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Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients. Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. Here the authors perform single-cell omics analyses in CVID-discordant monozygotic twins and show epigenetic and transcriptional alterations associated with activation in memory B cells.

IntroductionAutosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management.MethodsFifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES).ResultsThe median age on admission and age of diagnosis were 7 years (0.3–16.5) and 11 years (5–44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4−CD8−) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1–3). In total, one patient died from sepsis during adulthood before HSCT.ConclusionPatients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell’s important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Purpose Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course. Method We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023. Results We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission. Conclusion In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.

Granulomatous disease affects up to 20% of patients with Common Variable Immunodeficiency (CVID). Granulomas are comprised of highly activated immune cells, and emerge in response to antigenic triggers. In CVID granulomas however, the underlying pathophysiology is unclear and the specific trigger remains unknown. Granuloma formation in CVID is often compared to sarcoidosis, although clinical context and prognosis differ, suggesting a different pathogenesis. The aim of this study was to investigate if the cellular organization and proteomics of granulomas in CVID is different from other granulomatous diseases. Therefore, tissue slides from formaldehyde fixed paraffin embedded biopsies obtained from patients with CVID, sarcoidosis, tuberculosis and foreign-material induced pseudo-sarcoidosis were stained with hematoxylin and eosin and assessed for histopathological characteristics. Targeted spatial protein analysis was performed, and immune fluorescent multiplex assays were used to analyze the cellular organization. Histological analysis revealed that CVID granulomas were smaller, less circumscribed, with fewer multinucleated giant cells and minimal fibrosis compared to the other granulomatous diseases. Spatial protein analysis showed that granulomas in all diseases expressed CD68, CD11c, CD44, CD127, and PD-L1. However in CVID, reduced expression of the fibrosis-related protein fibronectin, but enrichment of CD163, CD3 and FAPα inside CVID granulomas was observed. Immunofluorescence analysis conformed a different cellular organization in CVID granulomas with increased influx of neutrophils, macrophages, T and B lymphocytes. In conclusion, granulomas in CVID display a different histological and cellular organization with increased influx of myeloid and lymphoid cells, compared to sarcoidosis, tuberculosis and pseudo-sarcoidosis, indicating a distinct pathogenesis underlying granuloma formation.

PurposeTo evaluate mortality risk factors in pediatric-onset common variable immunodeficiency disorders (CVID), we evaluated the largest single-institution cohort of pediatric-onset CVID patients. Previous publications on CVID have provided valuable descriptive data, but lack risk stratification to guide physicians in management of these patients.MethodsRetrospective chart review of 198 subjects with CVID at a single institution, of whom 91 had disease onset at a pediatric age. Clinical and laboratory data were collected at diagnosis and in follow-up. Odds ratios and Fisher tests were utilized to examine trends. This study was approved by an institutional review board.ResultsClinical features and laboratory results for subjects diagnosed with CVID at a pediatric age are similar to those who had adult-onset CVID. However, majority of the deceased subjects (13/18) were at a pediatric age at CVID symptom onset. These subjects had a lower age at mortality, multiple comorbidities, and often depression. The most common cause of death was infection. Lung disease (OR 5, p < 0.05) and infection with severe/opportunistic organisms (OR 9, p < 0.05) are directly related to increased mortality. Delay in diagnosis of CVID is also correlated with mortality. Intermediary markers correlating with mortality include anemia, GERD, and depression.ConclusionsThere are many similarities between patients with pediatric- and adult-onset CVID; however, the mortality of pediatric CVID in our cohort is striking. This is the first study to identify specific factors correlated with mortality in pediatric-onset CVID to guide pediatricians and subspecialists in managing these immunodeficient patients.

Common variable immunodeficiency (CVID) is the most prevalent antibody deficiency, characterized by remarkable genetic, immunological, and clinical heterogeneity. The diagnosis of pediatric CVID is challenging due to the immaturity of the immune response and sustained actively developing antibody affinity to antigens and immunological memory that may overlap with the inborn error of immunity. Significant progress has been recently done in the field of immunogenetics, yet a paucity of experimental and clinical studies on different systemic manifestations and immunological features of CVID in children may contribute to a delayed diagnosis and therapy. In this review, we aimed at defining the variable epidemiological, etiological, and clinical aspects of pediatric CVID with special emphasis on predominating infectious and non-infectious phenotypes in affected children. Conclusion : While pediatric CVID is a multifaceted and notorious disease, increasing the pediatricians’ awareness of this disease entity and preventing the diagnostic and therapeutic delay are needed, thereby improving the prognosis and survival of pediatric CVID patients. What is Known: • CVID is an umbrella diagnosis characterized by complex pathophysiology with an antibody deficiency as a common denominator . • It is a multifaceted disease characterized by marked genetic, immunological, and clinical heterogeneity. . What is New: • The diagnosis of pediatric CVID is challenging due to the immaturity of innate and adaptive immune response . • Increasing the pediatricians’ awareness of CVID for the early disease recognition, timely therapeutic intervention, and improving the prognosis is needed .

Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by remarkable hypogammaglobulinemia. The disease can develop at any age without gender predominance. The prevalence of CVID varies widely worldwide. The underlying causes of CVID remain largely unknown; primary B-cell dysfunctions, defects in T cells and antigen-presenting cells are involved. Although some monogenetic defects have been identified in some CVID patients, it is likely that CVID is polygenic. Patients with CVID develop recurrent and chronic infections (e.g., bacterial infections of the respiratory or gastrointestinal tract), autoimmune diseases, lymphoproliferation, malignancies, and granulomatous lesions. Interestingly, autoimmunity can be the only clinical manifestation of CVID at the time of diagnosis and may even develop prior to hypogammaglobulinemia. The diagnosis of CVID is largely based on the criteria established by European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency (ESID/PAGID) and with some recent modifications. The disease can affect multiple organs, including the liver. Clinical features of CVID patients with liver involvement include abnormal liver biochemistries, primarily elevation of alkaline phosphatase (ALP), nodular regenerative hyperplasia (NRH), or liver cirrhosis and its complications. Replacement therapy with immunoglobulin (Ig) and anti-infection therapy are the primary treatment regimen for CVID patients. No specific therapy for liver involvement of CVID is currently available, and liver transplantation is an option only in select cases. The prognosis of CVID varies widely. Further understanding in the etiology and pathophysiology will facilitate early diagnosis and treatments to improve prognosis.

The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain. Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review. In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients. Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication.

Common Variable Immunodeficiency (CVID) is a heterogeneous immune disorder characterized by a broad range of clinical manifestations. Its etiology is not yet fully understood. To gain insights into the immunological background of CVID in patients without a clearly defined genetic cause, we employed a genealogical research approach that included family members. This strategy aims to provide a more comprehensive understanding of immune dysregulation in CVID, of potential hereditary patterns, and subclinical immunological traits within families. Fifty-eight participants from nine families were included: Five families with a negative family history for CVID (FH-) and four families with a positive family history for CVID (FH+). Screening for known CVID-associated genes was negative in all cases. The non-affected family members completed a questionnaire covering medical history relevant to primary immunodeficiency. Flow cytometry was used to analyze T- and B-cell subsets in peripheral blood, while mucosal and systemic IgA and IgG levels were measured using a multiplex immunoassay. Immune aberrancies in CVID patients were observed in the B- and T-cell compartments. In both FH- and FH+ family members, symptoms suggestive of Primary Immunodeficiency (PID) were present in 32.1 to 61.5% (p = 0.29). B-cell subsets were 5- to 10-fold reduced compared with the 5th percentile of age specific reference values. A combination of T-cell and B-cell reductions was observed in eight of the nine families in a non-affected member. Serum and mucosal IgG and IgA levels in FH- families did not differ significantly from FH+ families. There were no significant correlations between systemic and mucosal IgA levels in non-affected family members from either FH- or FH+ families. Overall, our findings show that B- and T-cell aberrancies are present not only in CVID patients but also in non-affected family members, irrespective of family history. Systemic IgA does not reflect mucosal IgA, and systemic IgG replacement therapy does not restore mucosal antibody levels, highlighting compartmentalized immune regulation.

Purpose To investigate computed tomography (CT) findings of Granulomatous Lymphocytic Interstitial Lung Disease (GL-ILD) in Common Variable Immunodeficiency (CVID), also in comparison with non-GL-ILD abnormalities, correlating GL-ILD features with functional/immunological parameters and looking for GL-ILD therapy predictive elements. Methods CT features of 38 GL-ILD and 38 matched non-GL-ILD subjects were retrospectively described. Correlations of GL-ILD features with functional/immunological features were assessed. A logistic regression was performed to find a predictive model of GL-ILD therapeutic decisions. Results Most common GL-ILD CT findings were bronchiectasis, non-perilymphatic nodules, consolidations, Ground Glass Opacities (GGO), bands and enlarged lymphnodes. GL-ILD was usually predominant in lower fields. Multiple small nodules (≤10 mm), consolidations, reticulations and fibrotic ILD are more indicative of GL-ILD. Bronchiectasis, GGO, Reticulations and fibrotic ILD correlated with decreased lung performance. Bronchiectasis, GGO and fibrotic ILD were associated with low IgA levels, whereas high CD4+ T cells percentage was related to GGO. Twenty out of 38 patients underwent GL-ILD therapy. A model combining Marginal Zone (MZ) B cells percentage, IgA levels, lower field consolidations and lymphnodes enlargement showed a good discriminatory capacity with regards to GL-ILD treatment. Conclusions GL-ILD is a lower field predominant disease, commonly characterized by bronchiectasis, non-perilymphatic small nodules, consolidations, GGO and bands. Multiple small nodules, consolidations, reticulations and fibrotic ILD may suggest the presence of GL-ILD in CVID. MZ B cells percentage, IgA levels at diagnosis, lower field consolidations and mediastinal lymphnodes enlargement may predict the need of a specific GL-ILD therapy.