Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation..., Hellemonds+

[EndME]

Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity

Background: Many patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs).

Methods: Long COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge.

Results: We included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p<0.001), and signs of cognitive failure (41%) and depression (>24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8+ TEMRA-lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts.

Conclusion: Long COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1254899/full

 

[EndME]

We performed an immune assessment between 3-6 months after hospital discharge while clinical symptoms, evaluated with patient-reported outcome measures (PROMs), were longitudinally assessed for up to one-year post-discharge.

The patients are taken from Merel Hellemonds clinic in Rotterdam (CO-FLOW cohort). The very big caviat is that all these patients were hospitalised (48.6% respectively 61.1% required ICU treatment, average hospital stay was 17.0 resp. 15.0 days) at the beginning of the pandemic. As such patients tend to be older (median age 58.0 resp. 61.0) and male dominated (64.9% resp. 72.2% are male).

These assays were selected because we have previously shown that these assays revealed abnormalities in immune function in patients with various mental and somatic disorders (15–18, 32–35) and ME/CFS (unpublished data).

So they have some unpublished ME/CFS data, possibly as part of https://projecten.zonmw.nl/nl/project/immuunhandtekeningen-mecvs where A. Dik is the PI (and they rightfully don't see ME/CFS as mental or somatic disorder)

They first looked at NK cells, B-lymphocytes, T-lymphocytes, and CD4+ and CD8+ T-lymphocytes.

They found some abnormalities found in CD8+ TEMRA-lymphocytes, which has also been found in at least one other study looking at Long-Covid in non-hospitalised patients (albeit in a different context looking at reactivity towards the spike protein) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272838/.

 

[Hutan]

CCL7; EMP1; MAFF; DUSP2; SERPINB2; BCL2A1; MAPK6; MXD1; CXCL2; IL1A; PTX3; IL1B; CCL20; CCL2; BCL10; EGR1; IL6; ADM; TNFAIP3; TNF; IL1R1; IFI44; IFI44L; IFIT1; MX1; IFIT3; BAX; HMOX1; MRC1; ABCA1; ABCG1; MVK; NR1H3

(B) Fatigue was defined as a total score of ≥22 on the Fatigue Assessment Scale (FAS) questionnaire. Single gene expression levels in fatigued (n=35) and non-fatigued (n=34) long COVID patients, data are presented as mean values and are expressed relatively to the expression level of healthy controls (n=42); the intensity of red reflects higher expression (upregulation) and green reflects lower expression (downregulation). No statistically significant differences were found in the gene expression levels in monocytes between fatigued and non-fatigued long COVID patients (data not shown). Significant differences in single gene expression levels in long COVID groups as compared to healthy controls were assessed with a Wilcoxon signed rank test using Benjamini-Hochberg-method for multiple testing, *p<0.05, **p<0.01, and ***p<0.001.

So the fatigued Long covid cohort looked very similar to the unfatigued Long covid cohort. But these cohorts looked different to the healthy controls for a number of gene expression levels. Note the healthy controls had to self-report that they hadn't had Covid-19.

A group of age- and sex-matched healthy controls (HCs) without a history of SARS-CoV-2 infection (self-reported) was recruited among hospital visitors. HCs were asked whether they had been vaccinated against COVID-19 and were screened for fatigue and depression using the Fatigue Assessment Scale (FAS) and Hospital Anxiety and Depression Scale (HADS) questionnaires. HCs who showed indications of chronic depression or fatigue, based on established cut-off scores that are described below, were excluded. All other HCs were included in the study, as they were appropriately age- and sex-matched to the fatigued long COVID group