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

Front Immunol. 2023 Oct 10:14:1254899. doi: 10.3389/fimmu.2023.1254899. eCollection 2023.

Abstract

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.

Keywords: COVID-19; T-lymphocytes; fatigue; inflammation; long COVID; monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aftercare
  • COVID-19* / complications
  • Cytokines
  • Fatigue
  • Humans
  • Inflammation / complications
  • Monocytes
  • Patient Discharge
  • Post-Acute COVID-19 Syndrome
  • SARS-CoV-2
  • T-Lymphocytes*

Substances

  • Cytokines

Grants and funding

This work is part of the CO-FLOW study which is funded by the COVID-19 Program Care and Prevention of The Netherlands Organization for Health Research and Development (ZonMw, grant number 10430022010026), and Rijndam Rehabilitation and Laurens (both in Rotterdam, The Netherlands). This work was also funded by the H2020 EU MOODSTRATIFICATION project (grant number H2020-SC1-2016-2017/H2020SC1-2017-Two-Stage-RTD). The funding sources had no role in the study design, collection, analysis, and interpretation of data, writing of the report, and in the decision to submit the paper for publication.