Can every infection become a chronic disease?
A decade ago, Ziyad Al-Aly would have dismissed the idea that a routine viral infection could leave someone chronically ill months or years later.
For much of modern medicine, infectious diseases and chronic illnesses occupied largely separate domains. Infections like influenza or COVID-19 were acute events; people became sick, recovered and moved on. Chronic diseases like diabetes or heart disease followed a different path altogether.
“I used to think that a lot of the acute infections are inconsequential in the long term,” said Al-Aly, a professor of medicine at Washington University in St. Louis.
Today, he sees things differently.
“The pandemic sort of proved this to be a wrong model of thinking,” he said.
Triggering a lasting illness
The shift began in the earliest months of the pandemic. Even by March 2020, patients infected with SARS-CoV-2 gathered in online support groups to report they weren’t recovering after the expected two or three weeks. Many described crushing fatigue, brain fog, changes in smell or taste and a host of other lingering symptoms.
By May, the phenomenon had a name: long COVID.
What initially appeared to be a medical curiosity soon became one of COVID-19’s defining legacies. Governments and research institutions poured billions into studying the condition. Researchers and clinicians confronted a question few had seriously considered before: Could an infection trigger health consequences that persist for months, years or even decades?
Researchers still debate exactly why long COVID occurs and how many people might be affected. But the bigger implication extends far beyond SARS-CoV-2.
As scientists began investigating long COVID, they found evidence that lingering symptoms can follow many infections. In 2023, Al-Aly and colleagues published one of the first large studies describing “long flu,” finding that influenza infections can also be followed by months of lingering symptoms and elevated risks of adverse health outcomes.
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“What we didn’t really appreciate was that acute infections like the flu, like COVID, maybe perhaps all of them, can actually lead to chronic disease,” Al-Aly explained.
A growing body of evidence now supports that view, and if it continues to hold, it could fundamentally reshape how physicians, researchers and patients think about disease. Infectious illnesses would no longer be viewed as short-term threats that either kill a person or are quickly forgotten. Instead, they could become recognized as key contributors to chronic disease.
The implications stretch from vaccine policy and infection prevention to how societies measure the true burden of infectious disease.
A longstanding phenomenon comes into focus
The idea that infections may trigger lasting health problems is not entirely new. In the aftermath of the 1918 influenza pandemic, physicians documented survivors who struggled with prolonged fatigue, memory problems and even a wave of neurological illness that left lasting disabilities.
After the 2014–2016 Ebola epidemic in West Africa, researchers documented thousands of survivors suffering from persistent joint and muscle pain, hearing and vision loss and neurological symptoms years after recovery. Last year, researchers estimated that nearly 90% of Ebola survivors developed long-term health effects, known as post-Ebola syndrome.
Patients with Lyme disease have likewise reported ongoing symptoms including fatigue, pain and cognitive difficulties after a typical course of antibiotic treatment, a condition often referred to as post-treatment Lyme disease syndrome.
Researchers have long suspected that infections may trigger myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS, a debilitating condition marked by extreme fatigue and cognitive dysfunction. Many patients trace the onset of their illness to a viral infection, and studies have linked outbreaks of ME/CFS-like illness to pathogens ranging from Epstein-Barr virus to enteroviruses.
“Actually, there’s examples where almost every major pathogen — bacterial, viral — has been connected to a situation where people can develop chronic symptoms after the infection,” said Amy Proal, the co-founder and president of PolyBio, a non-profit research institute.
Researchers had documented these lingering symptoms for decades. Yet these conditions remained comparatively understudied, underfunded and underestimated until COVID-19 provided something previous outbreaks never had: scale.
An unprecedented scientific effort
Hundreds of millions of people around the world were infected with SARS-CoV-2, prompting an unprecedented scientific effort — backed by billions of research dollars and thousands of researchers — to understand every aspect of the virus.
Researchers are still debating exactly how many people develop long COVID. Estimates vary widely depending on how the condition is defined and how patients are identified.
Last month, researchers at Massachusetts General Brigham used artificial intelligence to analyze nearly half a million patient records and concluded that roughly 30 million Americans may have experienced the condition, substantially higher than many previous estimates.
Whatever the precise number, the consequences have been significant.
Millions of Americans report long COVID symptoms severe enough to interfere with daily activities, employment and quality of life. Some have been unable to return to work while others have reduced work hours, exhausted savings, applied for disability benefits or become dependent on caregivers.
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The economic toll is staggering. Economists estimate that long COVID imposes roughly $1 trillion in costs on the global economy annually.
The Centers for Disease Control and Prevention estimated that ME/CFS cost the U.S. economy roughly $18 billion to $51 billion annually through healthcare spending and lost productivity, while Lyme disease is estimated to cost between $345 million and nearly $1 billion per year.
For many researchers, the emergence of long COVID transformed what had once been viewed as a collection of relatively niche conditions into a major public health and economic concern. Yet despite the surge in attention, scientists still do not agree on the answer to a fundamental question: Why do some people recover fully while others remain sick for months or years?
The search for a cause
Today, researchers have proposed about five major theories to answer that question. Some believe the virus lingers in the body long after the initial infection. Others argue that the infection disrupts the immune system, awakens dormant viruses already present in the body, damages the microbiome or impairs the tiny energy-producing structures inside cells known as mitochondria.
“The jury is still out on this. I don’t think we really know the answer,” Al-Aly said. “There are still many, many uncertainties, including the underlying biologic mechanism.”
One leading theory is known as viral persistence. The idea is that some people never fully clear SARS-CoV-2 and that the virus continues hiding in tissues such as the gut, driving chronic inflammation and symptoms months or years later.
Proal believes evidence for that explanation is steadily growing. She points to studies that have detected viral genetic material in gut tissue long after acute infection and argues that viruses may persist in what scientists call reservoirs — tissues where they are less visible to the immune system.
“A little bit of the organism goes deeper into tissue where it’s a little bit more protected,” she said.
The gut and female reproductive tract are both considered relatively immune-tolerant environments where the immune system must coexist with outside forces, from food to a developing fetus. Some scientists believe those tissues could provide a refuge where viruses are more difficult to eliminate.
Not everyone is convinced.
“I completely disagree,” said Jennifer Snyder-Cappione, an assistant professor of virology, immunology and microbiology at Boston University.
Part of her skepticism stems from recent clinical trials testing whether antiviral medications can improve long COVID symptoms. If lingering SARS-CoV-2 infection is driving the condition, researchers reasoned that suppressing the virus should help patients recover. But several studies of extended treatment with Paxlovid, an antiviral used to treat COVID-19, have largely failed to show meaningful improvement in long COVID symptoms.
Instead, Snyder-Cappione suspects infections may reactivate dormant herpesviruses, which immunologists know remain in the body for life.
“The data is leaning much more heavily that having COVID-19 can cause reactivation of herpes viruses such as [Epstein-Barr virus] and [cytomegalovirus], EBV or CMV, which we’re basically all infected with globally,” she said.
She noted that the symptoms of long COVID share striking similarities with illnesses that can follow Epstein-Barr virus infection.
Others believe the answer may lie not in the virus itself but in the body’s response to it.
“There is more accumulating evidence that the immune system is involved in some way,” Al-Aly said. In some patients, researchers suspect the infection may leave the immune system chronically activated, triggering inflammation that damages blood vessels and organs long after the acute infection has ended.
This may help explain why some studies have reported women’s risk is about 30% to 60% higher than that of men.
“We know that women, particularly premenopausal women, are much more prone to developing long COVID and ME/CFS and a lot of these other conditions,” said Nadia Roan, a professor of urology at the University of California San Francisco.
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Women tend to have a more robust immune response than men, which is one of the reasons women are significantly more likely to have an autoimmune disorder, said Shannon Dunn, an immunology professor at the University of Toronto.
Long COVID is also more common among people in their 20s and 30s, when the immune system is typically at its strongest, according to Al-Aly.
“One of the explanations is that it could be related to the strength of the immune response,” he said. However, he cautioned that while this observation points toward a role for immune dysfunction, it does not explicitly prove an autoimmune mechanism.
Age and gender are not the only risk factors for long COVID. Severe initial illness, repeat infections and genetics can increase risk, although the picture remains incomplete.
Researchers have observed some intriguing similarities across infection-associated chronic illnesses: ME/CFS is more common among women, and some studies suggest persistent symptoms after Lyme disease may also disproportionately affect women. Post-Ebola syndrome and long flu, however, have not yet shown the same consistent demographic patterns.
Roan believes one reason the field has struggled to identify a single cause behind long COVID and other infectious diseases that cause chronic symptoms is that there may not be one.
“They’re all feasible, and I would say they’re not mutually exclusive,” Roan said. “Long Covid is not one condition, it’s multiple conditions.”
For now, researchers agree on far less than they would like. But they also say the debate itself reflects how quickly science has advanced.
Five years ago, scientists did not know whether long COVID existed. Today, they are debating the precise biological pathways that may be driving it.
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Ella Rae Greene, Editor In Chief
