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Non-infectious complications in common variable immunodeficiency (CVID) have emerged as a major clinical challenge. Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed. Non-infectious manifestations were present in 68.1% of patients, and they do not tend to be present in isolation. They include autoimmunity (33.2%), chronic lung disease (30.3%), lymphoid hyperplasia/splenomegaly (20.9%), liver disease (12.7%), granulomas (9.3%), gastrointestinal disease (7.3%), lymphoma (6.7%), and other malignancies (6.4%). In the lungs, interstitial disease and bronchiectasis were the most common findings, with lymphoma at this site being a rare ( = 6), but serious, manifestation. Bronchiectasis was not a prerequisite for the development of interstitial disease. In the liver, granulomas and nodular regenerative hyperplasia were the most common. Gastrointestinal disease may affect any segment of the intestinal tract, with lymphoid infiltrations and villous blunting being the leading histologic findings. With progression of organ-specific diseases, a wide spectrum of associated sequelae was observed. Lymphoma was more common in females ( = 0.036)-all B cell types except in one subject. Solid organ transplantations (liver, = 5; lung, = 4; combined lung and heart, = 2) and hematopoietic stem cell transplantations (for B cell lymphoma, = 1) have rarely been performed in this cohort, with mixed outcomes. Recent identification of monogenic defects, in ~10-30% of various CVID cohorts, has highlighted the molecular pathways that can affect both antibody production and broader immune regulation. In addition, cellular defects in both innate and adaptive immune systems are increasingly recognized in this syndrome.

Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection. Development of an enzyme-linked immunosorbent assay to detect antibodies to the SARS-CoV-2 spike protein in human sera and plasma.

Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the “CVID+” phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels – marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.

Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.

Common Variable Immunodeficiency (CVID), a complex primary immunodeficiency syndrome defined by defective B cell responses to infection and vaccination, has heterogeneous clinical manifestations. Gastrointestinal (GI) complications in CVID, both infectious and non-infectious, can cause significant impairment leading to malabsorption and frank malnutrition. In order to better characterize the spectrum of GI disease associated with CVID, we describe 114 patients with GI disease (15.6%) from our 728 patient single center CVID cohort. Norovirus, Giardia and Cytomegalovirus were the most frequently isolated infectious pathogens. CVID enteropathy was the most encountered GI diagnosis based on endoscopy, with only a minority of patients having Crohn’s disease (6.1%) or ulcerative colitis/proctitis (4.5%). Concurrent autoimmunity (30.7%), lung disease (18.4%) and malignancy (8.7%) were also present in significant proportion of subjects. Lastly, 16 of 47 (34%) who underwent whole exome sequencing demonstrated a culprit gene defect associated with CVID.

Common variable immunodeficiency (CVID) is the most common clinically significant primary immune defect. Although the hallmark of CVID is hypogammaglobulinemia, the intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects. Although 70% to 80% of patients have had recurrent sinopulmonary infections, autoimmunity and inflammatory complications are also common. The most common autoimmune conditions are immune thrombocytopenic purpura and hemolytic anemia, but other autoimmune complications arise, including rheumatoid arthritis, pernicious anemia, primary biliary cirrhosis, thyroiditis, sicca syndrome, systemic lupus, and inflammatory bowel disease. Treatment of autoimmunity includes highdose immunoglobulins, corticosteroids, selected immu no suppressants, and other immune modulators. This review focuses on autoimmune conditions associated with CVID, potential mechanisms of immune dysregulation, and therapeutic strategies.

PurposeLymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma.MethodsThe United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy.ResultsAmong 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations.ConclusionsWhile CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.

There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.

Common variable immunodeficiency (CVID) is a heterogeneous disorder commonly presenting with recurrent sinopulmonary infections. In all, 6%–10% of CVID patients develop an inflammatory bowel disease (IBD)-like disorder, making these patients a unique population to investigate immune-mediated gastrointestinal disease. This study examined whether defects in peripheral and/or intestinal lymphocytes are involved in disruption of the intestinal mucosa in CVID patients with inflammatory intestinal diseases.MethodsPeripheral blood (PB) T cells from healthy controls; CD or UC; CVID; and CVID with IBD were stimulated for 48 hours with anti-CD3+CD28 or phytohemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA); cytokine production was measured by enzyme-linked immunosorbent assay (ELISA). Cytokine expression from unstimulated lamina propria lymphocytes (LPLs) was compared by real-time polymerase chain reaction (PCR). Immunohistochemistry of mucosal biopsies was performed. Cell populations were quantified by morphometry.ResultsCVID/IBD PB T cells stimulated by anti-CD3+CD28 had trends for reduced IL-2, IL-10, IFN-γ, and TNF-α compared to controls. These differences were not apparent following stimulation by PHA/PMA. Constitutive production of inflammatory cytokines by LPLs was not detected. Histologically, CVID patients had reduced/absent plasma cells with reductions in intestinal IgM and IgA. CVID patients with and without gastrointestinal (GI) disease exhibited increased CD3+ T cells, specifically CD8+, in the colon compared to normal and IBD controls, suggesting immune dysregulation.ConclusionsIntestinal inflammation in CVID patients with IBD-like disease may be mediated by abnormal cytokine production through a T-cell receptor-mediated pathway. However, the variability observed suggests multiple, rather than singular, mechanisms are involved. Histologic features such as reduced intestinal plasma cells and lack of intestinal immunoglobulins may be useful markers in diagnosing CVID in a patient with GI disease refractory to conventional therapies. (Inflamm Bowel Dis 2011;)

For patients with significant antibody deficiencies, immunoglobulin therapy is the mainstay of treatment as it significantly reduces both the frequency and severity of infections. The formulations and delivery methods of immunoglobulin have evolved over time, and continued improvements have allowed for increased access to this effective medication. This review is an update on the current status of immunoglobulin therapy in immunodeficiency disorders, and discusses the mechanisms, forms and dosing, and indications for immunoglobulin replacement.