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.

The study findings were published on a preprint server and are currently being peer reviewed.

A significant proportion of patients develops long-lasting symptoms after acute corona virus disease 2019 (COVID-19). Different terms have been used to describe this condition, such as long COVID, post-acute COVID-19 syndrome, post-acute sequelae of COVID-19, long-haulers, or post COVID-19 condition.1, 2

In the current report we will use the term long COVID, consistent with most literature and long COVID is also the most commonly used terminology amongst patients.

Long COVID represents a wide spectrum of often disabling symptoms. Frequently reported symptoms are fatigue, impaired fitness, dyspnea, and cognitive impairment.3-5 Numerous studies showed the presence of these symptoms beyond 3 months after acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with evidence of persistence even two years after the acute illness.6

As patients with long COVID differ substantially regarding symptoms, severity, and recovery profile, attempts have been made to discern different clinical phenotypes of long COVID, without reaching consensus to date.7-9

Disabling fatigue is one of the most prominent and severe symptoms of long COVID. Among patients who had been hospitalized for acute COVID-19, proportions of up to 41% to 60% have been reported for patients that still suffer from fatigue one year after hospital discharge, without evident improvement beyond 6 months.5, 10, 11

Furthermore, the fatigue has been shown to negatively affect quality of life.12 This troubling problem thus requires in-depth evaluation regarding its pathogenesis, facilitating future interventions.

The prolonged fatigue state after acute COVID-19 shows clinical similarities with other post-infectious fatigue syndromes, such as that after Coxiella burnetii (Q fever) and Epstein-Barr virus (infectious mononucleosis) infection, and also shows similarities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).13-15 The latter is characterized by severe fatigue lasting more than 6 months and involves debilitating symptoms such as post-exertional malaise and cognitive problems.16

Immune activation, such as increased levels of circulating cytokines and increases of CD8+ T-lymphocytes, has been found in both post-infectious fatigue conditions and ME/CFS and is thought to play a role in the pathophysiology of these conditions.16, 17 Given the clinical similarities with post-infectious fatigue syndromes and ME/CFS, a similar immune activation may play a pathogenic role in long COVID.

To date, several studies have identified persistent inflammatory and T- and B-lymphocyte abnormalities among patients in the convalescent phase of COVID-19.18-21 However, a consistent and comprehensive association of these immune abnormalities with the diverse clinical symptoms of long COVID could not be established.18-20, 22, 23 Moreover, an in-depth immunological assessment among patients with and without the severe fatigue symptom of long COVID is lacking.

In the present study we examined patients who developed long COVID after hospitalization for COVID-19, and focused on the patients with the severe fatigue symptom. We performed an immunological assessment between 3-6 months after hospital discharge while clinical symptoms were longitudinally assessed up to one year post-discharge. We performed a comprehensive assessment of patient-reported outcome measures (PROMs).

Immunologically we determined the expression of various sets of inflammation-related genes in circulating monocytes along with serum levels of inflammation-regulating cytokines and leukocyte and lymphocyte subsets related to inflammation regulation. These assays were chosen as these have previously been shown to be related to immunological changes in patients with various mental and somatic disorders.24-30 The outcomes were compared to long COVID patients without fatigue and to a group of matched healthy individuals.


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