Post-COVID Fatigue Associated With Increased Expression Of Inflammatory Genes In Monocytes, Serum Pro-Inflammatory Cytokines And increased CD8+ T-Cells!
A new study by Dutch researchers from Erasmus MC, University Medical Center Rotterdam-Netherlands And Rijndam Rehabilitation, Rotterdam-Netherlands has found that post-COVID fatigue is associated with increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines and increased CD8+ lymphocytes.
It is already a common occurrence that a significant proportion of patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms.
The study team performed clinical and immunologic profiling of fatigued and non-fatigued long COVID patients and age and gender matched healthy controls (HCs).
The study included 37 long COVID patients with and 36 without severe fatigue and assessed inflammation-related monocyte gene expression, serum levels of inflammatory cytokines, and leukocyte and lymphocyte subsets 3-6 months after hospital discharge, and followed clinical symptoms up to one year.
Long COVID with fatigue represented a severe variant with many symptoms (median 9 [IQR 5.0-10.0] symptoms) and signs of cognitive failure (41%) and depression (>24%). Symptoms persisted up to one-year follow-up.
The study findings showed that fatigued patients had an increased expression of inflammatory genes in monocytes, increased serum IL-6, TNF-α, galectin-9, and CXCL10, and increased CD8+ T-lymphocytes compared to HCs.
Non-fatigued long COVID patients were arbitrarily divided in those with moderately severe disease (4 [2.5-5.0] symptoms, primarily impaired fitness, n=25) and those with mild disease (1 [1.0-2.0] symptom, n=11). Symptoms in non-fatigued long COVID patients persisted up to one-year follow-up.
Moderately severe patients showed reduced CD45RO- naïve CD4+ T-lymphocytes and CD25+FOXP3+ regulatory CD4+ T-lymphocytes and limited monocyte and serum (galectin-9) inflammation.
However, mild patients showed monocyte and serum (IL-6, galectin-9) inflammation and decreased CD4+ T-lymphocyte subsets (T-helper 1 cells).
Corresponding author and lead researcher, Dr Julia C. Berentschot from the Department of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam told Thailand Medical News
, “Long COVID with fatigue is associated with many concurrent and persistent symptoms up to one year after hospitalization and with clear signs of low-grade inflammation and increased CD8+ T-lymphocytes. We showed that long COVID is a clinical and immunologic heterogeneous disorder. Diagnostic tools and personalized therapies combatting the diverse immune abnormalities might be required to alleviate the persisting disabling complaints of the patients.”
The study findings were published on a preprint server and are currently being peer reviewed.
The study team are the first to examined the role of inflammatory genes, cytotoxic T-lymphocytes (CD8+ T cells), and pro-inflammatory cytokines in long-lasting severe fatigue experienced by a large number of coronavirus disease 2019 (COVID-19) patients.
PASC or Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that is commonly known as long COVID, includes a wide range of symptoms, often persisting beyond three months after the SARS-CoV-2 infection.
The most common manifestations of long COVID include fatigue, low fitness, shortness of breath (dyspnea), and reduced cognition.
To date, fatigue is the most reported symptom, with 41% to 60% of patients experiencing debilitating fatigue beyond six months and even up to a year.
It should also be noted that such long-lasting fatigue is also a characteristic of post-infectious syndromes from other pathogens such as the bacteria Coxiella burnetii and the Epstein-Barr virus that causes mononucleosis.
Also, it has been found that chronic fatigue syndrome (CFS), or myalgic encephalomyelitis (ME), also results in severe fatigue for six months or more, accompanied by reduced fitness and cognitive impairment.
Past studies have identified a connection between CFS-related fatigue and an increase in cytotoxic T-lymphocytes and cytokines.
Also, recent studies have also found an increase in T- and B-lymphocytes and inflammatory cytokines in patients convalescing from COVID-19.
To date however, a comprehensive clinical and immunologic profiling of long COVID patients associating immunological abnormalities with the clinical manifestations of long COVID is lacking.
The study team selected 37 patients who experienced severe fatigue as part of long COVID and 36 long COVID patients without severe fatigue. The team also used a control group of gender- and age-matched healthy individuals.
Detailed immunological assessments were conducted three to six months after COVID-19 hospital discharge, while clinical symptoms were monitored for a year following discharge. The study also assessed the patient-reported outcome measures (PROMs).
The study team tested the expression of genes involved in inflammation in the circulating monocytes using reverse transcribed complementary deoxyribonucleic acid (cDNA), which was then subjected to quantitative polymerase chain reaction (qPCR).
Furthermore, a highly sensitivity enzyme-linked immunosorbent assay (ELISA) was used to test the serum levels of various soluble cell surface markers and cytokines, including brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), T-cell immunoglobulin, and various interferons, interleukins, and chemokine ligands.
The study findings indicated that long COVID patients who experienced severe fatigue showed increased inflammation-related gene expression in the monocytes, as well as elevated serum levels of soluble cell surface markers and inflammatory cytokines, and CD8+ T lymphocytes.
The study team also referred to a few other studies that reported associations between increased cytotoxic T-lymphocytes and severe clinical variants of SARS-CoV-2 infections.
Interestingly, it was found that Long COVID patients without severe fatigue displayed improvement in fitness in the follow-up period but experienced a significant reduction in CD45RO- naïve CD4+ T-lymphocyte percentage, known as naive CD4+ lymphocytopenia.
These patients also had reduced CD4+ T regulatory lymphocytes. The serum levels of the non-fatigued long COVID patients with the moderately severe variant showed elevated Galectin-9 and interleukin-6 levels in the serum but a limited expression of inflammatory genes in the monocytes.
Shockingly, the study findings strangely revealed that patients with the clinically mild variant of long 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 long COVID patients with severe fatigue. However, their cytotoxic T-lymphocyte levels were not excessively high. In contrast to the non-fatigued long COVID patients with the moderately severe variant, the mild variant was not associated with naive CD4+ lymphocytopenia.
Further detailed comparisons of the immune profile of CFS or ME with that of long COVID fatigue showed similarities such as increased CD8+ T lymphocytes, increased expression of monocyte inflammatory genes, and elevated serum levels of pro-inflammatory cytokines.
The research also found associations between long COVID and symptoms of major depressive disorder.
The study team concluded that the research findings showed an increased expression of inflammatory genes and elevated levels of cytotoxic T cells and serum pro-inflammatory cytokines in long COVID patients with severe fatigue.
The study findings also revealed that non-fatigued long COVID patients exhibited other immunological features such as naive CD4+ lymphocytopenia and elevated serum levels of certain interleukins, the increase in CD8+ T lymphocytes is associated mostly with severe fatigue.
Also, the long-lasting fatigue and its debilitating effects on quality of life and fitness have also been associated with major depressive disorder.
The study team stressed that a proper personalized medicine approached is needed to deal with the immune abnormalities consisting of anti-inflammatory agents and interferon inducers to help alleviate many of the disabling symptoms of long COVID.
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