CVID Patients Research Articles

Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to “other PIDs” (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83–0.95, p < 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630–75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.

Infectious Complications Reporting in Common Variable Immunodeficiency: A Systematic Review and Meta-analysis.

ObjectivesCommon variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent infections.MethodsWe searched PubMed, Web of Science, and Scopus databases to find eligible studies from the earliest available date to January 2018 with standard keywords. Pooled estimates of the infection prevalence and the corresponding 95% confidence intervals were calculated using random-effects models.ResultsWe found that pneumonia (67.7%) was the most prevalent infection followed by upper respiratory tract (59.0%) and gastrointestinal infections (36.3%). Furthermore, bacterial complications (41.7%) were higher in CVID patients compared to viral (25.4%), parasitic (18.8%), or fungal (3.4%) infections. Patients with longer age at diagnosis presented with fewer disease comorbidities. There was an inverse correlation between T lymphocyte count and viral infections. Moreover, we found that immunoglobulin M (IgM) serum level was inversely correlated with hepatitis C and gastrointestinal infections, and IgG serum level was inversely correlated with infectious arthritis. Higher numbers of CD4 and CD8 T cells were associated with the lower frequencies of otitis media. CVID patients with infections had significantly lower percentages of CD3 T cells. In contrast, higher percentages of CD19 lymphocytes were found in CVID patients who had a history of infections.ConclusionsOur findings demonstrated that in addition to hypogammaglobulinemia, patients with CVID have an imbalance in the frequency of T lymphocytes, which is in parallel with the higher frequency of infectious complications.

Incidence of malignancy in patients with common variable immunodeficiency according to therapeutic delay: an Italian retrospective, monocentric cohort study

BackgroundCommon variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency and has a broad spectrum of clinical manifestations. Among non-infectious complications, an increased incidence of malignancies may have a special relevance for survival, but little is known about treatment efficacy on malignant complications.MethodsThis was a monocenter retrospective study on CVID patients, designed to provide preliminary data for the investigation of the possible link between therapeutic delay and tumor incidence.ResultsA total of 67 CVID subjects were included. The median diagnostic delay was 7.5 years (range: 0–63 years), and the median therapeutic delay was 8.5 years (range: 0–67 years). Malignancies were diagnosed in 18 (27%) patients. Eight out of 18 (44%) patients with a malignancy had lymphoma. Patients who developed a malignancy showed a longer therapeutic delay in comparison to patients with no malignancy, although no statistical significance was achieved (11 years vs 8 years, respectively, p = 0.424). We observed a lower frequency of malignancy in CVID patients with reduced therapeutic delay compared with patients with therapeutic delay ≥ 10 years. With a therapeutic delay of > 1 year, 74% had no tumor, and 25% had a tumor; with a therapeutic delay of > 10 years, 65% had no tumor and 35% had a malignancy. Among patients who had no malignancy, 64% had a therapeutic delay of < 10 years, and 36% had a therapeutic delay of ≥ 10 years. Among patients with malignancy, 47% of subjects had a therapeutic delay < 10 years, and 53% a therapeutic delay ≥ 10 years.ConclusionsThe observation of clinical characteristics of our patients with CVID may suggest that an early institution of IgG replacement therapy could be of benefit for the prevention of malignant complications.Name of the registry: Comitato Etico Regionale delle Marche. Trial registration number: 1505. Date of registration: 27/10/2016, Retrospectively registered URL of trial registry record: http://www.ospedaliriuniti.marche.it/portale/archivio13_cerm-ancona_0_446_1.html. The trial was not registered before the first participant was enrolled

IGA Antibody Induced by Immunization With Pneumococcal Polysaccharides Is a Prognostic Tool in Common Variable Immune Deficiencies.

The evaluation of the response to vaccination in patients with inborn errors of immunity is a tool to evaluate T-dependent and T-independent antibody residual function of B lymphocytes and it is part of the diagnostic definition for Common Variable Immune Deficiencies. Currently used classifications for Common Variable Immune Deficiencies patients are based on the frequency of B cell subsets, and have been proven as a valid instrument for identification of patients at higher risk of infectious and non-infectious complications. This 6-years period observational study delineated the measurement of specific IgA antibodies induced by a 23-valent pneumococcal polysaccharides vaccine by a standardized ELISA for the quantification of IgA antibodies to all 23 pneumococcal serotypes as an additional prognostic marker in 74 CVID patients. The inability to mount an IgA-mediated response against the pneumococcal polysaccharide antigens or the inability to maintain the antibody response over time identified poor IgA CVID responders with severe immunological impairment, great risk of co-morbidities, and poor prognosis. The division of CVID patient into specific IgA-non responders and IgA-responders discriminated better than other CVID classifications for infectious risk, while it overlapped for non-infectious complications. Our study suggested to add the evaluation of the antibody response by the 23-valent IgA assay in the clinical monitoring of CVID patients.

Understanding Genetic and Immune Cellular-Signaling Defects in Common Variable Immunodeficiency with Granulomatous Lymphocytic Interstitial Lung Disease

Abstract Common Variable Immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia, failure to mount vaccine responses, recurrent sinopulmonary infections. Furthermore, a subset of CVID patients develop various autoimmune and lymphoproliferative complications, highlighting the dysregulated immune mechanisms underlying the disorder. One such autoimmune complication is granulomatous lymphocytic interstitial lung disease (GLILD) which is a major cause of mortality in CVID. The clinical heterogeneity of CVID indicate that it is a collection of disorders with monogenic and polygenic defects. Due to the genetic and phenotypic complexity of CVID, our understanding of the immunopathogenesis of CVID and the development of its complications is limited. Our goal is to elucidate relationships between genetic variants and their downstream phenotypic and signaling defects in CVID patients with GLILD. We hypothesize that specific genetic variants will result in unique immune cellular (and signaling) signatures in CVID with GLILD. To identify these cellular and molecular signatures, we integrate whole exome sequencing and mass cytometry data. We examined cellular subsets affected by perturbed T and B cell receptor signaling pathways via mass cytometry, and then correlate these signatures with specific genetic variants identified through whole exome sequencing. These results will reveal mechanisms of immune dysregulation in CVID with GLILD. In CVID patients with GLILD, we find expansion of CD57+ CD8+ T cells, which may represent a class of senescent cells. We also find enrichment of CD21-low B cells within CVID patients, regardless of GLILD status.

Does Dysbiosis Drive CVID Enteropathy by Enhancing Bile Acid Cytotoxicity?

Abstract Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by defects in the humoral immune response. CVID patients commonly present with a gastrointestinal enteropathy characterized by intestinal malabsorption. CVID is linked with abnormal gut microbiota composition (i.e. dysbiosis), which may be a contributing factor to CVID enteropathy. Recently, we demonstrated that CD19−/− mice represent a spontaneous animal model of CVID enteropathy that develop an associated dysbiosis. We now expand upon this work to identify how microbial dysbiosis may contribute to CVID enteropathy. We first demonstrate a significant association between dysbiosis in CD19−/− mice with defects in bile acid (BA) homeostasis (increased luminal BA titers and decreased abundance of conjugated BA species). Enteropathy in CD19−/− mice is associated with enhanced apoptosis of intestinal epithelial cells (IECs). Adoptive transfer of WT B cells (but not CD19−/− B cells) reduces luminal BA concentrations, protects IECs from apoptosis, and resolves enteropathy, indicating that functional B cells are important regulators of BA homeostasis and gastrointestinal health. Additionally, dietary supplementation with a taurine conjugated BA also protects animals from disease demonstrating that enhanced BA deconjugation enhances disease severity. Finally, direct ablation of the ability of a model commensal microbe to deconjugate BAs also rescues animals from disease. Collectively, these data suggest that enhanced bacterial deconjugation of BAs in the gut contributes to CVID enteropathy by enhancing BA cytotoxicity to IECs. Thus, microbial BA deconjugation may represent a novel therapeutic target for the treat of CVID enteropathy.

Clinical and immunological features of 44 common variable immunodeficiency patients: the experience of a single center in Turkey

Introduction and objectivesCommon variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency characterized by hypogammaglobinemia. Its heterogeneous clinical features include recurrent respiratory tract infections and other complications such as gastrointestinal, autoimmunity, and lymphoproliferative disorders. The aim of this article is to evaluate the general characteristics of CVID patients. Materials and methodsClinical and immunological features of 44 CVID patients were evaluated retrospectively with long-term follow-up. Patients who participated in the study were diagnosed according to the criteria of the European Society for Immunodeficiency Diseases (ESID). ResultsThe median age at onset of symptoms was 2.75 years (range 6 months to 17 years), and the median age at diagnosis was 7.75 years (range 4–20 years). The average delay in diagnosis was 4.6 years (range 1–14 years). Positive family history was 18.2%. Before treatment, patients’ median total serum IgG was 271.5mg/dL, median IgA was 7.5mg/dL, and median IgM was 21mg/dL. Infections were the most common clinical manifestation, and 63.6% of patients presented with sinopulmonary infection as the first manifestation. Bronchiectasis developed in 23 CVID subjects, while bronchiectasis was detected prior to CVID diagnosis in eight patients. All patients received immunoglobulin replacement therapy, and one patient died because of granulomatous lymphocytic interstitial lung disease (GLILD). ConclusionsCVID is a heterogeneous group of immunologic disorders with unknown etiology. There are significant differences in the clinical presentation and prevalence of CVID-related complications among countries. Local guidelines for diagnosis and clinical follow-up are needed.

The Correlation between Common Variable Immunodeficiency and Atrial Fibrillation: Cardiac Implantable Electronic Devices‐associated infection by Stenotrophomonas maltophilia: A case report

BackgroundCommon variable immunodeficiency (CVID) is associated with systemic infections and autoimmune diseases which may elicit and perpetuate atrial fibrillation via inflammatory and oxidative mechanisms. CVID patients with early‐onset atrial fibrillation (AF) and chronic heart failure (CHF) are refractory to standardized cardiac ablation and frequently need sophisticated cardiac resynchronization therapy. Moreover, CVID‐CHF patients with cardiac implantable electronic devices (CIEDs) are vulnerable to opportunistic infection, especially Stenotrophomonas maltophilia bacteremia, which has high resistance to a variety of empirical antibiotics against gram negative bacteremia.Case presentation31 year‐old female with a past medical history of chronic refractory AF, CHF, thyroid cancer, non‐Hodgkin lymphoma, and factor V deficiency presented to the hospital with a fever of 104.0F for 2 days after recent dual‐chamber biventricular defibrillator replacement 2 weeks ago. 2 months ago, the patient was diagnosed with CVID due to recurrent cardiopulmonary infections. Upon this admission, the patient’s blood culture demonstrated S. maltophilia which was likely from the complications of CIEDs placement.ConclusionEarly‐onset Atrial fibrillation in young population may be a feature of CVID. Early recognition of CVID in these patients, especially with comorbidity of CHF, can mitigate the progression of AF with antioxidants as well as promptly identify and manage CIEDs‐associated infections, such as S. maltophilia.Figure 1

Comprehensive assessment of respiratory complications in patients with common variable immunodeficiency

BackgroundCommon variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by recurrent upper and lower respiratory tract infections and some noninfectious clinical complications. ObjectiveTo provide a detailed evaluation of respiratory presentations and complications in a cohort of Iranian patients with CVID. MethodsA retrospective cohort study was conducted on 245 CVID patients who were recorded in the Iranian primary immunodeficiency disorders registry network. Respiratory manifestations were evaluated by reviewing clinical hospital records, immunologic findings, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans. ResultsMost of the patients (n = 208, 85.2%) had experienced at least 1 episode of acute respiratory manifestation, and pneumonia was observed in 31.6 % (n = 77) of cases as a first disease manifestation. During the follow-up, pneumonia, sinusitis, and otitis media were documented in 166 (68.6%), 125 (51.2%), and 103 (42.6%) cases, respectively. Abnormal PFT measurements were documented in 53.8% of patients. Among these patients, 21.5% showed restrictive changes, whereas 18.4% of patients showed an obstructive pattern. Bronchiectasis was the most frequent radiological finding, confirmed in 27.2% of patients. Patients with bronchiectasis were older at the time of immunodeficiency diagnosis (P < .001) and had longer diagnosis delay (P < .001) when compared with patients without bronchiectasis. ConclusionThis study highlights the importance of monitoring the respiratory tract system even in asymptomatic patients. Pulmonary function tests and CT scans are the most commonly used techniques aiming to identify these patients early, aiming to reduce the rate of long-term respiratory complications.

Use of FEF25-75% to Guide IgG Dosing to Protect Pulmonary Function in CVID.

Immunoglobulin replacement therapy (IGRT) can protect against lung function decline in CVID. We tested whether increasing IgG dosage was beneficial in patients who exhibited a decline in forced expiratory flow at 25-75% (FEF25-75%) even though they were receiving IgG doses within the therapeutic range. Of 189 CVID patients seen over 12years, 38 patients met inclusion criteria, were seen on ≥ 3 visits, and demonstrated a ≥ 10% decrease in FEF25-75% from visits 1 to 2. FEF25-75%, forced expiratory flow at 1s (FEV1), and FEV1/FVC at visit 3 were compared among those with non-dose adjustment (non-DA) versus additional IgG dose adjustment (DA). Three FEF25-75% tiers were identified: top (> 80% predicted), middle (50-80%), and bottom (< 50%). DA and non-DA groups did not differ in clinical infections or bronchodilator use, although the non-DA group tended to use more antibiotics. In the top, normal tier, FEF25-75% increased in DA, but the change did not achieve statistical significance. In the middle moderate obstruction tier, visit 3 FEF25-75% increased among DA but not non-DA sets (11.8 ± 12.4%, p = 0.003 vs. 0.3 ± 9.9%, p = 0.94). Improvement in FEV1/FVC at visit 3 was also significant among DA vs. non-DA (7.2 ± 12.4%, p = 0.04 vs. - 0.2 ± 2.7%, p = 0.85). In the bottom, severe tier, FEF25-75% was unchanged in DA (- 0.5 ± 5.2%, p = 0.79), but increased in non-DA (5.1 ± 5.2%, p = 0.02). Among IGRT CVID patients with moderate but not severe obstruction as assessed by spirometry, increasing IgG dosage led to an increase in FEF25-75% and FEV1/FVC.

Gut Antibody Deficiency in a Mouse Model of CVID Results in Spontaneous Development of a Gluten-Sensitive Enteropathy.

Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as “common variable immunodeficiency” (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19−/− mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19−/− mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19−/− mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19−/− mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19−/− mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19−/− mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.

1746. Prevalence and Resistance Patterns of Cytomegalovirus Viremia in Immunocompromised Patients

BackgroundWe noted a recent increase in the number of patients with CMV viremia among immunocompromised children at our institution. The study was undertaken to determine the prevalence of CMV viremia and to evaluate factors associated with the development of antiviral drug resistance.MethodsA retrospective study of immunocompromised hosts 0–21 years of age who had CMV viremia (2007–2017). We collected demographic data as well as details of antiviral therapy and resistance testing.ResultsA total of 31 patients were identified including 10 (32%) during the last 2 years. The age range was 3 months to 20 years (median 12.6 years); 23 (74%) were male and 12 (39%) were African American. Among the 31 patients, 18 had hematopoietic stem cell transplantation, 5 had primary immunodeficiency (2 common variable immunodeficiency, 1 SCID, 1 Langerhans cell histiocytosis, 1 DiGeorge syndrome), 4 had malignancies receiving chemotherapy, 3 with heart transplantation and one 17 year old with newly diagnosed HIV infection who presented with CMV pneumonia and viremia. Antiviral resistance testing was performed on 7 CMV isolates: 5 due to persistent viremia (> 1 months) despite treatment, and 2 prior to starting antiviral therapy. CMV resistance was identified in 3 patients including 2 with CVID and one with Hodgkin’s disease status post bone marrow transplantation. The 2 CVID patients had other comorbidities including chronic diarrhea and malabsorption and were TPN dependent. Both were diagnosed with CMV colitis and one also had pneumonitis. One had received a prolonged oral valganciclovir course (> 1 year) prior to diagnosis of resistance and the other received long-term intermittent oral valganciclovir courses. The patient with Hodgkin’s disease received a prolonged IV ganciclovir course. All 3 tested positive for UL97 mutation and one had both UL97/UL54 gene mutations.ConclusionMost of our patients with CMV viremia were transplant patients. Antiviral drug resistance was detected among 3 of 31 (10%) of our patients during the study period. Two had malabsorption that may have resulted in sub-therapeutic blood levels. Treatment with oral valganciclovir should be avoided in patients with poor gut absorption because it may increase risk of drug resistance.Disclosures All authors: No reported disclosures.

The evaluation of neutropenia in common variable immune deficiency patients

ABSTRACTObjectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p = 0.001 and p = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p = 0.04 and p = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, p = 0.004).Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.

The German National Registry of Primary Immunodeficiencies (2012-2017).

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Alterations In Circulating Follicular Helper T Cells (cTFH) and Follicular Regulatory T Cells (cTFR) In CVID Patients

Alterations In Circulating Follicular Helper T Cells (cTFH) and Follicular Regulatory T Cells (cTFR) In CVID Patients

Perceived health of patients with common variable immunodeficiency-a cluster analysis.

Common variable immunodeficiency (CVID) is a complex disease with various influences on perceived health, which correlate with different outcomes, including new morbidity and mortality. Our hypothesis was that CVID patients fall into distinct clusters of perceived health which can inform care. Ward hierarchical cluster analysis and K-means cluster analysis were performed on data of 209 CVID patients to identify subgroups regarding their self-reported physical and mental health status, assessed by the physical (PCS) and mental component scores (MCS) of the Short Form-12 (SF-12). Four clusters of CVID-patients were identified. Cluster 1 was the largest cluster, characterized by a relatively high physical and mental health status (44·0%). In contrast, cluster 2 (21·1%) included patients with low physical and mental health status. Clusters 3 and 4 were mixed groups with high mental and low physical health (15·8%) and vice versa (19·1%). Significant differences between the clusters were found for patient-reported outcomes such as work ability and health literacy, but not for CVID-associated complications such as enteropathy, interstitial lung disease, granulomatosis, lymphadenopathy and autoimmune cytopenia or laboratory parameters such as immunoglobulin levels or B cell-based classification. The results suggest different subgroups of CVID patients with contrasting individual needs which, surprisingly, did not differ in clinical or laboratory characteristics. The main finding of this study is that patients with CVID fall into four distinct clusters according to perceived health, which are largely independent of CVID complications.

In This Issue

Abstract Suppressive Neutrophils in CVID Patients See article p. 93 Banded Neutrophils on the Move See article p. 207 Abin-1 as an NLR Interaction Partner See article p. 218 Migration of Salmonella enterica in the Lymph See article p. 260

The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity

BackgroundCommon variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. MethodsThe study population comprised patients with CVID, LRBA deficiency and age–sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. ResultsThe main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. ConclusionsOur findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients.

Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency.

We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher's exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios). Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups. Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions.

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

Abstract Common variable immunodeficiency (CVID) is characterized by low levels of Igs leading to increased risk of infections. Mucosal-associated invariant T (MAIT) cells are a recently identified population of innate T cells with potent antibacterial activity. We hypothesized that CVID is associated with alterations in MAIT cells. Cryopreserved PBMC from CVID patients and healthy controls were used to study the frequency, phenotype, and response to Escherichia coli stimulation of MAIT cells by flow cytometry. MAIT cell frequency and absolute counts were depressed in CVID. Residual MAIT presented elevated coexpression of CD38 and HLA-DR, and reduced expression of CCR6, whereas levels of CD127 (IL-7 receptor) were unchanged. CVID patients also had an accumulation of MAIT cells lacking the critical transcription factors eomesodermin and promyelocytic leukemia zinc finger protein. MAIT cell frequency was inversely associated with levels of soluble CD14, with coexpression of CD38 and HLA-DR, and accumulation of MAIT cells lacking eomesodermin or promyelocytic leukemia zinc finger protein expression. None of these changes were normalized by IgG replacement therapy. Finally, MAIT cells from CVID patients displayed poor IFN-γ responses to E. coli stimulation, in part due to defective Ag presentation, and these responses were increased by pretreatment with IL-7. Defective MAIT cell response may contribute to the increased incidence of microbial infections seen in CVID patients on IgG replacement therapy.