Up to one-third of the patients diagnosed with common variable immunodeficiency (CVID) may develop gastrointestinal (GI) and hepatic manifestations. This study aimed to evaluate the prognostic significance of enteropathy and liver disease in patients with CVID. We conducted a retrospective study including all consecutive adult patients with CVID followed in a tertiary care center in Spain from January 1990 to January 2023. A diagnosis of CVID-associated enteropathy (CVID-E) and CVID-associated liver involvement (CVID-L) was established when objective clinical, endoscopic, histologic, radiologic or hemodynamic findings were present. Relevant prognostic outcomes and their risk factors were studied, including survival, GI infections, and GI cancer. Eighty-nine patients with confirmed CVID were included, 26 of them (29.2%) had CVID-E and 23 (25.8%) had CVID-L. Nineteen (73.1%) patients with CVID-E suffered from GI infections, while 12 (46.2%) presented concurrent liver involvement. In comparison with the rest of the cohort, patients with CVID-E had more frequently liver involvement, GI infections, and GI cancer. Multivariate analysis identified CVID-E as an independent risk factor for GI infections. Twelve (52.2%) patients with CVID-L concurrently exhibited CVID-E, and patients with CVID-L presented more CVID-E, splenomegaly, and a trend toward more GI cancer and GI infections. CVID-L and age at CVID diagnosis emerged as independent risk factors for mortality. GI and hepatic involvements are common in patients with CVID and frequently occur together. These manifestations significantly affect the disease course, increasing the risk of GI infections, GI malignancy, and, in the case of liver disease, mortality.

Anesthesia Management of a Patient With Common Variable Immunodeficiency and End-stage Liver Disease Undergoing Laparoscopic Surgery: A Case Report.

Immunologic biomarkers of noninfectious complications and overall survival in common variable immunodeficiency.

Fasciitis-like primary breast pyoderma gangrenosum: A rare case report

Immunoglobulin replacement therapy (IRT) for primary immunodeficiency reduces infection risk and subsequent complications and can be lifesaving. However, IRT can cause severe systemic adverse events (AEs) that may limit adequate dosing. These AEs may be caused, in part, by activation and/or consumption of complement proteins, thereby lowering C1 esterase inhibitor (C1-INH) levels. Data suggest that C1-INH administration prior to intravenous immunoglobulin (IVIG) may reduce IVIG-related AEs. This case describes an adult with common variable immunodeficiency unable to tolerate IRT therapy (subcutaneous immunoglobulin [SCIG] 20% solution once weekly). She experienced AEs of severe neuropathy, described as burning and pins-and-needles sensation in the extremities and muscle twitching for several days post-treatment. Dose decreases of SCIG to 0.5 g did not improve the AE profile. Inability to tolerate IRT caused suboptimal dosing and inadequate primary immunodeficiency management, resulting in hospitalizations for pneumonia and sepsis. A trial of recombinant human C1-INH 4200 U was administered intravenously over approximately 5 min, 1 h prior to SCIG 1 g (Day 1). This dose was well tolerated with minimal AEs reported. SCIG 3 g was administered on Days 2 and 3 with no AEs reported. By continuing routine recombinant human C1-INH 4200 U prophylaxis, the patient was able to tolerate the recommended dose of SCIG 20 g once weekly without the debilitating neuropathy and other AEs previously experienced with SCIG alone. This case suggests that a patient with IRT-related AEs may benefit from C1-INH replacement therapy prior to SCIG/IVIG administration to improve tolerability.

Lessons from the American College of Allergy, Asthma and Immunology inborn errors of immunity survey: Advancing diagnostic and therapeutic strategies for the practicing allergist-immunologist.

Common Variable Immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. While infections are common, over 50% of patients exhibit autoimmune and immune activation related complications. Chronic inflammation from dysbiosis may affect the heart in CVID, though its relationship with gut barrier and echocardiographic findings is still unclear. This study investigates the associations between intestinal permeability, Trimethylamine N-oxide (TMAO) levels, immune activation, and cardiac function in CVID patients. The study included 31 CVID patients and 31 matched healthy controls. Serum zonulin, TMAO, soluble CD14 (sCD14), soluble CD25 (sCD25), Tumor Necrosis Factor-alpha (TNF-α), and IL-17 A levels were measured by ELISA. Cardiac function was assessed using speckle-tracking echocardiography (STE), focusing on global longitudinal strain (GLS). Increased levels of zonulin and TMAO were observed in CVID patients. sCD14 and sCD25 levels correlated strongly with TMAO. TMAO showed a negative correlation with Ejection Fraction and a positive correlation with Pulmonary Artery Pressure (PAP). No significant differences were found in serum TNF-α and IL-17 A levels in the compared groups. Compared to the control group (-19.90 ± 2.41), a remarkable reduction in mean GLS (-18.13 ± 3.13) was determined in the CVID group. These results are early indicators of myocardial dysfunction. Strain analysis showed a significant decrease in negative Apical 4-Chamber View Basal Longitudinal Strain (AP4B) and Apical 3-Chamber View Basal Longitudinal Strain AP3B values in the CVID group (p = 0.012 and p = 0.027). In this study, elevated serum zonulin and TMAO levels correlated with increased intestinal permeability and immune activation in CVID. High TMAO was linked to early myocardial dysfunction, highlighting the potential of microbiome-targeted therapies and advanced echocardiography for early cardiac risk detection in CVID.

The most prevalent primary immunodeficiency is selective immunoglobulin A deficiency (SIgAD), which is characterized by serum IgA levels equal to or less than 7 mg/dL with normal levels of IgG and IgM in a patient who is at least 4 years old. Most patients are asymptomatic; however, SIgAD increases the risk of respiratory and gastrointestinal infections, autoimmune disorders, transfusion reactions, and atopy. Our 4-year-old female patient had a history of recurrent severe infections requiring multiple hospital admissions, raising our suspicion of an immunodeficiency, especially with a family history of SIgAD. She had several episodes of pallor and jaundice that were caused by autoimmune hemolytic anemia, with the last episode being associated with a severe respiratory infection. This case highlights the importance of early diagnosis and ongoing follow-up of children with SIgAD to ensure prompt treatment of infections and autoimmune complications even before the age of four years. It also recommends regular monitoring and early supportive intervention to reduce disease flare-ups and monitor for progression to common variable immunodeficiency.

Primary immunodeficiencies (PIDs) are rare disorders caused by immune system defects that are commonly screened using multi-parameter flow cytometry (FCM). To counter the subjective and time-consuming manual data analysis of FCM data, we present PIDgeon, a fully automated computational pipeline based on artificial intelligence (AI) techniques. PIDgeon is designed to characterize PID immune profiles, suggest PID subtypes based on altered immune profiles, age, and immunoglobulin levels, and generate interpretable reports. The PIDgeon pipeline, including FlowSOM and extreme gradient boosting models, was trained and tested on standardized FCM data generated according to EuroFlow procedures on 74 healthy controls and 399 patients (281 lymphoid-PID patients and 118 non-PID diseased controls) collected by the Ghent University Hospital. Subsequently, multi-centric validation was performed on internal (n = 211) and external (n = 338) independent data sets collected across 4 EuroFlow centers. Validation demonstrated high accuracy in cell count enumeration, achieving correlation scores above 0.90 for the major lymphocyte subsets. Interestingly, PIDgeon showed high sensitivity (93% to 100%) in predicting PID with severe T-cell defects, such as severe combined immunodeficiency and late-onset combined immunodeficiency, and low false-negative rates (1.5% to 5.4%) for distinguishing other lymphoid-PID vs non-PID diseased controls across data sets. Additionally, PIDgeon gives a first hint toward prediction of subtypes of primary antibody deficiencies, such as common variable immunodeficiency. In summary, PIDgeon is an accessible and explainable AI-pipeline aligned with current clinical needs, aiding laboratory immunologists in early PID diagnostics and increasing data analysis efficiency.

Pigmented purpuric dermatosis is a benign type of chronic angiodermatitis prevalent in the general population, presenting with a relapsing-remitting course, with predominantly idiopathic aetiology and both humoral and cell-mediated immune pathogenesis. We report to our knowledge the first two cases of clinical association between such dermal capillaritis and the most clinically heterogeneous form of primary immunodeficiency: common variable immunodeficiency. Furthermore, in the light of already suggested triggers and pathophysiological mechanisms correlating pigmented purpuric dermatosis with various forms of secondary immunodeficiency, we complete our case descriptions by the proposal of a new putative aetiopathogenic actor that would likely account for the occurrence of the clinical association described.

Regulation of gene expression is central to the development of immune cells and their ability to respond to infection. As part of a clinical evaluation, we identified two sisters with recurrent infections, hypogammaglobulinemia, and memory B cell deficiency, diagnosed as common variable immunodeficiency. Whole exome sequencing identified a heterozygous variant (Leu50Ser, L50S) in a conserved region of EZH2, the catalytic subunit of the epigenetic gene repressor Polycomb Repressive Complex 2 (PRC2). EZH2-catalyzed histone H3 lysine 27 methylation (H3K27me) in bulk was not overall significantly disrupted by this variant, in patient samples or cell lines expressing EZH2-L50S. EZH2-L50S protein is expressed similar to wild-type and can form PRC2. However, we find that specific genomic regions that normally have high wild-type levels of H3K27me3 are deficient in the L50S context, particularly around gene promoters. EZH2-L50S is still recruited to these sites, but is not as active. Using recombinant purified PRC2, we determine that L50S affects methylation of nucleosomes and disrupts allosteric stimulation that normally amplifies H3K27me3, consistent with the location of L50 in the allosteric regulatory region of PRC2. Thus, variation of EZH2 L50, occurring at low frequency in the population may interfere with normal B cell gene expression patterns, contributing to immunodeficiency. This study has implications for genetic variation in PRC2 in the general population.

Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults, characterized by reduced serum immunoglobulin levels and impaired specific antibody responses. While immunoglobulin replacement therapy improves infection control, it has limited impact on phenotypic complications such as autoimmunity, polyclonal lymphoproliferation, enteropathy, and cytopenias, which may substantially affect patients’ quality of life (QoL). This study aimed to evaluate the relationship between distinct clinical phenotypes of CVID and QoL using the disease-specific CVID-QoL questionnaire. Materials and methods: This cross-sectional study included 30 adult CVID patients followed at the Immunology Clinic of Erciyes University Faculty of Medicine, diagnosed according to European Society for Immunodeficiencies criteria, and receiving regular intravenous immunoglobulin therapy. Demographic and clinical data were obtained retrospectively from medical records. Patients were classified into clinical phenotypes—uncomplicated, cytopenia, polyclonal lymphocytic inflammation (PLI), and enteropathy—based on dominant presentation at diagnosis. QoL was assessed using the CVID-QoL, which evaluates emotional functioning (EF), relational functioning (RF), and gastrointestinal/skin symptoms (GSS). Statistical analyses compared QoL scores across phenotypes. Results: The cohort comprised 16 females (53.3%) and 14 males (46.7%), with a mean age of 36.1 ± 11.2 years and a mean diagnostic delay of 11.7 ± 9.7 years. The most common phenotype was PLI (46.6%), followed by uncomplicated (36.6%), cytopenia (23.3%), and enteropathy (16.6%). Seven patients (23.3%) had 2 phenotypes simultaneously. Enteropathy phenotype was associated with significantly higher GSS scores ( P = 0.020). Patients with 2 phenotypes had significantly worse total CVID-QoL, EF, and GSS scores ( P = 0.006, 0.003, and 0.002, respectively), while RF scores were unaffected. Conclusion: Clinical phenotypes in CVID influence QoL to varying extents, with enteropathy and multiple concurrent phenotypes showing the greatest negative impact. These findings highlight the need for phenotype-based monitoring and targeted interventions to address both infection control and broader QoL determinants in CVID management.

Common variable immunodeficiency (CVID) is a primary antibody defect that leads to frequent infections, but inflammatory complications appear in 30-50%, leading to increased morbidity and mortality. We have previously shown that circulating bacterial 16S ribosomal DNA (rDNA), originating from gut commensals, is significantly increased in the serum of patients with CVID with inflammatory conditions (P = 0.0007). Here we examined the relationships between serum 16S ribosomal DNA (rDNA), isotype-switched memory (SM) B cells, serum IgA, IgA+ SM B cells, serum IFN-γ, and serum B cell-activating factor (BAFF). We found a significant inverse correlation between serum 16S ribosomal DNA (rDNA) concentrations and the numbers of isotype SM B cells, IgA+ SM B cells, and serum IgA levels in our large cohort, suggesting that loss of IgA in the mucosal barrier permits bacterial transcytosis. Loss of SM B cells and lower serum IgA concentrations were both associated with increased serum IFN-γ, as well as increased CXCL9 and serum BAFF concentrations. Serum BAFF was also significantly associated with IFN-γ levels and inversely correlated with baseline serum IgA. We conclude that loss of IgA, accompanied by mucosal defects in CVID, may permit bacterial transcytosis, resulting in excessive IFN-γ and BAFF production, both of which promote autoimmune and inflammatory complications in this immune defect.

Background: Common variable immunodeficiency is a heterogeneous disorder characterized by defects in antibody production and immune dysregulation, associated with infections and autoimmunity. Although structural and cognitive effects of CVID on the central nervous system have attracted attention in recent years, studies jointly addressing volumetric brain imaging and neurocognitive evaluation remain limited. Materials and Methods: In this retrospective cross-sectional study, 35 patients with common variable immunodeficiency and 40 age- and sex-matched healthy controls were evaluated. Cognitive performance was assessed in all participants using the Montreal Cognitive Assessment. High-resolution T1-weighted brain magnetic resonance imaging scans underwent automated segmentation using the volBrain platform, yielding quantitative volumetric measurements of cortical, subcortical, and cerebellar structures, as well as ventricles and cerebrospinal fluid. Intergroup comparisons were performed using independent t-tests and analysis of variance. Results: MoCA scores were significantly lower in patients with CVID. Volumetric analysis revealed prominent reductions in the volumes of total brain tissue, gray matter, cerebrum, cerebellum, limbic system, thalamus, and basal ganglia. Paralleling these findings, cerebrospinal fluid and lateral ventricle volumes were increased. Additional volume losses were detected in CVID patients with low MoCA scores. In CVID patients with autoimmunity, volume loss affected broader areas. Conclusions: CVID appears to be associated with structural brain changes and cognitive impairments. Chronic inflammation and immune dysregulation may contribute to these neurodegenerative processes. Regular neurocognitive monitoring and further prospective studies are warranted in patients with CVID.

PurposeThe impact of coronavirus disease 2019 (COVID-19) on patients with primary immunodeficiency (PID) remains insufficiently characterized. This study aimed to describe the clinical manifestations, disease course, and outcomes of COVID-19 in patients with PID.MethodsAdult patients with PID who had COVID-19 infection between March 2020 and August 2022 were screened. Demographic and clinical data were retrospectively collected from institutional databases, and additional information was obtained through a patient questionnaire.ResultsA total of 36 patients (19 males, 17 females; median age: 36.5 years) with various PID subtypes were included: 24 with common variable immunodeficiency (CVID), 3 with cytotoxic T-lymphocyte-associated protein-4 haploinsufficiency, 3 with X-linked agammaglobulinemia (XLA), 2 with hypogammaglobulinemia, 1 with lipopolysaccharide-responsive and beige-like anchor protein deficiency, 1 with DiGeorge syndrome, 1 with mitochondrial neurogastrointestinal encephalomyopathy syndrome, and 1 with CVID-like capillary malformation-arteriovenous malformation syndrome 2. Overall, 63.9% (n = 23) were managed as outpatients, while 36.1% (n = 13) required hospitalization. Admission to the intensive care unit was required in 19.4% (n = 7) of the cases. The overall case fatality rate was 8.3% (n = 3), which is higher than the rate observed in the general population. Although the majority experienced a mild clinical course, patients with XLA exhibited prolonged symptoms and persistent seropositivity. Risk factors associated with hospitalization included lymphopenia, elevated C-reactive protein and ferritin levels, dyspnea, COVID-19 Reporting and Data System score ≥ 4 on imaging, need for supplemental oxygen, prolonged symptoms, and extended polymerase chain reaction positivity.ConclusionsA subset of adult patients with PID may be at increased risk for severe COVID-19.

This study aimed to determine the frequency of neutropenia in patients with common variable immunodeficiency (CVID) and investigate its relationship with disease prognosis. Data from 84 patients diagnosed with CVID and followed between 2019 and 2024 at the Department of Adult Clinical Immunology and Allergy, Necmettin Erbakan University, were retrospectively reviewed. Patients were divided into two groups based on the presence or absence of neutropenia. Demographic data, clinical findings, laboratory parameters, and survival rates were compared. Statistical analyses included the Mann-Whitney U test, the Chi-square test, and the Kaplan-Meier survival analysis. A total of 84 patients diagnosed with CVID were included in the study, with a median age of 38 years (range, 20-79 years). Of the participants, 48.8% were females (n = 41). Neutropenia was observed in 28.5% of patients (n = 24). The most common presenting complaints included autoimmune cytopenias, such as anemia and thrombocytopenia. Compared to non-neutropenic patients (n = 60), those with neutropenic CVID had a significantly higher mortality rate (33.3% vs 6.7%, P = 0.004). According to Kaplan-Meier survival analysis, the 8-year survival rates were 57.5 and 92.5% for neutropenic and for non-neutropenic CVID patients (p < 0.001), respectively. This study suggests that neutropenia in CVID patients may be more than just a hematological issue; it could also serve as an important clinical marker associated with increased mortality. Recognizing and closely monitoring neutropenia is essential for effective CVID management.

Common variable immunodeficiency (CVID) is one of the primary immunodeficiency disorders. The phenotype of peripheral blood memory B cells is a useful tool in the classification of patients into clinically and functionally relevant groups. This study aimed to assess the level of naïve and switched memory B cells level and their correlation with the clinical phenotypes and complications in patients with CVID. This case control study included 30 adult patients with CVID and 30 normal controls, matched for age and sex. Complete blood count, cluster of differentiation 3 (CD3)+, CD4+, CD8+ T cells and CD19+27-IgD+ for naïve B cells and CD19+27+IgD- switched memory B cells levels were assessed. The mean age of the onset of symptoms was 16.9±15.1 years, the mean age of diagnosis was 27.30±14.39 years, with a diagnostic delay of 10.43±10.29 years, and the body mass index was significantly lower in CVID group. Infections including (upper respiratory tract infection, chronic diarrhea, pneumonia and bronchiectasis) were the most frequent phenotypes. CD4+, CD4+/CD8+ T cells, CD19+ and CD19+27+IgD- switch memory B cell, IgG, IgA, and IgM were significantly lower in CVID group than in the control group (p < 0.001 and p < 0.015, respectively). CD8+ T cells and CD19+27-IgD+ naïve B cells were significantly higher in the CVID group (p < 0.001). CD19+27-IgD+ naïve B cells level was significantly lower in cases with bronchiectasis with low baseline serum IgG in lymphadenopathy group (p=0.049), and higher level of CD3+ T cells in cases with splenomegaly. There was no significant difference in laboratory results in CVID patients presented with autoimmune diseases, Granulomas nor enteropathy. In conclusion, high level of CD19+27-IgD+ naïve and low level of CD19+27+IgD- switch memory B cells are characteristic features of CVID. Moreover, the reduced CD19+27-IgD+ naïve B cells level can be a predictor of the development of bronchiectasis in CVID patients.

Pregnancy and lactation in patients with common variable immunodeficiency: a single center experience.

Because few studies have focused on recurrent Campylobacter bacteremia, we investigated two clinical cases of patients with common variable immunodeficiency and repeated Campylobacter bacteremia over a period of 6-10 years. We analyzed and compared genomes from isolates obtained from both patients during follow-up. For patient #1, 18 isolates of Campylobacter coli and 17 isolates of Campylobacter jejuni were obtained from 2014 to 2024. For patient #2, 10 isolates of C. coli were obtained from 2019 to 2024. Next-generation sequencing was used to identify species, characterize antimicrobial resistance, perform multilocus sequence typing, and analyze core-genome single-nucleotide polymorphisms, as well as to uncover potential sources of contamination. For patient #1, all 18 C. coli isolates obtained from 2022 to 2024 were from the same clonal complex and source of contamination (chicken) and exhibited high levels of genomic resemblance based on core-genome single-nucleotide polymorphism analysis. Each C. coli isolate probably originated from the same initial strain. However, two clusters of C. jejuni were identified: one consisting of isolates from 2014 and the other consisting of the remaining isolates from 2022 to 2024. A 16S rRNA mutation in position A1387G was present in four C. coli isolates from 2022 and 2023, and this was associated with gentamicin resistance. One C. coli isolate was also resistant to ertapenem and exhibited an amino acid duplication within the PorA protein sequence. For patient #2, each C. coli isolate was from the same clonal complex, which was of porcine origin. Similar to patient #1, three of the isolates from 2023 had an A1464G 16S rRNA mutation and were gentamicin resistant. Retrospective analyses of antimicrobial use for both patients highlighted an association between antimicrobial selection pressure and the emergence of resistance markers, suggesting in vivo selection.

PurposeAntibody deficiencies, particularly Common Variable Immunodeficiency (CVID), represent a major health concern due to comorbidities linked to delayed diagnosis. Calculated globulin (CG) and the gammaglobulins derived from serum protein electrophoresis have been proposed as reliable indices for screening hypogammaglobulinemia. This study aimed to establish optimal cut-offs for CG and the gammaglobulins to identify patients with low IgG among hospitalized adolescents and adults from Algeria.MethodsSerum samples and clinical data were collected from hospitalized patients aged over 10 years. Total protein and albumin were determined by the biuret and bromocresol green methods, IgG was quantified by nephelometry, and gammaglobulins were determined by gel or capillary serum protein electrophoresis. In addition, a control group was included for cut-off verification.ResultsA total of 980 patients were recruited, including 762 adults (≥ 18 years) and 218 adolescents (10–17 years), with a median age of 47 years. The control group comprised 20 patients with confirmed CVID. The most frequent clinical manifestations were autoimmune disorders (33%), inflammatory disorders (31%), and severe infections (24%). Hypogammaglobulinemia was identified in 94 patients, including 6 with primary causes. IgG levels correlated significantly with both CG and gammaglobulins. Linear regression analysis showed that IgG accounted for 49% of the variance in CG and 75% in the gammaglobulins. A CG cut-off value of 22 g/L yielded a sensitivity of 80% and a specificity of 87%, whereas a gammaglobulin cut-off of 8.9 g/L achieved a sensitivity of 96% and a specificity of 88%. Gammaglobulin cut-off values were consistent between adult and pediatric groups, while differences in CG cut-offs were observed (adult group: 22.25 g/L; pediatric group: 24.15 g/L). Thirteen of the 20 patients with CVID in the control group (65%) had a CG level below 22 g/L.ConclusionCG and serum protein electrophoresis are reliable tools for screening hypogammaglobulinemia. Although both tests demonstrated satisfactory sensitivity and specificity, certain cases may be underestimated or overestimated. Therefore, thorough clinical evaluation and, whenever possible, direct immunoglobulin measurement remain essential.