Author Response: NETosis Markers such as Citrullinated Histones Myeloperoxidase and Elastase should not be Recommended as Predictors of COVID-19 Severity

NETosis Markers such as Citrullinated Histones Myeloperoxidase and Elastase should not be Recommended as Predictors of COVID-19 Severity."We appreciate the insightful comments and the opportunity to clarify several aspects of our study. 1irst, the author highlighted concerns regarding the limited documentation of comorbidities and the absence of medicationrelated variables that may influence NETosis markers.In our study, baseline comorbidities including diabetes, hypertension, and hypothyroidism were recorded and compared between COVID-19 patients and controls.Importantly, no statistically significant differences in demographic characteristics or these comorbidities were observed between the groups. 1 Additionally, patients with autoimmune diseases, malignancy, pregnancy, immunosuppression, or concurrent infections were excluded to reduce the potential confounding effects of conditions that could independently influence NETosis pathways. 1e acknowledge that certain medications may influence neutrophil extracellular trap (NET) formation; however, blood samples were collected at hospital admission in most patients, prior to major therapeutic interventions.Moreover, the primary aim of our study was to examine the association between NETosis markers and COVID-19 severity rather than to evaluate pharmacologic modulation of these biomarkers.Second, the author correctly notes that citrullinated histones, elastase, and myeloperoxidase may increase in several inflammatory, thromboinflammatory conditions and other diseases and are therefore not specific to COVID-19.Our study did not intend to suggest disease specificity.Instead, the objective was to explore the relationship between NETosis markers and disease severity within a cohort of confirmed COVID-19 patients.Furthermore, most commonly used inflammatory biomarkers in COVID-19, such as C-reactive protein, ferritin, interleukin-6, and D-dimer, are also nonspecific markers of systemic inflammation.In conclusion, our findings suggest an association between NETosis activity, particularly Cit-H3, and COVID-19 severity.While acknowledging the limitations of a single-center design and moderate sample size, our study provides exploratory evidence supporting further investigation of NETosis-related biomarkers in larger multicenter cohorts.These observations contribute to the growing evidence highlighting the role of NETosis in the pathophysiology of severe COVID-19. 2,3cid