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Commentary: Long COVID is real. Now the evidence is piling up

CHICAGO: Finally, the hunt for answers about long COVID is yielding some clues. A new study, led by the Icahn School of Medicine at Mount Sinai and the Yale School of Medicine and published in Nature, defines some critical differences in certain biomarkers of people with long COVID. The next step is even more critical: Coming up with a way to cure them.

A massive number of people in the US are dealing with lingering symptoms. Two new reports this week from the Centers for Disease Control and Prevention found that in 2022, about 18 million adults said they had ever had long COVID, with about 8.8 million currently suffering from the condition. In that time, roughly 1 million children had been affected – with about 360,000 children reporting an ongoing case.

Those millions of people don’t all have the same symptoms – some experience brain fog and extreme fatigue, while others may have shortness of breath or a racing pulse – and their susceptibility to the disease is formed by a likely long list of factors. Those could include their medical histories, their previous vaccinations, prior infections, and even their genes.

Because of that, long COVID has defied simple explanations. And so far, doctors must base their diagnoses on sometimes vague symptoms, rather than on a molecule that can be measured, or a true biomarker of the disease.

“Everyone wants a single biomarker, everyone wants a single treatment,” says David Putrino, director of rehabilitation innovation for the Mount Sinai Health System. “That’s not realistic for long COVID.”

A more realistic hope is that researchers can one day offer physicians a kind of “how to” manual for long COVID with a battery of tests to pinpoint what’s gone wrong and, ideally, treatments. The new study is an important step towards that goal, and should offer patients needed hope that answers could be on the way.


In what the researchers believe is a first, they did a detailed study of the differences between people with long COVID and those who are healthy (a mix of those who never had COVID-19 and those who recovered from their infection).

They wisely excluded anyone who had been hospitalised with COVID-19, so as not to confuse explainable lingering symptoms – for example, those caused by lung damage following a week of intubation – with the more mysterious ones that follow a mild infection.

When they compared an exhaustive list of measurements, a few stood out as being distinct features of long COVID. Among the strongest signal: Many people with long COVID had much lower levels of cortisol, which regulates our sense of alertness.

In a healthy person, the stress hormone hits a nadir around midnight, then rises to a peak somewhere between 6am and 8am. That lack of cortisol could help explain the bone-crushing fatigue experienced by some people with long COVID.

The researchers are already working to understand the root cause of that hormone imbalance, work that ultimately should point to treatment strategies. 

They also observed key differences in immune responses. People with long COVID showed signs of B-cell activation and T-cell exhaustion, indications that the body has been fighting something for a very long time, Putrino says.

That result lends credence to one theory about the cause of long COVID: Some people never fully clear the virus. Their immune system keeps reacting to what it perceives as a threat – for months on end. Researchers are now running clinical trials to see if treating people with longer courses of Pfizer’s antiviral Paxlovid could get rid of that lingering virus and help people feel better.


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The last big finding was that in some people with long COVID, other latent viruses – things like Epstein Barr virus that go dormant, but don’t disappear – were reactivated. One theory is that the immune system, exhausted by COVID-19, starts losing its ability to keep those latent viruses at bay, too.

None of these signals should be taken as the arrival of a simple test for the chronic condition. But that doesn’t mean the findings aren’t good news for the millions of people struggling with long COVID.

While not quite the comprehensive diagnostic toolkit many would like now, this short list still could be useful. Doctors can very easily run a full hormone panel to look for dysregulation and also test for evidence of latent virus reactivation, Putrino says.

And Putrino suggests more data will come soon. Moreover, this kind of research should become a template for studying other mysterious long-haul conditions, like ME/CFS, known more commonly as chronic fatigue syndrome, or long Lyme disease.

Finally, the work offers concrete, biological evidence that long COVID is real. That gives people with long COVID a helpful rejoinder to the skeptics who believe their condition is exaggerated or simply in their heads.

It’s important progress for the millions whose lives have been interrupted by chronic symptoms. And it’s a necessary step to finding cures.

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