Search Results (238)

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC. In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups. Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories. This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance. These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts. Full article

Tele-oncology expanded rapidly during the COVID-19 pandemic and remains central to cancer care, yet evidence on guideline adherence in tele-oncology is limited, particularly in Latin America. In Chile, the Explicit Health Guarantees (GES) program mandates oncology care standards but provides no process model for monitoring adherence. We evaluated the conformance and temporal performance of telemedicine-based oncology pathways against a guideline-derived reference model using process mining, based on event logs from 182 patients treated in 2020–2023 in a Chilean hospital network. Conformance was computed using PM4Py with token-based replay and alignment-based fitness, complemented by cohort, abstraction-level and robustness analyses with bootstrap confidence intervals and multiple-comparison-adjusted testing. Overall conformance was low (4.95% of cases fully conforming; mean alignment fitness 0.19, 95% CI 0.16–0.22) against a highly precise reference model (precision 0.90). Censoring-aware analyses showed that low conformance was driven predominantly by genuine structural deviations rather than incomplete observation alone. Event-level cohort signatures were observed, but patient-level analyses suggested that these patterns should be interpreted as exploratory. Crude differences in care duration by out-of-model activity status were largely explained by differential observation time after exposure adjustment. Process-mining conformance checking provides reproducible indicators for governing tele-oncology pathways when metrics are interpreted alongside methodological caveats. Full article

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid–metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts. Full article

Background: SARS-CoV-2 infection has been linked to an increased risk of hypertensive disorders during pregnancy, particularly preeclampsia (PE). As both conditions involve vascular and endothelial dysfunction, a mechanistic overlap has been proposed. This study examines the relationship between maternal COVID-19 and preeclampsia by analyzing inflammatory, endothelial, and angiogenic biomarkers in pregnancies with and without these complications. Methods: A case–control study was conducted, including four groups: healthy pregnancies before 2020 (n = 10), preeclampsia cases before 2020 (n = 10), COVID-19 cases without preeclampsia (n = 10), and COVID-19 cases with preeclampsia (n = 10). The groups were selected to be comparable in terms of gestational age at blood sampling. Biomarkers related to endothelial, inflammatory, and angiogenic pathways were measured. Results: Significant differences in biomarker levels were detected among the four groups. Regarding endothelial damage, sICAM1 levels were significantly higher in the COVID-PE group compared with the COVID-noPE group (p = 0.002). Additionally, vWF (p = 0.006), END1 (p < 0.001), and sVCAM1 (p = 0.030) levels varied significantly across groups. IL8 levels showed significant differences (p < 0.001), and were particularly elevated in preeclampsia cases (preCOVID-PE and COVID-PE groups) compared with controls (p = 0.005 and p < 0.001, respectively). Angiogenic markers sFlt-1, PLGF, and sFlt-1/PLGF exhibited significant group differences (p < 0.001). In contrast, maternal SARS-CoV-2 infection in the absence of preeclampsia was not associated with a significant alteration of the sFlt-1/PlGF ratio. Discussion: PE associated with SARS-CoV-2 infection preserved the classical angiogenic signature of preeclampsia, but showed additional endothelial and inflammatory biomarker alterations. These findings support an association between SARS-CoV-2 infection and a distinct endothelial and inflammatory biomarker profile in PE, warranting confirmation in larger prospective studies. Full article

No previous sub-Saharan studies have compared patients with community-acquired pneumonia (CAP) and COVID-19 pneumonia, the focus of this study. Consecutive adult patients hospitalized with CAP (n = 59) or COVID-19 pneumonia (n = 74) were compared regarding multiple characteristics, including cardiac biomarkers. In multivariable logistic regression analysis, differences were noted among various clinical features. Troponin I concentrations (p = 0.00028) and the Troponin I/NT-pro BNP ratio (p = 0.00048) were significantly higher in COVID-19 compared with CAP. After adjustment for age, these differences remained significant (troponin I p = 0.0019; ratio p = 0.00054), while BNP concentrations were now higher in CAP (p = 0.009). PCA demonstrated that BNP and NT-pro BNP contributed most strongly to the dominant cardiac biomarker signature, suggesting shared cardiopulmonary stress across both diseases. Exploratory subgroup analyses suggested higher troponin I levels among people living with HIV and COVID-19, although interaction modelling did not demonstrate significant effect modification by HIV status. Both CAP and COVID-19 pneumonia were associated with evidence of cardiac stress; however, COVID-19 demonstrated a relatively stronger myocardial injury signature characterized by higher troponin I concentrations and an increased Troponin I/NT-pro BNP ratio while CAP had evidence of greater hemodynamic cardiac strain, as evidenced by the higher levels of BNP. The findings suggest that the mechanisms of cardiac involvement may differ between viral and bacterial respiratory infections. Full article

Background/Objectives: Our prior epigenome-wide association study (EWAS) on multiple sclerosis (MS) identified myeloid-associated methylation signatures and an association with enhancer regions. Here we compared differential DNA methylation across three central nervous system inflammatory disorders: MS, neuromyelitis optica (NMO), and neurologic post-acute sequelae of COVID-19 (neuro-PASC). Methods: Whole-blood DNA was profiled on Infinium MethylationEPIC arrays. Analyses included EWAS at the CpG level, differentially methylation region (DMR) analysis, and gene regulatory-element enrichment using Locus Overlap Analysis (LOLA). Limma linear models were adjusted for race, EPIC array version, age, sex, disease-modifying treatment class, and blood cell composition. Results: All three diseases were associated with broad CpG-level differential methylation. The most robust findings were disease-specific DMR signatures in gene regulatory regions. All three diseases shared Lamin B1-anchored chromatin states as an architectural genomic feature but differed in immune regulatory transcription factor binding sites (TFBS), RNA polymerase (Pol II) occupancy, and DNase accessibility. MS was enriched for TFBS in myeloid CEBPB and SPI1/PU.1 and lymphocyte-associated RUNX3, EBF1, and BATF. MS hypomethylated DMRs were concentrated at active enhancers and myeloid TFBS, suggestive of chronic myeloid activation. NMO showed the clearest promoter and B lymphocyte associated profile. Neuro-PASC was associated with hematopoietic DNase accessibility and TFBS for BATF and EBF1. Conclusions: These results suggest that DNA methylation in MS, NMO, and neuro-PASC differ meaningfully in regulatory architecture rather than conforming to a single shared disease-associated methylation model. A long-term goal is to develop immune therapies for newly recognized diseases such as neuro-PASC. Full article

There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article

Type I interferons (IFN-I), including IFN-α, IFN-β, and IFN-ω, are central to antiviral defence and immune regulation. Autoantibodies targeting IFN-I (anti-IFN-I AAbs) have emerged as key pathogenic factors in severe coronavirus disease 2019 (COVID-19) and are detectable in systemic lupus erythematosus (SLE), a prototypic IFN-driven autoimmune disease. Here we compare the prevalence and clinical impact of anti-IFN-I autoantibodies (Aabs) in COVID-19 and SLE based on a structured review of 53 studies from 2014 to 2025 and highlight the clinical associations and therapeutic opportunities presented by these autoantibodies. In COVID-19, neutralising anti-IFN-α and/or anti-IFN-ω AAbs were consistently associated with severe disease and impaired antiviral responses, particularly in older male populations. In SLE, anti-IFN-α AAbs were variably detected; neutralising antibodies were associated with reduced interferon gene signatures in some cohorts but inconsistent correlations with disease activity. Therapeutically, anti-IFN-I AAbs in COVID-19 may inform risk stratification and early antiviral strategies, whereas in SLE, IFN-α blockade, including IFN-α kinoid vaccination, demonstrates modulation of IFN signatures but variable clinical benefit. Notably, these findings reveal an immunological paradox: the same neutralising mechanism that impairs antiviral defence in COVID-19 may attenuate chronic IFN-driven inflammation in SLE. Taken together, anti-IFN-I AAbs exert context-dependent effects: pathogenic in acute viral infection yet potentially modulatory in chronic IFN-driven autoimmunity. Prospective longitudinal studies are required to further clarify their translational utility and long-term clinical impact. Full article

The primary route of SARS-CoV-2 entry is via respiratory epithelium. However, many COVID-19 patients developed dermatological lesions, and SARS-CoV-2 RNA has been detected in the patients’ skin. Inflammatory skin diseases, psoriasis and atopic dermatitis (AD), significantly increased the risk of COVID-19. To evaluate the potential role of skin in SARS-CoV-2 host interactions, we utilized 3D human skin organoids (HSO) generated from human epidermal keratinocytes, as well as neonatal skin explants. HSO were treated with cytokines involved in acute and chronic skin inflammation and cytokine storm in severe COVID-19 disease: TNF-α, IL-6, IL-1β, and IFN-γ, individually and in combination. HSO were also treated with Th1 (TNF-α + IL-17) and Th2 (IL-4 + IL-13) cocktails inducing pro-psoriasis and pro-AD HSO changes, respectively. All individual cytokines, and especially their combinations, elevated the expression of ACE2 and TMPRSS2 at mRNA/protein levels. The Th2 cocktail induced only TMPRSS2, the Th1 cocktail predominantly induced ACE2. Topically applied Spike-pseudotyped lentiviral Tomato reporter, which binds ACE2 similarly to SARS-CoV-2, successfully transduced control and cytokine-treated HSO as well as neonatal skin explants. Cytokine treatment, especially TNF-α + IL-6 + IL-1β + IFN-γ and the Th1 cocktail, significantly increased viral entry. Transcriptomic analysis further revealed partial overlap between gene expression signatures induced by Spike-mediated entry in inflamed HSO and those observed in lung tissue from COVID-19 patients, supporting the biological relevance of skin models. Together, these findings demonstrate that inflammation may transiently alter the permissiveness of human skin to SARS-CoV-2 entry, suggesting that the skin may represent a previously underappreciated, although likely limited, interface in viral- host interactions. Full article

Background/Objectives: Although COVID-19 is generally more severe in males, data on sex-specific differences in the predictive value of commonly used inflammatory biomarkers remain limited. The study aimed to evaluate the sex-specific prognostic performance of selected biomarkers during the Alpha variant wave. Methods: In single-center study, univariate and multivariable regressions analyses, along with receiver operating characteristic curve (ROC) analyses, were performed to assess the association of acute-phase proteins, cytokines, and white blood cell indices (at admission and 7 days later) and disease severity and mortality in patients with severe-to-critical COVID-19. Results: At admission, the combined assessment of ferritin and D-dimer predicted disease severity in both sexes; however, optimal cut-off values and diagnostic performance (specificity and sensitivity) differed between males and females. In males, neutrophil and lymphocyte counts provided additional clinically relevant predictive value. Seven days after admission, the combination of ferritin, D-dimer, and fibrinogen in males, and ferritin, as an independent predictor within a model including lactate dehydrogenase, in females demonstrated strong predictive performance for severe-to-critical COVID-19. At this time-point, lymphocyte count in males was also identified as an independent predictor of disease severity. Notably, C-reactive protein and neutrophil count correlated with mortality in males with severe-to-critical disease. Conclusions: Severe COVID-19 is predicted by distinct acute-phase proteins and shared, sex-specific biomarkers, but with distinct cut-offs and predictive accuracy. In males, white blood cell indices also serve as independent predictors. Furthermore, prognostic utility changes of these biomarkers over the course of the disease, suggesting sex-specific and time-dependent role in COVID-19 pathogenesis. Full article

Background/Objectives: Long COVID-19 (LC-19), also known as Post-Acute COVID-19 Syndrome (PACS), is a chronic condition some people experience after an initial SARS-CoV-2 infection. The etiology of this complex, multifactorial disease remains largely unknown, although various theories have been propounded. This study aims to profile and compare the metabolic activity of cells of normal and LC-19 patients. Methods: A cohort of 20 individuals, 10 with LC-19 and 10 without LC-19, was selected based on their post-COVID-19 symptomatology. Saliva was tested for opportunistic viruses like Epstein–Barr virus (EBV) and Human Herpesvirus 6 (HHV-6). Lymphoblastoid cell lines derived from blood were analyzed using the Biolog Phenotype Mammalian Microarrays (PM-M1, PM-M6, and PM-M7) to assess metabolic activity across a wide array of growth substrates and effector molecules. Results: Unique metabolic profiles emerged across the controls and LC-19 groups. The SARS-CoV-2 infection causes an over two-fold enhanced utilization of glycolytic and anaerobic substrates and a reduced response to growth factors and effectors. The increased energy source utilization assessed in PM-M1 is unsustainable, and the LC-19 groups demonstrate this with a clear correlation with the number of LC-19 symptoms, demonstrating a trend consistent with metabolic reprogramming. The infection also results in a reduced response to growth factors and effectors, assessed in PM-M6 and PM-M7, with the level of reduction commensurate with the symptom burden. Conclusions: The data from the patient groups were analyzed and compared to construct a metabolic profile unique to individuals who developed LC-19, which could, in the future, be used for diagnosis and to identify targets for therapeutic intervention. Our study identified an LC-19-specific metabolic profile indicative of adaptive responses to stress, cellular dysfunction, and prolonged inflammation, leading to the reprogramming of bioenergetic pathways. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets. A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA). Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion. In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions. These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches. Full article

Evidence on hospitalised COVID-19 patients during the Omicron BA.5 wave from Eastern European, vaccine-heterogeneous cohorts remains limited. We conducted a retrospective single-centre cohort study of 395 consecutive adults admitted with laboratory-confirmed COVID-19 to a tertiary infectious-diseases unit in western Romania between 1 July and 31 October 2022. Median age was 72 years (IQR 65–81); 33.2% were unvaccinated, 42.8% had documented prior SARS-CoV-2 infection, and 41.3% were obese. Multivariable logistic regression identified independent predictors of in-hospital mortality and post-acute symptom burden. In-hospital mortality was 15.7% (62/395). Vaccination was independently associated with lower mortality (adjusted odds ratio [aOR] 0.55, 95% CI 0.30–0.99; p = 0.048), as was each 1% increase in admission SpO₂ (aOR 0.83, 95% CI 0.76–0.92; p < 0.001), whereas COPD independently increased mortality risk (aOR 2.42, 95% CI 1.15–5.10; p = 0.020). Interleukin-6 was the most discriminating admission biomarker for in-hospital mortality (AUROC 0.70). Bloodstream bacterial co-infection, detected in 22.5% of patients tested on clinical suspicion, was dominated by gut-derived organisms with case-fatality ≥30%. At discharge, 90.1% reported persistent symptoms, most commonly cognitive (24.6%). Prior SARS-CoV-2 infection independently predicted post-acute symptom burden (aOR 2.96, 95% CI 1.75–5.01; p < 0.001), with a specific cardiopulmonary signature. In this BA.5 cohort, vaccination remained protective; IL-6 was the most informative admission biomarker; bloodstream infections suggested gut translocation; and prior infection was an independent determinant of early post-acute symptom burden. Full article

An individual’s host genetics influence its susceptibility to both COVID-19 and coronary artery disease (CAD). We analyzed large-scale GWAS datasets encompassing 7.7 million SNPs to identify shared genetic architecture between the two diseases. We identified 24 pleiotropic risk loci for both COVID-19 and CAD, with three loci (1p31.1, 8p21.3, and 18q11.2) showing strong evidence for a single shared causal variant. Loci in the 8p21.3 and 18q11.2 regions showed a bidirectional causal association: COVID-19 to CAD or vice versa, while the 1p31.1 locus only showed a CAD to COVID-19 unilateral casual association in a Mendelian randomization analysis (GSMR). A fine mapping analysis of the three loci identified three lead pleiotropic variants (rs7515509, rs8192330, and rs4800403). The variant rs7515509 was spatially associated with AK5, PIGK, USP33, and ZZZ3; rs8192330 with DMTN, PIWIL2, and several other genes; and rs4800403 with GATA6 and CTAGE1. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients validated proxitropic variants (rs8192330 and rs4800403) with distinct expression signatures and prioritized DMTN and PIWIL2 as the likely causal genes. Overexpression of DMTN has been linked to the heme metabolism hallmark, disrupted iron distribution in COVID-19 patients with comorbid CAD, and subsequent stress erythropoiesis, oxidative stress, immunological dysfunction, and altered wound healing, while a lower expression of PIWIL2 has been observed in the cytoplasmic translation and regulation of mRNA metabolism. In conclusion, we identified shared genetic components for COVID-19 and CAD and prioritized DMTN and PIWIL2 as the likely causal genes for the observed shared genetic risk. COVID-19 may act as an acute stressor that unmask or accelerates underlying CAD. Full article

Coronavirus Disease 2019 (COVID-19) and other lower respiratory tract diseases (LRTDs), including bacterial pneumonia and acute respiratory distress syndrome, share overlapping clinical features but arise from distinct pathophysiological mechanisms. The molecular signatures that distinguish these diseases remain insufficiently characterized in African populations, where genetic background, endemic infections, and environmental exposures may substantially shape immune responses. We integrated spatially resolved single-cell transcriptomic profiles from lung autopsy specimens of 30 Malawian patients, including 10 with COVID-19, 12 with other LRTDs, and 8 non-LRTD controls. In total, 61,391 cells representing 15 cell types and 36,602 gene expression features were analyzed. Using an integrated machine learning framework that combined nine feature-ranking algorithms with incremental feature selection, we identified potential molecular signatures that could discriminate among disease states within this cohort. The optimal classification models achieved weighted F1 scores greater than 0.94, demonstrating a robust capacity to differentiate COVID-19 from other LRTDs in our dataset. Notably, the macrophage-associated state in COVID-19 was dominated by an IFN-γ response with upregulation of CD163 and HLA-DQA2, contrasting sharply with the type I/III interferon signature reported in European cohorts. In addition, we observed cell-type-specific COVID-19 signatures, including downregulation of CAV1 in AT1 cells, consistent with epithelial damage; dysregulation of SFTPC in AT2 cells, suggesting surfactant dysfunction; and upregulation of NFKBIA in neutrophils, indicating altered inflammatory regulation. Gene Ontology enrichment further revealed universal disruption of protein synthesis machinery, along with cell-type-specific alterations in immune activation, epithelial repair, and inflammatory signaling pathways. Full article