Factors influencing caspase-6 levels in patients with dyspnea associated with long COVID

BACKGROUND: Apoptosis is a genetically programmed form of cell death. It is essential for maintaining homeostasis in the body. A key feature of apoptosis is the maintenance of normal cell population, with caspases playing a central role and potentially contributing to the pathogenesis of specific long COVID phenotypes. Identifying the role of caspases and their association with clinical markers may provide additional evidence for the causes of this syndrome. AIM: To determine the role of caspase-6 in patients with dyspnea or its equivalents in long COVID. METHODS: A single-center, cross-sectional observational study was conducted over a 3-year period, when 878 patients sought medical care for dyspnea or its equivalents at an outpatient clinic, with 186 patients included in the study. RESULTS: All patients in the study had caspase-6 levels within the reference range. Caspase-6 concentration in the long COVID group (group 1, n = 86) was significantly lower than that in the control group (group 2, n = 100) with no history of COVID-19. To identify risk factors for decreased apoptotic activity and increased pro-inflammatory responses, 86 patients with long COVID and dyspnea were stratified into two subgroups based on caspase-6 levels: 33 patients (38.4%) with caspase-6 26.5 pg/ml and 53 patients (61.6%) with caspase-6 ≤ 26.5 pg/ml. Severe COVID-19 pneumonia was associated with a nearly 7-fold increase in the relative risk (RR) of reduced apoptotic activity and an increase in pro-inflammatory responses in the post-COVID period: RR 6.85; 95% confidence interval (CI) 1.02–143.74. It also increased the risk of elevated N-terminal pro-B-type natriuretic peptide level 120 pg/ml by more than 2-fold (RR 2.41; 95% CI 1.27–5.14), carotid-femoral pulse wave velocity 10.6 m/s by 4-fold (RR 4.10; 95% CI 1.45–11.77), aortic pulse wave velocity 8.3 m/s by 3-fold (RR 3.22; 95% CI 1.31–9.62), increased ferritin level 152.5 ng/ml. It reduced transferrin saturation 19.8% by 2.5-fold (RR 2.49; 95% CI 1.23–5.75), and increased tissue inhibitor of metalloproteinases-1 level 376.1 ng/ml by 69% (RR 1.69; 95% CI 1.10–2.72). CONCLUSION: Long COVID-related dyspnea is associated with reduced caspase-6 levels, which correlate with impaired apoptotic activity and heightened inflammatory responses. Proposed pathophysiological mechanisms underlying caspase-6 deficiency include activation of myocardial stress pathways, increased collagen deposition, hyperferritinemia, and arterial stiffness.