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Long Covid proven by biological markers – Yale study

A groundbreaking US study found clear differences in immune and hormone function between individuals with long COVID and those without, enabling researchers to diagnose with 94% accuracy between the two groups and confirming the condition is not “all in the head”.

Long Covid patients had exaggerated humoral responses directed against SARS-CoV-2, and in addition, their antibody responses were higher against other pathogens that weren’t SARS-CoV-2, especially Epstein-Barr virus (EBV), reported Akiko Iwasaki, PhD, of Yale University, US, and co-authors.

An algorithm that incorporated blood test and self-reported survey data showed diagnostic potential with an area under the curve (AUC) of 0.94, according to their study, which was published in the journal Nature.

“We found a number of immunological and hormonal factors that collectively are able to distinguish people with versus without long Covid at 94% accuracy,” Iwasaki told MedPage Today. “This study speaks to the underlying biological causes of long Covid, and provides a basis for future studies that interrogate various therapies targeting the root causes of this disease.”

She said the reduced cortisol levels found in the long Covid patients suggest hypothalamus-pituitary-adrenal imbalance.

“The elevated activated B cells and exhausted T cells suggest persistent antigen and potentially persistent virus infection. The EBV reactivation, which was demonstrated by others also, inform about a subset of patients who may benefit from EBV-targeting therapies.”

This work is “a crucial first step towards identifying a set of biological differences between people with and without long Covid” and may lead to novel blood biomarkers for an objective diagnosis of the condition, said co-author David Putrino, PhD, of Icahn Mount Sinai in New York City.

“The study provides physicians with important insights by highlighting the fact that people with long Covid show measurable signs of hormonal and immunological dysfunction, which should serve as further irrefutable evidence that long Covid is not a functional or psychosomatic diagnosis.”

Long Covid symptoms – those lasting more than three months after acute infection – affected 7.5% of US adults, according to 2022 CDC data. By June 2023, that percentage fell to 6%.

Symptoms of long COVID can include post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements.

In their analysis, Iwasaki and colleagues evaluated data from about 273 people with and without long Covid from Yale and two Mount Sinai locations.

They looked at several groups, including people with no previous SARS-CoV-2 infection, those who had fully recovered after Covid, and those with active long Covid symptoms for four months or longer after Covid. The median length of symptoms in the last group was 12 months after acute infection.

Participants completed questionnaires about symptoms, medical history, and health-related quality of life, and provided blood samples. Most acute infections in the long Covid group occurred early in 2020, when parental SARS-CoV-2 strains drove most new cases.

Long Covid participants had a mean age of 46 and convalescent controls had a mean age of 38, but the two groups did not differ in sex or hospitalisation for acute COVID. The aggregated medical history of the two groups did not differ in baseline prevalence of anxiety or depression.

Fatigue (87%), brain fog (78%), memory difficulty (62%), and confusion (55%) were the most common self-reported symptoms in the long Covid group. Postural orthostatic tachycardia syndrome (POTS) also was prevalent; 38% of people with long Covid in the study had formal diagnostic testing and clinical evaluation.

Half of participants with long Covid reported negative effects on employment status.

Serum cortisol was the most significant predictor of long Covid status. Other biomarkers indicated abnormal T cell activity and reactivation of multiple latent viruses, including EBV and other herpes viruses.

The findings on EBV, herpes viruses, and low cortisol are especially important, observed Dr Ziyad Al-Aly of Washington University and chief of research and development at the VA St Louis Healthcare System, who wasn’t involved with the research.

“They may help inform treatment trials,” he told MedPage Today. “For example, whether treating EBV or cortisol replacement would ameliorate symptoms and improve outcomes would need to be considered in the light of these findings.”

People with long Covid often are told the disease is “all in your head”, Al-Aly noted.

“This study provides objective evidence of significant differences in the immune profiles of people with long Covid versus matched controls,” he said. “I hope this puts the ‘it’s all in your head’ idea to rest.”

Study details

Distinguishing features of Long COVID identified through immune profiling

Jon Klein, Jamie Wood, Akiko Iwasaki, et al.

Published in Nature on 25 September 2023


Post-acute infection syndromes (PAIS) may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a PAIS known as “Long Covid” (LC). Individuals with LC frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the biological processes associated with the development and persistence of these symptoms are unclear. Here, 273 individuals with or without LC were enrolled in a cross-sectional study that included multi-dimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with LC. Marked differences were noted in circulating myeloid and lymphocyte populations relative to matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with LC. Further, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with LC, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with LC. Integration of immune phenotyping data into unbiased machine learning models identified key features most strongly associated with LC status. Collectively, these findings may help guide future studies into the pathobiology of LC and aid in developing relevant biomarkers.


Nature article – Distinguishing features of Long COVID identified through immune profiling (Open access)


MedPage Today article – Long COVID Blood Tests Show Distinct Immune and Hormone Function (Open access)


See more from MedicalBrief archives:


UK scientists ID unusual new long Covid symptom


US agency launches ‘overdue’ long Covid clinical trials


Long Covid’s impact on life quality worse than some cancers – UK study



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