ME/CFS, Chronic Fatigue Syndrome, compared
to Long Haul COVID
For many doctors, the strange symptomology of long
Covid calls to mind another mysterious, poorly understood condition:
myalgic encephalomyelitis, more familiarly
known as Chronic fatigue
syndrome. ME/CFS, as it is often abbreviated, is defined
by the presence of certain symptoms, including debilitating fatigue and
unrefreshing sleep, that last for six months or longer. ME/CFS-like syndromes
have been linked with infections for more than a century — including, most
recently, those caused by the viruses responsible for the
SARS and H1N1
pandemics in 2003 and 2009. Chiefly because of this association, several
experts told me that they anticipate a wave of new patients —
who, because their symptoms are severe enough and last for six months or
longer, will essentially be ME/CFS patients
whether they receive the diagnosis or not.
“I’m expecting to see an increase that could generate as many new cases over the
next two to three years as exist already in the U.S.,” says Anthony Komaroff, a
physician at Brigham and Women’s Hospital in Boston who has treated
ME/CFS for decades. In other words, as many as
2.5 million additional people could become afflicted with a disorder that some
have argued causes more illness and suffering than
H.I.V. “It’s not death,” Komaroff told me. “But might it be a fate
worse than death for some people? It’s possible.”
The underlying biology of ME/CFS is poorly
understood. Certain doctors long dismissed it as a psychological phenomenon, in
part because no one could figure out what caused it. For this and other reasons,
research into the syndrome has, in the view of many, not been commensurate with
the great costs it exacts — tens of billions of dollars yearly in medical bills
and lost productivity, to say nothing of the many lives spent hidden away,
sometimes bedbound, in darkened rooms.
These days, though, the medical community increasingly accepts the condition as
real, and doctors have even made some headway in managing its symptoms. No one
yet knows what the relationship between long Covid and
ME/CFS — itself an imprecise diagnosis — will prove to be. But some
experts think recent advances in the study of ME/CFS,
inconsistent and inconclusive though our understanding of it remains, may
provide insight into what ails long-haulers
and how to treat them. In the process, that research might also shed light on an
enduring medical conundrum: Why do certain infections, even as they resolve in
most cases, become a protracted, debilitating ordeal for a small group of
Even as doctors around the world have been flummoxed by long Covid and its
mysteries, the patients themselves have found one another online. Soon after the
pandemic started, the medical consensus, based on the World Health
Organization’s analysis of China’s experience, held that mild Covid-19 cases
should resolve in two weeks on average. So, as patients with supposedly mild
cases continued to experience symptoms long after that two-week mark — and in
some cases actually got worse as time dragged by — they knew something was
They named themselves early on. “Long-haulers” originated with an American woman
who started a support group and christened it the “long-haul Covid fighters,”
inspired by the trucker hat she was wearing when she was tested for Covid. “Long Covid” first emerged as a hashtag (#LongCovid), coined by an Italian in Lombardy, a
hard-hit region of the country. Similar terms arose in Spanish (#CovidPersistente), German (#MitCoronaLeben)
and other languages.
Many long-haulers report that medical
professionals respond to them with disbelief or brush off their symptoms as
merely psychological. Still, by September, the World
Health Organization’s use of “long Covid”
signaled that the term had crept into mainstream medical awareness. Doctors had
formulated their own phrasing as well: “post-acute
When trying to treat what ails long-haulers,
separating those with organ damage from the rest will be important, scientists
told me. “There are some people whose heart and kidneys are not going to work as
well for the rest of their lives,” Anthony Komaroff says. This doesn’t mean the
damage cannot be treated. Doctors can prescribe aspirin
and other drugs for the heart inflammation
seen in some Covid patients, for example, or anticoagulants to help with
The more puzzling matter, though, is how to understand and treat the many
patients who have little that’s measurably wrong with them, or whose Covid-related
injuries can’t explain their malaise, but who nevertheless feel physically and
In my conversations with them, long-haulers
detailed bewildering post-Covid symptoms — new sensitivities to smells and
tastes, brutal chest pains, migraines that felt like, in one woman’s words,
“someone stuck an ice pick in my head.” But what often seemed most disturbing to
patients were the deadening fatigue and cognitive issues that in some ways
Does INFECTION trigger ME/CFS and is it followed by Inflammation and an
Lauren Nichols, who is 32 and fell ill in March, told me she had become so
forgetful that she had to write notes to remind
herself to eat. Once, in the shower, she sat on the floor weeping because she
couldn’t recall how the doorknob worked. “It takes me hours to write email and
text messages,” she says. Kristen Tjaden, who is 34, contracted the coronavirus
One time, months after the illness, she couldn’t remember which hand was the
left one. She found she couldn’t do two things at once, like folding laundry and
listening to music — the mental strain was too great.
By November, things were gradually improving, but she just didn’t feel “like
this is my own brain,” she told me then. The problem isn’t so much
brain fog, she said, as “a brain hurricane.”
Scientists invariably mention the possibility that ongoing
inflammation and perhaps
autoimmune processes that result from having
fought off the virus could drive the strange constellation of symptoms. Avindra
Nath, clinical director of the National Institute of
Neurological Disorders and Stroke, told me that when fighting a
pathogen, the immune system sometimes conducts a very precise and surgical
attack, working like a guided missile.
But when that approach fails, it can begin “blanket bombing,” as he puts it.
Once the infection is gone, tamping down the resulting firestorm can prove
challenging. “You have persistent immune activation,” he says. And that
lingering inflammation could drive many
This notion that infection can unbalance the immune system has often been
invoked to explain the onset of autoimmune
diseases — conditions in which the immune system attacks the very body it’s
meant to protect.
- Multiple sclerosis, for example, has
long been associated with infection by the
- Rheumatic fever, a potentially deadly
autoimmune inflammation of the heart and brain, is caused by a strain of the
same streptococcus bacterium that we know from “strep” throat.
A form of autoimmune arthritis can erupt in human knees and other joints after
infection by the bacterium that causes Lyme disease,
ME/CFS mimics psychiatric disorders
In recent years, scientists have come to realize that the symptoms of certain
autoimmune diseases can even mimic psychiatric
In anti-NMDA receptor encephalitis, for
example, the immune system attacks glutamate receptors on neurons in the brain,
sometimes provoking behavior that resembles what’s seen in
It, too, can be triggered by viral infection. (It’s treatable.) There’s also a
pediatric condition that is similar to
obsessive-compulsive disorder called
pediatric acute-onset neuropsychiatric syndrome, or
PANS, that many think can be set off by
Certainly there is abundant evidence that the coronavirus can goad the immune
system into overreaction during the acute phase of infection.
Some children (and adults) develop a multisystem
Scattered reports suggest that the virus might trigger
Guillain-Barré syndrome, a frightening
autoimmune condition in which patients develop full or partial
paralysis (though most eventually recover).
immune system in overdrive
Some scientists have suggested that an exaggerated immune response to the
coronavirus, rather than the damage directly inflicted by it, is responsible for
many Covid deaths.
This sort of self-destruction is often described as a “cytokine storm.”
Ignacio Sanz, an immunologist at Emory University, and his colleagues recently
described more granular evidence of this self-attack in Covid-19.
Compared with a healthy control group, they discovered, severe Covid-19 patients
display high levels of antibodies directed at their own tissues — antibodies
usually seen in lupus and
rheumatoid arthritis, two
This does not necessarily mean that these patients have an autoimmune
condition, Sanz stresses. Those same antibodies are found in healthy people.
But not only are the levels of these antibodies relatively high in severe
Covid-19; the cells that produce them also appear to be even more primed for
aggression than they are in autoimmune disease.
In his view, this dynamic hints at an immune system
pushed into overdrive. Sanz suspects that in people who already have
a propensity to develop autoimmune disorders, the virus may tip their immune
systems into overt autoimmune disease.
Women more than Men
The fact that most long-Covid patients are women
may be an important clue in support of this hunch.
In general, women are more likely than men to develop
Akiko Iwasaki, an immunologist at Yale, has found that
female Covid patients tend to mount a stronger
response to the virus from T cells, which help defend against microbial
invaders, than their male counterparts.
Testosterone is a slight immune suppressant,
which may explain this disparity between women and men — and perhaps why
men are more likely to die from Covid-19. (The
female members of many species outlive the males, possibly because they have
superior immune systems.)
But one disadvantage of a more forceful immune response may be a greater
propensity to attack the self. “Women survive this,” Iwasaki says, “but maybe
there’s a cost.”
Fights the body itself
Iwasaki and her colleague Aaron Ring have, like Sanz, also identified what
seems to be immune misfiring in Covid-19. But instead of looking for antibodies
already associated with autoimmune disease, they used a new technique to search
for any antibody, including previously unidentified ones, that might bind with
some 3,000 proteins — out of tens of thousands — produced in humans.
Their findings, reported in a December preprint, which has not yet been
peer-reviewed, suggest a widespread autoimmune attack.
Compared with subjects from the healthy control group, severe Covid-19 patients
had elevated levels of antibodies directed at dozens of tissues, including the
brain, the lining of blood vessels and components of the immune system itself.
Why some infections might cause the immune system to attack the body in certain
individuals but not others is a longstanding medical mystery.
It may be that proteins on the invading microbe
resemble tissue in the human body, and that in pursuing the invader,
some people’s immune systems accidentally attack similar molecules in their own
organs. This idea is called molecular mimicry.
But Ring told me that the sheer number and variety of self-directed antibodies
he and Iwasaki discovered suggest some other process gone awry.
Some antibodies they observed were directed at
virus-fighting components of the immune system itself, and Iwasaki
posits a “vicious cycle” that begins with the immune system attacking itself,
undercutting its own antiviral response.
The body tries to compensate by ramping up other defenses, but these aren’t
well suited to fighting viruses and cause extensive
cellular damage. As injured cells burst and release debris, the
immune system, already in a frenzy, turns against the
debris as well, inflicting even more harm.
Some of those self-directed antibodies declined in number over the course of
Ring and Iwasaki’s study, indicating that they may subside naturally once the
virus is defeated.
But if the antibodies stick around in some
individuals, they could drive an ongoing attack at various sites in the body,
which might account for the symptoms of long Covid.
If that proves to be the case, Ring says,
potential treatments already exist, including
rituximab, a powerful drug that selectively depletes
How exactly might an autoimmune disease cause the
fatigue, cognitive failings and
other symptoms seen in those with long Covid?
Patients with other autoimmune diseases,
like rheumatoid arthritis
and inflammatory bowel disease,
often report debilitating fatigue and
They may even consider this fatigue to be worse than the pain or discomfort
emanating from what’s usually considered the site of attack — the gut and the
The chronic inflammation central to these
diseases causes the fatigue, doctors think.
It’s an illustration of just how tightly connected the immune system is with our
sense of well-being.
Long Covid and ME/CFS share features beyond
symptoms. Both are linked with infection. And the immune system is a focus of
research into both conditions.
Yet the idea that long Covid and
ME/CFS are overlapping disorders is not
Although many long-haulers may now
technically meet the criteria for ME/CFS,
Maureen Hanson, a molecular biologist who studies ME/CFS
at Cornell University, warns against assuming they are related. “We
don’t know how long people will actually remain ill,” she says.
And of course, there are thought to be millions of
people around the world with ME/CFS,
but “none of them got it because of SARS-CoV-2,” she adds. “We don’t know if
this new virus will cause the same disease.”
For patients, the “chronic fatigue” label
carries the stigma of not always having been taken seriously by the medical
establishment. But perhaps worst of all, the equation of the two conditions
implies a scary permanence. “ Chronic fatigue syndrome
is a syndrome that does not get better,”
Dayna McCarthy says. “From a psychological perspective, that’s just
devastating.” She counsels her patients not to read too much about
ME/CFS on social media.
Even so, the similarities are numerous enough that Anthony Fauci, head of the
National Institute of Allergy and Infectious Diseases, has raised them
repeatedly, telling Medscape in July that “it’s extraordinary how many people
have a postviral syndrome that’s very strikingly similar to myalgic encephalomyelitis/
Chronic fatigue syndrome. They just don’t get back to normal energy
or normal feeling of good health.”
Scientists have for years considered three nonmutually exclusive explanations
for how a viral infection might trigger ME/CFS:
- It changes the brain somehow, prompting ongoing fatigue and malaise;
- it becomes chronic, making the person ill indefinitely; or
- it triggers an autoimmune or inflammatory disease that continues to
torment people long after the offending microbe is gone.
These explanations feature in scientists’ thinking on long Covid as
ME/CFS is not understood
Yet for decades, physicians trying to treat ME/CFS
have been bedeviled by one obstacle above all others: They have no
way of objectively diagnosing the condition.
- Cardiologists see clogged arteries and consider
- Infectious-disease doctors detect viruses and bacteria and think
But there is no equivalent, empirically measurable dysfunction that indicates
ME/CFS. It “isn’t a diagnosis — it’s a
label,” Anne Louise Oaklander, a neurologist at Massachusetts General Hospital,
told me. “We don’t really understand what the
underlying biology is.”
In order to apply that ME/CFS label, a
physician must first rule out other possibilities. Then a patient must satisfy
three criteria, which are subjectively reported:
- incapacitating fatigue lasting more than six months;
- worsening symptoms after physical or mental exertion; and
- unrefreshing sleep.
- A fourth requirement is that patients suffer from at least one of the
- difficulties with thinking and memory; or
- orthostatic intolerance, a debilitating dysfunction of the autonomic
nervous system characterized by rapid changes in heart rate and blood
pressure when standing.
Even if scientists aren’t sure about the root cause of
ME/CFS, however, numerous studies in recent
years have documented biological differences in these patients.
There’s orthostatic intolerance, for one —
which, as one scientist pointed out to me, can’t be “psychological.”
And Nancy Klimas, a physician and scientist at Nova Southeastern University, and
others have observed that one set of cells in particular, called
natural killer cells, behave quite strangely in
Normally these cells sidle up to and destroy cells infected by viral invaders.
But in ME/CFS patients, Klimas has found
them to be listless and inert. She doesn’t
think that they’re defective; she hypothesizes that they’ve been
worked to exhaustion.
Klimas’s research on postexertional malaise
— which has involved collecting blood work on volunteers before, during and
after mild exertion — has also revealed numerous differences compared with
Some inflammation after exercise is normal.
But that immune activation is quickly brought under control, and an
anti-inflammatory signal eventually prevails.
In ME/CFS patients, that
continues unabated. The patients seem to respond to exercise as if
they were fighting the flu. “You can imagine what that feels like, like getting
hit by a truck,” Klimas says.
ME/CFS (and long-Covid) patients can suffer
from dysautonomia, an affliction of the
autonomic nervous system that can cause racing heart,
gut problems, dilated pupils, sweating and rapid changes in blood pressure when
It may be one reason they don’t feel rested after
The sympathetic nervous system — that part
of your body that swings into action when, for example, you’re chased by a bear
— seems to have been permanently switched on
in some patients. “Flight-or-fight all the time is not healthy,” Klimas says.
Long Haul COVID patients might benefit from ME/CFS Treatments and
Perhaps spurred by the sense that a storm of chronic illness is gathering,
the National Institute of Allergy and Infectious
Diseases hosted a video meeting in December devoted solely to long
Covid, with the goal of sharing what was known about the condition and also
identifying what remained unknown.
Physicians and scientists from the United States and elsewhere spoke, as
did some patients.
And Peter Rowe, director of the Children’s Center
Chronic Fatigue Clinic at Johns Hopkins University,
urged his fellow physicians to familiarize themselves with
ME/CFS. Even if the root cause isn’t well
understood, doctors have learned a lot about how to
manage some symptoms in recent years, he said, particularly
orthostatic intolerance, which is common in
both young ME/CFS patients and the few long-Covid
patients he has seen so far.
Rowe told me he is concerned that the health care workers who will be involved
in the long-haulers’ rehabilitations won’t know what
ME/CFS specialists have
He frets that physicians aren’t aware, for example, that
too much physical exertion can drastically worsen symptoms.
And he worries about the historical tendency to see the condition as
psychological in nature.
That thinking led to an overemphasis on treatments like
cognitive behavioral therapy or
graded exercise therapy, he says, which have
largely been abandoned as cure-alls for ME/CFS
in the United States, but not without first doing great harm to patients.
“It’s going to be extremely important not to make the mistakes that were made in
the early ’90s,” he said at the meeting. As he put it to me: “I’m concerned that
people haven’t learned the lessons of the past 25 years.”
Scientists have known for many decades that infections can trigger
long-lasting, often debilitating conditions — ones that feature fatigue and
cognitive dysfunction similar to what doctors are observing today in Covid-19
survivors. In other words, long Covid may simply be the latest example of a
postinfectious phenomenon that has mystified physicians for more than a century.
The “Russian flu” pandemic that occurred
between 1889 and 1892 left in its wake a now-familiar-sounding collection
of symptoms, including pain, numbness and fatigue-like complaints described as
“prostration” and “inertia,” Mark Honigsbaum writes in his 2013 book “A History
of the Great Influenza Pandemics.”
He quotes Josephine Butler, the British women’s rights crusader, who declared in
1892, three months after contracting the virus: “I am so weak that if I read or
write for half an hour I become so tired and faint that I have to lie down.”
Survivors of history’s worst influenza pandemic, the so-called Spanish flu of
1918-19, also reported lingering symptoms, including “loss of muscular
energy,” “apathy” and “melancholia” that sometimes lasted for years.
Much smaller outbreaks of similar disorders occurred with remarkable regularity
throughout the 20th century, with the notable difference that no one really knew
what gave rise to them.
In 1934, nearly 200 doctors and nurses in Los Angeles came down
with what doctors labeled “atypical poliomyelitis” — “atypical” because, unlike
true polio, it struck adults rather than children and caused neither death nor
paralysis. Yet some patients regarded the long-lasting
symptoms, which included pain, sleeplessness and difficulties with
concentration and memory, as worse than the original illness.
In 1956, after an outbreak in London, British doctors coined the term
“benign myalgic encephalomyelitis” to
describe the condition, which, in medical speak, roughly means “muscle pain with
brain and spinal cord inflammation.” Most of these patients recovered, but not
all. In London, 7 percent remained hospitalized three months later. After an
outbreak in Iceland, doctors found that only 31 percent had recovered six years
Doctors proposed that a milder relative of the
poliovirus must be at fault. But perhaps because no such virus could
be identified, a rival explanation gained currency.
In 1970, two British doctors reviewed records from 15 outbreaks and
dismissed the idea of an infectious cause. Instead, they concluded that “either
mass hysteria on the part of the patients or altered medical perception of the
community” could explain the phenomenon.
To support the “hysteria” claim, they cited the fact that most patients were
women. The resulting shift in how doctors thought about the disease would, some
have since argued, inflict tremendous harm on patients suffering from a very
real, if ill-defined, disease.
In 1985, after another apparent outbreak in Incline Village, Nev., near
Lake Tahoe, the media piled on, derisively calling the condition the “yuppie
flu” — or as Newsweek described it in 1990, “a fashionable form of
About this same time, scientists who were studying the condition settled on
“chronic fatigue syndrome” to describe it. The term still rankles many who see
it as greatly understating the severity of their condition. As the author Laura
Hillenbrand, who has the illness, once told The Times, it “is condescending and
so grossly misleading. Fatigue is what we experience, but it is what a match is
to an atomic bomb.”
After pursuing what seemed like promising leads, the quest to identify a single
infectious cause of these persistent illnesses — the proverbial chronic fatigue
virus — ultimately turned up little, and in 1992, a group of scientists,
including Anthony Komaroff, advanced a more complicated if less satisfying
“We think that this is probably a heterogeneous illness that can be
triggered by multiple different genetic and
environmental factors,” they wrote, “including
and exogenous infectious agents.” In other
words, the disease emerged from an interaction between each patient’s unique
makeup and any number of stressors in the environment — including, possibly, an
In the 2000s, researchers in rural Australia tried to confirm through
direct observation the proposed link with infection.
Previously, scientists studying the syndrome were always playing catch-up,
trying to figure out what had happened to patients who showed up at their
offices already ill.
But in the township of Dubbo, scientists collaborated with local doctors to
follow 253 patients who contracted infections more serious than the common cold
— those viruses weren’t linked with ME/CFS —
in order to see who might develop fatigue and other symptoms over the following
The scientists found that Dubbo residents could develop
chronic fatigue after several illnesses, among them
- Q fever, which is caused by bacteria carried by livestock;
- Ross River fever, spread by mosquitoes; and
- Epstein-Barr infection, transmitted via human saliva.
About 11 percent of the patients who contracted one of these infections still
had symptoms six months later, at which time
they met the criteria for Chronic fatigue syndrome.
Nine percent had persistent symptoms a year later.
No social or psychological factors foretold who developed long-term fatigue
and other symptoms. But one factor was broadly predictive: how sick patients
became during the initial phase of their illness. The
sicker they got, the more likely they were, after the infection
itself had cleared up, to develop fatigue, pain and
problems with memory and concentration.
From the Russian Influenza to Covid-19, these have been the abiding questions:
Where in the body is the dysfunction that drives these chronic symptoms?
And what distinguishes those who develop these long-term syndromes from
those who don’t?
A study conducted several years ago by Alice Russell and Carmine Pariante at
King’s College London suggests that the answer may lie in the different ways
individual immune systems respond to the same challenge.
Russell and Pariante decided to follow 55 subjects being treated for
hepatitis C, a chronic viral infection of the
They wanted to see if any of them developed persistent problems not from the
hepatitis virus itself but from the therapy meant to cure it.
At the time, treatment included injections of
interferon-alpha, a protein also made by our own bodies, which
activates the body’s antiviral defenses.
By giving patients interferon, doctors
essentially rev up their immune systems in much the same way an actual viral
For years, scientists have known that interferon
treatment can also lead to fatigue and
depression in some patients.
The therapy for these patients thus provided a way to simulate infection and
then study its long-term consequences without using an actual infectious agent.
Six months after the treatment concluded, one-third of
the patients reported persistent fatigue. At that point, nothing
appeared to be different about their immune function.
But by analyzing inflammatory markers in blood taken before and during the
interferon therapy, the scientists found two rough predictors:
- the more activated their immune system was before treatment, and
- the more inflamed they became during treatment,
the greater the likelihood of suffering from fatigue
“It may be that in one person, the immune system
is more reactive,” Pariante says, “so it doesn’t go
back easily to normal after the challenge. And this is the person
more likely to develop long-term fatigue.”
This relationship may be present in Covid-19 as well. Pariante points to a study
from Vita-Salute San Raffaele University in Milan showing that levels of
inflammatory markers during a coronavirus infection roughly predicted the
development of anxiety and
depression after. (Depression is not the same
as fatigue, of course, but scientists have for years hypothesized that aberrant
inflammation is responsible for some cases of
depression, just as they consider it a possible cause of
It still remains unclear, though, what biological dysfunction underlies those
persistent symptoms after interferon
treatment (or an actual infection) has run
This is the mystery at the heart of those ME/CFS
cases associated with infection, and maybe long Covid too: How does an
infection change your body so that you continue to feel terrible, and maybe even
worse, long after the infection has gone? And why can’t scientists pin down
whatever that change is?
Pariante and others suspect that something may shift in
the brain itself, where it’s harder to
detect anomalous immune activity.
Two very small studies have documented brain inflammation in
ME/CFS, one using positron emission tomography
and another employing a technique called magnetic resonance spectroscopy. As
always, in purely observational studies like these, it’s unclear if what’s
different about these patients — the brain inflammation — actually causes the
condition, results from it or is unrelated to it.
The infected Brain ?
But scientists know that certain cells in the brain, called
microglial cells, can assume different
personas: They can function like agreeable handymen, removing detritus and
ensuring that your synapses are clean and working properly. Or they can act like
vandals, interfering with the brain.
In animal studies, the shift is visible under a microscope, says Jarred
Younger, director of the Neuroinflammation, Pain and
Fatigue Laboratory at the University of Alabama at Birmingham, and
the senior author on one of those brain-inflammation studies. With repeated
infectious hits, microglia can become
“spiky.” “They look angry,” he says, “like they’re ready to fight.”
Younger thinks that in ME/CFS, these
cells may permanently change into that “angry”
version of themselves. He is currently studying the possibility and, should that
work pan out, he has a few drug candidates that might
calm microglia. These include low-dose
naltrexone, a drug that blocks opioid
receptors and is sometimes used to treat autoimmune disease — and also been
found to be effective, anecdotally, in ME/CFS
— as well as minocycline, an old
antibiotic that scientists know can exert an anti-inflammatory effect in the
infection triggers an autoimmune disease ?
Another explanation for misfiring immune systems — one that some researchers
put forward to explain long Covid — is that infection
triggers an autoimmune disease, and
that scientists have simply been unable to pinpoint where that self-attack is
Carmen Scheibenbogen, head of the chronic fatigue center at the Charité
university hospital in Berlin, thinks she may have
identified the target tissue.
Some ME/CFS patients have an autoimmune
disease in which antibodies interfere with certain receptors in the endocrine
system, she thinks — precisely the kind of molecular self-laceration that might
hamper the autonomic nervous system, producing the rapid pulse and other odd
symptoms often seen in ME/CFS patients.
Importantly, she and others have had some very preliminary
success treating the problem as an autoimmune disease.
If some portion of long Covid cases turn out to have the same or similar
condition, her research may have much broader bearing.
Multiple causes of ME/CFS ?
Unfortunately, though, no single treatment is likely to cure all cases of
ME/CFS. Scheibenbogen, Younger and other
ME/CFS experts I spoke with were in agreement:
The entity we call ME/CFS
probably has multiple causes. “It’s very unlikely this is a single
disease,” Younger says. “It’s a few things.”
Maybe the simplest explanation for why some
long-haulers aren’t recovering is that, even if they test negative,
they may in fact still harbor a Covid infection somewhere in their body.
Amy Proal, a microbiologist with the PolyBio Research Foundation, which focuses
on chronic inflammatory diseases, thinks that if people feel sick after an
infection, that may be because they in fact are still fighting a hidden
infection. “An incredibly logical explanation is that the driving factor is
still there,” she says.
The idea of a persistent Covid infection remains unproved, although several
studies hint at the possibility.
But if this turns out to be the case for some patients, it will be important to
separate them from those who might have an autoimmune
or inflammatory condition, Proal points out,
because treating one could aggravate the other.
Using immune suppressants to treat an
autoimmune condition, for example, could very
well make a lingering infection worse.
The HERPES connection ?
The notion that long-term infection is responsible for chronic illness has an
extensive history in ME/CFS research, where
herpesviruses, which establish a lifelong
presence in our bodies, have been put forward as the possible culprit. Nancy
Klimas of Nova Southeastern University has gradually moved away from the
suggestion that herpesviruses directly cause
ME/CFS, though. Her view is that they play a
secondary role. She suspects that, in some cases, ME/CFS
consists of a two-phase illness:
- an initial hit of some sort — infection or trauma, say — and then, because
that stressor lowers immunological vigilance,
- a second phase in which herpesviruses
already present in the body may spring back to life and lead to misery. And
then for reasons no one understands, the immune system can’t get that second
viral rebellion back under control.
“The issue isn’t the virus,” Klimas says. “The issue is immune
surveillance.” The problem isn’t necessarily their presence in our bodies, in
other words, but rather that, after some destabilizing event, the
immune system may lose the ability to manage viruses it
easily handled before.
The SHINGLES parallel
Anecdotally, at least, some long-haulers
are experiencing the type of viral reactivation Klimas describes.
In late October, seven months after contracting the coronavirus, Lauren Nichols
developed shingles — a reactivation of the
virus that causes chickenpox.
The episode, which featured burning, “out of this world” nerve pain, sent her to
the emergency room.
A lesion developed on the cornea of her left eye, threatening her vision.
Antiviral medication helped bring the
shingles under control.
Nichols, an administrator of a long-Covid support group, told me that
reactivation of Epstein-Barr,
cytomegalovirus and other
herpesviruses occurs in a small but significant
percentage of long-haulers on the site.
The LYME parallel
A similar argument over what drives chronic symptoms — persistent
infection versus lingering
inflammation from a past
infection — appears prominently in the study of
Lyme disease. Some people infected with
Borrelia burgdorferi, the tick-borne bacterium
that causes Lyme, fail to recover even after
antibiotic treatment. Patients may refer to this illness as “chronic
Lyme disease,” but doctors prefer to call it
“post-treatment Lyme disease syndrome,”
because they’re not sure an infection is still really there.
As in ME/CFS research, the debate over the
root cause of this post-Lyme illness has for
years polarized the field.
There are other similarities as well. The Lyme
problem is under-recognized but immense. Every year, an estimated 329,000 people
are infected by B. burgdorferi.
About 10 percent of those treated with antibiotics
develop lasting symptoms, including fatigue,
pain and occasionally
nervous-system conditions like
dysautonomia — heart rate, blood pressure and
other basic bodily functions in disarray. It appears to strike women more
than men, it has long been dismissed as psychological and the long-term
illness is often judged worse than the acute infection.
Like ME/CFS, post-Lyme
syndrome has no biological marker that allows for concrete diagnosis.
The three nonmutually exclusive ideas about what causes long-term symptoms
roughly correspond with those for ME/CFS:
- a persistent infection (or perhaps merely debris from the
- an autoimmune or inflammatory dysfunction triggered by the infection that
continues after the bacteria are gone; or
- changes in the nervous system that mirror Jarred Younger’s “angry
microglia” idea, but that are described by Lyme
researchers as “central nervous system sensitization.”
Perhaps the infection changes how the brain works in such a way that
once-easily bearable stimuli — pain, light, sound
— become unbearable.
The parallels between
ME/CFS and Lyme
reinforce the notion that many different infections — including the
Lyme spirochete — can trigger debilitating
It’s a lesson that we as a society have perhaps forgotten, Allen Steere, a
Lyme expert and rheumatologist at Harvard
Medical School, told me. “Now we have millions infected, and it becomes apparent
to people that this type of problem can follow.”
ME/CFS may be an array of problems
It’s a maddening prospect, but long Covid
may not be a single syndrome at all. It could, as seems to be the case with
ME/CFS, be an array of problems connected in
various ways with an initial trigger — in Covid’s case, the invasion of the
human body by a virus thought to be originally native to bats.
ME/CFS doctors and researchers have faced
this sort of frustrating complexity for years. It’s an unavoidable challenge in
managing a condition, be it ME/CFS or long
Covid, whose diagnosis is based almost entirely on the subjective reporting of
There are, after all, many ways to produce symptoms like
fatigue, brain fog and even
dysautonomia. As Peter Rowe puts it, treating
ME/CFS is like peeling an artichoke. “You’re
trying to remove treatable layers of problems
and see what the essence is,” he told me.
In the case of ME/CFS, scientists have
identified a few more leaves of the proverbial artichoke — a grab bag of
treatable, somewhat obscure conditions that seem to be associated with it.
- One is mast cell activation syndrome,
which can produce fatigue, pain and problems with thinking and memory;
infection can sometimes initiate it.
- Another is small-fiber neuropathy, a
condition in which the body’s nerves begin to misfire and can die off, causing
pain, fatigue and disruption to basic bodily functions like breathing.
Infections can sometimes trigger it, and given the current description of
long-Covid symptoms, Anne Louise Oaklander, a pioneer in understanding this
neuropathy, suspects it will be found to occur among
long-haulers as well. “Small-fiber
neuropathy is usually treatable,”
Oaklander told me, “and in some cases curable.”
Long Haul COVID patients might benefit from ME/CFS Treatments
long-haulers who contracted the novel
coronavirus early in the pandemic are just about to round the one-year mark.
Only with time will scientists be able to determine if long Covid and
ME/CFS are the same or overlapping syndromes,
or whether they’re distinct and unrelated.
For some ME/CFS specialists, however, long
Covid already seems like a variant of the condition they’ve spent their careers
Carmen Scheibenbogen told me that in her experience, 1 to 2 percent of all
patients infected with coronavirus meet the criteria for
ME/CFS six months later.
In New York, Susan Levine, an infectious-disease doctor who specializes in
ME/CFS, finds that
long-Covid patients respond to some of the
same treatments that help ME/CFS
patients, including low doses of naltrexone,
which is anti-inflammatory.
But she does point out that long-Covid patients differ in subtle ways. Among
ME/CFS patients, new
complications can emerge slowly.
Long-Covid patients see
new symptoms develop relatively quickly.
“It all happens in a compressed way,” Levine told me. “The only silver lining is
that I feel we can get these people earlier, soon after the Covid infection, as
opposed to the ME/CFS patients, who languished for years.”
The other possible silver lining, one expressed repeatedly by scientists and
patients alike, is the prospect that the explosion of long-Covid cases will spur
research, and that that research could yield treatments that may help the
long-suffering ME/CFS community.
“The disease has been ignored for decades and misjudged as a psychiatric
disease,” Scheibenbogen says. “We hope now that we get the awareness and
money for research — and pharmaceutical drugs.”
For the first time, scientists can follow thousands of patients infected by the
same virus at roughly the same time.
Funded by the C.D.C., Nancy Klimas has begun a study
on long-haulers in which she hopes to
prevent ME/CFS from taking root altogether. “We often talk about
the three-year mark as people shifting into long-term illness,” she told me. She
plans to intervene with drugs before that
milestone and hopefully prevent whatever it is that becomes self-perpetuating in
long-haulers may have one comparative
advantage, at least: Whereas their ME/CFS
counterparts in the past may have felt isolated and bereft of information,
long-haulers live in a connected world. They’ve
already been remarkably adept at organizing and making themselves heard, writing
opinion pieces in major medical journals and media outlets, even conducting
their own research.
If nothing else, the online organizing has been hugely important for some
patients’ mental health.
Lauren Nichols told me that, early on, she contemplated suicide because few —
neither doctors nor friends — believed her when she detailed her symptoms.
(Those with ME/CFS have an elevated risk of
suicide.) She connected with others who were going through similar experiences
only after reading an April Op-Ed in The New York Times. The author, Fiona
Lowenstein, had started a support group on her queer feminist website, Body
Politic. Nichols rushed to join and quickly became an administrator. “My mental
state changed — I said, ‘Oh, my God, I’m not crazy,’” she told me. “The Body
Politic support group prevented me from killing myself. And I really mean that.”
Moises Velasquez-Manoff is a contributing writer for the
LONG HAUL COVID
When Mount Sinai Hospital opened its Center for Post-Covid Care in May, it
was New York’s — and the country’s — first such facility. The doctors there
expected to treat patients who had been severely ill or hospitalized. By that
point, three months into the pandemic, they knew that the coronavirus could
cause harm to many parts of the body beyond just the airways where infections
most commonly begin. And they knew that medical treatments meant to save
patients’ lives could also take a toll. Recovery from having been put on a
ventilator, in particular, could be a lengthy process. Mount Sinai sought to
support patients recovering from severe Covid-19 by giving them access to a
multidisciplinary medical team that included lung, heart and kidney doctors,
rehabilitation specialists and psychiatrists for those whose mental health might
have been affected by their ordeals.
Hundreds of patients, most of them women, showed up soon after the center’s
doors opened. To the doctors’ surprise, however, many of them had experienced
only mild cases of Covid-19. They hadn’t been hospitalized. They were relatively
young and otherwise in good health, without the underlying conditions like
obesity and diabetes that are known to make Covid-19 worse. And yet, months
after their bodies had seemingly fought off the coronavirus, they still felt
quite ill. “We’ve heard of illnesses, viral illnesses, that have a prolonged
postviral phase,” Zijian Chen, the head of Mount Sinai’s recovery center, told
me. “But these usually don’t last for the months and months that we see here.
And because of that, we’re a little surprised that this is happening. It tells
us how much we don’t know about this illness.” The center has now seen more than
These patients have labeled themselves “Covid long-haulers.” What they’re
suffering from, they say, is “long Covid.” As a group, they report a strange
hodgepodge of symptoms, including fatigue, pain, shortness of breath, light
sensitivity, exercise intolerance, insomnia, hearts that race inexplicably,
diarrhea and cramping, memory problems and a debilitating “brain fog” that can
at times make it hard to put a cogent sentence together. In many cases, these
symptoms continue unabated from the acute phase of the illness — as if, on some
level, the infection never really went away. And for a subset of patients, new
symptoms emerge later, as if a different illness has established itself in their
This was the experience of Lada Beara Lasic, a nephrologist who contracted the
coronavirus in early April and later sought help at Mount Sinai’s post-Covid
center. After an initial three-week illness and some shortness of breath, she
thought she had mostly recovered. She even returned to work — for one day,
before she fell ill again with aches the following day. She tried working from
home in May but was troubled by fluctuating symptoms that gradually worsened
until, in June, she decided to take a leave of absence from her job to focus on
Lasic, who is 54 and has been working a few hours a day from home since
September, worries about the long-term consequences of what she suspects is an
immune system that can’t calm down. “We know that it’s not good for the body to
have inflammation,” she told me. “It may cause scarring, and that means
irreversible changes. The longer I have this disease and I’m inflamed, the worse
it is for my health in the future.”
Despite the crippling symptoms, it’s often hard to figure out precisely what is
wrong with patients like Lasic. Her blood work, for instance, has shown some
signs of inflammation and elevated liver enzymes, but little else. “Many of
these patients have had million-dollar work-ups, and nothing comes back
abnormal,” says Dayna McCarthy, a rehabilitation specialist at Mount Sinai.
Hearts, lungs, brains — all appear to be functioning normally. Among the only
things that can be said with any certainty about these patients is that they
recently received a diagnosis of Covid-19.
At Mount Sinai, most patients improve with time, McCarthy told me. But the
improvements can be maddeningly slow. And they’re not universal. A small
minority hasn’t improved in the many months since the first wave of the pandemic
crashed into New York City, she says. Some patients, including a few doctors and
nurses, can no longer work, because they are too fatigued or have trouble
focusing. Others have lost their jobs but can’t get disability benefits because,
subjective reports of misery aside, doctors can find nothing wrong with them.
“Initially this was sold as a virus infection that only affects the elderly, and
that is absolutely not the case,” McCarthy says. “I can’t think of anything
worse than this type of symptomology that affects young people.”
Zijian Chen estimates that about 10 percent of Covid-19 patients end up
developing symptoms that persist for months and months — a number that would
equate to roughly 100,000 chronically sick people in New York State alone. Some
surveys suggest the number is higher. A study from Ireland found that more than
half of Covid patients, whether they’d been hospitalized or not, reported
fatigue 10 weeks out; nearly a third hadn’t returned to work. In another study,
from the Faroe Islands, about half the patients with mild cases had at least one
symptom 18 weeks later. A third, much larger study, from China, reported that
three-quarters of those patients who were hospitalized with Covid-19 and then
discharged still experienced at least one symptom six months later.
The range of outcomes underscores how much remains unknown about this syndrome;
it also suggests that the number of people who now find themselves constantly
ill is probably significant. Recognizing this, scientists have begun studying
Covid patients with chronic symptoms at the National Institutes of Health and
elsewhere. And centers catering to these patients are opening or are in the
process of opening around the country, including at NYU Langone, Yale and the
University of Iowa.
Now, as we face the worst but hopefully final wave of the pandemic, many
people — long-haulers, those with
ME/CFS, scientists and doctors — worry about
the long-term consequences of tens of millions of people infected with a virus
that, it seems, can inflict lasting damage on the body.
The palpable fear is that years from now, after the dead have been buried and
victory over the coronavirus declared, some
long-haulers will continue to suffer; and that their ongoing ordeal
will be reckoned among the pandemic’s more awful, lasting legacies.