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...
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.
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.
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...
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?...
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 joints and the gut, 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...
