What Causes Long Covid? Here are the three leading theories science

They span three continents, but three researchers who have never met share a single focus that is vital to the still-raging pandemic: deciphering the causes of Long Covid and figuring out how to treat it.

Nearly two years ago in Italy, Infectious Diseases Pediatrician Danilo Buonsenso, who works at Gemeli University Hospital, began seeing children who, months after mild SARS-CoV-2 infections, were still suffocating and had debilitating fatigue and other symptoms. He now suspects that in some of them the cells and tissues that control blood flow are damaged and the tendency of the blood to clot increases. Small blood clots left over from a viral attack or fueled by its effects can suffocate the body’s bloodstream, to the detriment of the brain to the joints. “In some patients, we have specific areas where there is no blood flow,” or the flow is reduced, Buonsenso said. Does this lead to their prolonged symptoms? “I can’t say that’s true, of course. But it makes sense. “

In the United States, meanwhile, microbiologist Amy Proal can’t stop thinking about Long Covid’s second leading theory: that the coronavirus continues to injure people by persisting in the body, even after the acute infection has passed. Studies show that “the virus is able to persist in a wide range of places in the body,” especially nerves and other tissues, said Proal, who works for the PolyBio Research Foundation, a nonprofit organization in Washington state. She recently caught COVID-19 for the third time.

Down in Australia, immunologist Chansavath Phetsouphanh of the University of New South Wales, Sydney, is pursuing a third lead, motivated by what Long Covid patients’ blood reveals: the immune system went awry even 8 months after the first positive test. He predicted that immune cells galvanized to fight infection would calm down during this time. So “it was a surprise that these cells did not recover,” said Phetsouphanh, who is working to establish an international collaboration with Long Covid.

For each of these researchers – and many others investigating the causes of Long Covid – unraveling the complex syndrome with a still evolving definition is a difficult, step-by-step process. First, they need to show that a possible factor – such as minor clots, retained virus or immune abnormalities – occurs disproportionately in people with Long Covid. Then comes the hard part: proving that each of these traits, alone or in combination, explains why the coronavirus has turned millions of people into shadows of their former selves.

Everyone agrees that stand-alone operators are unlikely. The retained virus, for example, can attack the circulatory system, causing blood clots or chronic inflammation. “I see this as a triangle,” says Buonsenso, each trigger potentially explaining or even reinforcing the others.

The final challenge is to identify treatments that alleviate or reverse these abnormalities and help patients feel better. In the United Kingdom, home of the much-lauded effort to identify immediate treatments for COVID-19, researchers are launching a clinical trial that will be among the largest in the world to test potential Long Thevid therapies in a randomized, statistically stable way. But more such research is needed – and time is of the essence. In May, the U.S. Centers for Disease Control and Prevention said a review of medical records of nearly 2 million people suggested that at least one in five people diagnosed with COVID-19 had developed long-term conditions. Other studies have found approximately similar percentages. Some recent studies show that the risk for vaccinated people is slightly lower, but the strength of the vaccine to prevent the syndrome remains uncertain.

For Proal and others, assembling puzzle pieces is an emergency. “I consider Long Covid a huge emergency,” she said.

Small blood clots

A. Mastin / Science

In Rome, Buonsenso used sophisticated medical imaging techniques to better understand the role of blood clots. Called the SPECT-CT scan, it combines two different types of images: a single-photon emission computed tomography scan, which uses a radio tractor injected into a person’s veins to provide images of blood flow, and a standard CT scan for information about lung structure. By merging them, doctors can see which parts of the lungs are not receiving normal blood flow.

So far, Buonsenso has scanned the lungs of 11 young people who have severe long covids, including irregular heartbeat and shortness of breath during exercise. In six children, the lungs appeared normal. The other five images were striking: where there should have been bright orange and yellow, meaning pulsating blood, one lung was almost completely blue, indicating a small flow. Buonsenso believes that small blood clots or chronic damage to the lining of blood vessels can disrupt blood flow. He and his colleagues published their first evidence of such damage to a 14-year-old girl in July 2021. The Lancet Child and Adolescent Health.

The key question is what to do next. Buonsenso’s patients do not meet the current criteria for taking anticoagulants, which prevent blood clots from forming or prevent them from growing because no clots are seen on their scans. “You either say, ‘I’m sorry, but I can’t do anything outside of research,’ or you’re like a fearless doctor with mutual trust with the patient and family, and you make decisions together,” Buonsenso said.

With seriously ill children and their desperate parents in front of them, Buonsenso did not want to wait for a clinical trial to begin. Instead, he and his family decided to do what they could. All five patients are now taking anticoagulants – which run the risk of heavy bleeding – under close supervision.

He is encouraged by their progress. Several return to school, play sports and spend time with friends. Two were re-scanned. A teenager who is still suffering from symptoms shows little improvement. But in another, whose symptoms have largely disappeared, the images looked almost normal. The other three will be re-scanned this summer.

Of course, he can’t be sure that those who have improved have done so thanks to treatment. That’s why he’s hoping for resources to create a long-term clinical trial of Covid that includes a placebo group.

Like other doctors, Buonsenso was inspired by Long Covid patients who lobbied hard for treatment and shared successes and failures on social media. Martha Esperti, a 34-year-old graduate student who now lives in Paris, is one of them. Affected by COVID-19 more than two years ago, she was not hospitalized, but months later she struggled with fatigue, shortness of breath while walking, constant fever, joint pain and other symptoms. However, blood tests and other medical tests, such as X-rays of her lungs, were largely normal. Experts continued to insist on answers. Then, in the spring of 2021, I got a call from a pulmonologist who said, “Listen, I want you to take another test.”

Esperti was one of the first Long Covid patients in Europe to receive a SPECT-CT lung scan and looked exactly like the compromised lungs of sick children that Buonsenso later scanned. “My right lung is almost completely blue,” she said. She posted the photos on Twitter, where they were shared by thousands of people.

Like Buonsenso, Esperti’s doctors believe that the culprit is damage to small blood vessels and minor clots. The theory of sustainable microclots gained further faith in the summer of 2021, when Resia Pretorius, a physiologist at Stellenbosch University in South Africa, and her colleagues reported in Cardiovascular diabetology that such clots may remain in the blood of Long Covid patients. Her team found signs of excessive blood clotting in 11 people with Long Covid, but not in healthy people or another group with type 2 diabetes they used for comparison.

One challenge for clinicians looking to look for blood clots is that finding them is a difficult process, although Pretorius is working to make it more accessible to doctors. SPECT-CT scans identify clots indirectly, based on blood flow abnormalities.

The work of Pretorius and others corresponds to a nascent model in which the biology of acute and chronic COVID-19 seems to overlap. At the start of the pandemic, doctors recognized blood clots as a sign of an early, severe illness: many hospitalized patients had clots in their lungs, brains and elsewhere. Even people with a mild illness are at increased risk of heart attacks and strokes in the weeks after infection.

I think Long Covid is a huge emergency.

• Amy Proal
• PolyBio Research Foundation

“The two diseases – acute COVID-19 and Long Covid – are not very different,” said David Lee, an emergency physician at Grossman School of Medicine at New York University. He suspects that microcoagulation explains many chronic symptoms. According to him, at least 70% of patients with Long Covid have respiratory problems, and at least 30% suffer from dysautonomia, in which abnormalities in the autonomic nervous system impair heart rate, respiration and digestive function. Many suffer from fatigue and what is often called “brain fog”. Small clots in the brain could explain cognitive problems, Lee notes; or clots can kill small nerve cells from fibers and cause dysautonomy.

But there is still no solid evidence that microcoagulation causes long-term symptoms of Covid. To learn more, Lee launched a study of 20 Long Covid patients with respiratory symptoms and 20 healthy volunteers who had COVID-19 and recovered. Participants will undergo a SPECT-CT scan to see if any of them have damaged lungs. If scan anomalies are unique to some with Long Covid, this may be a step towards …