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

SNT Gatchaman

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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.

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). The latter is characterized by severe fatigue lasting more than 6 months and involves debilitating symptoms such as post-exertional malaise and cognitive problems. 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.

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).

Active EBV and CMV were assessed in randomly selected patients from the subgroups of long COVID to assess whether symptoms could be attributed to viral reactivation, as suggested in literature. EBV and CMV DNA load was measured using internal controlled quantitative real-time Taqman PCR based on assays performed as published previously. For EBV a value over the lower limit of detection of >100 I/mL indicated presence of active virus, and for CMV this was >50.IU/mL.

Viral load of EBV and CMV were tested in randomly selected 10 (27%) patients of long COVID with fatigue, 10 (40%) of long COVID without fatigue, moderately severe variant, and 9 (82%) of long COVID without fatigue, mild variant. We did not find detectable viral loads in any of these patients, and thus did not perform further tests on the remaining patients.

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):

In MDD it is thought that the inflammatory activation of the circulating monocytes represent an activation of the myeloid system in general, including the microglia in the brain, particularly in areas regulating emotion. Increased pro-inflammatory cytokines in the serum of MDD patients induce pro-inflammatory IL-6 cascades in the brain, hypothesized to further activate the microglia, compromising their function. Also a normal functioning T-lymphocyte system is essential to regulate mood: Mice without functioning T-lymphocyte system show signs of anxiety and depressive-like behavior. Last, inflammatory cytokines and CD4+ T-lymphocyte subsets are correlated with structural brain changes in MDD.

They conclude:

This study shows that long COVID patients with severe fatigue are most severely affected, with this group being characterized by many concurrent and persistent symptoms and by clear signs of immune alterations, specifically a definite state of low grade inflammation and high levels of CD8+ T-lymphocytes. Persistent symptoms and immune alterations were also present in long COVID patients without fatigue. Altogether the state of immune activation in long COVID shows resemblances to what has been earlier described in ME/CFS and MDD. The diversity of immune abnormalities indicates that personalized therapies combatting the diverse immune abnormalities may be required to alleviate the persisting disabling complaints of the patients.
 
I assume the 'personalised therapies' suggested at the end of the conclusion refers to biomedical not psychological therapies

Yes, definitely biomedical.

The long term disabling consequences of long COVID with and without fatigue make a search for adequate treatment an urgent need. We postulate that the immune abnormalities found in this study form immune derangements which could be targeted in individualized treatments to combat the long term sequelae of SARS-Cov-2 infection.
 
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.
 
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