Why is the tiredness of long-term Covid disease more than just feeling tired

In a recent study published in medRxiv * Prepress server, researchers in the Netherlands examined the role of inflammatory genes and cytotoxic T lymphocytes (CD8)+ T cells), and pro-inflammatory cytokines in the prolonged severe fatigue experienced by a large number of patients with coronavirus 2019 (COVID-19).

Stady: Severe fatigue as a symptom of prolonged COVID is characterized by increased expression of inflammatory genes in monocytes, increased pro-inflammatory cytokines in serum, and increased CD8+ T lymphocytes: a putative dysregulation of the immune brain axis, clotting process, and autoinflammation explaining the diversity of prolonged COVID symptoms.. Image Credit: eamesBot / Shutterstock


Acute after-effects of SARS-CoV-2 infection, known as COVID-19, include a wide range of symptoms, often lasting more than three months after infection with SARS-CoV-2. Typical manifestations of COVID-19 include fatigue, decreased fitness, shortness of breath (dyspnea), and decreased cognition.

Fatigue is the most frequently reported symptom, with 41% to 60% of patients experiencing debilitating fatigue for longer than six months and up to a year. This prolonged fatigue is also a feature of post-infectious syndromes from other pathogens such as bacteria. Coxiella Burnetti The Epstein-Barr virus, which causes mononucleosis. Chronic fatigue syndrome (CFS), or encephalomyelitis (ME), also results in severe fatigue for six months or more, accompanied by poor physical fitness and cognitive impairment.

Research has identified a link between CFS-related fatigue and an increase in cytotoxic T lymphocytes and cytokines. Recent studies have also found increases in T and B lymphocytes and inflammatory cytokines in patients recovering from COVID-19. However, there is no comprehensive clinical and immunological classification of long-term COVID patients linking immune abnormalities with clinical manifestations of prolonged COVID.

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The current study selected 37 patients who had experienced severe stress as part of prolonged COVID and 36 severe COVID patients without severe stress. They also used a control group of healthy, gender- and age-matched individuals.

Immunological assessments were performed three to six months after COVID-19 hospital discharge, while clinical symptoms were monitored for a year after hospital discharge. The study also evaluated patient-reported outcome measures (PROMs).

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

In addition, a highly sensitive enzyme-linked immunosorbent assay (ELISA) has been used to test serum levels of various soluble cell surface markers and cytokines, including brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), Granulocytes – macrophage colony-stimulating factor (GM-CSF), T-cell immunoglobulins, various interferons, interleukins, chemokines.


The results indicated that prolonged COVID patients who had experienced severe fatigue showed increased inflammation-related gene expression in monocytes, as well as elevated serum levels of soluble cell surface markers and inflammatory cytokines, and CD8.+ T lymphocytes. The authors also note a few other studies reporting associations between increased cytotoxic T lymphocytes and severe clinical variants of SARS-CoV-2 infection.

Long-term COVID patients without severe fatigue showed improved fitness in the follow-up period but experienced a significant decrease in CD45RO naive CD4+ Percentage of T-lymphocytes, known as naive CD4+ Lymphocytopenia. They also lowered CD4+ Regulatory T lymphocytes. Serum levels of non-exhausted long-term COVID patients with the moderately severe variant showed elevated levels of galectin-9 and interleukin-6 in serum but limited expression of inflammatory genes in monocytes.

Surprisingly, patients with the clinically mild variant of prolonged COVID who did not experience fatigue showed increased activation of monocyte inflammatory genes and elevated serum levels of Galectin-9 and interleukin-6, similar to prolonged COVID patients with severe fatigue. . However, the levels of cytotoxic T lymphocytes were not excessively elevated. In contrast to the long non-exhausted COVID patients with the moderately severe variant, the mild variant was not associated with naive CD4+ Lymphocytopenia.

Comparisons of the immune profile of CFS or ME with prolonged COVID stress showed similarities such as increased CD8+ T lymphocytes, increased expression of monocyte inflammatory genes, and elevated serum levels of pro-inflammatory cytokines. The study also found associations between prolonged COVID and symptoms of major depressive disorder.


Overall, the study observed increased expression of inflammatory genes and elevated levels of cytotoxic T cells and pro-inflammatory cytokines in the serum of severely fatigued COVID patients. While the long non-exhausted COVID patients showed other immunological traits such as naive CD4+ Lymphocytopenia and elevated serum levels of some interleukins, increase in CD8+ T lymphocytes are often associated with severe fatigue.

Long-term fatigue and its debilitating effects on quality of life and fitness have also been linked to major depressive disorder. The authors believe that targeting immune abnormalities with personalized therapies consisting of anti-inflammatory agents and interferon inducers can alleviate many of the disabling symptoms of the long-term coronavirus.

*Important note

medRxiv publishes primary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information

Journal reference:

  • Severe fatigue as a symptom of prolonged COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T lymphocytes. Putative dysregulation of the brain’s immune axis, the clotting process, and autoinflammation to explain the diversity of prolonged COVID symptoms: Julia C Berentschot, Hemmo A Drexhage, Daniel Aynekulu Mersha, Annemarie JM Wijkhuijs, Corine H GeurtsvanKessel, Marion P.G. Koopmans, Jolanda Voermans, Majenka HK and Majenka HK and L. Martine Bek, Gerard M Ribbers, Rita JG van den Berg-Emons, Joachim GJV Aerts, Willem A Dik, and Merel E Hellemons. MIDI DOI: https://doi.org/10.1101/2022.09.15.22279970And the