Heterogeneous leukocyte telomere trajectories and inflammatory resolution 12 months after mild COVID-19: an exploratory cohort study

BACKGROUND: The longitudinal interplay between leukocyte telomere length (LTL) and persistent immune activation after mild SARS-CoV-2 infection remains incompletely characterized. METHODS: In this exploratory observational study, 51 adults (76.5% female; mean age 39.0 ± 9.7 years) with RT-PCR-confirmed mild COVID-19 had blood sampled in the acute symptomatic phase and at 12 months. Relative LTL was quantified by qPCR (Cawthon T/S method, 36B4 reference). A 45-analyte multiplex bead-based immunoassay quantified circulating cytokines, chemokines and growth factors. Paired changes were assessed with Wilcoxon signed-rank tests; cross-sectional and longitudinal associations between immune mediators and LTL were evaluated by Spearman correlation with Benjamini-Hochberg false discovery rate (FDR) control and by multivariable linear regression adjusted for baseline LTL, age, sex and comorbidity burden. RESULTS: Forty-eight participants had paired LTL data. Group-level T/S ratio increased modestly between the acute phase and 12 months (mean Δ = +0.0094; Wilcoxon p = 0.041; Cohen's d_z = 0.31), but interindividual trajectories were markedly heterogeneous (52% increased, 33% decreased, 15% unchanged). Twenty of 45 cytokines decreased significantly between timepoints (FDR <0.05), consistent with systemic resolution of acute inflammation. Among residual immune mediators at 12 months, hepatocyte growth factor (HGF) was inversely associated with the LTL trajectory (Spearman ρ = -0.48; p = 0.0005; FDR = 0.024). This association persisted in a multivariable model adjusted for baseline LTL, age, sex and comorbidity count (β = -0.040; 95% CI -0.061 to -0.018; p = 0.0006), and the model explained 43% of variance in T/S₁. Cytokines previously highlighted in similar cohorts (IL-7, IL-9, IL-17A, EGF) showed univariable correlations that did not survive FDR correction. CONCLUSION: Twelve months after mild SARS-CoV-2 infection, leukocyte telomere trajectories are highly individual, while most acute-phase inflammatory mediators have resolved. Residual circulating HGF, a pleiotropic factor recognized as a component of the senescence-associated secretory phenotype but also involved in tissue repair, endothelial activation, and metabolic signaling, was the only mediator robustly associated with the longitudinal LTL trajectory after multiple-testing correction and may identify a subgroup with persistent tissue-remodeling or senescence-associated activity. This association is interpreted as exploratory and hypothesis-generating rather than as a validated biomarker. Given the absence of an uninfected control group, modest sample size, and qPCR-based LTL quantification, these findings should be interpreted as hypothesis-generating.