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Summary: Impaired immune response to COVID-19 (coronavirus disease 2019) vaccination has been reported in patients with inborn errors of immunity (IEI). Repetitive vaccinations are recommended for this vulnerable group. Due to the high diversity within IEI patients, additional safety and immunogenicity data are needed to better understand these aspects especially in less common immunodeficiency syndromes. In this prospective open-label clinical trial, we assessed the humoral immune response and the T‑cell response in patients with IEI or severe MBL (mannose-binding lectin) deficiency (IEI/MBLdef) after three vaccinations. A total of 16 patients and 16 matched healthy controls (HC) with suboptimal humoral response defined by anti-SARS-CoV‑2 RBD (severe acute respiratory syndrome coronavirus type 2 receptor binding domain) antibodies below 1500 BAU/ml (binding antibody units per ml) after the second COVID-19 vaccination were enrolled in this study and qualified for a third mRNA vaccine dose. After 4 weeks following vaccination, 100% of HC and 75% of IEI/MBLdef patients exhibited anti-SARS-CoV‑2 RBD antibodies > 1500 BAU/ml, although the difference was not statistically significant (75% vs. 100%; p = 0.109). Although post-vaccination IEI/MBLdef patients demonstrated significantly increased anti-SARS-CoV‑2 RBD antibodies and neutralizing antibodies compared to baseline, these responses were significantly lower in IEI/MBLdef patients compared to HCs. Notably, the third vaccination augmented the cellular immune response to both wild-type and omicron peptide stimulation. No serious adverse events were reported within the 4‑week follow-up period and, importantly, vaccination had little to no effect on the long-term disease activity and fatigue. This trial strongly supports the recommendation of repeated COVID-19 vaccinations for patients suffering from immunodeficiencies, especially when they exhibit an initially limited response to the vaccine. [ABSTRACT FROM AUTHOR]

Introduction: This study explores clinicians' diagnostic practices and perceptions in the context of granulomatous-lymphocytic interstitial lung disease (GLILD), a pulmonary manifestation of common variable immunodeficiency disorder. The aim was to gain valuable insights into key aspects, such as the utilization of radiological features for diagnostic purposes, indications for lung biopsy, preferred biopsy techniques, and the relative importance of different histopathological findings in confirming GLILD. Method: A survey targeting expert clinicians was conducted, focusing on their experiences, practices, and attitudes towards lung biopsy in suspected GLILD cases. Results: The survey revealed that the majority of respondents accepted high-resolution computed tomography as a sufficient alternative to biopsy for making a probable GLILD diagnosis in most patients. There was a consensus among most respondents that the presence of extrapulmonary granulomatous disease is adequate for making a diagnosis of GLILD where the chest imaging and clinical picture are consistent. When a biopsy was recommended, there was notable variation in the preferred initial biopsy technique, with 35% favouring transbronchial biopsy. Conclusion: Our findings underscore the complexity of diagnosing GLILD, indicating varied clinician opinions on the necessity and efficacy of lung biopsies. They highlight the need for further research and the development of consistent diagnostic criteria and management protocols, ultimately aiming to enhance the accuracy and safety of GLILD diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: Inborn errors of immunity (IEI) are characterized by an inherited dysregulation or absence of immune system components that can manifest clinically in complications that predispose an individual to feeding difficulties or impaired swallowing, digestion, and absorption. Treatment side-effects or altered requirements may further impair nutritional status. While adequate nutrition is necessary for optimal growth and immune function, little is known about nutritional intakes in IEI, and best practice nutrition guidelines are limited. This review aimed to synthesize current evidence on the dietary intakes, anthropometry and nutritional biochemistry in individuals with an IEI. Methods: A systematic review of literature published from database inception to March 2023 was conducted in accordance with the PRISMA guidelines. Articles eligible for inclusion reported anthropometric, biochemical, or dietary intakerelated measures in pediatric or adult patients with a diagnosed IEI. Identified articles were screened for eligibility; data was synthesized descriptively. Results: A total of 4488 studies were retrieved of which 34 were included. Across studies, 2894 IEI individuals were included (age range 4 weeks to 83y), predominantly focusing on ataxia telangiectasia (AT) and common variable immunodeficiency (CVID). A significant association between inadequate energy intakes and IEI was identified (n=6 studies); however, there was significant variability in adequacy of macro- and micronutrients across studies. Patients with IEI were at risk of malnutrition (range 30% to 70%); although anthropometric assessment measures were not consistent across studies. Biochemical assessments found patients were also at risk of micronutrient deficiencies including vitamin D. Discussion: This review identified few studies assessing dietary intakes, anthropometry and nutritional biochemistry in patients with IEI, with considerable heterogeneity across studies. Future longitudinal studies using consistent validated dietary assessment tools and anthropometric measures in diverse IEI patient populations are needed. This review reinforces the need for dietetic input in people with an IEI and the development evidence-based clinical practice guidelines for people with an IEI. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is a group of genetic disorders involving more than a dozen genetic loci and characterized by a deficiency in specific antibody isotypes leading to poor immune responses and recurrent infection. CVID affects approximately 1 in 10,000 to 1 in 50,000 people worldwide with substantial heterogeneity in disease severity, including asymptomatic individuals designated as hypogammaglobulinemia of undetermined significance (HGUS). As expected of humoral immunodeficiency, the molecular causes of CVID primarily affect the maturation, activation, or survival of B cells and plasma cells. In this retrospective analysis, we defined a cohort of 21 patients with a primary CVID or HGUS diagnosis in the v7 release of the All of Us Research Program database and performed gene annotation and variant effect prediction. Our analysis identified both known disease-causing variants and rare genetic variants overlapping with other immunodeficiency syndromes. [ABSTRACT FROM AUTHOR]

Background: Patients with inborn errors of immunity (IEI) are susceptible to developing cancer due to defects in the immune system. The prevalence of cancer is higher in IEI patients compared to the immunocompetent population and cancers are considered as an important and common cause of death in IEI patients. Objectives: To systematically review demographic, genetic and cancer-related data of IEI patients with a history of malignancy. Moreover, we performed a meta-analysis aiming to determine the frequency of cancer in patients with different types of IEI. Methods: We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (until September 2023) introducing terms related to IEI and cancer. Studies with human subjects with confirmed IEI who had developed at least one malignancy during their lifetime were included. Results: A total number of 4607 IEI patients with a cancer history were included in the present study. Common variable immunodeficiency (CVID) had the highest number of reported cases (1284 cases), mainly due to a higher relative proportion of patients with predominantly antibody deficiencies (PAD) and their increased life expectancy contributing to the higher detection and reporting of cancers among these patients. The most common malignancy was hematologic/blood cancers (3026 cases, mainly diffuse large B cell lymphoma). A total number of 1173 cases (55.6%) succumbed to cancer, with the highest rate of bone marrow failure (64.9%). Among the patients with monogenic defects in IEI-associated genes, the majority of cases had ATM deficiency (926 cases), but the highest cancer frequency rate belonged to NBS1 deficiency (50.5%). 1928 cases out of total 4607 eligible cases had detailed data to allow further statistical analysis that revealed BRCA2 deficiency had the earliest cancer development (~ 38 months), lowest cure frequency, and highest fatality rate (85%), while ATM deficiency had the lowest cure frequency and highest fatality rate (72%) among total cases reviewed with exclusion of Fanconi anemia. Conclusion: The overall reported cancer frequency in the cases reviewed with and without exclusion of Fanconi anemia was 11.1% (95% confidence interval: 9.8–12.5%) and 12.0% (95% confidence interval: 10.6–13.5%), respectively. Our study revealed that the incidence of cancer is significantly dependent on the molecular and pathway defects in IEI patients, and individualized early screening and appropriate treatment, might improve the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Background: Common Variable Immunodeficiency (CVID) represents a heterogenic group of primary immunodeficiencies (PID) characterized by impaired antibody production and susceptibility to infections. Non-infectious complications, such as autoimmune diseases, lymphoproliferative disorders, and malignancies, now significantly impact prognosis. Moreover, both hematologic and solid organ malignancies are more frequently observed in CVID patients compared to other PIDs. The risk factors for carcinogenesis in CVID remain largely unknown. Objective: This multicenter study aims to characterize the clinical profile of cancer in CVID patients in Spain and to identify independent risk factors associated with malignancy development, focusing on the role of immune dysregulation. Methods: A nationwide, cross-sectional study was conducted from November 2019 to May 2022, involving 17 hospitals treating PID patients in Spain. Data were collected systematically on demographics, infectious and non-infectious comorbidities, immunological parameters, and treatment. Statistical analysis, including multivariate logistic regression, was performed to identify risk factors associated to malignancy. Results: Of 250 CVID patients, 38 (15.26%) were diagnosed with cancer, predominantly non-Hodgkin lymphoma, gastric cancer, and lung adenocarcinoma. Cancer patients were significantly older (mean age 60.70 vs. 49.36 years, p<0.001) and had higher rates of immune dysregulation (81.58% vs. 59.7%, p=0.01). Immune dysregulation was an independent risk factor for cancer (OR 2.19, p=0.04), alongside previous immunosuppressant therapy (OR 2, p=0.031), higher IgM levels (OR 1.008 per SD, p=0.012), older age (OR 1.04, p<0.001), and lower CD4 cell counts at diagnosis (OR 0.997, p<0.001). Conclusions: This study highlights the increased cancer risk in CVID patients, with immune dysregulation, prior immunosuppressant use, elevated IgM levels, and lower CD4 cell counts as conjointly associated. These findings underscore the need for vigilant cancer screening and tailored management strategies in CVID patients to improve outcomes. Future research should focus on elucidating the molecular mechanisms linking immune dysregulation and malignancy in CVID. [ABSTRACT FROM AUTHOR]

The article discusses a case of hypercalcaemia in a 16-year-old male with a complex medical history, including trisomy 21 and intractable epilepsy, who was on a ketogenic diet. The hypercalcaemia was managed with various treatments, including denosumab and bisphosphonates, before ultimately ceasing the ketogenic diet, which led to the normalization of calcium levels. The article highlights the challenges of managing hypercalcaemia in patients on a ketogenic diet and emphasizes the importance of monitoring serum calcium levels and renal function in such cases. [Extracted from the article]

Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced levels of specific immunoglobulins, resulting in frequent infections, autoimmune disorders, increased cancer risk, and diminished antibody production despite an adequate B cell count. With its clinical manifestations being highly variable, the classification of CVID, including the widely recognized Freiburg classification, is primarily based on clinical symptoms and genetic variations. Our study aims to refine the classification of CVID by analyzing transcriptomics data to identify distinct disease subtypes. We utilized the GSE51405 dataset, examining transcriptomic profiles from 30 CVID patients without complications. Employing a combination of clustering techniques—KMeans, hierarchical agglomerative clustering, spectral clustering, and Gaussian Mixture models—and differential gene expression analysis with R's limma package, we integrated molecular findings with demographic data (age and gender) through correlation analysis and identified common genes among clusters. Three distinct clusters of CVID patients were identified using KMeans, Agglomerative Clustering, and Gaussian Mixture Models, highlighting the disease's heterogeneity. Differential expression analysis unveiled 31 genes with variable expression levels across these clusters. Notably, nine genes (EIF5A, RPL21, ANP32A, DTX3L, NCF2, CDC42EP3, CHP1, FOLR3, and DEFA4) exhibited consistent differential expression across all clusters, independent of demographic factors. The study recommends categorizing patients based on the four genes, NCF2, CHP1, FOLR3, and DEFA4—as they may assist in prognostic prediction. Transcriptomic analysis of common variable immunodeficiency (CVID) patients identified three distinct clusters based on gene expression, independent of age and gender. Nine differentially expressed genes were identified across these clusters, suggesting potential biomarkers for CVID subtype classification. These findings highlight the genetic heterogeneity of CVID and provide novel insights into disease classification and potential personalized treatment approaches. [ABSTRACT FROM AUTHOR]

The gut microbiota serves a crucial role in the development of host immunity. Immunocompromised patients are particularly vulnerable to dysbiosis not only by virtue of a defect in the immune system but also due to increased susceptibility to infection and multiple courses of antibiotic therapy. Fecal microbiota transplantation is by far the most effective option for restoring gastrointestinal homeostasis. However, it is contraindicated in patients with significant primary and secondary immunodeficiencies. This article presents the case of a 59-year-old patient with common variable immunodeficiency, after splenectomy at age 39 for primary immune thrombocytopenia, who manifested diarrhea of up to 10 stools per day accompanied by secondary malnutrition and cachexia. The patient was admitted to the hospital on multiple occasions due to this condition, with stool PCR tests confirming a HHV-5 (Cytomegalovirus, CMV) infection. Following the administration of valganciclovir, the patient's complaints diminished, although, upon cessation of the drug, the symptoms recurred. In addition, the patient had an intestinal infection with C. difficile etiology. Given that the patient's therapeutic options had been exhausted, after obtaining informed consent from the patient and approval from the bioethics committee to conduct a medical experiment, treatment of diarrhea was undertaken by fecal microbiota transplantation with the certified preparation Mbiotix HBI from the Human Biome Institute. The patient underwent two transplants, with a one-week interval between them. The initial procedure was performed using the endoscopic method, while the subsequent was conducted using the capsule method. Following the administration of the applied treatment, the patient's symptoms were successfully alleviated, and no adverse effects were observed. A microbiological analysis of the intestinal microbiota was conducted prior to and following transplantation via next-generation sequencing (NGS). No recurrence of symptoms was observed during the two-year follow-up period. To the best of our knowledge, this is the first fecal microbiota transplantation in an adult patient with primary and secondary immunodeficiency. [ABSTRACT FROM AUTHOR]

AbstractCommon variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency (PID) characterized by an impaired immunoglobulin production, in association with an increased susceptibility to infections and a diversity of clinical manifestations. This narrative review summarizes immunophenotypic abnormalities in CVID patients and their relevance for diagnosis and disease classification. A comprehensive search across four databases - PubMED, Web of Science, EMBASE and Google Scholar – yielded 170 relevant studies published between 1988 and April 31, 2023. Over the past decades, the role of immunophenotyping in CVID diagnosis has become evident by identifying “hallmark” immunophenotypic aberrancies in patient subsets, with some now integrated in the consensus diagnostic criteria. Furthermore, the role of immunophenotyping in subclassifying CVID in relation to clinical presentation and prognosis has been extensively studied. Certain immunophenotypic patterns consistently correlate with clinical manifestations and/or subsets of CVID, particularly those associated with noninfectious complications (i.e. low switched memory B cells, shifts in follicular helper T cell subsets, low naïve CD4+ T cells, low regulatory T cells, and expansion of CD21low B cells, often associated with autoimmunity and/or splenomegaly). Also, efforts to associate subset levels of innate immune cells, such as Natural Killer (NK) cells, invariant (i)NKT cells, innate lymphoid cells (ILCs), and dendritic cells (DCs) to CVID complications are evident albeit in a lesser degree. However, inconsistencies regarding the role of flow cytometry in classification and prognosis persist, reflecting the disease complexity, but probably also cohort variations and methodological differences between published studies. This underscores the need for collaborative efforts to integrate emerging concepts, such as standardized flow cytometry and computational tools, for a more precise CVID classification approach. Additionally, recent studies suggest a potential value of (epi)genetic-based molecular assays to this effort. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Liver involvement is an increasingly recognised complication of common variable immunodeficiency (CVID). Nodular regenerative hyperplasia (NRH), a subgroup of porto‐sinusoidal vascular disorder, and manifestations of portal hypertension (PH) unrelated to cirrhosis are the most common findings. Nonetheless, the evolution of liver disease over time remains unknown. Methods: Retrospective review of patients followed at the National Institutes of Health with CVID‐related liver disease and liver biopsy from 1990 to 2020. Clinical, imaging and histological follow‐up were recorded as part of clinical research protocols. Results: Forty patients were included, with a median age of 37.5 years at initial biopsy, 73% presenting with clear evidence of NRH, and a median fibrosis stage of 1. At biopsy, median platelet count was 100 × 109/L, spleen size 19.5 cm, hepatic venous pressure gradient 9.5 mmHg and 37.5% of patients had signs of PH. Cumulative incidence of PH was 65% at 5 years. In a subgroup of 16 patients, a follow‐up liver biopsy, performed at a median time of 3 years after the index biopsy, revealed an increase in fibrosis by ≥2 stages in 31% of cases and an increase to an overall stage of 2.2 (p = 0.001). No clinical or histological factors were associated with progression of fibrosis. Conclusions: In this CVID cohort, NRH is the most common initial histological finding; however, unexpectedly fibrosis progresses over time in a subgroup of patients. A better understanding of the underlying causal process of liver disease CVID might lead to improved outcomes. [ABSTRACT FROM AUTHOR]

Background: Infectious diseases remain a major cause of morbidity and mortality after hematopoietic cell transplantation (HCT). Secondary hypogammaglobulinemia is a risk factor for infectious diseases. Total immunoglobulin G (IgG) levels and the history of infectious diseases are an integral part of determining the indication for immunoglobulin replacement therapy. The clinical significance of IgG2 levels is not well established. Guidelines recommend using pathogen‐specific IgG to evaluate patients with potential secondary immunodeficiency. However, it is difficult in practice to perform such testing. IgG2 may correlate well with pathogen‐specific IgG but the clinical significance of IgG2 is not well established. Methods: To assess the prevalence of low IgG2 levels with normal IgG after HCT, we cross‐sectionally measured the levels of several immunoglobulins, including IgG, IgA, IgM, and IgG2, after HCT, and we assessed the correlation between them. Results: Among 121 patients who underwent cross‐sectional measurements of IgG, IgA, IgM, and IgG2 levels after HCT, 114 had normal IgG2 levels (normal IgG2 group, ≥ 100 mg/dL) and 7 had low IgG2 levels (low IgG2 group, < 100 mg/dL). These 7 patients were allogeneic HCT recipients. All 7 patients with low IgG2 had cGVHD and 4/7 patients had normal total IgG levels. Conclusion: IgG2 levels may be low even in patients with normal IgG levels years after allogeneic HCT. Therefore, our study suggests that when patients develop infectious diseases, especially multiple episodes, it is recommended to measure IgG2 levels to exclude the possibility of secondary hypogammaglobulinemia after allogeneic HCT. [ABSTRACT FROM AUTHOR]

Objectives: Common Variable Immunodeficiency Disorders (CVID) and Large Granular Lymphocytes leukemia (LGLL) exhibit diverse clinical manifestations including infections, dysimmunity, and lymphoproliferation. Recent decades have seen the discovery of new genes in the lymphopoiesis pathway, such as JAK–STAT. This case series supplemented by a literature review aims to describe clinical and biological characteristics of patients with both CIVD and LGLL. Methodology: Patients were included through a call for comments to French and Belgian centers and through a literature review via PubMed. Clinical characteristics were compared to two large French cohort involving CVID and LGLL patients. Results: Twelve patients were included. In all cases, CVID precedes LLGL (median diagnosis delay for LLGL was 7 years). Most cases presented with splenomegaly and autoimmune cytopenia. Ten out of 12 patients underwent splenectomy during follow up. Conclusions: Patients with LGLL and CVID differ from patients without immune deficiency in term of clinical presentation and prognosis. We suggest CVID may act as a trigger of LGL lymphocytosis, due to endogenous and exogenous antigenic pressure leading to the selection of a dominant LGL clone and stimulation of the JAK–STAT pathway. The role of splenomegaly and splenectomy in LGLL onset warrant further investigation in future studies. [ABSTRACT FROM AUTHOR]

Scarce data is available regarding primary immunodeficiency-associated cancers in children in low-middle-income countries. This study aimed to determine the incidence, clinical features and outcomes of primary immunodeficiencies (PIDs)-associated cancers in children presenting to Pakistan's largest public-sector specialised pediatric oncology center. Among 5,748 children with cancers registered over 5 years, only eight patients were found to have PID-associated pediatric malignancies with an incidence of 1.4 per 1,000 cases. The median age at the time of diagnosis was 6.5 years with a male-to-female ratio of 7:1. Only four types of PIDs were found to be associated with cancer in children at our center: Ataxia Telangiectasia in 37.5% (n = 3), hyper-IgE syndrome and IgG deficiency in 25% (each n = 2) and one case (12.5%) of common variable immune deficiency. Six different types of pediatric cancers were associated with PID with a predisposition towards hematological malignancies (n = 7, 87.5%). Only two patients (25%) survived. The median survival of the cohort was 3.5 months. Infection-related mortality was the cause of death in four patients (66%), and the type of PID was the only statistically significant factor associated with the outcome. It is concluded that a lesser proportion of PID-associated pediatric cancers are found in our center as compared to the reported data from high-income countries. PID-associated cancers in children have an abysmal prognosis and infection- related mortality is the major cause of treatment failure. Sensitisation of oncologists to look for any underlying PID, the introduction of PID-screening programs in children and consideration of PID-associated malignancies as a high-risk group for treatment may help improve the outcomes. [ABSTRACT FROM AUTHOR]

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence. [ABSTRACT FROM AUTHOR]

We aimed to assess gastrointestinal cancers risks in a large cohort of individuals with primary antibody deficiency (PAD) and their association with risk of autoimmune and inflammatory gastrointestinal diseases. Investigating a French national database of inpatient admissions between 2010 and 2018, we identified 12,748 patients with PAD and 38,244 control non-exposed individuals. We performed multiple exposed-non-exposed studies using conditional logistic regression. In comparison with non-exposed patients, PAD patients had increased risk of in situ gastric carcinoma (Odds Ratio (OR) =10.5 [95 % CI 2.2; 50.5]), malignant gastric tumor (OR=3.2 [95 % CI 2.2; 4.4]) and colorectal cancer (OR=1.2 [95 % CI 1; 1.5]). PAD patients had also increased risk of pernicious anaemia (OR=8 |95 % CI 5.6; 11.5]), Crohn's disease (OR= 4.4 [95 % CI 3.5; 5.6]), ulcerative colitis (OR=2.9 [95 % CI 2.4; 3.6]) and coeliac disease (OR=13.3 [95 % CI 9.1; 19.5]). Within patients with gastric cancer, those with PAD had increased risk of pernicious anaemia (OR=8.4 [95 % CI 1.5; 215]; p = 0.01) but not of H. pylori infection. Risk of gastric cancer is particularly high in PAD patients and notably risk of in situ gastric carcinoma in association with pernicious anaemia. It supports indication of early endoscopic screening in these patients. [ABSTRACT FROM AUTHOR]

Background and objectives: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections, with non-infectious complications such as granulomatous–lymphocytic interstitial lung disease (GLILD) affecting up to 30% of patients. Methods: Using high-throughput 16S rRNA gene sequencing, salivary, sputum, and fecal microbiome from CVID patients with GLILD, comparing them to CVID patients without GLILD—with immune dysregulation (dCVID) and only infections (iCVID)—and healthy controls was analyzed. Results: A total of 41 CVID patients, 7 with GLILD, and 15 healthy donors were included. Global fecal biodiversity was significantly lower in GLILD patients compared to CVID subgroups and controls. GLILD patients harbored different specific bacterial communities in all niches, with some keystone species common to dCVID. Conchiformibius, Micrococcales, and Capnocytophaga are more frequent in the sputum of GLILD patients. Saliva in GLILD shows higher frequencies of Conchiformibius and Haemophilusparainfluenzae. Fecal samples from GLILD patients have higher levels of Gemella morbilorum, Lacticaseibacillus, and Cellulosimicrobium. A non-assigned Conchiformibius spp. is consistently associated with GLILD across different niches and could be a potential pathobiont or relevant microbiological marker for GLILD. Cluster network and correlation analyses show profound dysbiosis in the sputum, saliva, and feces of GLILD patients. Conclusions: These findings highlight significant microbiome alterations in CVID patients with GLILD, particularly in the respiratory tract, suggesting a possible link to both local and systemic immune dysregulation. [ABSTRACT FROM AUTHOR]

Background: Personalized medicine requires the assessment of the impact of health care interventions on Health-Related Quality of Life. Research design and methods: We run an observational study of HRQoL in 140 CVID patients with biannual assessments over 8 years using a disease-specific tool, the CVID_QoL, and the GHQ questionnaires. Factors influencing changes in HRQoL scores were identified using multiple linear regression models with a stepwise procedure. Results: Infections frequency, female gender, and chronic enteropathy were associated with worse global CVID_QoL scores. The presence of permanent organ damage and older age contributed to the perception of being at risk of health deterioration, while chronic enteropathy was associated with fatigue. The presence of permanent organ damage was also associated with perceived difficulties in usual activities. The frequency of infections was the main risk factor for difficulties in long-term planning and perceptions of vulnerability. Before COVID-19, improved HRQoL scores were associated with reduced respiratory infections and changes in immunoglobulin replacement route and setting. The COVID-19 pandemic caused a sudden deterioration in all HRQoL dimensions, and a further deterioration in the emotional dimension was observed during the pandemic period. Patients who died during the study had worse CVID_QoL scores at all time points, confirming that HRQoL performance is strongly related to patient outcome. Conclusions: Periodic HRQoL assessments are needed to capture relevant issues that change over time in patients affected by long-term chronic conditions such CVID, possibly identifying areas of intervention. [ABSTRACT FROM AUTHOR]

Background: Common Variable Immunodeficiency Disorders (CVID) encompass a spectrum of immunodeficiency characterised by recurrent infections and diverse non-infectious complications (NICs). This study aimed to describe the clinical features and variation in NICs in CVID with and without interstitial lung disease (ILD) from a large UK national registry population. Methods: Retrospective, cross-sectional data from a UK multicentre database (previously known as UKPIN), categorising patients into those with CVID-ILD and those with NICs related to CVID but without pulmonary involvement (CVID-EP; EP= extra-pulmonary involvement only). Results: 129 patients were included. Chronic lung diseases, especially CVID-ILD, are prominent complications in complex CVID, occurring in 62% of the cohort. Bronchiectasis was common (64% of the cohort) and associated with greater pulmonary function impairment in patients with CVID-ILD compared to those without bronchiectasis. Lymphadenopathy and the absence of gastrointestinal diseases were significant predictors of ILD in complex CVID. Although the presence of liver disease did not differ significantly between the groups, nearly half of the CVID-ILD patients were found to have liver disease. Patients with CVID-ILD were more likely to receive immunosuppressive treatments such as rituximab and mycophenolate mofetil than the CVID-EP group, indicating greater need for treatment and risk of complications. Conclusion: This study highlights the significant burden of CVID-ILD within the CVID population with NICs only. The lungs emerged as the most frequently affected organ, with ILD and bronchiectasis both highly prevalent. These findings emphasise the necessity of a comprehensive and multidisciplinary approach in managing CVID patients, considering their susceptibility to various comorbidities and complications. [ABSTRACT FROM AUTHOR]

Natural antibodies (NAbs) occurring in individuals without prior exposure to specific antigens, provide direct first barrier protection against pathogens, and exert immunoregulation thus actively contributing to the maintenance of immune homeostasis, controlling inflammatory processes and preventing autoimmunity. Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by a compromised immune function that brings into focus the role of NAbs. Our aim was to explore whether NAb levels could serve as potential key indicators in CVID for monitoring disease progression and predicting outcomes. In this study, we analyzed a Hellenic cohort of 56 patients with CVID (31 newly diagnosed and 25 under immunoglobulin replacement therapy-IgRT) and 33 healthy controls, for total Ig levels and serum IgM and IgG NAb levels against five informative target-antigens of NAbs, namely, actin, DNA, carbonic anhydrase, F(ab΄)2 fragments of human IgG and TriNitroPhenyl. In addition, follow-up pre- and post- IgRT samples were analyzed in ten (10) patients of our cohort. Results showed that Ig-treated patients exhibited significantly lower IgM NAb levels than untreated patients and healthy controls against all panel antigens. In the follow-up samples, pre-treatment IgM NAb levels negatively correlated with total serum IgM. This imbalance was only partially restored after IgRT, with a significant decrease in IgM NAb levels observed in nine out of ten patients. Moreover, post-treatment patients with recurrent infections presented significantly lower IgM NAb levels, a reduction also observed in patients with bronchiectasis independently of treatment status. On the contrary, post-treatment patients with enteropathy had significantly higher IgM NAb levels against all panel antigens, an increase also noted in patients with autoimmune diseases. Regarding IgG NAbs, replacement therapy restored levels to those of healthy controls. In conclusion, impaired NAb levels are found in CVID patients, particularly related to certain phenotypes. Moreover, the significant decrease in IgM NAb levels after IgRT suggests a potential association with disease course and complications. The results suggest that administration of human IgM NAbs may be an effective combinatorial treatment in selected patients. Further research is needed to understand the functional roles of NAbs in CVID and its complex clinical phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) encodes a widely expressed cytosolic protein that participates in polarized vesicle trafficking. Homozygous loss-of-function LRBA mutations can lead to immune deficiency due to the lack of immune regulation, classified as a part of Tregopathies. We present a case of a 49-year-old female, with polyarthralgia in metacarpophalangeal and proximal interphalangeal joints bilaterally, and morning stiffness, leading to the diagnosis of rheumatoid arthritis treated with pulse steroid therapy. She had experienced sepsis and in-depth scrutiny revealed panhypogammaglobulinemia. After being referred to the immunology clinic, she was followed under the diagnosis of common variable immunodeficiency (CVID)-like inborn errors of immunity (IEI). Methods and Results: Physical examination and diagnostic follow-up revealed massive splenomegaly accompanied by portal hypertension, and ulcerations in the colon. She also presented with periodic hematuria and dysuria. Cystoscopic biopsy revealed mast cell-derived interstitial cystitis which has not been previously reported in LRBA deficiency in the literature to our knowledge. A multi-gene next-generation sequencing panel performed for immune deficiencies (264 genes and 524 amplicons), resulted in the identification of an apparently homozygous LRBA mutation (p.Arg722His) in the Beige and Chediak-Higashi (BEACH) domain. The SNP array showed copy neutral absence of heterozygosity of the entire chromosome 4, which is consistent with uniparental isodisomy of chromosome 4. Conclusion: In conclusion, this case study underscores the critical role of LRBA in immune regulation and highlights the clinical heterogeneity associated with LRBA deficiency. The patient's presentation with severe immune dysregulation, including massive splenomegaly, portal hypertension, and the novel finding of mast cell-derived interstitial cystitis, expands the clinical spectrum of LRBA mutations. The identification of an apparently homozygous LRBA mutation via next-generation sequencing further emphasizes the importance of genetic analysis in diagnosing monogenic defects manifested as CVID-like phenotype. This is the first reported case of LRBA deficiency due to whole chromosome UPD to our knowledge. Future research should focus on elucidating the full range of clinical manifestations and developing targeted therapies for patients with LRBA deficiency. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory bowel disease (IBD) is classified as very early-onset IBD (VEO-IBD) if it occurs before age six. VEO-IBD may progress with more severe and resistant inflammation findings in the gastrointestinal and non-gastrointestinal systems. Case report: We describe the clinical presentation of a 4-year-old female presenting with recurring episodes of bloody diarrhea, vomiting, abdominal pain, fever, arthritis, erysipelas, and bilateral ankle pain. Monogenic primary immunodeficiency (PID) was suspected due to her age, different clinical findings and the presence of atypical gastroscopic findings and deep transmural ulcerations resembling Crohn's disease. The gene analysis showed a homozygous mutation in the inducible T cell co-stimulator (ICOS) deficiency genes. Discussion/Conclusion: This case presentation shares our clinical experience and demonstrates the link between IBD progression and ICOS deficiency. [ABSTRACT FROM AUTHOR]

Introduction: The development of secondary hypogammaglobulinemia (sHGG) because of tumor treatment and/or the primary underlying hematologic disorder holds substantial clinical significance. B-cell-derived malignancies and anti-CD20 monoclonal antibodies (mAbs) represent important risk factors for the development of sHGG. In addition, the occurrence of acute thrombocytopenia (AT) induced by anti-CD20 therapy is a known, albeit rare, phenomenon. Case Presentation: A 54-year-old patient experiencing the first relapse of classical follicular lymphoma has commenced salvage therapy following the R-DHAP protocol. After rituximab infusion, platelet count dropped from 116 × 109/L to 13 × 109/L within 24 h. Reduced immunoglobulin G levels indicated moderate HGG; thus, we immediately administered intravenous immunoglobulins (IVIg). Within 5 days after initiation of IVIg, platelet count increased and stabilized at >50 × 109/L. Conclusions: It seems possible that anti-CD20 mAbs act like or activate similar mechanisms as autoantibodies in immune thrombocytopenia (ITP). Assuming that anti-CD20 therapy-induced AT is an ITP-like condition, HGG could be considered a potential risk factor. Thus, appropriate treatment of HGG with IVIg prior to anti-CD20 mAb therapy could potentially alleviate anti-CD20 therapy-induced AT. [ABSTRACT FROM AUTHOR]

The article discusses a 25-year-old female patient with common variable immunodeficiency (CVID) who developed diffuse large B-cell lymphoma, emphasizing the importance of monitoring for malignancies in CVID patients. Topics include the connection between CVID and increased cancer risk, the clinical significance of splenomegaly, and recommendations for ongoing cancer screening and management in patients with immunodeficiencies.

The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system's ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant. The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G (IgG) subclass deficiencies and isolated lgA, IgM, IgE deficiencies have all been described in the literature with variable prevalence. Methods: These isotype deficiencies have a variable presentation front asymptomatic to recurrent infections resistant to prophylactic antibiotics. Results: Atopic disorders and autoimmime diseases are common coniorbidities. lgE deficiency has been associated with impaired vaccille response and an increased risk of nialignancy, particillarly in patients with no allergic comorbidities and those with non-common variable immunodeficiency (CVID) liumoral immunodeficiency, ISM deficiency, IgGZ deficiency, aild CL)4 li/iiip//openia. Conclusion: Close monitoring for malignancy sliould be strongly considered for the patients who are nt risk. Treatment is variable and may include alitimicrobial therapies for illnesses and prophylactic antibiotics iii select patients, and immunoglobulin replacement can be considered for patients with refractory, recurrent infections. [ABSTRACT FROM AUTHOR]

Immunodeficiency disorders pose substantial burdens on the health-care system and the patients affected. Broadly, immunodeficiencies can be divided into primary immunodeficiency disorders (PIDDs) and secondary immunodeficiency disorders. This review will focus on PIDDs. The overall prevalence for PIDDs is estimated to be ~1-2% of the population but may be underestimated due to underdiagnosis of these conditions. PIDDs affect males slightly more often than females. The mortality rates differ based on the specific condition but can be extremely high if the condition is left undiagnosed or untreated. The most common causes of death are infections, respiratory complications, and cancers (e.g., lymphoma). Comorbidities and complications include infection, chronic lung disease, granulomatous lymphocytic interstitial lung disease, and autoimmune disorders. The disease burden of patients with common variable immunodeficiency (CVID) is estimated to be greater than patients with diabetes mellitus and chronic obstructive pulmonary disease. PIDDs have a serious impact on the quality of life of the patients, including sleep disturbance, anxiety, and social participation as well as other psychosocial burdens associated with these disorders. The financial cost of PIDDs can be substantial, with the cost of untreated CVID estimated to be $111,053 per patient per year. Indirect costs include productivity loss and time lost due to infusion and hospital visits. Secondary immunodeficiency is not fully discussed in this review but likely contributes equally to the burden of overall immunodeficiency disorders. Management of patients with PIDDs should use a comprehensive approach, including medical, nursing, psychiatric, and quality of life, to improve the outcome. [ABSTRACT FROM AUTHOR]

We evaluated some functional indices of neutrophils in 100 adult patients with a verified diagnosis of primary antibody production deficiency (44 patients with common variable immunodeficiency – CVID, and 56 patients with selective IgA deficiency – SigAD). The diagnosis was made according to the criteria of the Pan-American Group for Immunodeficiency and European Society for Immunodeficiency. The criteria for diagnosis were based on clinical data, medical history and results of laboratory tests. All patients with CVID received regular immunoglobulin replacement therapy, and the SIgAD patients received symptomatic treatment on demand. The examination was performed beyond the infectious episodes, inflammatory events or exacerbation of chronic disorders upon admission for planned hospitalisation, before any therapeutic and diagnostic procedures. In addition to standard clinical and laboratory examination appointed for the mentioned diseases, we assessed fnctional status of neutrophils: superoxide-anion radical production, NETosis, phagocytosis and apoptosis. Taking into account clinical manifestations, the patients with CVID were divided into 6 clinical subgroups: without CVID-related complications (13.6%); with infectious complications, i.e., bronchiectatic disease (15.9%), autoimmune syndromes (22.7%), polyclonal lymphoid infiltration (13.6%), enteropathic syndrome (34.1%), and malignant neoplasms (9.1%). Four phenotypes were identified in the patients with SIgAD: absence of SIgAD-related complications (28.6%); autoimmune syndrome (16.1%), non-malignant lymphoproliferation (3.6%) and enteropathy (28.6%). Higher incidence of non-infectious complications (autoimmune syndrome, non-malignant lymphoproliferation, enteropathies) was found in СVID compared to SIgAD patients (χ2 = 10.27; p = 0.001). Patients from the both groups showed changes in neutrophil reactivity compared to control values expressing higher basal generation of superoxide radicals (p < 0.001), NETosis activity (p = 0.005) and apoptosis (p < 0.001) with decreased phagocytic function (p < 0.001) and lower reserve for reactive oxygen species formation (p < 0.001). The maximal degree of changes in phagocytosis and superoxide-producing activity was observed in СVID; altered NETosis was revealed in SIgAD. The development of non-infectious complications was accompanied by a significant increase in stimulated NETosis indexes, thus suggesting a promising index in order to assess stability of clinical course and to predict development of complications in congenital defects of antibody production.

Abstract Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced levels of specific immunoglobulins, resulting in frequent infections, autoimmune disorders, increased cancer risk, and diminished antibody production despite an adequate B cell count. With its clinical manifestations being highly variable, the classification of CVID, including the widely recognized Freiburg classification, is primarily based on clinical symptoms and genetic variations. Our study aims to refine the classification of CVID by analyzing transcriptomics data to identify distinct disease subtypes. We utilized the GSE51405 dataset, examining transcriptomic profiles from 30 CVID patients without complications. Employing a combination of clustering techniques—KMeans, hierarchical agglomerative clustering, spectral clustering, and Gaussian Mixture models—and differential gene expression analysis with R’s limma package, we integrated molecular findings with demographic data (age and gender) through correlation analysis and identified common genes among clusters. Three distinct clusters of CVID patients were identified using KMeans, Agglomerative Clustering, and Gaussian Mixture Models, highlighting the disease’s heterogeneity. Differential expression analysis unveiled 31 genes with variable expression levels across these clusters. Notably, nine genes (EIF5A, RPL21, ANP32A, DTX3L, NCF2, CDC42EP3, CHP1, FOLR3, and DEFA4) exhibited consistent differential expression across all clusters, independent of demographic factors. The study recommends categorizing patients based on the four genes, NCF2, CHP1, FOLR3, and DEFA4—as they may assist in prognostic prediction. Transcriptomic analysis of common variable immunodeficiency (CVID) patients identified three distinct clusters based on gene expression, independent of age and gender. Nine differentially expressed genes were identified across these clusters, suggesting potential biomarkers for CVID subtype classification. These findings highlight the genetic heterogeneity of CVID and provide novel insights into disease classification and potential personalized treatment approaches.

Background: Individuals with inborn errors of immunity (IEI) have an increased risk of developing malignancies compared to their peers. We report a case of Hodgkin lymphoma in an adolescent with CD27 deficiency. Case report: A 15-year-old girl presented with cervical swelling and breathlessness for 3 days. Her past history was remarkable, with a history of recurrent respiratory infections. On examination, she had grade 2 clubbing, bilateral cervical lymphadenopathy, hepatosplenomegaly, and bilateral coarse crepitations. Biopsy showed overlapping immunomorphological features of classic Hodgkin lymphoma (HL), with features intermediate between diffuse large B-cell lymphoma and HL. A staging PET-CT revealed a stage III disease and bronchiectatic changes in bilateral lungs. The serum immunoglobulin levels showed hypogammaglobulinemia. Next generation sequencing demonstrated a homozygous missense variant in the CD27 gene (c.319C>T; p.Arg107Cys). She was treated with ABVD/COPDac chemotherapy along with supportive care. She is currently 16 months post-treatment. Conclusion: CD 27 deficiency is a rare IEI with a common variable immunodeficiency phenotype and a high propensity to develop lymphomas. Clinical suspicion, early detection, and management are warranted to prevent complications and mortality.

Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. "Fair or poor" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoimmune and inflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported "fair or poor" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD. [ABSTRACT FROM AUTHOR]

Abstract Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children’s hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.

Background: Autoimmune hemolytic anemia (AIHA) is a group of hematological disorders where there is autoantibody mediated destruction of red blood cells. It can be life threatening if not appropriately treated. Early diagnosis and work up and timely multipronged management is the key to success. Case report: We report four cases of diverse etiology - one each of post SARS-CoV-2 AIHA, idiopathic AIHA, drug-induced AIHA and common variable immunodeficiency (CVID) associated Evans syndrome. All were treated with steroids as the first line agent while the child with CVID required additional immunosuppressive therapy. Conclusion: This case series re-emphasizes the need to look for diverse etiologies in AIHA. The role of whole exome sequencing is discussed for a definitive diagnosis if accessible in selected cases.

Objective: Common variable immunodeficiency (CVID) can affect the quality of life (QoL), which can be better assessed with validated scales. Our goal was to validate the Turkish version of the Italian CVID-QoL questionnaire.. Materials and Methods: International recommendations for the cultural adaptation and translation process of the original scale were followed. CVID patients completed the Turkish CVID-QoL questionnaire between October 2019 and January 2020. The Short Form Health Survey (SF-36) was used as a comparative questionnaire. Reliability, reproducibility, factor analysis, content validity, convergent validity, and discriminant validity were analyzed. Results: Fifty CVID patients were included in the study. 64% of the patients (n=32) were male, the mean age of the patients was 36.68 ± 13.2 years, and the median duration of disease was 52.5 months. The instrument had good internal consistency in 50 patients [Cronbach's alpha: 0.92, emotional functioning (EF): 0.91, relational functioning (RF): 0.77]. Twenty-six patients answered the survey questions again within 14-21 days. Reproducibility was very high; QoL global, intraclass correlation coefficient (ICC)=0.80 (95% CI 0.56-0.91); EF, ICC=0.78 (95% CI 0.51-0.90); RF, ICC=0.82 (95% CI 0.59-0.92); Gastrointestinal and skin symptoms (GSS), ICC=0.89 (95% CI 0.76-0.95); (p<0.001, p<0.001, p<0.001, p<0.001). QoL global, EF and RF scores showed good convergent validity with the similar subscales of SF-36. The number of infections within the last 3 months had a significant impact on QoL global (p=0.038), EF (p=0.045) and RF (p=0.028). Conclusion: The Turkish version of the CVID QoL scale has appropriate validity and reliability among Turkish patients with CVID. [ABSTRACT FROM AUTHOR]