Rachel Robles contracted COVID in March 2020. The 27-year-old data analyst has not gone a single day without symptoms since. Most doctors did not believe her when she described how she had gone from running the Brooklyn Half Marathon the previous year to enduring such crippling fatigue that her couch felt like quicksand. How she suddenly struggled to put numbers together, despite her technical training. How no matter how many breaths she took, she always felt starved for air.
Three months in, one doctor told her, “COVID doesn’t last for 90 days. You either get over it or you die.”
That dichotomy — in which the only possible outcomes of COVID are either complete recovery or death — has turned out to be anything but true. Between 8 million and 23 million Americans are still sick months or years after being infected. The perplexing array of symptoms known as long COVID has left an estimated 1 million of those people so disabled they are unable to work, and those numbers are likely to grow as the virus continues to evolve and spread. Some who escaped long COVID the first time are getting it after their second or third infection. “It is a huge public health crisis in the wake of acute COVID infection,” says Linda Geng, a physician and codirector of Stanford Health Care’s long COVID clinic.
Though there is no longer debate that long COVID is a real phenomenon — both the Centers for Disease Control and Prevention and the World Health Organization have recognised its existence — the science is so new that many questions remain about how to define the condition, what causes it and how to effectively treat it. It has become clear, for example, that long COVID can assume a variety of different forms. “Not everyone has the same disease,” which means there are different causes, says Akiko Iwasaki, an immunologist at the Yale School of Medicine.
Scientists have proposed several different, yet interconnected, origin stories to explain these wide-ranging symptoms: The coronavirus could damage organs, spawn tiny blood clots, trigger autoimmunity, hide out in tissues or prompt new and ongoing symptoms in other, more subtle ways. To complicate matters further, these narratives are not mutually exclusive: Several could be occurring at the same time in a particular patient, or one could set off another in an unhappy sequence of events that keeps the patient in perpetual bad health. By tearing apart the theories one by one, researchers are gaining a greater understanding of this enigmatic illness and inching closer to therapies that don’t just mask symptoms but eliminate the root cause.
Listening to patients
Many of the earliest insights into long COVID have been gleaned from the experiences shared by patients. A survey by the Patient-Led Research Collaborative, a team of long COVID patients who are doing research into their condition, compiled a list of more than 200 different symptoms across 10 organ systems. These range from the most common complaints like fatigue, cognitive impairment, shortness of breath, irregular menstrual periods, headaches, heart palpitations, sleep problems, and anxiety and depression, to other afflictions like double vision, peeling skin, hair loss, tinnitus, tremors, food allergies and sexual dysfunction. The constellation of reported symptoms can vary from person to person, even changing over the course of the condition.
Because there is no agreed-upon definition of long COVID, no simple diagnostic test, and no way to clearly distinguish one subtype from another, the various manifestations of this mysterious condition often get lumped under one big umbrella, confounding researchers. Yet emerging research is providing the first evidence for several promising hypotheses.
One theory blames the illness on lingering organ or tissue injury caused by the initial infection with SARS-CoV-2, the virus behind COVID-19. Though the coronavirus enters the body through the respiratory tract, it can travel through the bloodstream to infect the kidneys, heart, nervous system and gut. In the process, it can set off waves of inflammation that reverberate throughout the body, causing collateral damage to multiple organs.
In one study, researchers at the University of Oxford compared brain scans of people before and after they got COVID and found that even mild cases can cause the brain to shrink by 0.2% to 2% more than in people who had not been infected. Because adults typically lose about 0.2% of their brain volume in regions related to memory every year, that translates to mental decline equivalent to 1 to 10 years of ageing. It’s too soon to know if this effect is temporary or might set up people for age-related disorders later in life.
When Heather-Elizabeth Brown, a 37-year-old in Detroit, got COVID in April 2020, it hit her so hard she spent 120 days in the hospital, many of them on a ventilator in a medically induced coma. The disease battered her veins and arteries, spawning blood clots and a stroke. It scarred her lungs, making it harder to breathe. It also damaged her heart, causing abnormal heart rhythms and high blood pressure. The assault on multiple organ systems left her with diabetes, brain fog and chronic pain. “I am not sure anyone has been able to assess the degree of damage,” she says.
Many experts believe the persistent health issues following a severe case of COVID are a distinct entity from the assortment of symptoms arising after an asymptomatic or mild infection with the virus, though both may be considered long COVID. “I think the clearest line in the sand is people who were hospitalised versus people who were not hospitalised,” says David Putrino, a director of rehabilitation innovation for the Mount Sinai Health System, whose team has treated thousands of long COVID patients. People like Brown who experience organ damage after hospitalisation, Putrino says, often benefit from physical rehabilitation, whereas others with long COVID can get worse when they exert themselves. “Understanding all of the different subtypes of long COVID becomes really important here.”
The majority of long COVID patients — more than 75%, according to some estimates — were never hospitalised for their original infection. For these people, uncovering the reasons for their enduring illness is less straightforward, though scientists have several leads.
Tiny blood clots, lingering damage
Resia Pretorius, a physiologist at Stellenbosch University in South Africa, believes that most long COVID symptoms can be traced back to microscopic blood clots that block tiny vessels and prevent oxygen from reaching the body’s tissues. Recent studies show that these microclots are triggered by the spike proteins dotting the surface of the coronavirus, which can mimic proteins involved in normal blood clotting.
Pretorius, who has been analysing blood plasma samples of COVID patients since the beginning of the pandemic, discovered that in long COVID patients, the microclots that form during acute COVID infection don’t break down the way they should. Proteins that prevent the clearance of clots remain trapped inside these insoluble, meshlike clumps of blood, along with inflammatory molecules that might have signalled something was amiss if they had been in the bloodstream. This could be one reason “why the individuals are so very, very sick but their typical laboratory results come back within normal ranges,” Pretorius says.
Some researchers are testing experimental treatments to eliminate these microclots. In Mulheim, Germany, physician Beate Jaeger is adapting a controversial approach called H.E.L.P. apheresis, previously used to filter bad cholesterol from the blood of patients with coronary heart disease. In the UK, cardiologist Amitava Banerjee of University College London is leading a clinical trial comparing the effectiveness of antihistamines, an anticlotting drug and an anti-inflammatory medication.
And in South Africa, Pretorius’s laboratory reported that a “triple therapy” — two antiplatelet treatments and one anticoagulant — restored 24 long-haulers to pre-pandemic health. That study was small and lacked controls, though. She worries that by the time solid evidence arrives for her hypothesis, it could be too late for some patients to benefit. “We need to find treatments for these individuals soon,” she says, “so that we don’t end up removing the microclots but still having patients that are not well because of the damage that is now irreversible.”
The body battling itself
Others posit that long COVID might arise when the body’s overzealous response to infection knocks the immune response off-kilter, inducing autoimmune disease. To neutralise the threat of a foreign pathogen, the immune system can produce billions of antibodies against various viral or bacterial proteins, some of which may look like human proteins. Known as autoantibodies, they can turn the body against itself.
“It is very difficult to shut them down once they are triggered because the stimulus that is triggering them is everywhere — it is essentially your own cells,” says Iwasaki. She and her colleague immunobiologist Aaron Ring found that COVID can amplify the production of autoantibodies, and others have shown these can persist for months after infection. Iwasaki believes that this link between the immune system and long COVID could explain why the illness primarily affects middle-aged women, who are the most vulnerable to autoimmune disorders.
The relationship is complicated: Infections can prompt autoimmunity, and preexisting autoimmunity can predispose a person to more serious infections or more persistent symptoms, which can lead to the accumulation of health issues over a lifetime. Sherri Klipowicz, a 36-year-old in Evergreen, Colorado, spent 14 years trying to get someone to pay attention to the new symptoms that appeared after a tick-borne illness. “Everything changed with my health after Lyme disease,” she says. “It is like the extinction line that you can see from the dinosaurs: dinosaur bones/no bones because of the asteroid.” When she got COVID in March 2020, her body experienced another seismic shift: Seizures, blurry vision, brain fog and fatigue became part of her reality.
For once, Klipowicz was grateful for her previous health struggles because she knew how to navigate the health care system and was undeterred when doctors said they had no idea what was going on. In April 2022, she received a diagnosis of mast cell activation syndrome (MCAS), a disorder that has been linked to long COVID.
A small study in Massachusetts during the first wave of the pandemic suggested that two common MCAS medications could prevent or treat certain aspects of long COVID. Klipowicz’s own MCAS treatment regimen has reduced the brain fog and dampened her other symptoms. But she has come to accept that her health may never return to what it once was. “There is no neat narrative of, I was sick and now I’m better,” she says.
Rousting hidden viral remnants
Some long COVID patients may continue to experience symptoms long after their initial infection because they still harbour the coronavirus, in some form, somewhere in their bodies. Amy Proal, a microbiologist at the PolyBio Research Foundation, a research nonprofit focused on infection-associated chronic disease, notes that other viruses and viral remnants have been known to persist in patient tissues: influenza in tonsils, enteroviruses in the stomach, Zika in semen, Ebola in breast milk. Recent research indicates that the new coronavirus also has the propensity to stick around.
For example, a study by Saurabh Mehandru, a gastroenterologist at the Icahn School of Medicine at Mount Sinai in New York, detected RNA and protein of SARS-CoV-2 in gut biopsies of people who had COVID four months earlier. Similar research has discovered bits of the coronavirus in body fat and even the brain. Because those studies looked for genetic material or protein rather than the entire virus, it is unclear if the virus traces identified in tissues are fully functional or shadows of their former selves. Still, even remnants of the virus could put the immune system on high alert, prompting chronic inflammation.
If this theory holds true, then vaccines or antivirals could ease long COVID symptoms by helping the body get rid of lingering virus. A survey of 26,000 people with long COVID by the biotech company 23andMe found that about 20% of respondents reported feeling somewhat better after receiving the COVID vaccine. Lisa McCorkell, cofounder of the Patient-Led Research Collaborative, says her long COVID symptoms — among them heart palpitations, dizziness, brain fog and fatigue — lessened after she got her shot. Though her illness persisted, she found she could push the envelope a little, taking a few more steps for exercise or logging a few more hours of work, without crashing. “My triggering point is much higher.”
Similar stories have emerged of long COVID symptoms dissipating after a five-day course of Pfizer’s antiviral drug Paxlovid. Stanford’s Geng recently posted a case report describing a 47-year-old long COVID patient whom she treated with the drug after a possible reinfection. Not only did the patient’s illness resolve quickly, but her long COVID symptoms also went away.
But Geng cautions that people should not read too much into a single case. “It is anecdotal and should not be taken as conclusive evidence for this model,” she says. Case reports, she adds, are merely observations that raise questions to be answered in well-designed studies. Geng is unaware of any clinical studies underway to test Paxlovid for long COVID.
One infection begets others
Even if the immune system successfully clears a COVID infection, the stress of doing so could allow dormant viruses that were previously held in check to reemerge and create new health issues. Anyone who has had shingles, for example, has experienced a reactivation of varicella-zoster, the virus that causes chickenpox. People can accumulate many persistent viruses over the course of a lifetime, according to Proal, and reactivation of one of these during a COVID infection may explain at least some long COVID symptoms.
Some evidence suggests that prior infection with Epstein-Barr virus (EBV), which causes mononucleosis, puts people at higher risk for developing long COVID. The reactivation of dormant EBV has been linked to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), an illness with striking similarities to long COVID.
Michael VanElzakker, a neuroscientist at Harvard Medical School and Massachusetts General Hospital, has hypothesised that viruses may cause ME/CFS and long COVID by triggering a malfunction in the almighty vagus nerve. This bundle of nerve fibers induces the “sickness response,” signalling the body to rest when it senses an infection somewhere in the body. VanElzakker contends that when the infection is located on the vagus nerve itself, this response is exaggerated, causing many of the debilitating symptoms seen in both conditions.
Nearly a year after developing long COVID, Robles, the twentysomething Brooklynite, was diagnosed with reactivated EBV and human herpesvirus 6 (HHV-6). She started Famciclovir, an antiviral for herpesvirus infections, and within five days her difficulty breathing had dramatically improved. Though several issues remained, Robles says the treatment got her to the point where she felt like her body “wasn’t constantly fighting to breathe.”
Eager to know whether her remaining symptoms were driven by active EBV or another mechanism entirely, Robles recently volunteered to undergo an endoscopy and colonoscopy so that her gastroenterologist, Mount Sinai’s Mehandru, could take gut biopsies and check them for signs of autoimmunity or bits of SARS-CoV-2. Mehandru warned her that they might not find anything. Yet Robles feels hopeful that by submitting pieces of herself to science, she will learn something more. “I feel like the closer I get to things, the more answers I’m getting,” she says.
Money, time and trials
For now, given the state of the science, treatment for long COVID amounts to a painstaking process of trial and error. Many patients, physicians and researchers are frustrated that there hasn’t been more progress. The NIH, which launched its US$1.2 billion “RECOVER” initiative to research the long-term effects of COVID in early 2021, has drawn criticism for a lack of urgency and its focus on gathering observations rather than testing interventions. In March 2022, Iwasaki, Putrino and other experts coauthored a policy briefing that blasted the effort as “achingly slow” and noted, among other things, that just 8 of 200 long COVID trials listed on the ClinicalTrials.gov database at the time of the report’s publication were funded by the NIH. “I get frustrated by the fact that we always just sort of throw our hands in the air and say, ‘Well, good science takes time.’ It’s not true,” Putrino says.
But the search for solutions may finally be gaining momentum. Stuart Katz, a cardiologist at NYU Langone Health and co-lead of the clinical science core for RECOVER, says that as of July 25, the initiative’s observational study had recruited 6,248 adults, 35% of its adult enrollment target. “We have really worked very hard to push it as fast as we could,” says Katz, who himself suffered from long COVID for about a year. The study will examine electronic health records as well as survey results, clinical tests, biological specimens and even autopsies in search of clues for what causes long COVID.
“No other study anywhere in the world is doing what RECOVER is doing in terms of this deep look and longitudinal follow-up into people who are exposed to SARS-CoV-2,” says Katz, who anticipates seeing the first batch of data from the initiative in mid-August. “We are still hopeful that this more rigorous approach will give us answers.”
For example, Katz hopes to identify clusters of symptoms that might define subtypes of long COVID, enabling researchers to design smarter studies that test therapies only in those patients most likely to benefit.
In May, the NIH announced a big push to fund clinical trials on new treatments, the first of which should begin by the end of 2022. And the Patient-Led Research Collaborative recently received US$3 million from other sources to pursue five long COVID projects, including creating a list of hypotheses, based on patient experiences, for researchers to pursue.
“Long COVID research has come at a pace that is faster than many other, if not all, diseases in previous history. That doesn’t mean that it’s an acceptable pace,” says the collaborative’s McCorkell. “It’s a very hopeful time, but there’s still so much more that can be done.”