Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumorsMethods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background.Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A).Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

Despite the progress in the understanding how COVID-19 infection may impact immunocompromised patients, the data on inborn errors of immunity (IEI) remain limited and ambiguous. Therefore, we examined the risk of severe infection course and hospital admission in a large cohort of patients with IEI. In this multicenter nationwide retrospective survey-based trial, the demographic, clinical, and laboratory data were collected by investigating physicians from 8 national referral centers for the diagnosis and treatment of IEI using a COVID-19-IEI clinical questionnaire. In total, 81 patients with IEI (including 16 with hereditary angioedema, HAE) and confirmed SARS-CoV-2 infection were enrolled, and were found to have a 2.3-times increased (95%CI: 1.44–3.53) risk ratio for hospital admission and a higher mortality ratio (2.4% vs. 1.7% in the general population). COVID-19 severity was associated with the presence of clinically relevant comorbidities, lymphopenia, and hypogammaglobulinemia, but not with age or BMI. No individuals with HAE developed severe disease, despite a hypothesized increased risk due to perturbed bradykinin metabolism. We also demonstrated a high seroconversion rate in antibody-deficient patients and the safety of anti-spike SARS CoV-2 monoclonal antibodies and convalescent plasma. Thus, IEI except for HAE, represent significant risk factors for a severe COVID-19. Therefore, apart from general risk factors, immune system dysregulation may also be involved in the poor outcomes of COVID-19. Despite the study limitations, our results support the findings from previously published trials.

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning “bins” yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27− CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes’ immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ over three years. Moreover, th-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.

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Fertility in CVID patients is not decreased, and their pregnancies could be considered more risky compared with those of the general population.