What Causes Long COVID?

Long COVID affects a sizable percentage (there is a lot of uncertainty about the exact proportion) of people who get COVID-19. The symptoms vary but among the most common are persistent fatigue, “brain fog,” cognitive impairment and symptoms that get worse after physical or mental effort, sometimes referred to as post-exertional malaise.

There are lots of theories, but the causes of long COVID are far clear. But results from a cross-sectional study published last week as a preprint (it hasn’t been vetted by a publisher or gone through peer review) found an association between low cortisol levels and long COVID.

Akiko Iwasaki

“Participants with long COVID demonstrated striking decreases in systemic cortisol levels, decreases which remained significant after accounting for differences in individual demographics and sample collection times,” wrote Akiko Iwasaki, Ph.D., a professor of immunobiology at Yale University School of Medicine and one of the corresponding authors, and her colleagues.

Eric Topol, a professor at Scripps Research who via Twitter and other social media has emerged as a leading expert voice on COVID-19, described the preprint last week as a “one of the best studies on long COVID.”

Iwasaki and her colleagues also found evidence of reactivation of latent herpesvirus infections among long COVID patients.

Cortisol is hormone produced by the adrenal glands that sit on top of the kidneys. It is commonly referred to as stress hormone because levels go up as part of the body’s fight-or-flight response. There are cortisol receptors throughout the body.

Persistently high cortisol levels are unhealthy — they keep the body in a high-alert mode — but low levels are found in conditions such as chronic fatigue syndrome.

Topol wrote in his substack, called Ground Truths, this study was the first to “reinforce” the potential importance of low cortisol levels as an “underpinning” of long COVID.

The study by Iwasaki and her colleagues is a joint effort by researchers at Yale and the Icahn School of Medicine at Mount Sinai in New York. This particular analysis included total of 215 people: 99 identified as having long COVID, 39 people who had COVID-19 but no persistent symptoms, 40 healthy, unvaccinated people who had COVID-19 and 40 healthy controls who hadn’t had COVID-19.

Serum cortisol levels were highest in the group that hadn’t had COVID-19, lower in the group that had had COVID-19 but no persistent symptoms and lowest among those with long COVID. Normally, low cortisol levels are associated with low levels of adrenocorticotropic hormone (ACTH), a hormone produced by pituitary gland, a small, pendulous gland at the base of the brain. But ACTH levels were not lower in these long COVID patients. The discordance, wrote the researchers, suggest “an inappropriately blunted compensatory response by the hypothalamic-pituitary axis.” The hypothalamus is the part of the brain that sends signals to the pituitary gland and therefore has sway over cortisol and other hormone levels. ]

“Our current finding of persistently decreased cortisol production in participants with long COVID more than a year following acute infection warrants expanded,” Iwasaki and her colleagues wrote in the preprint.

The possible connection between long COVID and reactivation of herpesvirus and the Epstein-Barr virus, a type of herpesvirus, was not a complete surprise. Previous research had identified a possible role for reactivation of latent infections. Other research has detected Epstein-Barr virus during the acute phase of COVID-19 in hospitalized patients, presence of the virus has been linked to the development of persistent symptoms.

In this study, a battery of tests related to antibodies against the Epstein-Barr virus showed higher concentrations of antibodies against Epstein-Barr in the people with long COVID. The results, wrote Iwasaki and her colleagues, “suggest that herpesvirus reactivation is not incidental following a SARS-COV-2 infection,” naming the virus that causes COVID-19.

They also reference recent findings that have linked Epstein-Barr infection to the development of multiple sclerosis.

“Whether EBV (Epstein-Barr virus) reactivation may also predispose people with long COVID to the development or exacerbation of autoimmune pathologies, as has been recently reported for people with multiple sclerosis will, require extensive longitudinal monitoring and surveillance of people with long COVID,” Iwasaki and her co-investigators wrote.