NY Times, Jan. 24, 2021
What If You Never Get Better From Covid-19?
By Moises Velasquez-Manoff
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 1,600 patients.
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 bodies.
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 her recovery.
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.
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
ME/CFS experts told me that they anticipate a wave of new patients —
long-haulers 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.
Marjorie Roberts, 60, who has “never been so sick in my whole
life.”Credit...Adam Ferguson for The New York Times
“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 unlucky patients?
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 amiss.
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 Covid-19 syndrome.”
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 blood clotting.
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 mentally enervated.
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 resembled dementia.
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 in April. 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
symptoms.
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 herpesvirus Epstein-Barr. 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, Borrelia
burgdorferi.
In recent years, scientists have come to realize that the symptoms of
certain autoimmune diseases can even mimic psychiatric disorders. 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 schizophrenia. 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 infection.
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 inflammatory syndrome.
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). 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 autoimmune diseases. 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.
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 autoimmune disease. 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.”
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
antibody-producing B-cells.
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 brain fog. 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 joints, respectively. 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 universally accepted. 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 well.
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 heart disease. Infectious-disease doctors detect viruses and
bacteria and think infection. 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 following: 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 ME/CFS patients. 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 healthy
people. 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 inflammatory spike
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 hearts,
gut problems, dilated pupils, sweating and rapid changes in blood
pressure when at rest. It may be one reason they don’t feel rested after
sleeping. 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.
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 learned. 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 fatiguelike 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 later.
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 hypochondria.” 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 explanation. “We think that this is
probably a heterogeneous illness that can be triggered by multiple
different genetic and environmental factors,” they wrote, “including
stress, toxins 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
infection.
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 year.
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 liver. 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 infection does. 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 months
later.
“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 ME/CFS.)
It still remains unclear, though, what biological dysfunction underlies
those persistent symptoms after interferon treatment (or an actual
infection) has run its course. 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.
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 brain.
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 directed. 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.
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 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.
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.
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
underrecognized 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 Lyme
spirochetes); 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 long-term syndromes. 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.”
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 symptoms. 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.”
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Continue reading the main story
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 treating. 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 ME/CFS.
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.”
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.
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