Long/post-COVID or post-acute COVID-19 (PASC) syndrome represents a heterogeneous nosological entity, despite the existence of similar or overlapping symptoms between patients. It is more common in hospitalized survivors, but, even those who have experienced mild acute COVID-19 have a wide range of frequent, persistent, and disabling symptoms. The most frequent symptoms are fatigue, muscle weakness, dyspnea, headache, cardiac arrhythmias, cognitive disorders, anxiety and depression, and thromboinflammatory events, such as ischemic stroke pulmonary embolism, and deep vein thrombosis. Despite the extensive research, it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many patients diagnosed with long COVID/PASC. In this study, researchers from the United Kingdom evaluated phenotypical and functional changes of monocytes in acute COVID patients and convalescents up to 9 months after hospital discharge.
The evidence of enhanced monocyte infiltrates in the lungs, kidney, heart, spleen, and muscles of deceased COVID-19 patients indicates a role that abnormal monocyte migration has in peripheral tissues. After being recruited to sites of inflammation, monocytes contribute to inflammatory disease, either directly or through differentiation into macrophages or dendritic cells in peripheral tissues. Patients with severe forms of COVID-19 were found to accumulate pro-fibrotic macrophages derived from monocytes in their lungs.
Chemokines are a class of chemotactic cytokines that play a key role in directing the migrating and positioning of immune cells within the human body. Acute COVID-19 is characterized by high expression of certain chemokines, which recruit neutrophils and monocytes to sites of infection. These chemokines are significant for the pathophysiological processes of COVID-19 by sustaining inflammation and causing collateral tissue damage. Depending on the number of amino acids between the first two cysteine residues, the chemokines are classified into four subfamilies, CXC, CC, CX3C, and XC. The names of the receptors correspond to the subfamily of chemokines they bind.
About the study
The authors investigated phenotypical and functional changes of monocytes in patients with acute COVID-19, COVID-19 convalescents diagnosed with long COVID syndrome, healthy controls, and individuals with respiratory syncytial virus (RSV) or influenza A (flu) infection, with similar mean follow-up times.
A group of patients with progressive fibrosing interstitial lung disease served as a control for severe, ongoing lung injury.
Results
This study included two groups of COVID-19 patients, 75 patients with acute COVID-19 and 142 COVID-19 convalescents diagnosed with long COVID syndrome, and followed up between 63 and 246 days after discharge.
The main symptoms of long COVID were fatigue (reported in 44% of convalescents) and shortness of breath (reported in 48% of convalescents). In all patients diagnosed with long COVID who reported shortness of breath and fatigue, a computed tomography (CT) scan showed residual lung abnormalities. The most common CT abnormalities were ground glass changes and reticulations. The shortness of breath and fatigue in long COVID patients did not correspond to the initial severity of acute COVID-19.
Phenotypical and functional changes of monocytes
Results revealed that a unique monocyte signature in long COVID breathless patients differed from that of patients with long COVID syndrome and persistent fatigue.
Patients with long COVID and shortness of breath, residual lung damage, and abnormal lung CT findings exhibited a unique monocyte signature characterized by high monocyte expression of the chemokine receptors CXC motif chemokine receptor (CXCR)-6 and adhesion molecule P-selectin glycoprotein ligand 1 (PSGL1). The highest expression was found in patients with residual lung CT abnormalities. The monocyte expression of the chemokine receptor CXCR6 did not decrease to normal levels for up to nine months. The level of PSGL-1 gradually decreased over time. Also, peripheral blood mononuclear cells from long COVID patients with shortness of breath showed an enhanced capacity to migrate towards the ligand CXCL6 (abundantly expressed in the lungs) compared to non-breathless COVID-19 convalescents and healthy controls. According to the authors, a unique monocyte signature in long COVID breathless patients, characterized by elevated monocyte expression of CXCR6 and PSGL-1, suggests a localized lung injury.
A unique monocyte signature found in patients diagnosed with long COVID syndrome and persistent fatigue was characterized by persistently reduced expression of the prostaglandin-producing enzyme cyclooxygenase-2 (COX-2) and the chemokine receptor CXCR2 up to 9 months after acute infection. The expression of the chemokine receptor CXCR2 did not increase to normal levels for up to nine months. The expression of COX-2 gradually increased over time. The authors stated that a unique monocyte signature in long COVID patients with persistent fatigue, characterized by reduced monocyte expression of COX-2 and CXCR2, indicates a generalized response involving monocytes and tissue macrophages.
Monocytes from post-RSV/flu patients did not exhibit changes in the expression of the COX-2, and the chemokine receptors CXCR2 and CXCR6.
The researchers also analyzed plasma levels of inflammatory proteins. Patients diagnosed with long COVID and shortness of breath had increased serum levels of matrix metalloproteinase (MMP)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. The capacity of monocytes to produce the cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α was significantly higher in non-breathless compared to breathless long COVID patients.
In post-RSV/flu individuals, the monocyte production of TNF-α was comparable to that in healthy controls. The monocyte production of TNF-α in patients with progressive fibrosing interstitial lung disease was significantly lower.
Conclusion
This study showed unique monocyte signatures in subgroups of long COVID patients and confirmed prolonged changes in innate immunity during COVID-19 convalescence. These results show that unique monocyte signatures define subgroups of long COVID patients. Given the heterogeneity of clinical presentations, it seems likely that distinct pathophysiological pathways cause different long COVID phenotypes.
This article is published in the European Respiratory Journal.
Journal Reference
Scott NA et al. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID. European Respiratory Journal 2023 61: 2202226. (Open Access) https://erj.ersjournals.com/content/61/5/2202226
