The emergence of SARS-CoV-2 variants of concern (VOCs) during the COVID-19 pandemic necessitates investigation into their clinical differentiation and outcomes. This study aimed to examine these differences among VOCs, considering multiple related factors. An observational cohort study was conducted on patients diagnosed with SARS-CoV-2 infection via nasopharyngeal/oropharyngeal swab who visited the emergency department of a public Greek hospital between October 2020 and July 2022 during different VOC circulation in the region. Data on clinical manifestations, outcomes, and medical history (comorbidities, prior SARS-CoV-2 infection, vaccination status against COVID-19) were collected through a questionnaire and medical records for those hospitalized. A total of 913 patients were included in this study (813 adults ≥18 years old, 100 children <18 years old). Significant differences were observed across VOCs for both adults and children. A lower proportion of children developed symptoms during the non-Omicron variants, 73.5%, compared to Omicron variants, 86.4%. Fever, dyspnea, and taste and smell disorders were observed more frequently among non-Omicron adult cases, in contrast to upper respiratory symptoms, which were more common symptoms among Omicron infections. The non-Omicron variants were associated with higher rates of hospitalization at 30.6%, pneumonia at 23.0%, and death at 6.1% compared to Omicron variants at 8.0%, 5.0%, and 1.8%, respectively. Vaccination against COVID-19 was shown to be a protective factor for severe outcomes. Our findings suggest distinct clinical presentations and outcomes associated with different VOCs. Despite the fact that current VOCs circulating are less severe, the COVID-19 vaccine continues to play a protective role for severe cases.

Predominantly antibody deficiencies (PADs) are the most prevalent types of inherited errors of immunity (IEI) and are characterized by a broad range of clinical manifestations, such as recurrent infections, autoimmunity, lymphoproliferation, atopy and malignancy. The aim of this study was to identify genetic defects associated with PADs in order to improve diagnosis and personalized care. Twenty patients (male/female: 12/8, median age of disease onset: 16.5 years, range: 1–50) were analyzed by next-generation sequencing (NGS) using a custom panel of 30 genes associated with PADs and their possible disease phenotype. The detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and inheritance, and the penetrance patterns were evaluated by PCR–Sanger sequencing. Novel and rare mutations associated with the phenotype of common variable immunodeficiency (CVID) in genes encoding the transcription factors NFKB1, NFKB2 and IKZF1/IKAROS were identified. Alphafold3 protein structure prediction was utilized to perform a comprehensive visualization strategy and further delineate the mutation-bearing domains and elucidate their potential impact on protein function. This study highlights the value of genetic testing in PADs and will guide further research and improvement in diagnosis and treatment.

Background and Objectives: Severe combined immunodeficiency (SCID) represents a group of rare and potentially fatal monogenic disorders arising from pathogenic variants in a broad spectrum of genes. Diagnostic delays beyond the first few months of life have been associated with poor overall survival and hematopoietic stem cell transplantation (HSCT) outcomes. Therefore, the aim of our study was to apply an NGS assay enabling the rapid and reliable diagnosis of SCID. Materials and Methods: We developed a targeted NGS panel of 30 genes implicated in the pathogenesis of most SCID cases and we applied it to three Greek infants with suspected SCID. Results: Each patient displayed a distinct immunophenotype—T⁻B⁻NK⁻, T⁻B⁻NK⁺ and T⁻B⁺NK⁻, respectively—and was found to harbor pathogenic or likely pathogenic variants in the analyzed SCID-related genes. In particular, patient 1 carried two heterozygous ADA variants (c.58G>A, p.Gly20Arg and c.956_960del, p.Glu319Glyfs); patient 2 harbored two discrete pathogenic variants in the DCLRE1C gene (a large deletion of exons 1–3 and the nonsense mutation c.241C>T, p.Arg81*), causing Artemis deficiency; and patient 3 carried a hemizygous IL2RG missense variant (c.437T>C, p.Leu146Pro), associated with X-linked SCID. All variants were confirmed by Sanger sequencing. Conclusions: Our method successfully identified the underlying genetic defects in all patients, thereby establishing a molecular diagnosis of SCID. These findings highlight the potential of targeted NGS assays for achieving rapid and accurate molecular diagnosis of SCID, which is crucial for the timely treatment of life-threatening conditions in affected children.