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Unique monocyte signatures in subgroups of long COVID patients indicate that long COVID phenotypes could be driven by distinct mechanisms

More than two years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long-COVID-19 or post-acute COVID-19 syndrome. A recent study by 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 results showed unique monocyte signatures in subgroups of long COVID patients.

WHO defines long COVID as: “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation”. Long COVID syndrome encompasses a wide range of organ dysfunction. 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, cough, headache, cardiac arrhythmias, palpitations, cognitive impairments, anxiety and depression, and thromboinflammatory events, such as ischemic stroke pulmonary embolism, and deep vein thrombosis. Despite the extensive research on long COVID, it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many patients.

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.

About the study

This study included two groups of COVID-19 patients, 75 patients with acute COVID-19 and 142 convalescent patients who were followed up between 63 and 246 days after discharge. In a group of 142 convalescents, 31% had chest radiological abnormalities associated with COVID-19. The main symptoms of long COVID were fatigue (found in 44% of convalescents) and shortness of breath (found in 48% of convalescents).

The authors investigated phenotypical and functional changes of monocytes in patients who had acute COVID-19 or long COVID syndrome. The same parameters were also evaluated in healthy controls and individuals with respiratory syncytial virus (RSV) or influenza A (flu) infection, with similar mean follow-up times. All healthy controls tested negative for anti-spike protein receptor binding domain antibodies. Positive control for severe, ongoing lung injury was a group of patients with progressive fibrosing interstitial lung disease.


A computed tomography (CT) scan performed in patients diagnosed with long COVID and shortness of breath and/or fatigue showed residual lung abnormalities in all patients. The most common CT abnormalities were ground glass changes and reticulations. A combination of abnormal chest radiology and shortness of breath was used to confirm an unresolved lung injury. The shortness of breath and fatigue registered in convalescent patients did not correspond to the initial severity of acute COVID-19.

Patients with acute COVID-19 had increased monocyte expression of the chemokine receptor CXCR6 and the adhesion molecule P-selectin glycoprotein ligand 1 (PSGL1).

Patients with long COVID, characterized by residual lung damage, shortness of breath, and abnormal radiological findings exhibited a unique monocyte signature characterized by high monocyte expression of CXCR6 and PSGL1. The highest expression was found in patients with residual radiological lung abnormalities. The monocyte expression of the chemokine receptor CXCR6 did not decrease to a healthy control level for up to nine months, but the level of PSGL-1  gradually decreased over time. 

Monocytes from post-RSV/flu patients did not exhibit changes in the expression of the chemokine receptor CXCR6. These findings suggest that the chemokine receptor CXCR6 may be crucial for the migration of monocytes and monocyte-driven lung injury.

Peripheral blood mononuclear cells from long COVID patients with shortness of breath showed an enhanced capacity to migrate towards the ligand CXCL16 (abundantly expressed in the lungs) compared to their non-breathless convalescent counterparts and healthy controls.

Researchers also analyzed plasma levels of inflammatory proteins. Patients diagnosed with long COVID and shortness of breath had increased serum levels of MMP-1, adhesion molecule VCAM-1, and E-selectin. The capacity of monocytes to produce the cytokines IL-1β and 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, whereas the monocyte production of TNF-α in patients with progressive fibrosing interstitial lung disease was significantly lower.

Patients diagnosed with long COVID syndrome and persistent fatigue also had a unique monocyte signature, characterized with persistently reduced expression of the prostaglandin-producing enzyme cyclooxygenase-2 (COX-2) and the chemokine receptor CXCR2 up to 9 months after acute infection. Monocyte expression of CXCR2 was not restored to normal levels, but the expression of COX-2 gradually increased over time. In contrast, monocytes from post-RSV/flu patients did not exhibit changes in the expression of the COX-2 and CXCR2.

In conclusion, this study confirmed prolonged changes in innate immunity during COVID-19 convalescence. 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 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.

According to the authors, 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)

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