In a recently published study medRxiv* In a pre-print server, researchers in the Netherlands investigated the role of inflammatory genes, cytotoxic T-lymphocytes (CD8).+ T cells) and pro-inflammatory cytokines in chronic fatigue syndrome in 2019 coronavirus disease 2019 (Covid-19) patients.

Study: Severe fatigue as a long-term covid marker is characterized by monocyte gene expression, increased serum pro-inflammatory cytokines and increased CD8+ T-lymphocytes: immune-brain axis dysregulation, coagulation process and auto-inflammation differential long-term covid markers To clarify.  Image credit: eamesBot / ShutterstockResearch: Chronic fatigue is a chronic covid-induced gene expression in monocytes, increased serum pro-inflammatory cytokines and increased CD8+ T-lymphocytes: Immune-brain axis dysfunction, coagulation cascade and auto-inflammation. Long to explain the difference in symptoms of covid. Image credit: eamesBot / Shutterstock


Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), commonly known as prolonged covid, include a wide variety of symptoms, usually lasting three months after the onset of SARS-CoV-2 infection. Typical symptoms of prolonged covid include fatigue, low physical fitness, dyspnea, and cognitive decline.

Fatigue is the most commonly reported symptom, with 41% to 60% of patients experiencing fatigue for more than six months and up to one year. This prolonged fatigue is characteristic of post-infectious diseases from other pathogens such as bacteria. Coxiella burnetii and the Epstein-Barr virus that causes mononucleosis. Chronic fatigue syndrome (CFS), or myalgic encephalomyelitis (ME), can also cause severe fatigue, decreased physical activity, and cognitive impairment that lasts for six months or more.

Research has identified a link between CFS-related fatigue and an increase in cytotoxic T-lymphocytes and cytokines. Recent studies have found increases in T- and B-lymphocytes and inflammatory cytokines in patients recovering from Covid-19. However, there is a lack of comprehensive clinical and immunological profile of chronic Covid patients that correlates immunological abnormalities with chronic covid clinical manifestations.

About the study

This study selected 37 patients with severe fatigue as part of prolonged Covid and 36 patients with prolonged Covid without severe fatigue. They also used a gender- and age-matched control group of healthy individuals.

Immunological assessments were conducted three to six months after discharge from the hospital for COVID-19, and clinical symptoms were monitored for one year after discharge. The study evaluated patient-reported outcome measures (PROMs).

The researchers tested the expression of genes involved in inflammation in circulating monocytes using reverse transcribed complementary deoxyribonucleic acid (cDNA), which was subjected to quantitative polymerase chain reaction (qPCR).

In addition, a high-sensitivity enzyme-linked immunosorbent assay (ELISA) was used to test the blood levels of various soluble cell surface markers and cytokines, including brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony- stimulatory factor (GM-CSF), T-cell immunoglobulin, and various interferons, interleukins, and chemokine ligands.


The results indicated that prolonged COVID patients with severe fatigue had increased inflammation-related gene expression in monocytes, as well as elevated serum soluble cell surface markers and inflammatory cytokines and CD8.+ T lymphocytes. The authors also cited a few other studies that reported associations between cytotoxic T-lymphocytes and severe clinical differences between SARS-CoV-2 infections.

Long-term covid patients without severe fatigue showed improvement in fitness during follow-up but significant decrease in CD45RO. Mild CD4+ T-lymphocyte percentage, known as naive CD4+ Lymphotopenia. They also reduced CD4+ T regulatory lymphocytes. Non-debilitated long-term covid patients with moderate to severe differentiation showed elevated serum levels of galactin-9 and interleukin-6 but limited expression of inflammatory genes in monocytes.

Interestingly, patients with mild clinical variants of chronic Covid who did not experience fatigue showed activation of monocyte inflammatory genes and elevated serum levels of galactin-9 and interleukin-6, similar to chronic Covid patients with severe fatigue. However, their cytotoxic T-lymphocyte levels were not excessively high. In contrast to those with moderate-to-severe variants in non-fatigued long-term covid patients, the mild variant was not associated with astrocytic CD4.+ Lymphotopenia.

A comparison of the immune profile of CFS or ME with prolonged covid fatigue has shown similarities such as increased CD8.+ T lymphocytes, monocyte inflammatory genes expression and elevated serum levels of pro-inflammatory cytokines. The study also found a link between prolonged Covid and severe depressive symptoms.


Overall, the study observed increased levels of cytotoxic T cells and serum pro-inflammatory cytokines in long-term covid patients with severe fatigue. Long-term covid patients showed other immunological features, such as naive CD4.+ Lymphocytopenia and elevated serum levels of some interleukins, increased CD8+ T lymphocytes are often associated with severe fatigue.

Chronic fatigue and reduced quality of life and physical fitness are associated with major depressive disorder. The authors believe that targeting immune dysfunction with personalized therapies that include anti-inflammatory agents and interferon inducers could alleviate many of the long-term disabling symptoms of Covid.

* Important notice

medRxiv It publishes original scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as proven information.

Journal Reference:

  • Severe fatigue is characterized by increased gene expression in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes as long-term covid markers. Disease-brain axis, coagulation cascade and auto-inflammatory dissociative disorders to explain differences in long-term covid symptoms: Julia C Berenshott, Hemo A Dreshaj, Daniel A Ainekulu Mersha, Annemarie JM Wikhuijs, Corinne H Grootsvan Kessel, Marion PG Koopmans, Jolanda Voermans, Majanka. H Heijenbrok-kal, L. Martine Bek, Gerard M Riberers, Rita JG van den Berg-Emons, Joachim GJV Aerts, Willem A Dik, and Merel E Hellemons. medRxiv.2022. DOE:,

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