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by Hannah Thomasy

Even mild COVID can do serious damage to the lungs, heart, and brain.

The vast majority of COVID-19 cases are mild or asymptomatic; many people will spend a week or two at most with a headache, sore throat, coughing, and maybe a fever. Because of that — and because everyone in the U.S. can now get vaccinated, which greatly reduces the chances of having a severe COVID case — many people are returning to life as normal, despite a recent surge in cases caused by the new Omicron BA.5 subvariant. But a mild case can be misleading, because once the initial infection subsides, you may not be in the clear. Long COVID, with symptoms that last months or even years, occurs in some people with mild cases, and even in those who were initially asymptomatic. And it can do serious damage to the heart, brain, and lungs.

Estimates on the prevalence of long COVID are hugely variable, from 2.3% of cases to more than half of cases. Some of this variation may have to do with differences in the populations studied and how exactly long COVID is defined (which symptoms are assessed and the time elapsed since the initial illness). Severity of symptoms can also vary widely between people. Although some people might be bothered by a persistent cough, others have symptoms so severe that they’re unable to return to work.

“This syndrome has maybe half a dozen different monikers — post-COVID, long COVID, long haulers, post-acute sequelae of COVID — and I think that in many ways reflects the heterogeneity of the presentation. And also reflects, frankly, the lack of consensus as to what's actually going on here,” says Roger McIntyre, M.D., a professor of psychiatry and pharmacology at the University of Toronto.

In an attempt to learn more about this condition — and eventually figure out how to treat it — researchers are investigating how mild COVID infections can go on to have serious impacts on major organ systems such as the lungs, heart, and brain. Here’s what we know so far.

Impact of Mild COVID on the Lungs COVID is well-known for its ability to cause severe lung damage in the short-term in people with more severe cases. But even mild COVID can do long-lasting damage to the lungs. In a study of self-reported long-haulers (the majority of whom were not initially hospitalized for the disease), nearly 80% reported persistent shortness of breath.

Physical abnormalities in the lungs have been noted as well. A study of 67 people with persistent symptoms who had not been hospitalized from COVID used CT scans to measure air trapping in the lungs. Air trapping is, as the name suggests, when air gets trapped in the lungs — meaning the person is unable to breath out fully. This can indicate dysfunction or inflammation in the small airways of the lung. The study found that more than half of patients had air trapping. On average, air trapping affected about 25% of the total lung.

Scientists emphasize that more research will be needed to determine whether these results hold true for people infected with more recent variants like Omicron and whether these changes are permanent or reversible.

At this point, it’s also unclear how to treat or prevent post-COVID lung abnormalities.

Impact of Mild COVID on the Heart Mild cases of COVID can also cause long-term damage to the cardiovascular system. Anecdotal reports of this began to appear less than a year into the pandemic, and a large-scale study published earlier this year confirmed early fears. The study, which included more than 150,000 people who had tested positive for COVID, found substantially elevated risk for more than a dozen kinds of heart and vascular disorders over the year following initial infection compared to people who had not had COVID.

Though these disorders were more common in people who had severe COVID, people who were not hospitalized still had increased risk for most of the conditions studied. For example, people who had not been hospitalized with COVID had a 23% increased risk of stroke, a 37% increased risk of heart failure, and a 50% increased risk of inflammatory heart disease.

“It’s very, very clear this is happening even in people who did not have severe disease,” says Ziyad Al-Aly, M.D., lead author of the study, director of the Clinical Epidemiology Center at Washington University in St. Louis, and the Chief of Research and Education Service at the Veterans Affairs St. Louis Health Care System.

Just because someone doesn’t get long COVID symptoms from the first infection, doesn’t mean they won’t develop it during a second or third infection, Al-Aly says. With each new infection, “you’re playing Russian roulette again.”

Currently, patients with post-COVID cardiovascular problems are treated based on their symptoms, Al-Aly says. A patient with arrhythmia after COVID, for example, would be treated in the same way as any other patient with arrhythmia. But understanding exactly how the virus continues to affect the heart and blood vessels for months after the initial infection is important for the development of more effective treatments.

Although there are several hypotheses about how this long-tern damage could be occurring, Al-Aly says that one possibility is that the virus, or even just viral fragments, hides in various tissues in the body long after the acute phase of the infection. “Those fragments could continue to irritate the immune system and produce something called low grade chronic inflammation that may in turn produce organ damage,” he says.

If this is the case, treatments, including antivirals, that help people clear the virus might help prevent long-term effects, he says. Although there have been a few anecdotal reports of long COVID symptoms improving after antiviral treatment or vaccination, these still need to be tested in clinical trials.

Impact of Mild COVID on the Brain Estimates of the prevalence of cognitive problems after mild COVID vary. One study found that 1.2% of people reported memory problems three to four months after illness, but another study found memory problems in almost 16% at roughly the same time point. “Brain fog,” a non-medical term generally concerned with difficulties related to attention and memory, was reported by more than 80% of people with long COVID, according to one study.

Brain fog and cognitive problems, along with fatigue, are some of the most common symptoms of long COVID, says McIntyre. They also have some of the largest impacts on quality of life. McIntyre says he’s even seen these symptoms in patients whose initial infections were asymptomatic.

But doctors are seeing much more than just brain fog. People with long COVID report an incredibly wide array of neuropsychiatric symptoms, including anxiety, depression, dizziness, insomnia, confusion, short- and long-term memory loss, and difficulty with verbal communication.

Because of the variation between people in brain structure, cognition, and baseline risk for neuropsychiatric disorders — and because most people aren’t being tested before their infections — it can be difficult to tell which differences are actually due to COVID. Luckily, long-term biomedical data collection projects such as the UK Biobank allow this kind of before-and-after analysis, at least in terms of brain structure. Using the Biobank data, researchers analyzed brain scans of hundreds of people who had been scanned before and after COVID and compared them with non-infected people who had two scans over similar time periods.

What they found is concerning: People who had recovered from COVID (and who were not hospitalized) had greater reductions in overall brain volume, as well as greater reductions in grey matter thickness in regions of the brain related to smell.

On average, the second scan occurred about 5 months after the person was diagnosed with COVID. Further research is needed to determine whether this damage is permanent or not.

McIntyre says it’s important to figure out exactly how COVID infections result in organ damage. Right now, there are a lot of possibilities for how the virus might damage the brain. Like those in the lungs, cells in the brain have the ACE2 receptor, which the virus uses to enter cells. So one hypothesis, he says, is that the virus is infecting brain cells, causing toxicity over time.

“Secondly, it could be friendly fire. In other words, your own immune system, in the process of tackling the virus, could inadvertently be causing collateral damage,” he says.

“Thirdly, a lot of people believe the reason why you're seeing brain changes is because there's very, very small blood vessel disease, because the blood vessels get affected by COVID,” he says, “and the tiny blood vessels in the brain are getting blocked, and that's what's leading to the problem.”

Antiviral and immune-modulating drugs are being considered for the treatment of long COVID in general, McIntyre says. He himself is running a study on whether an antidepressant called vortioxetine, which has been shown to improve cognitive function in people with depression, might help improve cognition and quality of life in those with long COVID.

But there’s a long way to go before scientists fully understand this complex disease, let alone develop effective therapies.