Common variable immunodeficiency

Molecular basis of common variable 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.

Exhausted phenotype of follicular CD8 T cells in CVID

Etanercept treatment of cutaneous granulomas in common variable immunodeficiency

Low IgG trough and lymphocyte subset counts are associated with hospitalization for COVID-19 in patients with primary antibody deficiency

The Duke University Medical Center (DUMC) Experience with Common Variable Immune Deficiency (CVID)

35-Year-Old Man With Episodic Fever and Cough

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Common variable immunodeficiency

Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency

Background:Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency characterized by low serum antibody levels and recurrent infections. The cellular response to immunization in patients with CVID has not been fully investigated. In this study, we aimed to characterize vaccination-induced influenza-specific memory B-cell responses in CVID.Methods:Eleven individuals affected with CVID and 9 unaffected control individuals were immunized with the 2010-2011 non-adjuvanted seasonal influenza vaccine. Blood samples were collected on the day of vaccination and at week 8 and week 16 after vaccination, and PBMCs were immunophenotyped by flow cytometry. Influenza specific serology was determined using hemagglutination inhibition and microneutralization against vaccine antigens. Influenza-specific memory B-cell responses were determined by ELISpot.Results:Individuals with CVID showed wide variability in the frequency of CD19+ B cells in blood. The CVID group had significantly reduced frequencies of CD19+CD27+ memory B cells. Frequencies of circulating T follicular helper (CD4+CXCR5+) cells were similar between those with CVID and healthy controls. In terms of serology, compared to healthy controls, the CVID group overall showed significantly reduced boosting to vaccine antigens by hemagglutination inhibition and microneutralization assays at 8 weeks compared to controls and failed to maintain responses by 16 weeks compared to controls, resulting in a post-vaccination geometric mean titer (GMT) ≥ 40 to strain A/H1N1 in only 27% at 8 weeks, and 22% at 12 weeks for patients with CVID vs 78% and 75%, respectively for healthy controls. In addition, there was a GMT ≥ 40 to A/H3N2 in only 9% at 8 weeks and 22% at 12 weeks for patients with CVID vs 56% and 50%, respectively for healthy controls. Healthy participants showed significant increases in flu-specific IgM-secreting memory B cells after vaccination, whereas patients with CVID showed non-signifi-cant mild increases. Before vaccination, patients with CVID had significantly lower frequencies of background level influenza-specific IgG and IgA memory B cells. Half of the patients with CVID showed an increase in influenza-specific IgG-secreting memory B cells post vaccination, whereas the other half showed none. All control participants exhibited an increase in influenza-specific IgG-secreting B cells. None of the patients with CVID developed influenza-specific IgA memory B-cell response post vaccination, compared to 5/8 in healthy controls. At week 16, the frequency of influenza-specific memory B-cell responses decayed but to non-zero baseline in healthy controls and to zero baseline in patients with CVID.Conclusions:Together, these data demonstrate that patients with CVID respond heterogeneously, but as a group poorly, to non-adjuvanted influenza vaccine, with a subgroup unable to generate influenza-specific memory B-cell responses. No patient with CVID was able to maintain memory response for prolonged periods. Together, our results suggest a defect in Ig class switching and memory B-cell maintenance in patients with CVID during a de novo vaccine immune response.

Common variable immunodeficiency (CVID) is a clinically and molecularly heterogeneous disorder with a varied clinical presentation 1. The age of onset varies from early childhood to much later in life, and the disease is characterized by recurrent bacterial infections, hypogammaglobulinaemia and impaired antibody responses. In addition to recurrent infections, which can be mild or serious, CVID patients often develop inflammatory and autoimmune disorders, malignancies and systemic granuloma formation, as well as gastrointestinal (GI) problems 2. Most CVID cases are sporadic, but there are also families with more than one affected member. A small proportion of patients with CVID present in patterns resembling autosomal recessive or dominant inheritance, and mutations in several genes involved directly or indirectly in B cell differentiation, have been identified. This small subset of CVID patients have defects in inducible co-stimulator (ICOS), CD19, CD20, CD21, CD81, lipopolysaccharide-responsive beige-like anchor (LRBA), B cell-activating factor (BAFF) receptor and CXCR4 [the latter causing WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome] 3. Additionally, two autosomal dominant defects affecting the genes for NFκB2 and PIK3CD have been described recently. The NFκB2 mutation causes haploinsufficiency and results in a CVID-like phenotype with childhood onset, autoimmune features and adrenal insufficiency 4. Nuclear factor kappa B2 (NF-κB2) is the principal downstream effector in the non-canonical NF-κB pathway and is required for appropriate B cell development. Dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic P110δ and the p85α subunits of phosphoinositide 3-kinase (PI3 kinase) causes hyperactive PI3 kinase signalling, leading to early-onset autoimmunity, recurrent viral infections and bronchiectasis 5, 6. This suggests that clinical trials with PI3 kinase inhibitors are warranted. Most recently, a CVID-like syndrome, characterized by hypogammaglobulinaemia, a progressive loss of circulating B cells, immune dysregulation and lymphocytic infiltration of the brain, lung and gut was recognized to be caused by heterozygous mutations in the CTLA4 gene 7. CVID patients can be divided into those who exclusively experience infections (bacterial, viral or opportunistic) and, as a result, often develop chronic lung disease, and a second group who in addition develop an inflammatory condition. In the former subset, where recurrent infections are the primary symptom of concern, affected patients will have a near-normal life expectancy provided that they receive adequate treatment with intravenous immunoglobulin (IVIg) and/or antibiotics. Patients in the inflammatory subset are extremely prone to develop granulomas, autoimmune conditions and malignancies. Granulomas can develop in multiple locations, including the skin, lungs, liver and gut. Autoimmune conditions such as colitis, cytopaenia, hepatitis and malignancies, including leukaemia, lymphoma and colon cancer, are relatively frequent 1. This subset will generally have a reduced life expectancy and lower quality of life. Additionally, there is a third group encompassing conditions which are not considered 'classic' CVID: these are defects in T cell development, resulting in a 'CVID-like' condition with early-onset bronchiectasis, autoimmune disease and recurrent viral infections. These conditions (examples are LRBA deficiency 8 and gain-of-function mutations in the P110δ and the p85α subunits of PI3 kinase 5, 6) remain a diagnostic challenge, as it is unclear whether patients are suffering from 'true' CVID or a different type of hypogammaglobulinaemia with secondary B cell deficiency 9. Because both the genetics and clinical presentation of CVID are so variable, clinical diagnosis usually occurs by a lengthy process of eliminating other disorders. B cell phenotyping, T cell function assays, antigen (including neo-antigen) challenges, lymphokine studies, functional testing to measure processes such as phosphorylation of proteins, flow-based assays for surface and intracellular antigens, enzyme-linked immunosorbent assay (ELISA) and measurement of antibody production following vaccination with conjugate (Hib and Prevnar) and unconjugated (Pneumovax) vaccines are required to rule out other primary immunodeficiencies (PIDs). Because, in most cases, CVID may not be due to a single gene defect, molecular approaches thus far have been largely unrewarding, and successful in only a minority of CVID patients in identifying a genetic cause. Patients with a CVID-like phenotype and low numbers of circulating B cells may have mutations in the BTK gene, the cause of X-linked agammaglobulinaemia (XLA) or in genes causing autosomal recessive agammaglobulinaemia, including λ5, Igα, Igβ, B cell linker protein (BLINK) and γH 10. Recently, a homozygous mutation in the p85α subunit of PI3 kinase and a dominant negative mutation in E47 were found to cause agammaglobulinaemia 11, 12. The complexity of the molecular basis of CVID and the heterogeneity of the clinical phenotype requires a carefully designed treatment plan. The primary therapy is infusion of immunoglobulin, which can be either intravenous or subcutaneous, and is dosed based on the patient's immunoglobulin trough levels and clinical response, including frequency of infections. Prophylactic antibiotics help to prevent the development of chronic lung disease and immunosuppressive therapy of autoimmune complications are needed in some patients. Occasionally haematopoietic stem cell transplantation is required. As new causative genetic mutations are identified, new possibilities of gene defect-specific interventions become available. Promising results have been reported from recent studies using rituximab and azathioprine for the treatment of granulomatous lymphocytic interstitial lung disease associated with CVID 13. In terms of future directions for research into CVID, a key priority is to establish a more comprehensive set of diagnostic criteria for the differentiation of CVID and the less well-defined CVID-like conditions summarized here. Identification of novel CVID biomarkers will help to achieve this goal. Additional work in isolating causative genetic variants by whole exome/genome sequencing provides new opportunities to assist in genetic counselling and more specific therapies. Finally, research into better management of difficult-to-treat CVID symptoms such as subclinical infections, inflammatory complications and GI problems should be undertaken. The author would like to thank Meridian HealthComms Ltd for providing medical writing services. H. D. O. has received consultancy fees from CSL Behring.

Purpose: Common variable immunodeficiency (CVID) is the most common primary immune disorder (1). The past infusion of IVIG, a treatment for CVID, has been shown to be a risk factor for Hepatitis C infection (2). In addition, up to 20% of patients with CVID show elevated liver enzymes requiring liver biopsy and up to 40% of these patients may show chronic hepatitis on biopsy (3). Knowledge of hepatic disorders associated with CVID will help caregivers identify and treat these disorders in patients with CVID. The aim of this study was to discern the prevalence of hepatic complications in patients with CVID. Methods: A meta-analysis was performed to critically analyze the prevalence of hepatic complications associated with CVID. Databases included MEDLINE, EMBASE, [email protected], Cochrane, CAB, and OVID Healthstar. Search terms included a search for the Medical Subject Heading (MeSH) term “common variable immunodeficiency.” Articles were also searched with the MeSH term “gastrointestinal disease” and the keyword “hypogammaglobulinemia”. Articles searched were from 1950 to 2009. Additional articles were found in references of selected articles. Non-English abstracts were excluded. The pooled estimates of the complication rates were calculated using random-effects logistic regression analysis, after applying sample weights according to the sample size of the study, as implemented using STATAs (STATA Corp, College Station, TX) xtlogit command. Heterogeneity among studies was assessed with the Pearson chi-square test. Results: These searches yielded a total of 2,414 articles. Case series of hepatic complications in the CVID population were included in the analysis. Of these identified citations, 2,206 were excluded based on abstract. An additional 187 were excluded after full review. There were 21 articles included. See Table 1.Table: Table. Combined estimates for prevalence of hepatic complications among patients with CVIDConclusion: This study represents the first published meta-analysis of the prevalence of hepatic complications in patients with CVID. Hepatomegaly, Hepatitis C, cholelithiasis, and hepatic granulomas were the most frequently observed hepatic complications. Future multicenter prospective collaborative registries might help to better define hepatic disorders and treatment in patients with CVID.

Common variable immunodeficiency and IgG subclass deficiency in central Alabama hemochromatosis probands homozygous for HFE C282Y

IntroductionSelected IgA deficiency (IgAD) and common variable immune deficiency (CVID) are humoral immunity deficiencies frequent in children. In both these types of immunodeficiency, autoimmune diseases are present in 20–30% of patients, but the disease profiles are different between adults and children. Autoimmune diseases of the gastrointestinal tract (IBD) and celiac disease are typical for children with IgAD and CVID. Diagnosis is based on clinical symptoms, histology of jejunum and antibodies often preceding the onset of disease. However, the diagnosis of IBD and celiac disease is difficult in immune deficiency patients due to weaker or absent production of antibodies, and different jejunum histology, particular in CVID patients.AimDetection of antibodies for autoimmune diseases in children with diagnosis of CVID and IgAD.Material and methodsThe study included 43 children with CVID and 63 children with IgAD diagnosis. Antibodies typical for celiac disease (for endomysium, tissue transglutaminase and gliadin) were tested in IgA class (CVID patients), IgG class (IgAD, CVID patients) and found in 16 patients (3 – CVID, 13 – IgAD).ResultsAntibodies for IBD (for Saccharomyces cerevisiae antigen – ASCA, goblet cells – Gab, neutrophil’s cytoplasm – ANCA, pancreatic cells – Pab) were noted in 17 patients (7 – CVID, 10 – IgAD). Celiac disease was diagnosed in two children with mild and unspecific clinical symptoms followed by introduction of a gluten-free diet. The remaining children with present antibodies but without clinical symptoms involving the gastrointestinal tract are under careful clinical observation with antibody assay every 6 months.ConclusionsThe antibodies are produced despite impaired humoral immunity but the level might be low so the lower limit of positive results is postulated.