Five Patients Are Helping Doctors Crack The Long Covid Mystery

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Five Patients Are Helping Doctors Crack The Long Covid Mystery

One felt her heart would explode out of her chest, another lost her ability to speak, and three others experienced unrelenting fatigue that left them confined to a bed, a bath or a wheelchair for much of each day.

The youngest is 23, and the oldest is 65. All but one work in health-related fields. Each has a different set of debilitating symptoms, but all have at least one thing in common-an immune system sent haywire by the coronavirus-making them representative of the biggest group of people living with long Covid. As researchers strive to understand the condition, resemblances to other chronic ailments are coming into focus and providing insight into causes and treatments.

It’s been two years since a group of UK doctors and researchers first warned of Covid-19’s long-term effects. Harvard University economist David Cutler puts the total cost of long Covid in the US at $3.7 trillion. That’s equal to more than 80% of government outlays for the pandemic through the end of July. And scientists still don’t know what causes it, how many people it affects or how to prevent and treat it. Their view is clouded by more than 200 symptoms attributed to what the World Health Organization calls “post Covid-19 condition,” many of which could have different causes.

The number of proven therapies is “zero,” says Eric Topol, founder of the Scripps Research Translational Institute in La Jolla, California. “With so many millions of people impaired, the need for accelerating clinical trials with promising immune-system- modulating or virus-inactivating agents is beyond urgent.”

Not all cases are serious, and many resolve on their own. But with the ranks of sufferers estimated to be at least 140 million worldwide, the need is rising. “We did a remarkable job developing vaccines for Covid in less than a year,” says Ziyad Al-Aly, director of the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System in Missouri. “We need to approach long Covid with the same urgency, because this will have serious social, economic and perhaps even political ramifications.”

Women make up a disproportionate share of long-Covid patients. Those interviewed for this story suffer from a combination of exhaustion, rapid heart rate and other bewildering symptoms that suggest the SARS-CoV-2 virus has damaged their nervous systems. Research from the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, shows that even mild Covid lung infections can cause blood vessel damage, clotting and a breakdown of the barrier between the brain and the bloodstream. This can allow bloodborne proteins to leak into a patient’s brain, triggering dangerous inflammation, according to a study released by Avindra Nath, the institute’s clinical director, in July. Other research suggests the process is associated with brain shrinkage-equivalent to that caused by as much as a decade of normal aging-that may addle memory and thinking. “There are people who contracted SARS-CoV-2 in spring of 2020 who have not recovered back to their functional baseline,” says Michelle Monje Deisseroth, a professor of neurology at Stanford University who collaborated with Nath. “Without being alarmist, this is a neurological public-health crisis.”

Now researchers are trying to disentangle those common features from a range of potential causes. Top suspects include abnormal activation of the immune system, blood clots, a reactivation of viruses that caused infections years earlier and the possibility that lingering remnants of the coronavirus itself are skirmishing with the body’s defenses. “If we bunch everything together, it’s too complex,” says Akiko Iwasaki, an immunobiologist at the Yale School of Medicine in New Haven who’s trying to find ways to divide the patients into subsets. “We can’t even identify the right patients for the right therapy.”

New inquiry in this direction is offering leads for potential treatments: drugs that calm an overactive immune system, removal of abnormal proteins from plasma and pressurized chambers that push oxygen into the blood, to name a few. Dozens of trials slated for completion in the next year promise to yield clues for Covid long-haulers, as they’re called.

Among them is Carrie Anna McGinn, a 40-year-old community health worker in Canada who used to enjoy weekends hiking in the Jacques-Cartier National Park, about 30 miles from her home in Quebec City. In December 2020, while afflicted with Covid, she began suffering from exhaustion and tachycardia, an abnormally high heartbeat that periodically sent her pulse racing beyond 160 beats a minute.

Seven months later, while enrolled in a study into Covid’s effects on the heart, she learned the cause: a condition called postural orthostatic tachycardia syndrome, or POTS. Even standing at the kitchen sink doing the dishes can bring on the feeling that she’s about to faint, and her doctor advised her to use a wheelchair to conserve her energy. “It’s almost like I’m wrapped in a lead blanket,” says McGinn, who was diagnosed with chronic fatigue syndrome (CFS) in July and told two months later that she’ll never be well enough to work again. “It still feels like I’m running a marathon when I’m just standing there washing my hair.”

Researchers say POTS occurs when Covid damages the autonomic nervous system that controls heart rate, blood pressure, digestion and body temperature. Although some sufferers recover, the majority live with it as a long-term, chronic condition.

POTS can be a foreboding sign. With time, patients often resemble those with chronic fatigue syndrome, Yale’s Iwasaki says. A study of 41 long-Covid patients published in December found almost half met the diagnostic criteria for chronic fatigue syndrome. Acute infections are believed to be a leading cause of the syndrome, which leaves at least a quarter of sufferers bed- or house-bound for long periods.

Patients who’ve had chronic fatigue for at least four years have less than a 4% chance of recovery, says Emily Taylor, vice president for advocacy and engagement at Los Angeles-based Solve ME/CFS, a nonprofit that supports research into the condition, also called myalgic encephalomyelitis. For long-haulers whose disease dates to the start of the pandemic, “we’ve got maybe two years to figure out an intervention before it’s going to be potentially a different set of challenges,” she says.

Before the pandemic, 1.5 million Americans had ME/CFS, costing $36 billion to $51 billion annually in treatment and lost productivity, researchers estimated in April. If only a fraction of long-haulers develop the condition, the number of chronic fatigue patients could swell to as many as 9 million, driving those costs as high as $362 billion, they said.

Even after receiving the standard two-dose initial immunization, Morgan Baker got Covid at the end of July 2021, right before the start of her senior year at Yale University. She lost her sense of taste and smell, labored to breathe and suffered from migraine headaches and painful sensitivity to light. During the fall semester, Baker noticed her energy and concentration dwindling, while her Fitbit showed her heart was racing as high as 122 beats per minute when she was only studying. “I didn’t realize the degree to which that was happening until I hit a point where I couldn’t function,” says Baker, who’s now 23 years old.

Her doctor recommended exercise, so Baker rode her bike to the gym the next morning and walked and jogged for 30 minutes on a treadmill. Hours later, she felt ill and took a three-hour nap. She was wiped out for a week. The episode fits the description of post-exertional malaise, which has been reported in almost three-quarters of people suffering with long-haul symptoms for at least seven months, according to a 2021 study.

Nath, the neurological institute director, sees parallels between the group most commonly afflicted by long Covid and those most likely to develop lupus and other conditions where the immune system attacks healthy issues: typically women around the age of 40. A study of 34 people with POTS found their blood contained immune markers similar to those seen in lupus and rheumatoid arthritis patients, as well as human antibodies directed at the autonomic nervous system. In many autoimmune conditions, “the virus is the triggering event, but most of the damage is caused by the immune system,” Nath says. “Once it gets hyperactivated, it’s very hard to shut it down, and it just starts attacking the host.”

In a study released in August, Yale’s Iwasaki attempted to outline the immune abnormalities in long-haul patients. Her most striking findings were related to cortisol, a hormone that helps regulate bodywide functions including blood pressure and inflammation. Cortisol deficiency can cause fatigue, muscle weakness and gastrointestinal upsets-all common among long-haulers. In Iwasaki’s study, long-Covid patients’ cortisol levels were roughly half those found in people who had never been infected or had fully recovered. “It’s one of the strongest physiologic markers that we’ve seen” for long Covid, says David Putrino, a neuroscientist at the Icahn School of Medicine at Mount Sinai in New York who collaborated on Iwasaki’s study.

Low cortisol can be replaced with synthetic steroids, which showed some benefit in chronic fatigue patients 30 years ago. Nath has begun a trial to test the effect on neurologic symptoms of higher doses given intravenously over just five days. The trial will also compare steroids with injections of antibody-rich immunoglobulin, which showed promise in a small observational study whose results were published in March.

One of the participants in that trial was Lisa Toran, a neurologist in Wenatchee, Washington, who’s been beset by chronic pain and other symptoms for almost two years. Soon after coming down with Covid in November 2020, Toran got a migraine headache and lost her sense of smell. Parts of her face went numb, and she became sensitive to light and sound. Days later, her heart raced even when she was lying down.

Ten days in, she began to feel better. She took a walk with her daughters-one 3 years old, the other 14 months-to a park near their home. Soon after, Toran’s symptoms flared. Her standing heart rate hit 160 beats a minute. Food virtually stopped moving through her digestive tract-a condition called gastroparesis-and she began suffering allergic reactions to foods such as kiwifruit that she’d eaten “a million times.”

Intravenous immunoglobulin, or IVIG, which contains a wide variety of antibodies that augment the immune system, is used as a therapy for autoimmune nerve disorders such as Guillain-Barré syndrome, a rare, mysterious short-term paralysis that sometimes occurs after viral infections. Processing enough for just one treatment requires separating the gold-colored plasma from the cellular components of thousands of pints of blood from healthy donors. Doctors don’t fully understand how IVIG works, but six weeks after falling ill with Covid and feeling no better, Toran went for an infusion.

It didn’t go well. Four hours after treatment, she felt tingling and burning pain in her arms that spread throughout her body. For the next few months, she spent almost the entire day submerged in a bathtub. “That’s the only thing that made my skin feel better,” she recalls. “Everything was so painful.”

Meanwhile, her long-Covid symptoms worsened. She had difficulty swallowing and was afflicted by gastric reflux and painful urinary tract infections. By April 2021, five months after catching Covid, Toran was so desperate that she decided to give immune therapy another try. “I was just getting sicker and sicker, and I felt like there was nothing else,” she says. “I was like, ‘I’m going to die, or I’m going to do IVIG.’ ”

Cautious after her earlier travails, she eased into the treatment, taking ibuprofen before small infusions every two weeks and graduating to a full dose once a month. By February, 10 months after starting her second round of IVIG, she was back working full time and felt well enough to stop the treatment.

IVIG is not a panacea. First, there’s the expense: Toran’s health insurer paid $377,828.64 for her 29 treatments, leaving her with $5,415.03 in out-of-pocket costs. There are no clinical studies to help confirm whether it was the infusions that triggered her improvement, and Toran wonders whether her symptoms may have eased naturally with time. “I struggle with that with my own patients that I’m seeing for post-Covid symptoms when they’re severe,” she says. “I always wonder, ‘Should I do IVIG?’ I mean, it’s hard to know. We need the trials.”

Similar questions surround a therapy for brain fog and exhaustion developed at the Sagol Center for Hyperbaric Medicine and Research in Israel. There, long-Covid patients undergo daily 90-minute sessions in a hyperbaric oxygen chamber. Shai Efrati, a professor of neuroscience at Tel Aviv University who led a two-month study of 73 long-Covid patients, says the therapy promotes the growth of mitochondria, the power source of cells, leading to improved energy metabolism and function.

The cost of the treatment and accompanying brain scans can range from about $35,000 to $80,000, Efrati says. Other studies are testing whether similar metabolic effects can be achieved with lower-cost drug compounds, including amino acid combinations, dietary supplements or low doses of naltrexone, a medication used for decades to treat alcohol and opioid dependence.

Anne Bhereur, a 46-year-old physician in Montreal, has been getting some relief from a far cheaper, more accessible therapy for persistent chest pain. It came on around the same time she developed difficulty speaking, shortness of breath, dizziness and brain fog during her acute Covid illness in December 2020. Months later, when she felt her heart racing for no apparent reason and recognized other tell-tale characteristics of post-exertional malaise, Bhéreur started recording her vital signs.

“I looked while in the shower, and my pulse was 180,” she says. A medical-grade pulse oximeter attached to her finger measured the oxygen level in her blood at 85%-well below the normal range of 95% to 100%. Lung function tests came back normal, though, and her doctor told her she was fine and to “just be less anxious.”

Bhereur wasn’t convinced. She underwent an MRI scan in August 2021 as part of a study that showed there was inflammation in the tissue surrounding her heart. She began taking colchicine, an anti-inflammatory based on an ancient remedy for swelling and gout. The drug, which costs as little as $10 for a month’s supply, eased her chest pain and shortness of breath, Bhéreur says, while ivabradine, a drug more commonly prescribed for heart-failure patients, lowered her heart rate. “I didn’t think my lungs were the problem, but I knew something was wrong,” she says. “Imagine patients being told the same thing, but [they] don’t understand that the problem can lie elsewhere. That’s a big issue.”

Thao Huynh, an epidemiologist and cardiologist at McGill University Health Centre in Montreal who led a study that Bhereur and McGinn were part of, says scans on more than 100 long-Covid patients showed 30% had signs of active inflammation around their heart and an additional 40% had scar tissue; almost all also had elevated blood markers for inflammation. That’s reason enough for her to prescribe colchicine for cases such as Bhéreur’s.

The drug is among many being widely used to treat long Covid, but for most, there’s no proof they help. To address that, UK researchers have begun enrolling about 4,500 patients in an open-label study of colchicine and two other drug therapies. Participants will get a 12-week course of the generic, Bayer AG’s blood thinner Xarelto and a combination of the antihistamines famotidine and loratadine, or they will get no drug therapy at all. The trial is designed to test potential treatments that “people everywhere can benefit from,” says Amitava Banerjee, a cardiologist and professor of clinical data science at University College London who’s leading the research.

The study enables other experimental medications to be added or substituted 6 or 12 months into the trial. There’s growing evidence that long-Covid symptoms are being driven by vestiges of the coronavirus that persist in the body, Banerjee says, suggesting that an antiviral such as Pfizer Inc.’s Paxlovid could be a worthy addition to the trial. “Part of the problem is that we’re trying to treat something while we’re at the same time figuring out what the hell causes it,” he says. “The next six months is going to tell us a lot in terms of mechanism.”

Mady Hornig, an associate professor of epidemiology at the Columbia University Mailman School of Public Health in New York, says she’s frustrated that physicians aren’t talking to colleagues from other specialties to understand the extent of long Covid’s systemic effects and to glean ideas and strategies for treating it. “I’m trying to have more empathy for the doctors, because they’re going to their medical bags and these toolkits are empty,” she says. “Why aren’t they interested in talking to one another and getting together?”

Hornig developed a raft of medical problems, including sticky lung secretions, after getting Covid in April 2020. Chronic nausea and diarrhea left her bedridden for weeks and required her to be hospitalized for five days almost two years later, when tests showed her entire GI tract was inflamed. She now takes as many as five medications to ease her gastric upsets, nausea, heartburn and inflammation. Tests have repeatedly shown levels of a molecule involved in blood-clot formation are more than double what they should be, indicating ongoing inflammation of her blood vessels.

If lingering virus is indeed the problem, “I’d love to be able to get on an antiviral,” says Hornig, who studies chronic fatigue syndrome and related conditions. “I don’t know how you can live like this forever.”

(Except for the headline, this story has not been edited by NDTV staff and is published from a syndicated feed.)

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