Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals

Abstract

Background: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R-SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R-SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19.

Methods: Baseline serum R-SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R-SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS.

Results: Baseline albumin-adjusted serum R-SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R-SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = -9.48, p = 0.023).

Conclusion: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R-SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.

Keywords: COVID-19; Coronavirus disease 2019; Long COVID-19; Oxidative stress; Post-COVID-19 syndrome; Redox.

Graphical abstract

Fig. 1

Flowchart indicating the total number of study participants, number of exclusions and reasons for exclusion.

Fig. 2

(A) Baseline serum R–SH (μM) are significantly reduced in mild COVID-19 subjects as compared to healthy controls (****p < 0.0001). (B) Baseline serum R–SH (μM) significantly discriminated between subjects with mild COVID-19 and healthy controls (area under the curve = 0.68). Abbreviations: PCS, post-COVID-19 syndrome; R–SH, free sulfhydryl groups.

Fig. 3

(A) Graphical representation of numbers and proportions of serum samples measured for R–SH (μM) per time point in subjects who classified as having PCS anytime during study follow-up vs. subjects without PCS. (B) Comparison in estimated marginal means (EMM) of serum R–SH (μM) in patients with and without developing PCS at 6 months (B₁), 12 months (B₂), and 18 months (B₃) follow-up. The error bars represent 95 % confidence intervals. (C) Comparison in % changes from baseline in estimated marginal means (EMM) of serum R–SH (μM) derived from linear mixed-effect model analysis in patients with and without developing PCS at 6 months (C₁), 12 months (C₂), and 18 months (C₃) follow-up. Abbreviations: PCS, post-COVID-19 syndrome.

Fig. 4

Comparison in estimated marginal means (EMM) of serum R–SH (μM) in patients with and without long viral RNA shedding (≥21 days) in the nasopharynx/throat. Abbreviations: NPT, nasopharynx/throat.