Long COVID patients have distinct hormonal, immune differences

Long COVID patients have clear differences in immune and hormone function from patients without the condition, according to a study led by the Icahn School of Medicine at Mount Sinai and Yale School of Medicine. Their research, published in the journal Nature, is believed to be the first to show specific blood biomarkers that can accurately identify patients with long COVID.

The Centers for Disease Control and Prevention says one in 13 adults (or 7.5%) in the United States has long COVID symptoms lasting more than three months after having COVID-19. Many of these patients have no clear cause for their symptoms — which may include cognitive impairment or ‘brain fog’, extreme fatigue, shortness of breath and chronic pain — with the study providing new evidence for why these may exist.

Investigators analysed a total of 271 patients from three sites — The Mount Sinai Hospital, Mount Sinai Union Square and Yale School of Medicine — between January 2021 and June 2022. Researchers divided them into three groups: those with no prior SARS-CoV-2 infection; those who had fully recovered from a clinically confirmed case of COVID-19; and those with active long COVID symptoms for at least four months after confirmed COVID-19 infection.

Each patient was asked to complete a detailed set of questionnaires about their symptoms, medical history and health-related quality of life. The researchers took blood samples from all patients, identified biomarker differences and similarities between the groups, and then applied machine learning analyses to better understand which biomarkers were most effective in allowing the algorithm to identify patients with long COVID.

Overall, the algorithm was able to differentiate between people with and without long COVID with 96% accuracy and detect the condition based on distinctive features detected in the blood of participants in the long COVID group. Some of the most pronounced differences between the long COVID group and the two control groups were related to immune and hormonal dysfunction. This was characterised by biomarkers indicating abnormal T cell activity, reactivation of multiple latent viruses (including the Epstein–Barr virus and other herpesviruses) and significant reductions in cortisol levels.

“These findings show us that people with long COVID are living with a disease process that is observable using the blood testing protocols laid out in the study, but also varies from patient to patient depending on their specific medical history,” said principal investigator Dr David Putrino, Director of the Abilities Research Center at Icahn Mount Sinai. “This means that physicians must listen to their patients and perform a wide variety of physiological and lab tests, while adopting a highly personalised approach to the medical management of long COVID.

“There is no ‘silver bullet’ for treating long COVID, because it is an illness that infiltrates complex systems such as the immune and hormonal regulation. Complex illnesses require complex treatment solutions and we need more rapid research to better understand long COVID and discover new and promising therapies.”

“We are excited to see such clear differences in the immune phenotypes in people with and without long COVID,” added co-principal investigator Dr Akiko Iwasaki, from Yale School of Medicine. “These markers need to be validated in larger studies, but provide a first step in dissecting the disease pathogenesis of long COVID.”

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