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When do infections lead to long COVID? Scientists close in on triggers and treatments for post-viral syndromes
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Jasiek Krzysztofiak/Nature. Adapted from CDC & Engin Akyurt via Unsplash
In 2004, Amy Proal got an infection that changed her life. “I was in my pre-med, last year of college, and totally tanked,” she says. “No one could tell me what it was, everybody said my blood work was fine — sent to a psychiatrist, the usual story.” She started reading papers from her sickbed and soon realized that she wasn’t the only one with unexplained symptoms that lingered after an infection.
A year later, she was diagnosed with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). She managed to improve her symptoms with antivirals and other drugs, and went on to do a PhD in microbiology, studying the lasting consequences of pathogens. In 2018, she co-founded PolyBio, a foundation in Medford, Massachusetts, that advances research on infection-associated chronic illnesses. “Then,” Proal says, “COVID hit.”
COVID-19 killed millions of people, and left millions of others with lingering health problems caused by the SARS-CoV-2 virus. The chronic condition became known as long COVID. A 2024 study estimated that 400 million people around the world have long COVID1, with an annual economic burden of around US$1 trillion.
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The condition’s existence prompted a surge of interest in post-acute infection syndromes. Over the past six years, thousands of studies have explored the mechanisms underlying long COVID, its similarities to other post-infection conditions and potential treatments. In December 2020, the US government allocated $1.15 billion to study the chronic consequences of SARS-CoV-2 and, last year, Germany announced €500 million ($580 million) in funding for research into post-infectious diseases. “The COVID pandemic has shone a light on this family of post-acute infection conditions,” says David Putrino, a neuroscientist at Icahn School of Medicine at Mount Sinai in New York City.
Nonetheless, the conditions’ health and financial burden still strongly outweighs the funding. “It’s not a priority, despite having a major destructive influence on our society,” says Chris Ponting, a geneticist at the University of Edinburgh, UK.
The community is working to understand the basic biology underlying these conditions and find reliable disease markers, the lack of which is the main obstacle to developing treatments. How acute infections trigger chronic illnesses remains unclear, but many researchers think the field is closing in on explanations. “We certainly don’t have the answer,” says Michael Peluso, an infectious-disease clinician at the University of California, San Francisco. “But we have a lot of leads.”
In 1894, a few years after an epidemic of respiratory disease swept the world, English physician Thomas Dowse described a cluster of symptoms that lingered long after infection. He called the condition ‘post-influenza exhaustion’. Numerous other chronic illnesses, including post-polio syndrome, post-Ebola syndrome and post-treatment Lyme disease syndrome, have since been linked to pathogens. Symptoms vary, but fatigue and neurological features are common. “Almost every infection, viral, bacterial, parasite, is associated with chronic symptoms where a subset of people don’t recover,” Proal says.