Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS

Abstract

Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS). A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear. Methods: Here, SARS-CoV-2 spike protein was analyzed in the serum of 121 PCS patients with predominant fatigue and exertional intolerance, of whom 72 met diagnostic criteria for ME/CFS, 37 post-COVID recovered healthy controls, and 32 pre-pandemic healthy controls. Results: Spike protein was detected in the serum of 11% of recovered controls, 2% of PCS patients, and 14% of ME/CFS patients between 4 and 31 months after SARS-CoV-2 infection, but not in pre-pandemic samples. The occurrence and concentration of spike protein did not correlate with infection or vaccination timepoints. In ME/CFS patients, spike protein presence was not associated with the severity of symptoms or functional disability. In 5 out of 22 patients who under-went immunoglobulin depletion, spike protein levels were reduced or undetectable after treatment, indicating binding to immunoglobulins. Conclusions: In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS.

Keywords: COVID-19; ME/CFS; SARS-CoV-2; chronic fatigue syndrome; long COVID; post-COVID syndrome; spike protein; viral persistence.

Figure 1

The serum spike RBD concentration of pre-pandemic healthy controls (ppHCs), post COVID healthy controls (pcHCs), post-COVID syndrome (PCS) patients, and post-COVID ME/CFS patients. Spike RBD was quantified in the serum of ppHC (n = 32), pcHC (n = 37), PCS (n = 49), and ME/CFS (n = 72) patients. (A) The frequency of spike RBD positive (black) and spike RBD negative (grey) individuals in the different study cohorts. Percentages inside the bars indicate the frequency of spike-positive individuals. (B) The individual serum spike RBD concentration [pg/mL] of study cohorts. ns = not significant.

Figure 2

The correlation analysis of spike RBD in the serum of post-COVID study groups with the time since SARS-CoV-2 infection or vaccination. The spike RBD concentration in serum of post-COVID healthy controls (pcHCs, n = 37), post-COVID syndrome (PCS) patients (n = 49), and post-COVID ME/CFS patients (n = 72) was correlated with (A) the time since last SARS-CoV-2 infection, (B) the time since the last SARS-CoV-2 vaccination, (C) the time since the last contact with spike protein either during SARS-CoV-2 infection or vaccination, and (D) the duration of illness for patients. Correlation was assessed using Spearman’s rank-order correlation. Graphs are fitted with a simple linear regression line (black line) and 95% confidence intervals (dotted black lines). Correlation coefficient (r) and significance level (p) are displayed at the top of each graph.

Figure 3

Spike RBD concentration in serum of post-COVID ME/CFS patients before immunoadsorption (IA) (IA-ME/CFS) and four weeks after IA. Patients who responded to IA are indicated by dotted black background and those who did not are indicated by a white background based on the improvement in SF-36 physical function four weeks after therapy [24]. Spike RBD concentration [pg/mL] in patients’ serum was determined before (blue bar) and four weeks after IA (black bar).