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Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are often used in hypertensive patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, binds the ACE2 receptor on the cell surface. This study aimed to identify the risk factors influencing COVID-19 infection in hypertensive patients. Methods: This is a part of a single-center, retrospective, observational study investigating patients ≥ 20 years old at Kenwakai Hospital (Nagano, Japan). COVID-19 was diagnosed by polymerase chain reaction. All patients received antihypertensive drugs. Results: Among 316 patients (mean age, 75.0 ± 13.4 years; men, 55.1%), COVID-19 was diagnosed in 39 (12.3%). Multiple logistic regression analysis after adjustment for age, sex, and smoking status identified increased serum creatinine (Scr) as a significant risk factor for COVID-19 (odds ratio [OR] 1.10; 95% confidence interval [CI] 1.00–1.20; p = 0.046). Conversely, lower serum chloride was associated with COVID-19 (OR 0.92; 95% CI 0.85–0.99; p = 0.047). There was no significant association between COVID-19 and the use of ACEIs and ARBs. Conclusions: Scr was independently associated with COVID-19 risk, whereas ACEI/ARB use was not associated with COVID-19 risk in Japanese hypertensive patients, suggesting that these users need not discontinue or change their treatment. The study population included a very high proportion of patients with advanced chronic kidney disease, which makes the cohort substantially different from the general hypertensive population. However, our results can help guide targeted treatment strategies, improving patient outcomes in healthcare settings. Full article

The Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by profound immune dysregulation where interleukins play a central role in determining disease severity and response to interventions. This review summarizes the role of interleukins in the immunopathogenesis of COVID-19, with particular emphasis on differences observed across major SARS-CoV-2 variants. Pro-inflammatory interleukins like IL-1β, IL-6, IL-2, IL-17 and IL-18 are critically involved in cytokine storm, hyperinflammation, and acute respiratory distress syndrome, whereas anti-inflammatory cytokines like IL-10 contribute to immune regulation and resolution of inflammation. Elevated levels of IL-1α, IL-1β, IL-4, IL-8, IL-9, IL-16, IL-18 have been documented in the Delta variant as compared with the Omicron variant, with IL-6 being the most frequent interleukin reported to be increased across all SARS-CoV-2 variants relative to the ancestral Wuhan strain. Elevated IL-2, IL-4, IL-6, and IL-10 levels have been associated with Omicron sub-variants. The review encompasses interleukin-based therapeutic strategies, where several IL-1 and IL-6 inhibitors were studied across clinical trials, but only tocilizumab has shown some promise against severe COVID-19. IL-2, IL-6, IL-15 and IL-21 levels were positively correlated with IgG and neutralizing antibody activity after vaccination with longevity of post-vaccination immunity being determined by IL-2 and IL-7. Full article

Kaposi’s Sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are oncogenic gammaherpesviruses with high prevalence in sub-Saharan Africa. Both viruses are typically acquired during childhood, establishing lifelong latency. While viral reactivation into the lytic cycle has been mainly studied in adult HIV-infected populations—and more recently in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection—the dynamics of KSHV and EBV infection in children remain poorly understood. Here, we characterize pediatric patients (n = 175; median age 4.6 years; IQR 2.0–8.3) presenting with inflammatory conditions during the COVID-19 pandemic in South Africa (from July 2020 to February 2024). Including a healthy, non-inflammatory control group, we found widespread exposure to SARS-CoV-2 (70.9% seropositivity), with 72.6% of the children being seropositive for EBV and 19.4% for KSHV. There were no significant differences in seroprevalence between children with inflammatory conditions and healthy controls for any of these viruses, although SARS-CoV-2 antibody titers were significantly higher in the inflammatory group, while EBV immune responses were lower in children presenting with inflammation. Among the KSHV-seropositive children, no active viremia was detected (as determined by the absence of viral DNA in the peripheral blood). In contrast, 34.4% of EBV-seropositive children had detectable EBV viral load, with a modestly higher proportion in the inflammatory group. However, EBV viral load levels were comparable between children diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C), Kawasaki Disease (KD), and other inflammatory conditions. Logistic regression analyses revealed that increasing age was significantly associated with higher risk of SARS-CoV-2 and EBV seropositivity, but not KSHV. Notably, the risk of EBV DNA detection in the peripheral blood decreased with age. In summary, this study suggests effective immunological control of gammaherpesvirus infections in HIV-negative paediatric patients, even in the presence of inflammatory conditions that might otherwise trigger viral reactivation. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in dysregulated inflammatory and coagulation pathways that drive immunothrombosis and contribute to adverse clinical outcomes. While individual cytokines and endothelial biomarkers have been associated with disease severity and mortality, the prognostic relevance of combined inflammatory and endothelial signatures remains incompletely characterised. To identify inflammatory cytokines and markers of endothelial activation associated with mortality in patients with severe COVID-19 requiring supplemental oxygen. This retrospective observational study included 73 consecutive adults admitted to a dedicated supplemental oxygen unit with severe COVID-19. Plasma concentrations of IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, von Willebrand factor (VWF) antigen and propeptide, ADAMTS13 antigen and activity, and ADAMTS13 autoantibodies were measured on admission using ELISA-based assays. Associations with mortality were assessed using non-parametric analyses, age-adjusted logistic regression, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Increasing age was independently associated with mortality. After adjustment for age, higher IL-1α concentrations were associated with increased odds of death, whereas a higher IL-6/IL-10 ratio was independently protective. In multivariable models, including non-ratio variables, ADAMTS13 autoantibody levels remained independently associated with mortality. In ratio-based multivariable analysis, both the ADAMTS13 activity/autoantibody ratio and the IL-6/IL-10 ratio were independently protective, while age was no longer significant. IL-10 and ADAMTS13 autoantibodies demonstrated moderate discriminative performance for mortality prediction (AUC ~0.70). A combined biomarker model incorporating IL-1α, IL-8, IL-10, and ADAMTS13 autoantibodies yielded very high predicted mortality probabilities. Our findings highlight IL-1α and ADAMTS13 autoantibodies as independent predictors of mortality in severe COVID-19, reflecting the interplay between inflammatory and endothelial pathways. Biomarker ratios capturing immune and endothelial balance—particularly the ADAMTS13 activity/autoantibody ratio—may enhance risk stratification and support integrated prognostic models. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children presents with a heterogeneous clinical spectrum, whereas multisystem inflammatory syndrome in children (MIS-C) is a distinct immunological entity characterized by a hyperinflammatory phenotype and a distinct biological architecture. Identifying routine biomarkers with early discriminatory utility is essential for rapid differentiation between MIS-C and coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective comparative study of 144 pediatric patients with COVID-19 or MIS-C admitted to a single specialized medical center. The analyses integrated classical statistical methods, Benjamini–Hochberg false discovery rate correction (FDR), penalized regression models, and machine learning algorithms to identify biomarkers with discriminative value, using only routine laboratory tests. Results: MIS-C was associated with an intense inflammatory profile, characterized by increases in C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), lymphopenia, and selective electrolyte disturbances, highlighting a coherent biological architecture. In contrast, COVID-19 showed limited associations with traditional inflammatory markers. Predictive models identified a stable core of biomarkers with excellent performance in Random Forest analysis (area under the curve, AUC = 0.95), and reproducible thresholds (CRP ~3.7 mg/dL, NLR ~3.3, PLR ~376; potassium ~4.2 mmol/L). These findings were independently confirmed using penalized Ridge regression, where the reduced model achieved superior discrimination compared to the full 13-variable model (AUC = 0.93 vs. 0.89) and maintained stable performance under internal cross-validation, reinforcing the clinical relevance of this compact biomarker panel. Conclusions: MIS-C is clearly distinguished from COVID-19 by a specific and reproducible immunological signature. The identified biomarkers may represent a potential foundation for the development of simple clinical algorithms for pediatric triage and risk stratification, opening the prospect of a simplified scoring tool applicable in emergency settings. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a wide range of clinical manifestations modulated by genetic factors. The aim of this study was to identify genetic determinants of severe COVID-19 affecting protein sequence to gain insight into disease pathogenesis. Variants prioritized in two patients requiring lung transplant were tested in the Milan FOGS cohort (487/869 cases/controls), highlighting an independent association between the p.F8S low-frequency variant of interferon alpha receptor 2 gene (IFNAR2) and severe disease (OR = 1.73 [1.24–2.42], p = 0.001), replicated in the COVID-19 Host Genetics Initiative cohort (26,167/2,061,934 cases/controls). In the FOGS cohort, the p.F8S variant was linked to higher circulating IL-6 levels. In keeping, bulk transcriptomic analysis in PBMCs at the peak of infection (n = 57) showed that carriers of the p.F8S variant had upregulation of immune signaling and pathogens response (p < 0.05). Functional flow cytometry experiments in healthy donors (n = 12) revealed that membrane IFNAR2 protein expression was reduced in B lymphocytes, but higher in dendritic cells (p < 0.05). Finally, by interrogating a public scRNAseq resource of PBMC of people with COVID-19, we showed that p.F8S carriers had upregulation of immune pathways specifically in dendritic cells (p < 0.05). These results suggest that the p.F8S variant may influence COVID-19 severity by enhancing adaptive immune response, thereby favoring inflammation. Full article

Complete or partial loss of smell (anosmia), sometimes in association with distorted olfactory perceptions (parosmia), is a common neurological symptom affecting nearly 60% of patients suffering from post-acute neurological sequelae of COronaVIrus Disease of 2019 (COVID-19) syndrome, called long COVID. Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) may gain access from the nasal cavity to the brain (neurotropism), and the olfactory route has been proposed as a peripheral site of virus entry. COVID-19 is a risk factor for developing Alzheimer’s Disease (AD), an age-dependent and progressive neurodegenerative disorder characterized in affected patients by early olfaction dysfunction that precedes signs of cognitive decline associated with neurodegeneration in vulnerable brain regions of their limbic system. Here, we summarize the recent literature data supporting the causal correlation between the persistent olfactory deterioration following SARS-CoV-2 infection and the long-delayed manifestation of AD-like memory impairment. SARS-CoV-2 infection of the olfactory neuroepithelium is likely to trigger a pattern of detrimental events that, directly and/or indirectly, affect the anatomically interconnected hippocampal and cortical areas, thus resulting in tardive clinical dementia. We also delineate future advancement on pharmacological and rehabilitative treatments to improve the olfactory dysfunction in patients recovering even from the acute/mild phase of COVID-19. Collectively, the present review aims at highlighting the physiopathological nexus between COVID-19 anosmia and post-pandemic mental health to favor the development of best-targeted and more effective therapeutic strategies in the fight against the long-term neurological complications associated with SARS-CoV-2 infection. Full article

Background/Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to pose a significant global health challenge due to its high transmissibility and potential for severe clinical outcomes. Early identification of patients at risk of hospitalization is essential for effective triage in emergency departments and for the optimal allocation of healthcare resources. Methods: This prospective study included 84 patients aged over 18 years who presented to the emergency department on 23 December 2020, with suspected SARS-CoV-2 infection. Initially, 100 patients were evaluated, and 16 were excluded based on predefined exclusion criteria. The mean age of the participants was 53.65 ± 13.62 years, and 39 (46.4%) were women. Results: At admission, the mean signal peptide, CUB domain, EGF (SCUBE-1) level among SARS-CoV-2 patients was 0.16 ± 0.08 ng/mL. There was no significant difference in SCUBE-1 levels between patient and control groups (n = 59 vs. 25), but levels differed significantly between hospitalized and home-treated patients (n = 37 vs. 22; p = 0.001). Neutrophil count (p = 0.001) and NLR (p = 0.010) were higher in patients than controls and also higher in hospitalized than home-treated patients (p = 0.003 and p = 0.015). ROC analysis revealed that SCUBE-1 predicted hospitalization with 84.6% sensitivity and 88.9% specificity. A positive correlation was observed between SCUBE-1 levels and length of hospital stay (p = 0.007, r = 0.554), with a median stay of 9.0 (5.0–11.0) days. Conclusions: SCUBE-1 levels were significantly associated with disease severity in SARS-CoV-2 patients and may serve as a promising biomarker to support clinical decision-making for hospitalization versus home-based management. Full article

The COVID-19 pandemic has profoundly affected societies around the world. Although the emergency phase of coronavirus disease 2019 (COVID-19) has ended, the threat it poses remains persistent. This review aims to clarify the mechanisms of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection to support effective management of the disease. A central focus is the host cellular response to the viral infection, with particular emphasis on the role of cytokines. Cytokines play a dual role in antiviral defense: they contribute to the inhibition of viral replication and facilitate the clearance of pathogens, yet dysregulated cytokine responses can result in severe immunopathology. Interferons (type I, type II, and type III) and other cytokines are pivotal in activating intracellular antiviral mechanisms and in orchestrating the recruitment of immune cells through extracellular signaling. Effective immune responses to viral infections are governed not only by primary immune cells—such as dendritic cells, T lymphocytes, and B lymphocytes—but also by the local cytokine milieu shaped by infected and neighboring cells. Given the presence of endogenous inhibitors and autoantibodies in vivo, it is essential to evaluate the functional activity of cytokines in clinical samples. We propose a novel approach to quantify biologically active cytokine levels. Full article

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated not only with respiratory illness but also with profound vascular and coagulation disturbances. Long COVID (LC) is characterized by persistent symptoms such as fatigue, dyspnea, cognitive impairment, and palpitations. Mechanistically, SARS-CoV-2 induces direct endothelial injury, promotes a pro-inflammatory cytokine milieu, and activates platelets, leading to immunothrombosis and impaired fibrinolysis. Consequently, patients exhibit microthrombosis, elevated plasma D-dimer, fibrinogen dysregulation, and persistent hypercoagulability. Clinically, this translates into an increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, as well as arterial thrombotic events such as myocardial infarction and stroke, which may persist months after acute infection. Understanding the interplay between endothelial injury, inflammation, and coagulation is crucial for risk stratification and the development of preventive and therapeutic strategies. We conducted a systematic narrative review of the literature, including human clinical and mechanistic studies identified through PubMed, Scopus and Web of Science up to 30 September 2025. This review synthesizes current evidence on vascular complications in LC, highlighting endothelial dysfunction as a central pathophysiological nexus linking the acute phase of SARS-CoV-2 infection with chronic LC manifestations. Full article

Posterior Reversible Encephalopathy Syndrome (PRES) is a rare but potentially reversible neurological manifestation associated with Multisystem Inflammatory Syndrome in Children (MIS-C). We report an eight-year-old boy who developed PRES secondary to MIS-C following asymptomatic SARS-CoV-2 exposure. The patient presented with fever, seizures, decreased consciousness, and visual disturbances. MRI revealed characteristic bilateral parieto-occipital and posterior temporal cortical–subcortical hyperintensities, while CT scans were normal. The patient achieved full neurological recovery with corticosteroid therapy, blood pressure control, and supportive management. This case underscores the importance of early MRI in detecting PRES when clinical or CT findings are inconclusive, emphasizing the need for heightened awareness among pediatric clinicians to prevent irreversible neurological sequelae. Full article

The coronavirus disease 2019 (COVID-19) pandemic remains a significant public health threat globally with significant socio-economic impacts. People living with human immunodeficiency virus (HIV) (PLWH) have a high risk of severe outcomes of COVID-19 due to immunosuppression. Clinical manifestation of COVID-19 in HIV patients largely remains unclear. We carried out a pilot study to investigate the clinical laboratory data and circulating cytokines in PLWH infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Tatarstan, Russia. Serum samples were collected from three groups: PLWH with COVID-19 (PLWH/COVID-19), COVID-19-only, and uninfected controls. We found an increased risk of severe COVID-19 in PLWH/COVID-19 patients compared to COVID-19-only. Four fatal cases were in PLWH/COVID-19, while there was no fatality in COVID-19-only. Pro-inflammatory cytokines, such as IL-5, IL-6, IL-9, and IL-15, were elevated in PLWH/COVID-19 compered to COVID-19-only. These preliminary findings highlight the potential for more severe COVID-19 in PLWH/COVID-19 where pro-inflammatory cytokines could play pathogenic role. Full article

The impact of physical health conditions on coronavirus disease of 2019 (COVID-19) severity in World Trade Center disaster-exposed populations remains understudied. We examined the association of type, number and diagnosis time of pre-existing health conditions with COVID-19 severity, using the WTC Health Registry (WTCHR). We analyzed 3568 WTCHR enrollees with self-reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a 2021 follow-up survey. COVID-19 severity was measured by self-reported symptom duration (<2, 2–4, and >4 weeks) and hospitalization (hospitalized versus not). Pre-existing gastroesophageal reflux disease (GERD), respiratory conditions, cardiovascular conditions, and diabetes were self-reported and categorized into four groups (no diagnosis, post-9/11, pre-9/11, and undefinable). We used multinomial logistic regression and binary logistic regression to analyze the association of comorbidities with COVID-19 symptom duration and hospitalization, respectively, adjusting for post-traumatic stress disorder and demographic factors. Analysis was also conducted separately by enrollee type: rescue and recovery workers (RRW) vs. community members (non-RRW). Having all four health conditions post-9/11 was associated with longer symptom duration after SARS-CoV-2 infection (>4 weeks) among RRW (AOR: 2.66, 95% CI: 1.03–6.87). Reporting a post-9/11 respiratory condition was associated with an increased risk of being hospitalized among RRW and an increased risk of longer symptom duration (>4 weeks) among non-RRW. While post-9/11 diabetes was associated with an increased risk of longer symptom duration among RRW, post-9/11 GERD and pre-9/11 cardiovascular conditions were associated with an increased risk of longer symptom duration and being hospitalized among non-RRW, respectively. The impact of certain health conditions on COVID-19 severity varied across enrollee types and time of diagnosis. Given the lasting health impacts of 9/11-related exposures, targeted medical surveillance and proactive healthcare interventions are critical for mitigating the risk of severe COVID-19 illness in this population. Full article

Background/Objectives: Quantitative computed tomography (CT) metrics are widely used to assess pulmonary involvement and to predict short-term severity in coronavirus disease 2019 (COVID-19). However, it remains unclear whether baseline artificial intelligence (AI)-based quantitative high-resolution computed tomography (HRCT) metrics of pneumonia burden provide incremental prognostic value for in-hospital composite adverse outcomes beyond routine clinical factors, or whether these imaging-derived markers carry any exploratory signal for long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection among hospitalized patients. Most existing imaging studies have focused on diagnosis and acute-phase prognosis, leaving a specific knowledge gap regarding AI-based quantitative HRCT correlates of early deterioration and subsequent reinfection in this population. To evaluate whether combining deep learning-derived, quantitative, HRCT features and clinical factors improve prediction of in-hospital composite adverse events and to explore their association with long-term reinfection in patients with COVID-19 pneumonia. Methods: In this single-center retrospective study, we analyzed 236 reverse-transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients who underwent baseline HRCT. Median follow-up durations were 7.65 days for in-hospital outcomes and 611 days for long-term outcomes. A pre-trained, adaptive, artificial-intelligence-based, prototype model (Siemens Healthineers) was used for pneumonia analysis. Inflammatory lung lesions were automatically segmented, and multiple quantitative metrics were extracted, including opacity score, volume and percentage of opacities and high-attenuation opacities, and mean Hounsfield units (HU) of the total lung and opacity. Patients were stratified based on receiver operating characteristic (ROC)-derived optimal thresholds, and multivariable Cox regression was used to identify predictors of the composite adverse outcome (intensive care unit [ICU] admission or all-cause death) and SARS-CoV-2 reinfection, defined as a second RT-PCR-confirmed episode of COVID-19 occurring ≥90 days after initial infection. Results: The composite adverse outcome occurred in 38 of 236 patients (16.1%). Higher AI-derived opacity burden was significantly associated with poorer outcomes; for example, opacity score cut-off of 5.5 yielded an area under the ROC curve (AUC) of 0.71 (95% confidence interval [CI] 0.62–0.79), and similar performance was observed for the volume and percentage of opacities and high-attenuation opacities (AUCs up to 0.71; all p < 0.05). After adjustment for age and comorbidities, selected HRCT metrics—including opacity score, percentage of opacities, and mean HU of the total lung (cut-off −662.38 HU; AUC 0.64, 95% CI 0.54–0.74)—remained independently associated with adverse events. Individual predictors demonstrated modest discriminatory ability, with C-indices of 0.59 for age, 0.57 for chronic obstructive pulmonary disease (COPD), 0.62 for opacity score, 0.63 for percentage of opacities, and 0.63 for mean total-lung HU, whereas a combined model integrating clinical and imaging variables improved prediction performance (C-index = 0.68, 95% CI: 0.57–0.80). During long-term follow-up, RT-PCR–confirmed reinfection occurred in 18 of 193 patients (9.3%). Higher baseline CT-derived metrics—particularly opacity score and both volume and percentage of high-attenuation opacities (percentage cut-off = 4.94%, AUC 0.69, 95% CI 0.60–0.79)—showed exploratory associations with SARS-CoV-2 reinfection. However, this analysis was constrained by the very small number of events (n = 18) and wide confidence intervals, indicating substantial statistical uncertainty. In this context, individual predictors again showed only modest C-indices (e.g., 0.62 for procalcitonin [PCT], 0.66 for opacity score, 0.66 for the volume and 0.64 for the percentage of high-attenuation opacities), whereas the combined model achieved an apparent C-index of 0.73 (95% CI 0.64–0.83), suggesting moderate discrimination in this underpowered exploratory reinfection sample that requires confirmation in external cohorts. Conclusions: Fully automated, deep learning-derived, quantitative HRCT parameters provide useful prognostic information for early in-hospital deterioration beyond routine clinical factors and offer preliminary, hypothesis-generating insights into long-term reinfection risk. The reinfection-related findings, however, require external validation and should be interpreted with caution given the small number of events and limited precision. In both settings, combining AI-based imaging and clinical variables yields better risk stratification than either modality alone. Full article