health professionals.

Please consider completing the form below. The information you supply is optional and will only be used to compile a demographic profile of our subscribers. Your personal details will never be shared with a third party.

Thank you for taking the time to complete the form.