Common Variable Immunodeficiency Research Articles

Determinants of Relapse and Treatment-Free Survival Following Splenectomy in Patients with Immune Cytopenias

Background: Splenectomy has historically been a treatment option for patients with immune cytopenia not responding to standard treatment. Despite being a highly effective treatment option, current guidelines recommend this strategy as a third-line treatment. There is a need for more evidence regarding predictive response factors that could help adequately select the ideal candidate for splenectomy, its effectiveness, and related complications. The study aims to identify factors associated with relapse in patients diagnosed with immune cytopenia who have undergone splenectomy. Methods: Retrospective cohort study including patients with immune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES), who underwent splenectomy between January 1990 and March 2023 in a tertiary referral center in Mexico City. Response criteria were based on the 2019 American Society of Hematology guidelines for ITP and the 2020 First International Consensus Meeting for AIHA. We defined early surgical complications as those occurring in the first 30 days from splenectomy; a durable response after splenectomy was described as lasting one year or more. Results: With a median follow-up of 100 months (interquartile range [IQR] 55.6 - 141.7 months), 173 patients were analyzed: 70% were female, 83% had primary ITP, 10% AIHA, and 7% ES. Only 15% had secondary autoimmune cytopenia: 4% systemic lupus erythematosus, 4% antiphospholipid antibody syndrome (APS), and 4% both; 3% had other autoimmune diseases; one (0.5%) patient had common variable immunodeficiency (CVI). Before splenectomy, all the patients received corticosteroids as first-line treatment, 13% rituximab, and 10% thrombopoietin receptor analogs (TPO-RA). Splenectomy was performed as the second-line treatment (2L) in 43% of the cases and as a third or later line of therapy (>2L) in 57%. When analyzing periods, there is a decline in the frequency of splenectomy as 2L: 62% from 1990-2010, 48% from 2011-2015, and 33% from 2016-2023. The median time from diagnosis to splenectomy was 6.3 months (IQR 2.6 - 19.9 months), 10.9 months (IQR 3.7 - 30.9 months), and 16.5 months (IQR 3.5 - 49.5 months) in the respective periods. The global response rate after splenectomy was 97.7%: complete response in 91.9%, partial response in 5.8%, and durable responses in 77.5%. The relapse rate after splenectomy was 32.0%, significantly lower in patients undergoing splenectomy as 2L vs. >2L: 20.0% vs. 40.8% (p<0.001). The relapse rate after splenectomy was the same in the different periods (p = 0.244). The number of patients free of a new line treatment after splenectomy at 100 months was significantly higher in patients undergoing splenectomy as 2L vs. >2L: 82.7% vs. 65.3% (p=0.014). When analyzing factors associated with relapse requiring a new line of treatment, splenectomy as the 2L (HR 0.403; 95% CI 0.206-0.788, p = 0.008) and post-splenectomy thrombocytosis (HR 0.301; 95% CI 0.144-0.6, p = 0.001) were associated with higher treatment-free survival in the multivariate analysis (See Table 1 and Figure 1). The rate of early surgical complications was 14%: severe infections (8.7%), bleeding (5.2%), and thrombosis (3.5%). Late surgical complications occurred in 8%: thrombosis (5.8%), infections (2.9%), and bleeding (2.3%). Five patients (3%) died during the follow-up period: 3 related to thrombocytopenia, one to splenectomy (abdominal sepsis in a patient with CVI), and one due to prostate adenocarcinoma. The use of TPO-RA before splenectomy and the diagnosis of APS were associated with post-surgical thrombosis in the multivariate analysis: OR 6.8 (95% CI 1.9 - 23.5, p = 0.002) and OR 4.3 (95% CI 1 - 17.8, p = 0.044), respectively. Conclusions: At our center, splenectomy is frequently employed as a very early 2L treatment. However, this tendency has diminished due to improved access to new drugs. Interestingly, splenectomy as 2L vs. >2L is associated with better outcomes which contrast with current recommendations. In a center where splenectomy is frequently performed, the procedure is associated with a reasonable rate of complications. In patients with immune cytopenia, splenectomy as a second-line treatment is a valid, effective, relatively safe, and cost-effective option, particularly in low-income areas with limited access to new therapies.

Whole Exome Sequencing of Patients with Adult-Onset Evans Syndrome: A Cohort of 80 Patients

Introduction Loss of tolerance toward several self-antigens suggests an underlying genetic predisposition. A previous study (1) conducted in children with Evans syndrome revealed a high prevalence of pathogenic mutations in genes involved in primary immunodeficiencies. Whether these findings are restricted to children is unknown. In this study, we assessed the prevalence of constitutional genetic variants in a cohort of patients with adult onset Evans syndrome. Patients and methods We consecutively included from November 2021 to June 2023 patients that had been diagnosed with adult onset (≥18 years) Evans syndrome (association of immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia (wAIHA) and/or autoimmune neutropenia (AIN) according to international guidelines (2,3)), and identified in France throughout the network of the national reference center for adult' autoimmune cytopenia. We excluded patients with a systemic lupus (according to Systemic Lupus International Collaborating Clinics criteria (4)), and patients with indolent B cell malignancies at Evans syndrome onset. Clinical and biological data were retrospectively collected using a standardized form. Patients underwent whole-exome sequencing after written and informed consent was obtained. Gene variants already published and/or with in vitro confirmed consequences were considered as genetic diagnoses. Clinical interpretation of variants was performed according to the ACMG guidelines (5). A patient was classified as having a genetic diagnosis if carryinghemizygous/heterozygous pathogenic or likely pathogenic variant (for X-linked or autosomal dominant conditions), or 2 pathogenic or likely pathogenic variants in the same gene (for autosomal recessive conditions). Results We identified 80 patients (40% female, median age 31 years at Evans syndrome diagnosis [range 18-76]) with adult-onset Evans syndrome from 19 centers. Median age at first cytopenia was 28 years [range 1-73], and 13 patients (16%) were under 18 years at first cytopenia. 78 patients (96%) had ITP (chronic in 87%), 59 (73%) had wAIHA (with at least one relapse in 58%), and 38 (47%) had AIN (chronic in 74%). Median delay between first and second cytopenia was 18 months (range 0 - 329) and 28 patients (35%) had synchronous onset of cytopenia. Twenty-four patients (30%) had associated immune manifestation (involving endocrine system in 9%, lung in 9%, gastrointestinal tract in 6%, skin in 5%, central nervous system in 4%) and 28% had antinuclear antibody titers ≥ 1/160. Lymphoproliferation was found in 56%, including lymphadenopathy in 41% and splenomegaly in 35%. Nine patients (11%) had lymphoma or cancer history. Twenty patients (25%) had humoral immune defect, including 13 (16%) with a common variable immunodeficiency (CVID)-like phenotype. In the whole cohort, 9 patients (11.25%) had a genetic diagnosis that could be linked to Evans syndrome, with heterozygous variants in CTLA4, STAT3, NFKB1, CYBB, TNFAIP3, DDX41, MYH9 and homozygous variant in PIK3CG. Twenty (25%) patients had genetic testing prior to this study (targeted Sanger sequencing [N=3], or NGS panel [N=17]), resulting in 2 genetic diagnoses ( CYBB and TNFAIP3). A family history of immune manifestations in first-degree relatives was found in 56% of the patients with genetic diagnosis versus 20% of patients without (P=0.0308). However, the proportion of patients with CVID-like phenotype, associated immune disorder, lymphoproliferation, cancer/lymphoma, positive antinuclear antibodies, or pediatric onset of first cytopenia was not significantly increased in patients with genetic diagnosis. Discussion As expected, the proportion of genetic diagnoses in patients with adult onset Evans syndrome was lower that what was previously described in children, but led to a significant impact on clinical management in some patients. We did not find clinical or biological features associated with a genetic diagnosis, suggesting that genetic testing should be considered in every adult patient diagnosed with Evans syndrome in the absence of any obvious underlying cause or condition. References (1) Hadjadj J et al., Blood 2019; 134: 9-21. (2) Provan D et al., Blood Adv 2019; 3: 3780-817. (3) Jäger U et al., Blood Rev 2020; 41: 100648. (4) Petri M et al., Arthritis Rheum 2012; 64: 2677-86. (5) Richards S et al., Genet Med 2015; 17: 405-24.

Endoscopic and histopathological hints on infections in patients of common variable immunodeficiency disorder with gastrointestinal symptoms

Background and aimsCommon variable immunodeficiency disorder (CVID) patients may have gastrointestinal (GI) involvement and suffer from infections, which are poorly understood. This study aimed to evaluate the clinical, endoscopic, and histopathological features of CVID patients with GI symptoms and determine their correlation with infections.MethodsWe performed a retrospective study on 21 CVID patients with GI symptoms who underwent endoscopic examination in Peking Union Medical College Hospital from 2000 to 2020. The clinical, infectious, endoscopic, and histopathological features were reassessed.ResultsChronic diarrhea was the most prevalent GI symptom, observed in 95.2% of our CVID cohort. Over 85% of patients had low body weight and malabsorption. Small bowel villous atrophy was found in 90.5% of patients under endoscopy and mostly confirmed by histopathology. GI infections were identified in 9 (42.9%) patients. Of these, 7 patients with diffuse and obvious nodular lymphoid hyperplasia (NLH) of small bowel under endoscopy had significantly higher infection rate (85.7% vs 21.4%, p < 0.05), predominantly with Giardia and bacteria. Small bowel biopsies showed 95% of patients lacked plasma cells and 60% had increased intraepithelial lymphocytes (IELs), but not significantly different between GI infection and non-infection group. Most patients improved after intravenous immunoglobulin and anti-infection therapy.ConclusionsCVID could involve GI tract, particularly small bowel. Obvious NLH under endoscopy could be a hint for GI infection in CVID patients. Comprehensive endoscopic and histopathological evaluation may be helpful in CVID diagnosis and identification of potential co-infection, leading to proper treatment.

Features of the immune status and comorbidities in children with alopecia areata

Increased incidence of alopecia has been noted in children at the present time. Participation of autoimmune (immunopathological) mechanisms in pathogenesis of this disease necessitates additional study of immune status and characteristics of comorbid pathologies. The aim of our study was to specify the features of immune status and comorbidities in children with alopecia areata. The observation group consisted of children with various types of alopecia areata (n = 57), a comparison group included children without clinical manifestations of alopecia or a history of alopecia (n = 157). We performed a comparative evaluation of major lymphocyte subpopulations (CD3+, CD3+CD4+, CD3+CD8+, CD3+CD19+), interleukins (IL-4, IL-6), immunoglobulins (IgA, IgM, IgG), parameters of phagocytic activity (absolute phagocytosis, percentage of phagocytosis, phagocytic number and phagocytic index) and IgE to house dust and cat hair. Analysis of comorbidities was also performed. Statistical processing was carried out with Jamovi software. We have found that the focal clinical form of alopecia prevailed over the subtotal and total forms by 1.8 times (p = 0.033) in the observation group rather than in comparison group, with common variable immunodeficiency being more often (1.4-fold), chronic tonsillitis (3.9-fold), allergic rhinitis (3.9-fold) and autoimmune thyroiditis, which was absent in the comparison group. Among the children with alopecia, disturbances of the T-cell link were revealed, i.e., a higher median levels of the relative and absolute numbers of CD3+CD4+ cells (p = 0.001 to 0.003), larger proportions of elevated values for IgA (4.1-fold), IgM (7.3-fold), IgG (13.2-fold) with p-levels of 0.0001 to 0.0008; increased IL-4 (8.1-fold) and IL-6 (4.6-fold), with p = 0.002-0.004, along with medium and relatively strong correlations with alopecia. In children with alopecia, we have determined a 3.3-fold proportion of reduced values of absolute phagocytosis and 3.7-fold reduced percentage of phagocytosis (p = 0.0012 to 0.028), with an sufficient correlation (weak to moderate strength) with alopecia, as well as lower values of the median phagocytic index and phagocytic number in the observation group (p &lt; 0.001) associated with a average-strength correlation. Hence, an imbalance of the immune system components was revealed in children with alopecia which manifested with signs of immune hyperfunction, characteristic, e.g., of autoimmune and allergic processes, accompanied by more frequent registration of autoimmune thyroiditis and allergic rhinitis. Moreover, distinct signs of immune deficiency, are found, characterized by a decrease in phagocytic activity and higher incidence of common variable immunodeficiency and chronic tonsillitis.

Phenotype and oxidative burst of low-density neutrophil subpopulations are altered in common variable immunodeficiency patients.

Common variable immunodeficiency disorder (CVID) is the most common form of primary antibody immunodeficiency. Due to low antibody levels, CVID patients receive intravenous or subcutaneous immunoglobulin replacement therapy as treatment. CVID is associated with the chronic activation of granulocytes, including an increased percentage of low-density neutrophils (LDNs). In this study, we examined changes in the percentage of LDNs and the expression of their surface markers in 25 patients with CVID and 27 healthy donors (HD) after in vitro stimulation of whole blood using IVIg. An oxidative burst assay was used to assess the functionality of LDNs. CVID patients had increased both relative and absolute LDN counts with a higher proportion of mLDNs compared to iLDNs, distinguished based on the expression of CD10 and CD16. Immature LDNs in the CVID and HD groups had significantly reduced oxidative burst capacity compared to mature LDNs. Interestingly we observed reduced oxidative burst capacity, reduced expression of CD10 after stimulation of WB, and higher expression of PD-L1 in mature LDNs in CVID patients compared to HD cells. Our data indicate that that the functional characteristics of LDNs are closely linked to their developmental stage. The observed reduction in oxidative burst capacity in mLDNs in CVID patients could contribute to an increased susceptibility to recurrent bacterial infections among CVID patients.

B-2 lymphocytes and the balance of pro and anti-inflammatory cytokines in infectious and autoimmune phenotypes of common variable immune deficiency

Objective: comparative characteristics of the subpopulation composition of B- lymphocytes and the cytokine spectrum of peripheral blood in infectious and non-infectious manifestations of CVID.Materials and methods: the results of observation of 10 people diagnosed with CVID have been presented. Six patients the clinical manifestation had an infectious phenotype of the disease of synopulmonary localization. Four patients were diagnosed with Crohn's disease, hemolytic anemia, and autoimmune hepatitis. The level of cytokines IL-4, IL-10, IL-17, TNF-α, IFN-γ in blood serum was determined by the ELISA, the phenotypic characteristic of B cells of peripheral blood cells was carried out by flow cytofluorimetry.Results: the proportion of memory B cells in the healthy donors is 30% of all B-lymphocytes, on infectious manifestation of CVID – 12%, with autoimmune – 14%. The number of switched memory B-lymphocytes relative to the total pool of B-2 cells in infectious manifestation is greater (2.3%) than in autoimmune ones (1.4%). In patients with infectious manifestations the content of IFN-γ and TNF-α was increased inrelation to healthy donors of the comparison group, there were no differences in the serum amount of IL-17, with autoimmune manifestations, the content of all these cytokines was increased, IFN-γ and TNF-α being to a greater extent.Conclusion: impaired formation of memory B-lymphocytes and cytokine dysregulation of immune processes are detected regardless of the variant of clinical manifestation of CVID. The nature and degree of changes differ depending on the clinical phenotype of the disease.

In-depth blood immune profiling of Good syndrome patients.

Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID). Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61). All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected. Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

Genetic characteristics of common variable immunodeficiency patients with autoimmunity.

Background: The pathogenesis of common variable immunodeficiency disorder (CVID) is complex, especially when combined with autoimmunity. Genetic factors may be potential explanations for this complex situation, and whole genome sequencing (WGS) provide the basis for this potential. Methods: Genetic information of patients with CVID with autoimmunity, together with their first-degree relatives, was collected through WGS. The association between genetic factors and clinical phenotypes was studied using genetic analysis strategies such as sporadic and pedigree. Results: We collected 42 blood samples for WGS (16 CVID patients and 26 first-degree relatives of healthy controls). Through pedigree, sporadic screening strategies and low-frequency deleterious screening of rare diseases, we obtained 9,148 mutation sites, including 8,171 single-nucleotide variants (SNVs) and 977 Insertion-deletions (InDels). Finally, we obtained a total of 28 candidate genes (32 loci), of which the most common mutant was LRBA. The most common autoimmunity in the 16 patients was systematic lupus erythematosis. Through KEGG pathway enrichment, we identified the top ten signaling pathways, including "primary immunodeficiency", "JAK-STAT signaling pathway", and "T-cell receptor signaling pathway". We used PyMOL to predict and analyse the three-dimensional protein structures of the NFKB1, RAG1, TIRAP, NCF2, and MYB genes. In addition, we constructed a PPI network by combining candidate mutants with genes associated with CVID in the OMIM database via the STRING database. Conclusion: The genetic background of CVID includes not only monogenic origins but also oligogenic effects. Our study showed that immunodeficiency and autoimmunity may overlap in genetic backgrounds. Clinical Trial Registration: identifier ChiCTR2100044035.

Common variable immunodeficiency-an independent risk factor for atherosclerotic cardiovascular diseases.

Atherosclerosis, a disease of chronic inflammation of the arterial wall, is the main cause of most cardiovascular diseases (CVDs). Common variable immunodeficiency (CVID), a group of diseases characterized by frequent infections due to defective antibody production and lack of human immunoglobulins, plays a role in immune activation and inflammation. Thus, it can be hypothesized that CVID increases the risk for atherosclerotic CVDs. On the other hand, it is also possible that CVID patients are protected from atherosclerotic CVDs based on their life-long immunoglobulin therapy. Here, we examined whether patients with CVID have an increased risk for atherosclerotic CVDs or whether they are protected from these diseases. Using an electronic patient database registry search of a population of 83 CVID patients and their age- and sex-matched, tenfold larger control population we demonstrate that CVID patients have a statistically significantly higher risk for coronary heart disease (OR 2.4, p = 0.015) and peripheral vascular disease (OR 12.5, p < 0.001). Regarding cerebrovascular disease, there was a trend towards CVID patients having more strokes or ischemic attacks, but the difference was not statistically significant (OR 2.0, p = 0.133). The combined OR for CVID patients for atherosclerotic CVDs was 2.6 (p = 0.001). CVID population had more hypertension, but smoking was more seldom. There were no statistically significant differences in the incidence of diabetes or levels of serum total, HDL or LDL cholesterol, or glycosylated hemoglobin A1c between CVID patients and their controls. CVID patients had infections more frequently and the OR for autoimmune diseases was 3.8 (p < 0.001). Finally, a multivariate logistic analysis showed that CVID is an independent risk factor for atherosclerotic CVDs (p = 0.002). The present study demonstrates for the first time that CVID is an independent risk factor for atherosclerotic CVDs. Further studies are required to fully understand the exact mechanisms behind this.

Telomere biology disorders may manifest as common variable immunodeficiency (CVID)

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15–35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5–1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes—despite their low prevalence—into the molecular screening of patients with antibody deficiencies.

High Frequency of Genetic Variants Influencing Diagnosis and Bleeding Pattern in Patients with Presumed Primary Immune Mediated Thrombocytopenia (ITP)

Introduction Immune mediated thrombocytopenia (ITP) is a platelet disorder in which the immune system attacks and destroys the body's own platelets. Mechanisms leading to low platelet count in ITP are multifactorial, involving both increased peripheral platelet destruction and decreased platelet production. This is caused by autoantibodies targeting megakaryocytes and platelet-specific glycoproteins, as well as cytotoxic T cells directly acting on platelets. Although antibodies in some cases can be found in patients with ITP, there is no well-established diagnostic test and the diagnosis is thus, one of exclusion. While most cases of ITP resolve within 3 months with or without treatment, some patients do not respond to conventional treatment and develop a refractory ITP. It is likely that in the group of patients diagnosed with refractory ITP, some does not have an immune mediated thrombocytopenia, but other causes of low counts (PLC)s. With the development of high throughput sequencing and the increasing knowledge of inherited bleeding disorders, the possibility to identify the underlying cause of disease in these patients is steadily growing. In ITP, there is a high degree of interindividual differences in bleeding rates, where some patients have no bleeding symptoms despite of unmeasurable PLC, whereas other patients show severe bleeding symptoms at PLC &amp;gt; 30 x10 9 /L. The underlying etiology of these discrepancies is currently unknown and complicates the clinical care of these patients. We hypothesize that genetic defects influence the bleeding pattern in true ITP patients as well as being one of the underlying causes of thrombocytopenia in patients misdiagnosed with “refractory ITP”. The aim of this pilot study was to investigate whether upfront genetic screening of patients suspected of ITP could be a valuable diagnostic tool to determine presence of inherited thrombocytopenia, secondary thrombocytopenia and genetic variants that might affect bleeding pattern. Method Patients were included after informed consent following the declaration of Helsinki. We performed whole genome sequencing (WGS) in patients diagnosed with presumed ITP at the Skåne University Hospital, Sweden. Whole genome sequencing was performed at the Center for Genomic Medicine at Rigshospitalet, Copenhagen. An in-silico gene panel consisting of 113 genes known to be associated with bleeding disorders as well as 86 genes associated with ITP (Using the VarSeq gene prioritisation algorithm phorank) was analysed and pathogenicity was classified according to the ACMG/AMP guidelines. Patients' medical records were examined, laboratory work up was performed and clinical data regarding demographics and information regarding bleeding was collected. A final evaluation of susceptible variants took place at multiple disciplinary team conferences. Results Twenty-one patients were enrolled (9 women, 12 men, 17 were adults and 4 children). Mean age of adult patients was 50,5 years and mean age of paediatric patients was 11,5 years. Out of 21 patients, 7 were shown to have genetic variants with relevance to their disease. All variants were found in adult patients. Two patients had variants related to inherited thrombocytopenia (X-linked thrombocytopenia(WAS) and monoallelic Bernard-Soulier Syndrome(GP1BB)), 4 had variants in genes related to secondary ITP (3 with variants associated with common variable immunodeficiency (NFKB1, TNFRSF13B) and 1 with systemic lupus erythematosus (TREX1)) and 1 had a variant associated with platelet dysfunction (platelet delta storage pool deficiency (UNC13D)). Only the variant associated with X-linked thrombocytopenia was previously described (class 5) whereas the remaining 6 variants were initially classified as variants of unknown significance (VUS). Functional work-up and co-segregation studies indicated them as probably pathogenic (class 4) but confirming studies are still pending. Conclusion In this pilot study, 33% of patients with presumed primary ITP had variants with relevance to their clinical phenotype, and we were able to diagnose 1 patient with an inherited bleeding disorder (X-linked thrombocytopenia). Whole genome sequencing seems to be a useful diagnostic tool in the work up of patients with thrombocytopenia where ITP is suspected to ensure the diagnosis and could also add important information when assessing bleeding risk in individual patients.

Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.

Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54years vs. 49years, p = 0.0004). These patients also had lower serum IgA (13mg/dL IQR 60mg/dL vs. 28.4mg/dL IQR 66mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population. These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication.

High occurrence of autoimmune and lymphoproliferative manifestations in adults with common variable immunodeficiency in southernTaiwan.

There are no reported case series of common variable immunodeficiency (CVID) from southern Taiwan. A 20-year review was performed in adult CVID from a southern Taiwan medical center. Patients with ages of 18 years or older were enrolled from May, 2003 to April, 2023. Twelve patients were identified, 8 females/4 males aged 23 to 68 (38.9±13.4) with one to 11 years (5.0±3.3) delay of diagnosis after disease onset. There were concomitant autoimmune disorders in 7 (58 %), splenomegaly in 10 (83%), lymphadenopathy in 4 (25%) and B-cell lymphoma in 2 (17%). All received intravenous immunoglobulin (IVIg) infusion with improved autoimmune-mediated arthritis in 2. Patients with higher IgG trough levels (above 500mg/dL) had a better survival than those with lower IgG trough levels. Adult CVID in southern Taiwan has a high occurrence of autoimmune and lymphoproliferative manifestations. Early diagnosis with IVIg infusion might improve the presentations.

Navigating the management complexity in long-term asymptomatic immunodeficiency

Background: Common variable immunodeficiency disorder (CVID) is a condition associated with recurrent infections and non-infectious outcomes, including lung disease like bronchiectasis and granulomatous and lymphocytic interstitial lung diseases (GLILD), autoimmune disease, enteropathy, and lymphoma. Treatment involves initiation of replacement immunoglobulin (Ig), which is a lifelong commitment. Prior to Ig replacement, life expectancy for patients with CVID was less than 15 years. With replacement Ig, it has improved to over 50 years. In most cases, patients present to a clinician with a history of recurrent infections, and treatment is indicated. However, in patients with asymptomatic disease, the best timing to start treatment can be difficult to determine. Case: We present a case of an otherwise healthy male who had an incidental diagnosis of CVID. Results: Workup revealed hypogammaglobulinemia for over 30 year. Discussion: Though successful in reducing infections, Ig replacement can come with many side effects, as well as a heavy medical burden to the patient and the healthcare system. It is also a big life adjustment, and can greatly affect a patient's quality of life. In the military, a diagnosis of an immunodeficiency, and the need for monthly intravenous immunoglobulin (IVIG) can be detrimental to deployment readiness, and a patient's military career. Risks and benefits need to be weighed prior to initiating Ig therapy.

In-depth immune profiling reveals advanced B- and T-cell differentiation to be associated with Th1-driven immune dysregulation in common variable immunodeficiency

Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by low levels of antibodies. In addition to infections, many patients also suffer from T-helper 1-driven immune dysregulation, which is associated with increased mortality. The aim of this study was to perform in-depth characterization of the T and the B cell compartments in a well-defined cohort of patients affected by CVID and correlate the findings to the level of clinical immune dysregulation. We used mass cytometry, targeted proteomics, flow cytometry and functional assays to delineate the immunological phenotype of 15 CVID-affected patients with different levels of immune dysregulation. Unbiased clustering of T cell mass cytometry data correlated with CVID-related immune dysregulation and plasma protein profiles. Expanded CXCR3+ T-bet-expressing B cells correlated with effector memory CD4+ T cell clusters, and increased plasma levels of CXCR3-ligands. Our findings indicate an interplay between B cells and T cells in CVID-related immune dysregulation and provide a better understanding of the underlying pathological mechanisms.

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia.

This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future.

Long term management of complex patient with common variable immunodeficiency – a case report

Long term management of complex patient with common variable immunodeficiency – a case report

Common Variable Immunodeficiency and Selective IgA Deficiency: Focus on Autoimmune Manifestations and Their Pathogenesis

Inborn errors of immunity (IEI) are multifaced diseases which can present with a variety of phenotypes, ranging from infections to autoimmunity, lymphoproliferation, and neoplasms. In recent decades, research has investigated the relationship between autoimmunity and IEI. Autoimmunity is more prevalent in primary humoral immunodeficiencies than in most other IEI and it can even be their first manifestation. Among these, the two most common primary immunodeficiencies are selective IgA deficiency and common variable immunodeficiency. More than half of the patients with these conditions develop non-infectious complications due to immune dysregulation: autoimmune, autoinflammatory, allergic disorders, and malignancies. Around 30% of these patients present with autoimmune phenomena, such as cytopenia, gastrointestinal and respiratory complications, and endocrine and dermatologic features. Complex alterations of the central and peripheral mechanisms of tolerance are involved, affecting mainly B lymphocytes but also T cells and cytokines. Not only the immunophenotype but also advances in genetics allow us to diagnose monogenic variants of these diseases and to investigate the pathogenetic basis of the immune dysregulation. The diagnosis and therapy of the primary humoral immunodeficiencies has been mostly focused on the infectious complications, while patients with predominant features of immune dysregulation and autoimmunity still present a challenge for the clinician and an opportunity for pathogenetic and therapeutic research.

Severe gastrointestinal cytomegalovirus infection with underlying common variable immunodeficiency in a middle aged lady

Cytomegalovirus is a common herpes virus infection found worldwide and by adulthood majority become seropositive. In immunosuppressed state it may reactivate to cause tissue invasive disease in gastro intestinal tract, liver, lungs, brain and retina with or without viremia. It is commonly seen in bone marrow transplant, organ transplant, AIDS and autoimmune disease requiring intense immunosuppressive therapy. Common variable immunodeficiency is a condition that affects both arms of the immune system and can lead to opportunistic infections. Chance is more when CD4 counts falls below 50 cells/microlt.

Evaluating Drug Prescription Patterns in Undiagnosed Common Variable Immunodeficiency Patients.

To compare the consumption of antibiotics (AB), systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding the diagnosis of common variable immunodeficiency (CVID) among CVID patients and matched controls and to estimate whether the level of consumption was associated with the risk of a subsequent CVID diagnosis. We conducted a nested case-control study, identifying all individuals (n=130 cases) diagnosed with CVID in Denmark (1994-2014) and 45 age- and sex-matched population controls per case (n=5850 controls) from national registers. Drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals. In the 3 years preceding a CVID diagnosis, we observed more frequent and higher consumption of all three drug classes. The association between consumption and risk of subsequent CVID diagnosis was statistically significant for all drug classes. The association was stronger with higher consumption and shorter time to CVID diagnosis. The fraction of cases compared to the controls redeeming ≥1 prescription of the included drugs during the study period was higher for AB (97% vs 52%), systemic steroids (35% vs 7.4%), and inhaled bronchodilators/glucocorticoids (46% vs 11.7%) (p<0.001). CVID patients have significantly higher use of AB, systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding CVID diagnosis than controls. Prescribing these drugs in primary healthcare could be an opportunity to consider (proactive) screening for CVID. Further studies are needed to identify optimal prescription cutoffs that could endorse its inclusion in public health policies.