Emily Waltz
Particles of the SARS-CoV-2 virus (blue) inside an infected cell.Credit: NIH/SPL
Researchers looking for biological drivers and markers of long COVID have linked the syndrome to herpes viruses, as well as to reduced levels of a stress hormone1.
The exploratory study drew both praise and criticism from scientists contacted by Nature. “A major weakness of this paper is the very small sample size,” says infectious-disease specialist Michael Sneller at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. “I would take with a huge grain of salt all these findings unless they are confirmed in larger studies.”
But Danny Altmann, an immunologist at Imperial College London who was not involved in the study, says such reports are exactly what the long-COVID research community needs. “We’re really desperate to work out which drugs to test” for long COVID, he says. “The more studies we have like this, the more it enables us to race off and plan appropriate randomized, controlled trials.”
The study, posted on the preprint server medRxiv, has not yet been peer reviewed.
The disease that lingers
Long COVID consists of a constellation of sometimes debilitating symptoms that last for months or years after a SARS-CoV-2 infection. It is common — affecting anywhere from 5% to 50% of people who contract COVID-19 — but researchers have few clues to its causes.
The latest study, led by immunobiologist Akiko Iwasaki at Yale School of Medicine in New Haven, Connecticut, involved performing tests that generated thousands of data points for each of 215 participants in an attempt to reveal key immunological features that distinguish people with long COVID from healthy individuals. The study included 99 people with long COVID — those who reported persistent symptoms after SARS-CoV-2 infection — and 116 healthy participants who had either never had COVID-19 or had recovered after SARS-CoV-2 infection.
Most strikingly, the study found that in the long-COVID group, levels of cortisol, a stress hormone that has a role in regulating inflammation, blood sugar levels and sleep cycles, were about 50% lower than in healthy participants. The authors also found hints that in people with long COVID, Epstein–Barr virus, which can cause mononucleosis, and varicella-zoster virus, which causes chickenpox and shingles, might recently have been ‘reactivated’. Both of these viruses are in the herpes family, persist indefinitely in the body after infection and can start to multiply again after a period of quiescence.
People in the long-COVID group also had unusual levels of certain types of blood and immune cell, as well as dysfunctional immune cells, suggesting that their immune systems are working overtime.
Iwasaki cautions that the results do not suggest that low cortisol levels or herpes viruses cause long COVID, but that their association with the syndrome warrants further study. The findings build on previous reports associating low cortisol levels and Epstein–Barr virus with long COVID, including a Cellpaper published in March.
With only 215 participants, the Iwasaki’s study is relatively small, and only a subset of the participants were included in some parts of the work. For example, in the analysis of cortisol levels, the researchers included all 99 people with long COVID, but only 40 of the 116 healthy people. “The small number of controls compared to the long-COVID group is problematic” because it makes the study less statistically robust, says Sneller, who is leading a separate study on the drivers of long COVID.
Iwasaki says that samples were collected from the remaining healthy volunteers later and are being sent for analysis this week.
Another limitation of the study is that Iwasaki’s team did not analyse participants’ samples for the presence of the Epstein–Barr and varicella-zoster viruses, instead measuring levels of antibodies against the viruses.
Members of the long-COVID group had higher levels of these antibodies than did the healthy people, which suggests a more recent reactivation of the virus, Iwasaki says. However, the only way to determine definitively whether there is current reactivation is to test for viral DNA in the blood.
Iwasaki’s team is now running such tests. Her group also plans to test participants’ cortisol levels throughout the day, because the stress hormone’s levels tend to fluctuate, and to examine how immune features vary at different time points after infection.
“This is an exploratory, hypothesis-generating study, and clearly not the conclusion to what long COVID is, but it does begin to open doors,” says Iwasaki.
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