The symptoms of long COVID are diverse and long-lasting. The majority of cases (up to 69%) exhibit myalgia, brain fog, depression, breathlessness and fatigue. A recent study by UK researchers assessed the phenotypical and functional changes of monocytes in acute COVID patients and in convalescent patients 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”. Despite the extensive research on long COVID, it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many patients.
There is evidence of enhanced monocyte infiltrates in the lungs, kidney, heart, spleen and muscle of deceased COVID-19 patients, which 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 COVID-19 were found to accumulate pro-fibrotic macrophages derived from monocytes in their lungs.
About the study
The 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 convalescent patients, 48% had shortness of breath, and 31% had chest radiological abnormalities associated with COVID-19. Fatigue was another main symptom of long COVID, found in 44% of all convalescent patients.
A quantitative computed tomography scan from symptomatic long COVID patients with shortness of breath and/or fatigue showed that all of these patients had residual lung abnormalities. The most common 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. In convalescent patients, the shortness of breath and fatigue did not correspond to the initial severity of acute COVID-19 disease.
The scientists investigated both phenotypical and functional changes in monocytes in patients with acute and long COVID. The same parameters were also assessed in healthy controls and in individuals with respiratory syncytial virus (RSV) or influenza A (flu) with similar mean follow-up times. All healthy controls tested negative for anti-Spike 1 receptor binding domain antibodies. The patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury.
The results showed that long COVID patients with ongoing fatigue and long COVID patients with breathlessness had different inflammatory profiles, which lasted for up to 9 months after acute infection. 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 also exhibited high monocyte expression of CXCR6 and PSGL1. The highest expression was found in patients with residual radiological lung abnormalities.
Also, 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.
The monocyte expression of the chemokine receptor CXCR6 did not decrease to healthy control levels up to 9 months, but PSGL-1 levels 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.
Plasma levels of inflammatory proteins were also analyzed. In the group of long COVID patients with shortness of breath, the serum levels of MMP-1, adhesion molecule VCAM-1, and E-selectin were increased. 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 controls, whereas monocytes from patients with progressive fibrosing interstitial lung disease produced significantly lower levels of TNF-α.
The researchers then demonstrated that long COVID patients with persistent fatigue have a unique monocyte signature. They exhibited persistently reduced monocyte 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. Monocytes from post-RSV/flu patients did not exhibit changes in the expression of the COX-2 and CXCR2.
This study showed prolonged changes in innate immunity during COVID-19 convalescence, indicating that monocyte migration could play a key role in COVID-19 pathophysiology. A unique monocyte signature in long COVID breathless patients was characterized by elevated monocyte expression of CXCR6 and PSGL-1, which suggests localized lung injury. A distinct monocyte signature in long COVID patients with persistent fatigue was characterized by a reduction in monocyte expression of COX-2 and CXCR2. This indicates a generalized response involving monocytes and tissue macrophages.
Researchers concluded that they showed unique monocyte signatures that define subgroups of long COVID patients. Given the heterogeneity of clinical presentations, it seems likely that different long COVID phenotypes are caused by distinct pathophysiological pathways.
This article is published in 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