Date: Fri 31 Jul 2020 13:30 EDT
Source: Science [abridged, edited]
[se·que·la /sēˈkwelə/ noun Medicine plural
a condition which is the consequence of a previous disease or injury.
“the long-term sequelae of infection”]
[AA’s] neuroscience lab reopened last month [June 2020] without her. Life for the 38-year-old is a pale shadow of what it was before [17 Mar 2020], the day she first experienced symptoms of the novel coronavirus. At University College London (UCL), [her] students probe how the brain organizes memories to support learning, but at home, she struggles to think clearly and battles joint and muscle pain. Her early symptoms were textbook for COVID-19: a fever and cough, followed by shortness of breath, chest pain, and extreme fatigue. [Her] symptoms waxed and waned without ever going away. She’s had just 3 weeks since March  when her body temperature was normal.
“Everybody talks about a binary situation, you either get it mild and recover quickly, or you get really sick and wind up in the ICU,” [she said], who falls into neither category. Thousands echo her story in online COVID-19 support groups. Outpatient clinics for survivors are springing up, and some are already overburdened.
The list of lingering maladies from COVID-19 is longer and more varied than most doctors could have imagined. Ongoing problems include fatigue, a racing heartbeat, shortness of breath, achy joints, foggy thinking, a persistent loss of sense of smell, and damage to the heart, lungs, kidneys, and brain. The likelihood of a patient developing persistent symptoms is hard to pin down because different studies track different outcomes and follow survivors for different lengths of time. One group in Italy found that 87% of a patient cohort hospitalized for acute COVID-19 was still struggling 2 months later.
Data from the COVID Symptom Study, which uses an app into which millions of people in the USA, United Kingdom, and Sweden have tapped their symptoms, suggest 10% to 15% of people — including some “mild”
cases — don’t quickly recover. But with the crisis just months old, no one knows how far into the future symptoms will endure, and whether COVID-19 will prompt the onset of chronic diseases.
Researchers are now facing a familiar COVID-19 narrative: trying to make sense of a mystifying illness. Distinct features of the virus, including its propensity to cause widespread inflammation and blood clotting, could play a role in the assortment of concerns now surfacing. “We’re seeing a really complex group of ongoing symptoms,” says Rachael Evans, a pulmonologist at the University of Leicester.
Survivor studies are starting to probe them. This month [July 2020], researchers across the United Kingdom, including Evans, launched a study that will follow 10 000 survivors for 1 year to start, and up to
25 years. Ultimately, researchers hope not just to understand the disease’s long shadow, but also to predict who’s at highest risk of lingering symptoms and learn whether treatments in the acute phase of illness can head them off.
For Gotz Martin Richter, a radiologist at the Klinikum Stuttgart in Germany, what’s especially striking is that just as the illness’ acute symptoms vary unpredictably, so, too, do those that linger. Richter thinks of 2 patients he has treated: a middle-aged man who experienced mild pneumonia from COVID-19 and an elderly woman already suffering from chronic leukemia and arterial disease who almost died from the virus and had to be resuscitated. Three months later, the man with the mild case “falls asleep all day long and cannot work,” Richter says. The woman has minimal lung damage and feels fine.
Early in the pandemic, doctors learned that SARS-CoV-2, the virus that causes COVID-19, can disrupt a breathtaking array of tissues in the body. Like a key fitting neatly into a lock, SARS-CoV-2 uses a spike protein on its surface to latch onto cells’ ACE2 receptors. The lungs, heart, gut, kidneys, blood vessels, and nervous system, among other tissues, carry ACE2 on their cells’ surfaces — and thus are vulnerable to COVID-19. The virus can also induce a dramatic inflammatory reaction, including in the brain. Often, “The danger comes when the body responds out of proportion to the infection,” says Adrija Hajra, a physician at Albert Einstein College of Medicine in New York City. She continues to care for those who were infected in the spring and are still recovering.
Despite the novelty of SARS-CoV-2, its long-term effects have precedents: Infections with other pathogens are associated with lasting impacts ranging from heart problems to chronic fatigue. “Medicine has been used to dealing with this problem” of acute viral illness followed by ongoing symptoms, says Michael Zandi, a neurologist at UCL. Even common illnesses such as pneumonia can mean a months-long recovery. “I see a lot of people who had [the brain inflammation] encephalitis 3, 4 years ago, and still can’t think, or are tired,” Zandi says. Infections with certain bacteria and Zika virus, among others, are linked to Guillain-Barre syndrome, in which the immune system attacks nerve tissue, causing tingling, weakness, and paralysis. (Some cases of Guillain-Barre after COVID-19 have been reported, but “it’s not definite [there’s] a spike,” says Rachel Brown, a UCL neurologist who works with Zandi.)
Based on experience with other viruses, doctors can “extrapolate and anticipate” potential long-term effects of COVID-19, says Jeffrey Goldberger, chief of cardiology at the University of Miami. Like SARS-CoV-2, some other viruses, such as Epstein-Barr, can damage heart tissue, for example. In those infections, the organ sometimes heals completely. Sometimes, scarring is mild. “Or,” Goldberger says, “it could be severe and lead to heart failure.”
Michael Marks, an infectious disease specialist at the London School of Hygiene & Tropical Medicine who’s helping lead the UK survivor study, says he’s not too surprised at emerging aftereffects. “What we’re experiencing is an epidemic of severe illness,” he says. “So, therefore, there is an epidemic” of chronic illness that follows it.
But outcomes following SARS-CoV-2 also appear distinct in ways both hopeful and dispiriting. Early this year , many doctors feared the virus would induce extensive, permanent lung damage in many survivors because 2 other coronaviruses, the viruses that cause the 1st severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, can devastate the lungs. One study of healthcare workers with SARS in 2003 found that those with lung lesions 1 year after infection still had them after 15 years. “We expected to see a lot of long-term damage from COVID-19: scarring, decreased lung function, decreased exercise capacity,” says Ali Gholamrezanezhad, a radiologist at the Keck School of Medicine at the University of Southern California who in mid-January  began to review lung scans from COVID-19 patients in Asia. Hundreds of scans later, he has concluded that COVID-19 ravages the lungs less consistently and aggressively than SARS did, when about 20% of patients sustained lasting lung damage. “COVID-19 is in general a milder disease,” he says.
At the same time, the sheer breadth of complications linked to COVID-19 is mind-boggling. In late April 2020, [AA] collaborated with Body Politic, a group of COVID-19 survivors, to survey more than 600 who still had symptoms after 2 weeks. She logged 62 different symptoms and is now readying the findings for publication and developing a 2nd survey to capture longer term ailments. “Even though it’s one virus, it can cause all different kinds of diseases in people,” says Akiko Iwasaki, an immunologist at Yale University who is studying lingering effects on the immune system.
By now it’s clear that many people with COVID-19 severe enough to put them in a hospital face a long recovery. The virus ravages the heart, for example, in multiple ways. Direct invasion of heart cells can damage or destroy them. Massive inflammation can affect cardiac function. The virus can blunt the function of ACE2 receptors, which normally help protect heart cells and degrade angiotensin II, a hormone that increases blood pressure. Stress on the body from fighting the virus can prompt release of adrenaline and epinephrine, which can also “have a deleterious effect on the heart,” says Raul Mitrani, a cardiac electrophysiologist at the University of Miami who collaborates with Goldberger.
Mitrani and Goldberger, who co-authored a June  paper in Heart Rhythm urging follow-up of patients who might have heart damage, worry in particular about the blood enzyme troponin, which is elevated in 20% to 30% of hospitalized COVID-19 patients and signifies cardiac damage. But other patients are affected without apparent risk factors:
A paper this week [end of July 2020] in JAMA Cardiology found that 78 of 100 people diagnosed with COVID-19 had cardiac abnormalities when their heart was imaged on average 10 weeks later, most often inflammation in heart muscle. Many of the participants in that study were previously healthy, and some even caught the virus while on ski trips, according to the authors.
Severe lung scarring appears less common than feared — Gholamrezanezhad knows of only one recovered patient who still needs oxygen at rest. Scarring seems most likely to accompany underlying lung disease, hypertension, obesity, and other conditions.
Then there’s the nervous system, a worrying target. Severe complications seem relatively rare but aren’t limited to those whom the virus renders critically ill. Brown, Zandi, and colleagues described 43 people with neurologic complications this month [July 2020] in the journal Brain.
Separately, doctors are starting to see a class of patients who, like [AA], struggle to think clearly — another outcome physicians have come upon in the past. After some severe viral infections, there are “those people who still don’t feel quite right afterward, but have normal brain scans,” Brown says. Some neurologists and patients describe the phenomenon as “brain fog.” It’s largely a mystery, though one theory suggests it’s similar to a “postviral fatigue related to inflammation in the body,” Brown says.
The most bedeviling and common lingering symptom seems to be fatigue, but researchers caution against calling it chronic fatigue syndrome. Iwasaki is especially struck by the number of young, healthy, active people — people like [AA] — who fall into the long-hauler category. As she and others struggle to find ways to help them, she wonders what might head off their symptoms. One possibility, she says, is monoclonal antibodies, which are now being tested as a treatment for acute infection and might also forestall lasting immune problems.
Hers is one of several survivor studies now underway. While Goldberger’s hometown of Miami faces a surge of acutely ill patients, he is looking ahead, applying for funding to image the heart and map its electrical activity in COVID-19 patients after they leave the hospital. Gholamrezanezhad is recruiting 100 patients after hospital discharge to follow for up to 2 years for lung assessments. Across the Atlantic Ocean, Richter has recruited 300 volunteers in Germany for long-term follow-up, including lung scans. In the United Kingdom, patients will soon be able to sign up for that country’s survivor study, with many giving blood samples and being examined by specialists. The researchers will probe patients’ DNA and examine other characteristics such as age and health history to learn what might protect them from, or make them susceptible to, a range of COVID-19-induced health problems. Knowing who’s at risk of, say, kidney failure or cardiac arrhythmia could mean more targeted follow-up. The UK researchers are also keen to see whether patients who received certain treatments in the acute phase of illness, such as steroids or blood thinners, are less prone to later complications.
The COVID Symptom Study welcomes anyone infected, and with 10% to 15% of people who use the app reporting ongoing symptoms, it has already yielded a welter of data, says Andrew Chan, an epidemiologist and physician at Harvard Medical School. As he and his colleagues parse the data, they are identifying distinct “types” of acute illness, based on clusters of symptoms. Chan wonders whether certain early symptoms correlate with specific ones that linger.
One of the few systematic, long-term studies of COVID-19 patients with mild acute symptoms is underway in San Francisco, where researchers are recruiting 300 adults from local doctors and hospitals, for 2 years of follow-up. “We don’t have a broad idea of what’s happening” after the initial illness, says Steven Deeks, an HIV researcher at the University of California, San Francisco, who is leading the study.
More than 100 people ranging in age from 18 to 80 years have signed up so far. Cardiologists, neurologists, pulmonologists, and others are assessing the volunteers, and blood, saliva, and other biological specimens are being banked and analyzed.
The message many researchers want to impart: Don’t underestimate the force of this virus. “Even if the story comes out a little scary, we need a bit of that right now,” Iwasaki says, because the world needs to know how high the stakes are. “Once the disease is established, it’s really hard to go backward.”
[Byline: Jennifer Couzin-Frankel]