Several important findings can be drawn from this preliminary report. First, we demonstrated that preinfection uncontrolled BP is associated with long-COVID sequelae in HD patients. Second, both hypertension and long COVID resulted in elevated IL-6 and IL-17 concentrations, peaking in patients with both conditions and decreasing over time after infection possibly reflecting Th17-related systemic inflammation during the acute phase of COVID-19.
IL-6 and IL-17 are both cytokines that play important roles in the immune response to SARS-CoV-2 [13, 17]. IL-6 is produced by immune cells and controls the activation, differentiation, and survival of T cells. It also activates Th cells of the TH17 lineage, which produce IL-17 causes autoimmunity, chronic inflammation, and CD4-positive T-cell activation, which triggers Th17 differentiation [13, 18]. IL-17 is produced by Th17 cells and participates in many pro-inflammatory and autoimmune processes [17]. While these cytokines are produced by different cell types and have different functions, there is evidence to suggest that they can also interact and influence each other's activity. This cross-talk between IL-6 and IL-17 has been implicated in various diseases, including COVID-19.
Several common mechanisms, such as chronic inflammation, endothelial dysfunction, and chronic activation of the renin-angiotensin-aldosterone system (RAAS) may explain the association between uncontrolled preinfection BP, high serum IL-6 and IL-17 concentrations, and long COVID in HD patients. Elevated IL-6 and IL-17 production in hypertensive HD patients can be further stimulated by the SARS-CoV-2 persisting or by the cytokines/chemokines produced by other immune cells, resulting in a dysregulated immune response and long COVID. In addition, both hypertension and COVID-19 are associated with endothelial dysfunction [19, 20], which may lead to increased expression of adhesion molecules and proinflammatory cytokines, including IL-6 and IL-17. Chronic activation of the RAAS may be another possible pathway. In animal models, angiotensin II has been shown to stimulate the production of IL-6 and IL-17 [21, 22], and there is evidence that this mechanism may also be relevant in humans [23, 24]. Besides, the binding of SARS-CoV-2 to ACE2 receptors may disrupt the RAAS system [25, 26], leading to the upregulation of the cytokines production and the associated hyperinflammatory response in HD patients with long COVID.
Limitations
The main limitations of our study are its cross-sectional design and the small sample size; therefore, our findings only revealed associations and causality could not be established. In addition, due to sample-size limitations, it was not possible to perform a detailed subgroup analysis and we could not rule out the effects of other potentially confounding variables (age, gender, dialysis vintage, other cardiovascular risk factors, etc.) on the results. Notwithstanding these limitations, our study is the first to report IL6 and IL-17 serum concentrations as a possible link between hypertension and long COVID in HD patients, providing a starting point for future investigation. Further research is needed to fully understand the mechanisms underlying this association and to develop effective treatments for long COVID.