Diagnosis Of Common Variable Immunodeficiency Research Articles

Equine common variable immunodeficiency: Lessons from 100 clinical cases

SummaryThe clinical manifestation of recurrent fevers and infections alerts the clinician to the possibility of an underlying immunodeficiency. Common variable immunodeficiency (CVID) in the horse is a rare late‐onset, nonfamilial immunological disorder of B cell depletion and/or dysfunction with resultant inadequate antibody production. The most common clinical presentations in horses with CVID are recurrent upper and/or lower respiratory infections, meningitis and/or ataxia, cholangiohepatitis, infectious colitis, infectious dermatitis and severe gastrointestinal parasitism. Immune‐mediated and lymphoproliferative conditions are additional clinical features. The diagnosis of CVID in horses is based on a persistent hypogammaglobulinaemia primarily caused by a serum IgG concentration below 10.00 g/L in at least two different measurements, often accompanied by a serum IgM concentration below 0.50 g/L. Most horses with CVID show a persistent peripheral blood B cell distribution below 6% of total circulating lymphocytes, indicating severe B cell paucity or depletion, but the B cell distribution can be within the normal reference interval. Post‐mortem findings add diagnostic information about the distribution of B and T cells in lymphoid tissues. Clinical management of horses with immunodeficiency is intense and expensive, and these factors weigh on the difficult decision of elective euthanasia. To date, no genetic mutation has been identified in horse patients with CVID, and the large number of breeds of single‐affected individuals in a same herd or immediate lineage from various parts of the United States and the world do not point at an obvious inheritable mechanism of disease or environmental risk factors. This article describes the clinical and immunological findings in 100 equine cases, and comparisons with the disease in human patients.

Common variable immunodeficiency, cross currents, and prevailing winds.

Common variable immunodeficiency (CVID) is a heterogenous disease category created to distinguish late-onset antibody deficiencies from early-onset diseases like agammaglobulinemia or more expansively dysfunctional combined immunodeficiencies. Opinions vary on which affected patients should receive a CVID diagnosis whichconfuses clinicians and erects reproducibility barriers for researchers. Most experts agree that CVID's most indeliable feature is defective germinal center (GC) production of isotype-switched, affinity-maturated antibodies. Here, we review the biological factors contributing to CVID-associated GC dysfunction including genetic, epigenetic, tolerogenic, microbiome, and regulatory abnormalities. We also discuss the consequences of these biological phenomena to the development of non-infectious disease complications. Finally, we opine on topics and lines of investigation we think hold promise for expanding our mechanistic understanding of this protean condition and for improving the lives of affected patients.

Evaluating Drug Prescription Patterns in Undiagnosed Common Variable Immunodeficiency Patients.

To compare the consumption of antibiotics (AB), systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding the diagnosis of common variable immunodeficiency (CVID) among CVID patients and matched controls and to estimate whether the level of consumption was associated with the risk of a subsequent CVID diagnosis. We conducted a nested case-control study, identifying all individuals (n=130 cases) diagnosed with CVID in Denmark (1994-2014) and 45 age- and sex-matched population controls per case (n=5850 controls) from national registers. Drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals. In the 3 years preceding a CVID diagnosis, we observed more frequent and higher consumption of all three drug classes. The association between consumption and risk of subsequent CVID diagnosis was statistically significant for all drug classes. The association was stronger with higher consumption and shorter time to CVID diagnosis. The fraction of cases compared to the controls redeeming ≥1 prescription of the included drugs during the study period was higher for AB (97% vs 52%), systemic steroids (35% vs 7.4%), and inhaled bronchodilators/glucocorticoids (46% vs 11.7%) (p<0.001). CVID patients have significantly higher use of AB, systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding CVID diagnosis than controls. Prescribing these drugs in primary healthcare could be an opportunity to consider (proactive) screening for CVID. Further studies are needed to identify optimal prescription cutoffs that could endorse its inclusion in public health policies.

FRI568 Hashimoto’s Thyroiditis With Negative Antibodies In Association With Common Variable Immunodeficiency

Abstract Disclosure: I.C. Ebrahim: None. K.F. Brown: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None. Introduction: Common variable immunodeficiency (CVID) is associated with several autoimmune manifestations including Hashimoto’s thyroiditis (HT). We report a 47-year-old male with CVID and HT with negative thyroid antibodies (Abs). Case Report: A 47-year-old male, while undergoing coronary calcium scan in 2021, was found to have scattered lung nodules. Follow-up Ct scans showed interval increase in size of lung nodules and a PET scan confirmed bilateral lung nodules which demonstrated hypermetabolic activity and scattered hypermetabolic lymph nodes, suggesting infectious or inflammatory processes. PET scan also revealed thyromegaly with diffusely increased uptake, suggesting thyroiditis. Serum immunoglobulins were measured: IgA &amp;lt; 5 mg/dL (normal 70-400), IgG 334 mg/dL (normal 700-1600), and IgM &amp;lt; 25 mg/dL (normal 40-230). Serum immunoglobulins levels from depository serum samples collected in 2005 also showed similarly low values. CBC was normal, excluding any bone marrow disorders. There was no family history of immunodeficiency or thyroid disorders. On review of systems patients did not have any symptoms of hypothyroidism. Exam: thyroid 50-gms diffusely enlarged with no palpable nodules; heart and lung exam was normal. Laboratory tests including comprehensive metabolic panel, serum complement CH 50, leukemia/lymphoma panel, T/B - lymphocyte/Natkiller, CRP were all normal. Thyroid functions: TSH 5.6 mc1U/mL (0.27-4.2), Free T4 1.20 ng/dL (0.93-1.71), TPO Ab &amp;lt; 9 IU/mL (0-34), TG Ab &amp;lt; 1.0 1U/mL (0.0-0.9), thyrotropin receptor Ab &amp;lt; 0.3 IU/L (&amp;lt;1.0), thyroid stimulating immunoglobulin &amp;lt; 0.10 1U/L (0.06-0.55). Serum thyroid Ab levels from depository samples collected in 2005 also showed normal values. FNA of thyroid showed atypical lymphoid infiltrates and an excision biopsy of the thyroid isthmus confirmed lymphocytic thyroiditis. A PET avid right inguinal lymph node biopsy showed a reactive lymph node. Additional lab evaluation also showed low post vaccination pneumococcal titers. With pan-hypoglobulinemia and low vaccine response, a diagnosis of CVID was made. Patient preferred watchful waiting than iv immunoglobulin therapy. Additionally, the patient has HT with negative thyroid Abs and although patient had mild subclinical hypothyroidism patient elected no treatment. Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults. Autoimmune manifestations occur in 22% of CVID patients and these include autoimmune cytopenia, pernicious anemia, rheumatoid arthritis, vitiligo, and/or HT. Interestingly, our patient did not manifest any thyroid Abs thus it may be postulated that thyroid follicles destruction in HT is mediated predominantly by thyroid-specific B and T cells rather than by thyroid antibodies. Presentation: Friday, June 16, 2023

THU243 Fitting Together The Pieces Of The Puzzle Between Isolated ACTH Deficiency And Immunodeficiency: DAVID Syndrome

Abstract Disclosure: K.V. Buchanan: None. A.C. Hurst: None. A.P. Ashraf: None. Objectives: DAVID syndrome is a rare genetic disorder with common variable immunodeficiency (CVID) and anterior pituitary hormonal deficiencies due to a pathogenic variant in NFKB2. We aim to describe asymptomatic ACTH deficiency identified after the diagnosis of CVID in a patient with DAVID syndrome. Methods: A retrospective chart review of a patient with DAVID syndrome was performed. Results: The patient is a 15 year and 9-month-old female with weight in the 71st percentile and height in the 64th percentile, who was diagnosed with DAVID syndrome at 10 years through a Primary Immunodeficiency panel which identified a pathogenic variant in NFKB2 c.2557C&amp;gt;T,p.Arg853* and a variant of unknown significance in STAT2 c.1301C&amp;gt;T (p.Thr434Met). The panel was performed due to the patient’s history of recurrent sinus infections, hypogammaglobulinemia, and alopecia totalis. The patient did not have symptoms of ACTH deficiency including hypoglycemia and hypotension. After the genetic diagnosis was made, an anterior pituitary hormone evaluation was performed which showed an ACTH &amp;lt;5 pg/ml, AM cortisol &amp;lt;0.2 mcg/dL, TSH 3.48 uIU/ml, FT4 0.82 ng/dL, thyroid peroxidase antibody 29 IU/mL (normal &amp;lt;9), somatomedin-c 44 ng/mL (reference range 152-593), LH 5.36 mIU/mL, and FSH 14.25 mIU/mL. Adrenal insufficiency was diagnosed since the patient did not show incremental cortisol response (serum cortisol &amp;lt;0.2 mcg/dL at 30 and 60 minutes) post Cosyntropin stimulation test. The patient had normal electrolytes. Hydrocortisone replacement therapy was initiated. A growth hormone stimulation test was not performed since the patient had normal height and interval height velocity. The thyroid function remained stable, and the patient attained menarche at age 14. Conclusions: This patient is unique in having asymptomatic, acquired, isolated ACTH deficiency diagnosed in later childhood, despite having frequent sinopulmonary infections since infancy as part of DAVID syndrome. Further research needs to be done to elucidate how NFKB2 variants contribute to acquired, isolated, central ACTH deficiency or autoimmune pituitary disease. Presentation: Thursday, June 15, 2023

Autoimmunity and Freiburg classification in common variable immunodeficiency

Up to 25% of patients with common variable immunodeficiency (CVID) debut with autoimmunity, which is related to the Freiburg classification, which is based on flow cytometry. to determine the frequency and type of autoimmune diseases and their association with the Freiburg classification in adults with CVID. A cross-sectional, analytical and observational study was carried out with 33 patients belonging to the Primary Immunodeficiency Clinic of a third level hospital, with a diagnosis of CVID. They were divided into 3 phenotypes according to the Freiburg classification. Of the 33 patients studied, 66.6% presented autoimmune diseases, 19 of them (86.3%) had cytopenia; 42.1% belonged to Freiburg group Ia, 36.8% to Ib and 21% to phenotype II. In 36.6% of the patients, autoimmune cytopenia were the first manifestation of CVID; and up to 70% of them belong to the Freiburg phenotype Ia (p = 0.086). Patients with autoimmune cytopenia had a lower percentage of isotype-switched memory B cells (p = 0.018), no higher percentage of CD21low B cells (p = 0.226). Classification by CVID phenotypes allows the identification of the patient's profile according to the percentage of memory B cells with isotype change, which is useful to intentionally search for non-infectious complications of the disease.

Missed Opportunities to Diagnose Common Variable Immunodeficiency: a Population-Based Case–Control Study Identifying Indicator Diseases for Common Variable Immunodeficiency

PurposeDelayed diagnosis of common variable immunodeficiency (CVID) remains a serious problem. We investigated whether some diseases diagnosed during out-patient visits or admission to hospitals could act as indicator conditions for CVID diagnosis.MethodsIn this nested case–control study, we identified 128 cases diagnosed with CVID in Denmark (1999–2013) and 640 age-, gender-, and region-matched controls. We obtained data on diseases diagnosed at hospitals in the five years before CVID diagnosis from The National Hospital Registry. We grouped hospital diagnoses in 33 major disease categories and 210 subcategories. We used conditional logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) to estimate associations between disease exposure and subsequent CVID.ResultsDuring the five years preceding a CVID diagnosis, cases had four times as many hospital contacts as the controls (p < 0.001). A diagnosis in 18 major disease categories showed a significant OR for subsequent diagnosis of CVID. The most substantial association with a subsequent CVID diagnosis was a diagnosis of lower respiratory tract infections (OR: 29.9; 95% CI: 14.2–63.2) and lung diseases (35.1; 15.0–82.5). We observed a similar association when we removed the last year before diagnosis from analysis and overall, in the years < 1, ≥ 1–3, and ≥ 3–5 before diagnosis, although the absolute number of exposures was small. Twenty-eight specific diseases displayed an at least 3-fold risk of subsequent CVID diagnosis.ConclusionTargeted screening for antibody deficiency in patients diagnosed with specific diseases associated with CVID may lead to earlier CVID diagnosis and treatment and thereby potentially reduced morbidity and mortality.

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant.

(1) Background: Mutations in NFκB1, a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in NFκB1, c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the NFκB1 gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations.

Allergic Diseases as a Clinical Phenotype Marker in Patients with Common Variable Immunodeficiency

Introduction: Patients with common variable immunodeficiency (CVID) have been shown to be more predisposed to develop allergic diseases because of mucosal immune defects and immune dysregulation. The aim of this study was to determine the prevalence, and clinical and laboratory characteristics of various allergic diseases in patients with CVID. Methods: The study included patients aged ≥18 years who were followed up for a diagnosis of CVID. Patients were separated into 5 groups according to the clinical phenotypic characteristics of lymphoproliferation, autoimmunity, gastrointestinal diseases, allergic diseases, and malignancy. Atopic dermatitis (AD), drug hypersensitivity reaction (DHR), allergic rhinitis (AR), and asthma were accepted as allergic diseases. Results: The most commonly seen clinical phenotypes were lymphoproliferation in 41 (48.8%) patients and allergic diseases in 31 (37%). AD was determined in 2 (2.4%) patient, DHR in 5 (6%), AR in 7 (8.3%), and asthma in 21 (25%). The delay in diagnosis of patients with allergic disease was determined to be shorter compared to those without allergic disease (p = 0.042). Serum total immunoglobulin E level, CD19⁺ B cell, switched memory B cell, and natural killer cell counts were determined to be higher in the CVID patients with allergic disease compared to those without (p = 0.007, p = 0.022, p = 0.023, p = 0.017, respectively). Conclusion: Allergic diseases should be considered as a marker of clinical phenotype in CVID because of the clinical and immunological differences. Early diagnosis and treatment of allergic diseases in patients with CVID can improve quality of life.

Novel NFkB Variant V213E: Phenotypic Description &amp; Molecular Modeling

Abstract BACKGROUND: Mutations of NFkB1 are a known cause of inborn errors of immunity resulting in immunodeficiency due to the role of NFkB1 as a transcriptional regulator of immunomodulating proteins. We present a patient with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Our proband, a 22-year-old male, presents with a clinical picture of immunodeficiency, and has a maternal cousin with a similar gene mutation but differing phenotype. Next generation panel sequencing (NGPS) was utilized to discover a novel, single point mutation variant in NFkB1, V213E, that is present in our proband. METHODS: The novel single-point mutation V213E in the NFkB gene was modeled in-silico using the I-TASSER homology modeling software. Molecular dynamics simulations of both the wild type and variant mutant form fitted to accommodate the novel mutation were conducted and analyzed to assess for possible pathogenicity of the novel mutation. RESULTS: This variant replaces Valine with Glutamic Acid at position 213 in the transcription regulator’s sequence. We perform molecular modeling to analyze the proteomic impact and difference in molecular dynamics (MDS) which depicted suppressed dynamics in the ankyrin region and death domain of the protein complex. Analysis of the proband’s family showed no significant family history except for the maternal cousin with a mutation in NFkB1. CONCLUSION: This case both highlights the heterogeneity in phenotype of NFkB1 pathogenic variants as shown in this patient, full penetrance of the variant mutation, and suggests the pathogenicity of a new variant through protein modeling techniques and molecular dynamic simulations.

Inter-laboratory variation in B cell subsets reporting and its clinical implications

Common variable immunodeficiency (CVID) affects approximately 1 in 30,000 individuals and is caused by defective B cell differentiation. Clinical presentations and laboratory anomalies guide the diagnosis of CVID. Given switched memory B cell levels below 70% of the related age adjusted reference interval are considered consistent with CVID, we sought to assess the performance of laboratories in the B cell subsets program offered by RCPAQAP.

COMMON VARIABLE IMMUNODEFICIENCY WITH UNUSUAL PERIPHERAL NEUROPATHY AND ASSOCIATED IL-7 RECEPTOR MUTATION

<h3>Introduction</h3> Common variable immunodeficiency is the most common symptomatic primary immunodeficiency, characterized by hypogammaglobulinemia and presenting with a broad range of symptoms including recurrent bacterial infections, autoimmunity, and neoplastic conditions. We present a case of common variable immunodeficiency associated with peripheral neuropathy and a pathogenic heterozygous variant of interleukin-7 receptor (IL7R) gene. <h3>Case Description</h3> The patient is a thirty-eight-year-old female with a history of recurrent infections since childhood including pneumonia and sinus infections status post-tonsillectomy and sinus surgery. She subsequently developed severe left leg and lower back pain which progressed to left foot drop and decreased sensation over the leg with accompanied paresthesia. Labs showed profound hypogammaglobulinemia with scarce levels of IgG (55mg/dl) and IgM (21mg/dl) and lack of IgA (2mg/dl) and IgE (<0.3 IU/ml). Further workup included normal lymphocyte proliferation with deficient polysaccharide and protein response. The patient's lack of IgG antibody production is an important criterion for the diagnosis of common variable immunodeficiency. Genetic panel was performed and significant for a single pathogenic variant in IL7R. <h3>Discussion</h3> We present a case of recurrent sinopulmonary infections with associated peripheral neuropathy prompting further evaluation, revealing the diagnosis of common variable immunodeficiency. Mononeuropathy is a rare finding in common variable immunodeficiency, although should elicit further evaluation if the etiology is unclear. Additional workup was significant for a single pathogenic variant in IL7R. This gene is associated with autosomal recessive severe combined immunodeficiency when homozygous. Further genetic testing is indicated to determine the clinical significance of this variant.

A UNIQUE CLINICAL PRESENTATION OF COMMON VARIABLE IMMUNODEFICIENCY: MALAKOPLAKIA OF RECTUM.

<h3>Introduction</h3> Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults and present with a broad range of clinical manifestations including granulomatous diseases. Malakoplakia is a rare chronic granulomatous disease (CGD) that can affect multiple organs and shown as a manifestation in immunocompromised individuals. In this case report, we present rectal malakoplakia as a clinical manifestation of a CVID in patient for the first time. <h3>Case Description</h3> This is a 62-year-old man with no significant past medical history except hypertension. He did not report recurrent infections, autoimmune disorders or malignancy. Recently, the patient underwent first screening colonoscopy, had a resection of one tubular polyp of rectum and the biopsy of polyp contained malakoplakia. Underlying etiology for rectal malakoplakia was investigated and all results were unremarkable except serum protein electrophoresis showing hypogammaglobulinemia without monoclonal gammopathy. Serum immunoglobulin levels were low (IgG: 538, IgA: 65 and IgM: 14, mg/dL). Flow cytometry analyses of lymphocytes showed markedly decreased absolute cell counts of CD4⁺ (221/ul) and CD19⁺ (28/ul) cells with low memory and switched-memory B-cells. <h3>Discussion</h3> This is a unique case of a completely asymptomatic patient who was incidentally found to have rectal malakoplakia. Work up for malakoplakia led to the diagnosis of CVID. CVID present with a broad range of clinical manifestations including granulomatous disease, however, rectal malakoplakia - a rare chronic granulomatous disease, was never reported as a manifestation of CVID. Although this patient is currently asymptomatic, it will be crucial to closely monitor his immune profile and clinical manifestations.

Autoimmune disorders associated with common variable immunodeficiency: prediction, diagnosis, and treatment

ABSTRACT Introduction Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Due to the wide spectrum of the CVID manifestations, the differential diagnosis becomes complicated, ends in a diagnostic delay and increased morbidity and mortality rates. Autoimmunity is one of the important complications associated with CVID. While immunoglobulin replacement therapy has considerably decreased the mortality rate in CVID patients, mainly infection-related mortality, other complications such as autoimmunity appeared prevalent and, in some cases, life threatening. Areas covered In this article, genetics, responsible immune defects, autoimmune manifestations in different organs, and the diagnosis and treatment processes in CVID patients are reviewed, after searching the literature about these topics. Expert opinion Considering the many phenotypes of CVID and the fact that it remained undiagnosed until older ages, it is important to include various manifestations of CVID in the differential diagnosis. Due to the different manifestations of CVID, including autoimmune diseases, interdisciplinary collaboration of physicians from different fields is highly recommended, as discussed in the manuscript. Meanwhile, it is important to determine which patients could benefit from genetic diagnostic studies since such studies are not necessary for establishing the diagnosis of CVID.

Complicated ways of diagnosing common variable immune deficiency (case report)

Common variable immunodeficiency (CVID) is one of the most frequent forms of primary immunodeficiencies with predominant antibody deficiency. Unlike most other primary immunodeficiencies, this variant often manifests in adults thus creating certain difficulties in its detection. Manifestations of common variable immune deficiency are very diverse: infectious syndrome (respiratory tract infections, septic arthritis), diarrheal clinical pattern of both infectious and non-infectious genesis, autoimmune syndrome (autoimmune cytopenias, systemic rheumatic diseases), lymphoproliferative syndrome (benign lymphoid proliferation, lymphomas), interstitial lung disease and sarcoidosis-like granulomatous changes are quite common. Due to the lack of a distinct clinical pattern, the common variable immunodeficiency is often diagnosed too late. Such patients are observed for a long time by various specialists, and the absence of pathogenetic therapy (intravenous immunoglobulins) leads to steady progression of the disease and, often, to lethal outcome. The article presents a clinical observation illustrating the difficulties in making this diagnosis. A woman hospitalized with pneumonia presented with a mass in colonic submucosa. After excluding tuberculosis and lymphoma, a diagnosis of colon lipoma was made on the basis of histological examination. A few years later, the patients submandibular lymph nodes were periodically enlarged. Upon repeated histological examination, the diagnosis of granulomatous necrotizing lymphadenitis was established, the patient was referred to a rheumatologist to rule out systemic vasculitis. This diagnosis was not confirmed, but further examination revealed a sharp decrease in the gamma fraction of serum proteins. Therefore, an immunologists counseling was recommended to rule out immunodeficiency. The following blood serum analysis revealed an extremely low IgG and IgM content, with absence of detectable immunoglobulin A. On the basis of these findings, the diagnosis of common variable immune deficiency was made for the first time. Replacement therapy with high-dose intravenous immunoglobulins with control of pre-transfusion Ig levels was recommended, with further transition to a supporting treatment schedule. Hence, one may state that general practitioners are still poorly aware of primary immunodeficiencies, especially if non-infectious manifestations dominating in the clinical pattern. Routine analysis of total protein content and protein fractions can provide information that allows to suspect deficiency of antibodies and, therefore, to assess contents of distinct serum immunoglobulins in order to confirm CVID diagnosis.

Lymphoma as an Exclusion Criteria for CVID Diagnosis Revisited.

Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.

Evaluation of Laboratory and Sonographic Parameters for Detection of Portal Hypertension in Patients with Common Variable Immunodeficiency

Timely detection of portal hypertension as a manifestation in a subgroup of patients with common variable immunodeficiency (CVID) represents a challenge since it is usually not associated with liver cirrhosis. To identify relevant markers for portal hypertension, we evaluated clinical history, laboratory parameters, and abdominal ultrasound including liver elastography and biomarkers of extracellular matrix formation. Twenty seven (6%) of 479 CVID patients presented with clinically significant portal hypertension as defined by either the presence of esophageal varices or ascites. This manifestation occurred late during the course of the disease (11.8 years after first diagnosis of CVID) and was typically part of a multiorgan disease and associated with a high mortality (11/27 patients died during follow up). The strongest association with portal hypertension was found for splenomegaly with a longitudinal diameter of > 16 cm. Similarly, most patients presented with a liver stiffness measurement (LSM) of above 6.5 kPa, and a LSM above 20 kPa was always indicative of manifest portal hypertension. Additionally, many laboratory parameters including Pro-C4 were significantly altered in patients with portal hypertension without clearly increasing the discriminatory power to detect non-cirrhotic portal hypertension in CVID. Our data suggest that a spleen size above 16 cm and an elevated liver stiffness above 6.5 kPa should prompt further evaluation of portal hypertension and its sequelae, but earlier and better liquid biomarkers of this serious secondary complication in CVID are needed.

Application of the diagnostic criteria for Common Variable Immunodeficiency in resource-limited settings.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic humoral deficiency; however, its heterogeneous presentation makes the diagnosis difficult. The present study is aimed to verify the CVID diagnostic criteria as established by the European Society for Immunodeficiencies in 42 CVID patients from our outpatient clinic. Information was collected from their medical records and when needed, lymphocyte subpopulations in peripheral blood (PB) were performed by flow cytometry. All the patients fulfilled the clinical working definition for CVID and showed decreased serum IgG and IgA at diagnosis. Over two-thirds of the patients had decreased memory B cell percentages. However, the remaining patients exhibited other quantitative B cell defects in PB. Evaluation of vaccination responses was only found in 13 records and 69% were not responsive. None of the patients were subjected to vaccination studies to both, T-cell dependent and independent antigens. The two required tests to evaluate T cell responses were performed in 84.2% of the patients and reported normal. Without the support of third-party payers, only 34.2% of our patients would have completed the required evaluations. Further efforts are needed to speed up CVID diagnosis in low-resourced settings, increasing the availability of the required resources and optimizing the healthcare supply chain.

Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4+: p = 0.005; CD8+: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.

Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic immunodeficiency in adults. Little is known about the manifestations of CVID presenting in older adults. Herein, we performed a phenotypic characterization of patients diagnosed older than age 40. A retrospective chart review of 79 patients seen at UF Health between 2006 and 2020 with a verified diagnosis of CVID per the ICON 2016 criteria was conducted. Patients were classified according to four phenotypes: no-disease-related complications, autoimmune cytopenias, polyclonal lymphoproliferation, and unexplained enteropathy. Patients diagnosed with CVID from age 2 to 40 (n = 41, "younger cohort") were compared to patients diagnosed with CVID age 41 and older (n = 38, "older cohort"). Among the younger cohort, pathologic genetic variants, positive family history for immunodeficiency, autoimmunity (49% vs 24%, p = 0.03), and splenomegaly (46% vs 16%, p = 0.004) were more common, as was the "autoimmune cytopenias" phenotype (24% vs 3%, p = 0.007). Among the older cohort, lymphoma (11% vs 0%, p = 0.049) and the "no disease-related complications" phenotype (79% vs 57%, p = 0.03) were more commonly seen. Comorbidities such as bronchiectasis (27% vs 21%, p = 0.61), GI involvement (34% vs 24%, p = 0.33), and GLILD (5% vs 8%, p = 0.67) were equally present among both the younger and older cohorts, respectively. The lower incidence of autoimmunity and splenomegaly, as well as overlapping clinical features with immunosenescence, may make diagnosing CVID in older patients more challenging; however, the disease is not more indolent as the risks for lymphoma, bronchiectasis, and GLILD are similar to those of younger patients.