Cases Of Common Variable Immunodeficiency Research Articles

Electronic health record signatures identify undiagnosed patients with common variable immunodeficiency disease.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases.

Dysimmunity in common variable immunodeficiency is associated with alterations in oral, respiratory, and intestinal microbiota

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections. Its aetiology remains unknown, and some patients present with severe non-infectious autoimmune or inflammatory complications with elevated associated morbimortality. Recently, intestinal dysbiosis has been proposed as a driver of immune dysregulation. In this study, we assessed the oral, respiratory, and gastrointestinal microbiota of 41 CVID patients (24 with dysimmune and 17 with infection complications) and 15 healthy volunteers using 16S rRNA gene sequencing to explore associations between microbiome profiles and CVID phenotypes. Profound differences in the composition of the microbiota in saliva, sputum, and stool were detected between dysimmune CVID patients and healthy individuals. Globally, respiratory species diversity and faecal bacterial richness were lower in CVID individuals with immune complications. Although a single species could not be identified as a robust predictor of dysimmunity, a combination of around 5–7 bacterial species in each type of sample could predict this severe phenotype with an accuracy of around 90% in the study population. Our study provides new insights into these previously unexplored but highly interrelated ecological niches among themselves and with patient profiles. Our data suggest that this disease-related systemic dysbiosis could be implicated in the immune dysregulation associated with severe cases of CVID.

Evaluation of MicroRNA-125b-5p and Transcription Factors BLIMP1 and IRF4 Expression in Unsolved Common Variable Immunodeficiency Patients.

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals. Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry. The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miRexpression (71.0% and 85.0%, respectively). Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.

Association of common variable immunodeficiency and rare and complex connective tissue and musculoskeletal diseases. A systematic literature review

To perform a systematic literature review (SLR) on the association of common variable immunodeficiency (CVID) and rare and complex connective tissue and musculoskeletal diseases, namely systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), relapsing polychondritis, antiphospholipid syndrome, immunoglobulin (Ig) G4-related disease, as well as undifferentiated and mixed connective tissue disease. An SLR on studies and cases about the association of CVID and rare and complex connective tissue and musculoskeletal diseases was performed. Animal studies were excluded. 170 publications fulfilled the inclusion criteria. Sjögren's syndrome was the most frequent connective tissue disease in CVID-patients. Most case reports exist on SLE and CVID with SLE mostly preceding the manifestation of CVID. Multiple cases were published reporting the concurrence of CVID and inclusion body myositis and single cases were found on CVID and antisynthetase syndrome, polymyositis, limited SSc and relapsing polychondritis, respectively. There are no cases of CVID and antiphospholipid syndrome, IgG4-related disease, as well as undifferentiated and mixed connective tissue disease. The concurrence of CVID and complex connective tissue and musculoskeletal diseases, especially SS, IIM, SSc and relapsing polychondritis is rare but relevant. The measurements of Ig-levels should be performed before the initiation of immunosuppressive therapy to allow for the differentiation of primary and secondary Ig-deficiency and substitute IG if necessary.

COVID-19 in complex common variable immunodeficiency patients affected by lung diseases.

In the general population, the risk of severe COVID-19 is associated with old age, male sex, hypertension, obesity and chronic diseases. Chronic lung diseases are listed as additional risk factors for hospitalization and ICU admission. The purpose of this review is to define whether chronic lung diseases, such as bronchiectasis and interstitial diseases, represent a risk for a severe SARS-CoV-2 infection in patients affected by common variable immunodeficiency (CVID), the most common symptomatic primary antibody defect. CVID patients with SARS-CoV-2 infection have been reported since the beginning of the pandemic with a wide range of clinical presentations ranging from asymptomatic to mild/moderate and severe COVID-19. The meta-analysis of 88 CVID cases described in large cohorts and case reports demonstrated that CVID patients with chronic lung involvement have an increased risk for severe COVID-19 in comparison to CVID without lung diseases (50 vs. 28%, relative risk 1.75, 95% confidence interval 1.04--2.92, P = 0.043). Differently from the general population, age and metabolic comorbidities did not represent a risk factor for severe course in this patient's population. Underlying chronic lung diseases but not age represent a risk factor for severe COVID-19 in CVID. Prompt therapeutic intervention should be adopted in SARS-CoV-2 positive CVID patients with chronic lung diseases independently of their age.

Investigating the Variation of TREC/KREC in Combined Immunodeficiencies

T-cell receptor excision circles (TREC)/Kappa-deleting recombination excision circles (KREC) assay has been recently recognized for detecting patients with primary (T- and/or B-cell) immunodeficiency (PID). We aimed to investigate the alterations of these biomarkers in some combined immunodeficiency patients compared to the healthy controls in different age groups. TREC and KREC were assessed in a total of 82 PID patients, most of them with exact genetic diagnosis (3 months to 42 years); using quantitative real-time-polymerase chain reaction (PCR). Patients had a final diagnosis of common variable immunodeficiency (n=23), ataxia-telangiectasia (AT) (n=17), hyper-IgE syndrome (HIES) (7 with DOCK8 deficiency, 4 with signal transducer and activator of transcription 3 (STAT3) deficiency, and 8 children with unknown genetic defects), Wiskott-Aldrich syndrome (WAS) (n=20), purine nucleoside phosphorylase (PNP)deficiency(n=1), dedicator of cytokinesis2 (DOCK2) deficiency (n=1), recombinase activating gene1 (RAG1) deficiency (n=1). Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients with defects in DOCK2, PNP, and RAG1. STAT3-deficient patients were normal for both biomarkers. All patients showed a significant difference in both markers compared to age-matched healthy controls. Our findings highlight that apart from severe types of T/B cell defects, this assay can also be used for early diagnosis the patients with late-onset of disease and even PIDs without a positive family history.

Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells.

Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.

Clinicopathologic features of Good’s syndrome: Two cases and literature review

BackgroundGood’s syndrome (GS) is an immunodeficiency disease, causing thymoma, low or absent B-cells, hypogammaglobulinemia, and defects in cell-mediated immunity. The most common clinical presentation is recurrent infection, followed by refractory diarrhea, due to the immunodeficiency. However, there are only few reports on intestinal endoscopy and pathology.Case summaryWe report here two typical GS cases with diarrhea as the prominent manifestation. Both cases presented with thymoma combined with immunodeficiency, characterized by hypogammaglobulinemia, low or absent B lymphocytes, and decreased T-cells with inverted CD4+/CD8+ T-cell ratio, while two GS patients were evaluated by endoscopy revealed mucosal edema and fine-granular or nodular appearance changes in the small intestine. Histological examination showed chronic inflammation and villous atrophy. A very interesting finding is that the inflammatory cell infiltration in the two GS cases was different. In one case, predominantly CD138+ plasma cells with only scattered CD3+ T-cells infiltration were revealed, while in another, it showed predominantly T-cells infiltration without plasma cells in the lamina propria. Although GS cases shared various clinical characteristics with common variable immunodeficiency (CVID) cases, they still differed from CVID cases in terms of its late onset, lack of familial clusters, low or absent peripheral blood B lymphocytes, absence of lymphoid hyperplasia, and plasma cells infiltration in the lamina propria in some patients. Although both patients had been diagnosed previously with recurrent diarrhea, respiratory infection, and thymoma, the association between these conditions and the possibility of GS was not recognized. The patients had remained misdiagnosed for 2 and 4 years, respectively, even after receiving the diagnosis of thymoma. The rarity of GS was likely the primary cause for the lack of disease recognition. Reporting of these cases will help to alert clinicians and raise awareness of this disease.ConclusionGS should be considered among the differential diagnoses for patients with unexplained recurrent diarrhea and opportunistic infection. Although it was regarded as a subset of CVID with thymoma, GS had a different clinical-pathological feature from CVID.

Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect.

Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals. Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR. We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: -0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients. Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects.

Like father, but not like daughter: familial cases of common variable immunodeficiency and de novo hereditary angioedema type 1/2

Hereditary angioedema (HAE) is an autosomal dominant condition, but spontaneous mutations can occur in 15% of cases. Genetic abnormalities have been found in less than 20% of patients with common variable immune deficiency (CVID). Neither of these conditions have a known association. We present a case of a father with CVID and a daughter with de novo hereditary angioedema.

M295 EOSINOPHILIC FASCIITIS IN COMMON VARIABLE IMMUNODEFICIENCY WITH HYPEREOSINOPHILIA

Eosinophilic fasciitis is a rare disorder that presents with scleroderma-like changes of connective tissues. There have been two cases of common variable immunodeficiency (CVID) associated with eosinophilic fasciitis reported in Europe. We report the first case of CVID associated with eosinophilic fasciitis in the United States in the setting of hypereosinophilia.

M284 EARLY PRESENTATION OF HYPOGAMMAGLOBULINEMIA IN A 6-MONTH-OLD WITH COMPOUND HETEROZYGOUS MUTATIONS IN TNFRSF13B

Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterized by abnormalities in B cell development and defective immunoglobulin production that typically presents in adolescents and adults in the third decade of life. While a genetic basis of most CVID cases remains elusive, variants in the TACI-encoding gene TNFRSF13B have been identified in up to 10% of cases. We describe a 6-month-old presenting with panhypogammaglobulinemia, recurrent infections, and failure to thrive (FTT).

Eosinophilic fasciitis in common variable immunodeficiency with hypereosinophilia

Eosinophilic fasciitis or Shulman disease is a rare disorder that presents with scleroderma-like changes of connective tissues accompanied by elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and transient peripheral eosinophilia. 1 Mazori D.R. Femia A.N. Vleugels R.A. Eosinophilic fasciitis: an updated review on diagnosis and treatment. Curr Rheumatol Rep. 2017; 19: 74 Crossref PubMed Scopus (34) Google Scholar To date, there have been 2 cases of common variable immunodeficiency (CVID) associated with eosinophilic fasciitis reported in Europe. Here, we report the first case of CVID associated with eosinophilic fasciitis in the setting of hypereosinophilia in the United States.

GLILD Revisited: Pulmonary Pathology of Common Variable and Selective IgA Immunodeficiency.

Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.

Vedolizumab therapy in common variable immune deficiency associated enteropathy: A case series

A number of gastrointestinal complications occur in common variable immunodeficiency (CVID). Infections are one cause, but various forms of severe non-infectious enteropathy also lead to substantial morbidity. The presence of T cell lymphocytic infiltrates in the mucosa have suggested that vedolizumab, a humanized monoclonal antibody which binds to alpha4 beta7 integrin and inhibits the migration of effector T-lymphocytes into gastrointestinal tissues, would be an effective treatment. A previous report of 3 CVID cases suggested benefit in 2 subjects. In this study 7 CVID patients with severe enteropathy were treated with vedolizumab. Four of the 7 completed vedolizumab induction therapy but 3 subjects had acute decompensation during induction and treatment was stopped. While one subject showed improvement, 6 of the 7 patients were withdrawn from therapy. While vedolizumab may be of use in some CVID subjects, it was not ultimately found helpful in most of these patients.

Somatic Mutations in T Cells As Possible Regulators of Immunodeficiency

▪The pathogenesis of common variable immunodeficiency (CVID) and many other immunodeficiencies is elusive, and no cure for these diseases exists. The characteristic features of CVID are immunoglobulin deficiency and recurrent infections, but autoimmunity co-manifests in 30% and lymphoproliferation in 50% of CVID cases. The failure to produce sufficient quantities of immunoglobulins is attributed to B cells, but as T cells are critical players in adaptive immune response and autoimmune disease, they have also suggested to play a role in CVID. As monogenic germline mutations account only for 2-10% of CVID cases, the etiology of CVID remains unknown in most cases.To study if somatic mutations in T cells contribute to immunodeficiencies, we recruited patients with broad immune dysregulation: 8 patients with late-onset CVID, and 9 patients with other type of immunodeficiency and/or severe autoimmunity. All patients signed informed consent and the declaration of Helsinki principles were followed. Study design and key patient characteristics are depicted in the Figure. To discover somatic mutations in T cells, we sequenced both CD4+ and CD8+ cells with a custom gene panel comprising of 2500 immune-related genes with an average coverage of 500x. Somatic variants were identified using the GATK MuTect2 toolset by using a panel of 21 healthy controls' CD4+ and CD8+ cells as a background. Variants were called using paired samples (CD4+ vs CD8+ and vice versa). This approach identifies variants that have occurred in mature T cells. To complement this approach, we performed variant calling also in single-sample mode to identify variants originating from hematopoietic progenitors.Paired-sample analyses revealed 44 somatic mutations in mature T cells in 10/17 (59%) patients: 30 (68%) in CD8+ and 14 (32%) in CD4+ cells. The mutations included 2 frameshift-, 37 missense-, and 5 nonsense variants. In silico tools (both Polyphen-2 and SIFT) predicted 19 (51%) of the missense mutations to be damaging. The Catalogue Of Somatic mutations In Cancer (COSMIC) database included 9/44 (20%) of all mutations. Also, pathway analysis annotated 20% of the mutated genes to be involved in inflammatory response regulation, 27.5% in protein phosphorylation regulation, and 22.5% in positive regulation of cell proliferation. Interesting mutation findings included two patients with STAT5B mutations (N418K and T628S) with a low variant-allele (VAF) frequencies (3.2-3.6% in CD4+ cells), one patient with a KRAS T58I mutation (VAF 7.9% in CD8+), and two patients with distinct C5AR1 mutations (R197W and T62M). Complementing the paired-sample variant calling strategy, single-sample analyses revealed mutations associated with clonal hematopoiesis with low VAFs (2.2-5.5%) in T cells in 4 (23.5%) patients. Three patients had DNMT3A mutations and one patient 4 distinct TET2 mutations (2 nonsense-, 1 frameshift-, and 1 missense mutations).CD4+ and CD8+ T-cell receptor (TCR) repertoires were profiled with deep TCR beta chain (TCRB) sequencing. Healthy controls' CD4+ and CD8+ cells (n=27) were used as comparators. Although some CVID patients harbor major (17-20% of CD8+) T-cell clones, overall CD4+ or CD8+ clonality did not significantly differ from age-matched healthy controls. As a marker of selective pressure, CVID patients' CD4+ and CD8+ cells harbored more clones that shared a CDR3 amino-acid but had distinct nucleotide CDR3 sequences than healthy controls (7.0% vs 3.3% of all amino-acid rearrangements, p=0.021 for CD8+; 4.3% vs 3.5% p=0.013 for CD4+). These TCRs were not enriched with pathogen-specific (such as cytomegalovirus or Epstein-Barr virus) TCRs. Moreover, high CD4+ clonality was associated with a lower frequency of switched-memory-B cells.In conclusion, somatic mutations in T cells occurred in 59% of patients with immunodeficiency in this study, and some of the mutated genes (such as STAT5B) have previously been implicated for the pathogenesis of autoimmunity and lymphoproliferation. Also, clonal hematopoiesis in T cells was discovered in 23.5% of patients. The overall T-cell clonality was not increased, but CVID patients showed slight selective pressure in the TCR repertoire. Our results demonstrate that further research on somatic mutations in immunodeficiencies is needed, as they may contribute to disease pathogenesis in a subset of immunodeficiency patients. DisclosuresMartelius:Gilead: Other: lecture fee; Octapharma: Other: travel grant; CSL Behring: Other: lecture fee and travel grant; MSD: Other: lecture fee and travel grant; Sanguin: Other: travel grant and grants. Kankainen:Medix Biochemica: Consultancy. Seppänen:CSL Behring: Other: Chairing and speaker fees. Mustjoki:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding.

Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.

The Significance of B-cell Subsets in Patients with Unclassified Hypogammaglobulinemia and Association with Intravenous Immunoglobulin Replacement Requirement.

Patients with unclassified hypogammaglobulinemia (UCH) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients is insufficient. To evaluate B-cell subsets in cases with UCH and common variable immunodeficiency (CVID) and their association with treatment requirement in UCH patients. The study included 41 UCH, 25 CVID, and 36 healthy individuals between the ages of 4-18 years. The absolute count of total memory and switched memory B-cells were lower in the CVID cases in comparison to the control group. Additionally, the absolute count of marginal zone-like B cells in the 4-10 year age group, and the absolute count of switched plasmablasts in the 10-18 year age group were lower in CVID cases when compared to both the control and UCH groups. The UCH group was categorized based on IVIG replacement therapy. Therefore, the percentage of switched memory B cells was significantly lower in the IVIG-receiving group (10.6% ± 3.10%) compared to the control group (14.0% ± 5.60%). However, there was no significant difference between the IVIG-receiving group and the CVID group. Regarding the comparison of the non-IVIG replacement group and the CVID group, the absolute count of total memory B cells, marginal zone-like B cells, and switched memory B cells were significantly higher in the UCH group. B-lymphocyte subsets in UCH cases that did not require IVIG replacement were similar to the control group. On the other hand, the percentage of switched memory B-cells in the UCH cases that required IVIG replacement was not different from that of the CVID cases.

In vitro chromosomal radiosensitivity in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is one of the predominant antibody deficiency disorders, some evidence of which indicates that chromosome instability is present in these patients. An increased risk of cancer in patients with CVID has been documented. This study was undertaken to highlight radiation sensitivity in CVID patients and to clarify the genetic basis of this defect in these cases. Stimulated lymphocytes of the studied subjects were exposed to low-dose gamma-rays in the G2 phase or the G0 phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of healthy individuals, ataxia telangiectasia (AT) cases and a group of acute lymphoblastic leukemia (ALL) patients were investigated in the same way as controls. By two methods of analysis (one-way ANOVA and unpaired t-test), the CVID cases were significantly more radiosensitive than healthy controls based on the results of the G2 and the G0 assays. First-degree relatives of CVID patients were radiosensitive by the micronucleus assay which showed a significant difference as compared with normal controls (p = 0.001). In conclusion, this study may support that chromosomal radiosensitivity in CVID patients is a marker of genetic predisposition to the disease. The results might be a clue to describe the increased risk of cancer in CVID patients.

A Rare Case of Collagenous Colitis in a Patient With Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most prevalent form of severe antibody deficiency in adults, and can present with chronic diarrhea. Collagenous colitis (CC), a subtype of microscopic colitis, is a rare condition that presents with persistent secretory diarrhea. Here, we describe a case of a man with both CC and CVID. A 23 year-old man was referred to GI after 2 visits to the ED for several months of intractable intermittent watery diarrhea and signs of malabsorption. Prior to presenting to our institution, the patient was admitted 3 times for diarrhea and abdominal pain, treated with metronidazole for presumed infectious diarrhea, and with rifaximin for small intestinal bacterial overgrowth (SIBO). Treatments produced temporary relief. On presentation to our institution, he reported 20 watery, non-bloody bowel movements daily, diffuse abdominal pain, and an 8-pound weight loss over 3 weeks. Initial labs were notable for an elevated CRP of 90mg/L (normal < 5 mg/L) and negative celiac serologies. Stool studies were negative for infection, and fecal calprotectin was minimally elevated. Stool electrolytes showed an osmotic gap < 50 mOsm/kg, consistent with a secretory diarrhea. Further testing revealed significantly decreased levels of IgA, IgG, and IgM, leading to a diagnosis of CVID. Further questioning at this time revealed a history of childhood sinusitis and Salmonella gastroenteritis. EGD revealed no small bowel endoscopic or histologic abnormality. A diagnosis of CC was made on colonic mucosal biopsy. The patient was treated with budesonide with complete resolution of symptoms. There are 7 reported cases of CVID associated with CC. CC has an estimated incidence of 4/100,000 person years, with a clear female predominance, and mean age of diagnosis of 65. Classic findings on histopathology include a thickened subepithelial collagenous band. With CVID, a condition of autoimmune dysregulation with an incidence of 1/100,000, concomitant autoimmune diseases are present in roughly 25% of patients, and can often be the presenting disorder. Persistent diarrhea is itself a fairly common presentation of CVID, but is more often due to infection, SIBO, celiac sprue, or villous atrophy.Chronic diarrhea is a common presenting symptom of CVID, but is rarely attributed to CC. As seen with our patient, a heightened suspicion for atypical presentations of immune-mediated causes of intractable diarrhea is warranted in the context of a CVID diagnosis.