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Study using circulating spike protein and macrophage dysregulation liquid biomarkers reveals heterogeneity in PASC

In a recent study posted to the medRxiv* preprint server, researchers designed a liquid biomarker panel consisting of macrophage and monocyte-related soluble factors and circulating spike proteins to understand profiles of immune dysregulation in patients with post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC).

Study: Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19. Image Credit: ker_vii/Shutterstock


While the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in widespread hospitalizations and death, another cause for concern is the persistent and long-term impairment of cardiac, respiratory, and neuropsychiatric fitness in individuals infected with SARS-CoV-2. Commonly called long COVID, PASC has been reported in 12.7–87% of COVID-19 patients.

Recent research on the clinical and epidemiological characterization of PASC has indicated that reservoirs of viral ribonucleic acid (RNA) and proteins such as spike protein persisting in the body could be responsible for generating recurrent T cell immune responses that cause many of the PASC symptoms. Other studies have suggested that tissue damage due to the viral infection could be responsible for some of the organ-specific symptoms of PASC.

However, an understanding of the underlying mechanisms of PASC, such as innate and adaptive immune dysregulation, is lacking.

About the study

In the present study, the researchers designed a liquid biomarker panel to profile the plasma of 181 individuals from an earlier digital health research cohort study that included individuals with and without PASC after mild to moderate COVID-19, and a control group of uninfected individuals. The biomarkers in the panel consisted mainly of soluble monocyte and macrophage factors and circulating spike proteins from SARS-CoV-2.

The plasma levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) and a range of interleukins (IL) were measured. Different types of enzyme-linked immunosorbent assays (ELISA) were used to quantify soluble macrophage activation markers such as CD206 and CD163, profile antibodies against SARS-CoV-2 spike and nucleocapsid protein, and detect circulating spike protein.


The results reported strong dysregulation of macrophage- and monocyte-related soluble factors such as chemokines and pro-fibrotic and pro-inflammatory cytokines in individuals with PASC. The authors observed that, with a few exceptions, these factors display a correlation pattern independent of the ongoing symptoms of PASC.

In many individuals, especially those experiencing PASC, circulating SARS-CoV-2 spike protein were detected in the plasma. However, since the subsets of PASC cases that displayed persistent levels of viral proteins versus those with macrophage dysregulation were very small, the clinical characteristics of PASC could not be reliably correlated to these biomarkers.

The authors believe that the chemokine and cytokine data indicated the role of macrophage and monocyte factors in regulating the balance of T helper type 1 and type 2 (TH1 and TH2) cells in PASC. Interleukin 33 (IL-33) is a cytokine which is thought to play a major role in the severity of COVID-19 symptoms, along with granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies suggest that IL-33 is involved in mediating the polarization of T helper type 2 cells and the development of chronic pulmonary fibrosis.

The study also identified two correlation patterns specific to PASC that involved MCP-1/CCL2, a range of interleukins, type I interferons, and soluble CD162 and CD206. These correlations suggest transitions from pro-inflammatory TH1 responses during acute COVID-19 to TH2 responses, which result in macrophage-related lung fibrosis in PASC.

The spike protein levels correlated with the antibody titers but not with any of the soluble factors. In a few cases with high circulating spike protein levels, the plasma levels of tumor necrosis factor and interleukins 1β, 6 and 8 were also high. However, the subset of participants in the cohort study exhibiting this pattern was too small to draw conclusions.


Overall, the results suggest that even eight months after infections, PASC patients exhibited pronounced dysregulation of macrophage- and monocyte-related soluble factors. Correlation and regression analyses found patterns involving persistently high IL-5 and IL17F levels and IL-8 and MCP-1/CCL2. The researchers could not find a correlation between the soluble macrophage or monocyte factors and the levels of circulating spike protein.

According to the authors, the study’s findings indicate PASC subtypes involving immune dysregulation and viral protein reservoirs. Further studies with larger subsets are required to establish clinically defined subtypes.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Journal reference:

  • Christoph Schultheiss, Edith Willscher, Lisa Paschold, Cornelia Gottschick, Bianca Klee, Lidia Bosurgi, Jochen Dutzmann, Daniel Sedding, Thomas Frese, Matthias Girndt, Jessica I. Hoell, Michael Gekle, Rafael Mikolajczyk, and Mascha Binder. (2022). Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19. medRxiv. doi:

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