Elena S. Resnick

Morbidity and mortality in common variable immune deficiency over 4 decades

The demographics, immunologic parameters, medical complications, and mortality statistics from 473 subjects with common variable immune deficiency followed over 4 decades in New York were analyzed. Median immunoglobulin levels were IgG, 246 mg/dL; IgA, 8 mg/dL; and IgM, 21 mg/dL; 22.6% had an IgG less than 100 mg/dL. Males were diagnosed earlier (median age, 30 years) than females (median age, 33.5 years; P = .004). Ninety-four percent of patients had a history of infections; 68% also had noninfectious complications: hematologic or organ-specific autoimmunity, 28.6%; chronic lung disease, 28.5%; bronchiectasis, 11.2%; gastrointestinal inflammatory disease, 15.4%; malabsorption, 5.9%; granulomatous disease, 9.7%; liver diseases and hepatitis, 9.1%; lymphoma, 8.2%; or other cancers, 7.0%. Females had higher baseline serum IgM (P = .009) and were more likely to develop lymphoma (P = .04); 19.6% of patients died, a significantly shorter survival than age- and sex-matched population controls (P < .0001). Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications (hazard ratio = 10.95; P < .0001). Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and gastrointestinal disease with or without malabsorption, but not with bronchiectasis, autoimmunity, other cancers, granulomatous disease, or previous splenectomy.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts

To the Editor: The clinical diversity of common variable immunodeficiency disorders (CVIDs) required division of these patients into distinct clinical phenotypes to provide more homogeneous groups for immunopathologic studies as well as individual patient prognosis. By using data on clinical complications and disease progression from 334 patients with CVID from 7 European centers including Oxford (‘‘Northern European cohort’’), distinct clinical phenotypes were defined with relatively little overlap: 83% of the patients had only 1 clinical phenotype. The prognostic significance of the defined phenotypes was confirmed by significant correlation with survival. Comparison of data in 2 independent databases (DEFI and Mount Sinai) (see this article’s Online Repository at www. jacionline.org) showed that it was feasible to confirm clinical phenotyping criteria in replicate cohorts, using identical definitions for each clinical complication and laboratory finding. In addition, further associations were sought to improve the criteria for clinical phenotyping and survival. Predictors of clinical phenotypes were previously limited to IgM serum levels for the lymphoproliferative (LP) phenotype and malignancy as well as low peripheral CD8 counts for autoimmunity. Further searches for predictive laboratory measurements were undertaken on the combined cohorts. Since the dates of diagnosis for complications in patients in 2 cohorts (Oxford and the DEFI study) were known, the interval from the diagnoses of CVID and the first disease-related complication was calculated to search for the earliest date for reliable prognosis. Initially, it was important to confirm the concept of clinical phenotyping in CVIDs. The proportions of patients in the independent replicate cohorts with features of only 1 clinical phenotype were similar between cohorts when the original criteria were used (see Fig E1 in this article’s Online Repository at www.jacionline.org). By using the discovery (Northern European; n 5 334) cohort, further associations between complications were found to improve the phenotyping criteria. Considering the LP phenotype, no significant correlation was found between granuloma or lymphoid interstitial pneumonitis (LIP) and hepatomegaly, and so hepatomegaly was discarded. Lymphadenopathy remained as a criterion for LP, since although only 1 patient of 11 in the extended Oxford cohort did not also have granuloma or LIP, there were 29 patients with persistent lymphadenopathy in the Mount Sinai cohort of whom 10 had no obvious symptoms of granuloma and/or LIP.When autoimmunity was split into 2 categories, autoimmune cytopenias and organ-specific autoimmune diseases, only cytopenias showed decreased survival (P 5 .0001); organ-specific autoimmunity was not associated with cytopenias or the other clinical phenotypes. Lymphoid malignancies were excluded in the revised phenotyping criteria since CVID may not be the primary event. Thus, the revised phenotyping criteria were as follows:

Perspectives on common variable immune deficiency

Common variable immunodeficiency (CVID) is considered to be a collection of genetic immune defects with complex inheritance patterns. While the main phenotype is loss of B cell function, the majority of the genetic mechanisms leading to CVID remain elusive. In the past two decades there have been increasing efforts to unravel the genetic defects in CVID. Here, we provide an overview of our current understanding of the genetic basis of these defects, as revealed over time by earlier linkage studies in large cohorts, analysis of families with recessive inheritance, targeted gene approaches, and genome‐wide association studies using single nucleotide polymorphism arrays and copy number variation, and whole genome studies.

The many faces of the clinical picture of common variable immune deficiency.

Purpose of reviewTo summarize the recent advancements in common variable immune deficiency (CVID), specifically CVID genetics, clinical discoveries and treatment implications. Recent findingsLarge genomic studies have implicated new genes in the pathogenesis of CVID, and basic science studies have contributed to our knowledge of potential mechanisms. Cohort studies have further defined the immunologic parameters and clinical presentation of CVID, as well as the factors that contribute to morbidity and mortality in this disease. Immunoglobulin remains the mainstay of treatment, although there may be a role for immunosuppression and other therapies. SummaryCVID is a genotypically and phenotypically heterogeneous primary immune deficiency, the genetic and clinical characteristics of which are under active investigation. Further, discovery may yield important new treatment protocols that can continue to reduce the morbidity and mortality from this disease.

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0×10−9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P =4.8×10−16). Clec16a knock down (KD) mice showed reduced number of B cells and elevated IgM levels compared to controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

Lymphoid Proliferations of Indeterminate Malignant Potential arising in Adults with Common Variable Immunodeficiency Disorders: Unusual Case Studies and Immunohistological Review in the Light of Possible Causative Events

Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.

Genetic sharing and heritability of paediatric age of onset autoimmune diseases

Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h2). SNP-h2 estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h2 in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Burden of copy number variation in common variable immunodeficiency

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.

Treatment of common variable immune deficiency

Introduction: Common variable immune deficiency (CVID) is a relatively common primary immune deficiency characterized by low serum immunoglobulins and absent or poor responses to vaccines. Most patients suffer from frequent infections but about 50% of patients also have autoimmune or inflammatory conditions of uncertain pathogenesis, requiring additional therapy. Areas covered: The authors review standard therapy on immunoglobulin treatment for CVID, an approach to the treatment of infections, and the modalities currently in use for treating inflammatory complications, including lung disease, granuloma, autoimmunity, gastrointestinal disease, lymphoma and other malignancies. Expert opinion: Immunoglobulin replacement and treatment of infections are central requirements for CVID treatment. Inflammatory complications that arise may be treated with low doses of short-term corticosteroids, but other targeted therapies and/or immunomodulators may be required. As many patients do well with standard therapy, hematopoietic stem cell transplant has not been an established therapy in CVID. While preliminary experiences with allogeneic stem cell transplantation have been reported, gene therapy has not emerged as a treatment option at this time.