Biomarkers unveil insights into post-COVID-19 syndrome variability

In a recent study published in the EClinicalMedicine Journal, researchers studied a prospective observation cohort of patients with post-coronavirus disease 2019 (COVID-19) syndrome (PCS) to evaluate biomarkers such as cardiovascular function and hand grip strength and symptom severity at different time points following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort. Image Credit: Starocean/Shutterstock.comStudy: Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort. Image Credit: Starocean/


More than two years after the beginning of the COVID-19 pandemic, PCS, also commonly known as post-acute sequelae of COVID-19 (PASC) or long coronavirus disease (long COVID), has been defined and added to the International Classification of Diseases, Tenth Revision (ICD-10) codes by the World Health Organization (WHO).

It comprises a wide range of symptoms, with fatigue, myalgia, headaches, dyspnea, and exertion intolerance being common, and orthostatic disturbance and cognitive and neurological symptoms also being observed in some cases.

Post-COVID-19 syndrome often manifests within the three months following COVID-19 and has been observed to occur even after mild to moderate SARS-CoV-2 infections.

The symptoms often last a minimum of two months, although cases have been reported where many of the debilitating symptoms have continued for close to a year.

Furthermore, while a plethora of studies have investigated the clinical presentations of PCS over the short and medium terms of three to nine months, there is a lack of data on the long-term implications of PCS on health and well-being.

About the study

In the present study, the researchers conducted a 20-month follow-up of a prospective observational cohort of patients with PCS that was part of a study initiated in August 2020 to characterize the persistent symptoms of exertion intolerance and debilitating fatigue experienced after SARS-CoV-2 infections.

Patients were recruited for the study based on a confirmed diagnosis of a previous mild to moderate SARS-CoV-2 infection, with exertion intolerance along with post-exertional malaise, and persistent fatigue with a Chalder Fatigue Score of moderate to high, and the absence of preexisting respiratory, cardiac, psychiatric, or neurological conditions, or organ-dysfunction related to COVID-19.

Neurologists examined the patients and underwent comprehensive cardiological and pulmonary examinations to rule out serious COVID-19-related organ dysfunction.

Fatigue, exertion intolerance, post-exertional malaise, and additional debilitating symptoms persisting for more than three months and impairing daily activities were used as criteria to diagnose PCS.

The diagnosis for PCS-associated myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was obtained using the Canadian Consensus Criteria (CCC), and the occurrence of post-exertional malaise lasting for a minimum of 14 hours to distinguish it from ME/CFS linked to other diseases.

A quantitative CCC was used to assess the occurrence and severity of the cardinal symptoms of PCS. Fatigue associated with ME/CFS was diagnosed using the Chalder Fatigue Score, which rates mental fatigue across four items on the scale and physical fatigue across seven things.

The extent to which chronic fatigue impaired daily activities was assessed using the Bell disability scale. Gastrointestinal function and orthostatic intolerance were also evaluated to detect autonomic dysfunction symptoms, which patients with PCS often experience.

The clinical biomarkers used to characterize the severity and variety of symptoms experienced by patients with PCS were postural tachycardia syndrome, diminished hard grip strength, and orthostatic hypotension.

Laboratory parameters explored as potential biomarkers included ferritin, interleukin-8 in erythrocytes, antinuclear antibodies, mannose-binding lectin, and serum phosphatase.


The findings indicated that patients with PCS-associated ME/CFS experienced persistent symptoms with high severity for close to 20 months after the SARS-CoV-2 infection. In contrast, PCS patients without ME/CFS showed improvements in overall health over time.

Furthermore, while post-exertional malaise and fatigue were characteristic of PCS with and without ME/CFS, these symptoms were more pronounced in PCS cases with ME/CFS.

Additionally, while inflammatory biomarkers reduced with time in PCS patients with and without ME/CFS, antinuclear antibodies remained high.

Furthermore, decreased hand grip strength was associated with the persistence of PCS symptoms, especially in patients exhibiting ME/CFS. PCS patients with ME/CFS were also affected to a greater degree than PCS patients without ME/CFS by various other PCS symptoms, such as low emotional well-being and difficulty with social functioning.

However, irrespective of the difference in how pronounced post-exertional malaise was in PCS patients with and without ME/CFS, persistent post-exertional malaise remained a hallmark of PCS and poor prognosis.


Overall, the findings suggested that in most cases of PCS, symptoms of fatigue and post-exertional malaise persist for more than 20 months after recovering from COVID-19.

Furthermore, patients who develop ME/CFS experience more severe symptoms, suggesting that the occurrence of ME/CFS in PCS cases can be used for improved monitoring and management of patients with persistently severe symptoms.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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