[Preprint] Severe fatigue in long COVID characterized by inc inflammatory genes in monocytes, proinflammatory cytokines & CD8+ T-lymphocytes, 2022

Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes. A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms
Julia C Berentschot, Hemmo A Drexhage, Daniel A Aynekulu Mersha, Annemarie JMWijkhuijs, Corine H GeurtsvanKessel, Marion PG Koopmans, Jolanda Voermans, Majanka H Heijenbrok-Kal, L. Martine Bek, Gerard M Ribbers, Rita JG van den Berg-Emons, Joachim GJV Aerts, Willem A Dik, Merel E Hellemons

Background
A significant proportion of patients with SARS-CoV-2 infection develops long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immunologic profiling of fatigued and non-fatigued long COVID patients and age and gender matched healthy controls (HCs).

Methods
We 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.

Results
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. Fatigued patients showed 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- naive CD4+ T-lymphocytes and CD25+FOXP3+ regulatory CD4+ T-lymphocytes and limited monocyte and serum (galectin-9) inflammation. Mild patients showed monocyte and serum (IL-6, galectin-9) inflammation and decreased CD4+ T-lymphocyte subsets (T-helper 1 cells).

Conclusion
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.

Link | PDF (MedRxiv)

 

Hospitalised patients (alpha variant). Healthy controls, non-infected, vaccinated.

I can't find (or I'm not following) figures relating to patient sub-categories vs HC.

Noting findings of increased EBV antibodies in the recent Iwasaki pre-print, this paper found no increase in EBV / CMV viral load itself (at least detectable by the method used).

They spend time discussing overlap with immunological abnormalities (esp monocytes) seen in ME/CFS and major depressive disorder. They suggest there may be commonalities with microglial dysfunction, which could vary the phenotype depending on involved centres relating to mood or energy production (limbic system vs brainstem??). However, there is always the risk that the questionnaires used to evaluate for depression in LC/ME aren't capturing the right thing.

They made comment about depressed mice (who presumably don't fill out questionnaires):

They conclude:

 

Yes, definitely biomedical.

 

To give a bit of context. Hemmo Drexhage was also part of setting up the research program for ME by ZonMw. He is interested in the similarities between auto-immune and mental health diseases on an immunological, neurological basis. There's a strong focus on the microglia in his work. I'm therefore not surprised with the comparison to MDD, but his approach is as far as I'm aware very much a biomedical one. The treatments that are proposed in the paper are also immune modulators and no behavioral interventions. I think this is the type of work we can expect from the Erasmus Medical Center in Rotterdam for ME as well.

 

An article about the study which also mentions ME:

News Medical
Why fatigue from long COVID goes beyond simply feeling tired

Quote:
Fatigue is the most reported symptom, with 41% to 60% of patients experiencing debilitating fatigue beyond six months and even up to a year. This 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. 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.

Research has identified a connection between CFS-related fatigue and an increase in cytotoxic T-lymphocytes and cytokines. Recent studies have also found an increase in T- and B-lymphocytes and inflammatory cytokines in patients convalescing from COVID-19. However, a comprehensive clinical and immunologic profiling of long COVID patients associating immunological abnormalities with the clinical manifestations of long COVID is lacking.