FDG-Avid Granulomatous Lymphocytic Interstitial Lung Disease With Common Variable Immunodeficiency.

ABSTRACT: A 26-year-old woman with known common variable immunodeficiency was referred for FDG PET/CT because of interstitial pulmonary abnormalities and enlarged mediastinal and hilar lymph nodes. FDG PET showed a combination of ground-glass abnormalities and pulmonary nodules, both displaying increased FDG uptake. In addition, multiple FDG-avid axillary, mediastinal, hilar, and inguinal lymph nodes were found. The abnormalities were diagnosed as granulomatous-lymphocytic interstitial lung disease. Cytology of mediastinal lymph nodes yielded only benign disease, without further specification, whereas histology of an excised axillary lymph node showed reactive changes, but no malignancy.

Comparison of chest computed tomography and 3-T magnetic resonance imaging results in patients with common variable immunodeficiency.

BACKGROUND: Patients with common variable immunodeficiency (CVID) have an increased incidence of pulmonary infections and require frequent follow-up computed tomography (CT) scans. PURPOSE: To evaluate the diagnostic performance of 3-T magnetic resonance imaging (MRI) in patients with CVID. MATERIAL AND METHODS: In this prospective study, 3-T MRI was performed in 20 patients with CVID. The patients were imaged with CT and MRI scans on the same day. The MRI protocol included a T2-weighted HASTE sequence (TR=1400 ms, TE=95 ms, slice thickness (ST)=3 mm), T2-weighted BLADE sequence (TR=5379 ms, TE=100 ms, ST=3 mm), and 3D VIBE sequence (TR=3.9 ms, TE=1.32 ms, ST=3 mm). Mediastinal and parenchymal changes were compared. A modified Bhalla scoring system was used in the evaluation of CT and MRI scans. RESULTS: A total of 17 (85%) patients had parenchymal abnormalities identified by CT or MRI. Similar findings were detected with CT and MRI in the assessment of the severity of bronchiectasis (P=0.083), bronchial wall thickening (P=0.157), and mucus plugging (P=0.250). Consolidations were detected with both modalities in all patients. There was excellent concordance between the two modalities in the evaluation of nodules >5 mm (nodule size 5-10 mm, P=0.317; nodule size >10 mm, P=1). However, MRI failed to detect most of the small nodules (<5 mm). CONCLUSION: 3-T MRI detected mediastinal and parenchymal alterations in patients with CVID and provided findings that correlated well with CT. Despite a few limitations, MRI is a well-suited radiation-free technique for patients requiring longitudinal imaging.

Norovirus infection as a model of chronic or recurrent infection in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency (PID) in general population. PID are genetic diseases that share a dysfunction in the immune system entailing a greater risk of both chronic and recurrent infections. These patients can also develop chronic gastrointestinal infections caused by norovirus with persistent viral dissemination, which can be detected months after primoinfection. Additionally, a proportion of CVID patients show a typical severe enteropathy presenting with recurrent diarrhoea, intestinal malabsorption, inflammatory lesions, and villous atrophy. Some studies have related this enteropathy with chronic intestinal infection caused by norovirus.

Norovirus infection as a model of chronic or recurrent infection in common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency (PID) in general population. PID are genetic diseases that share a dysfunction in the immune system entailing a greater risk of both chronic and recurrent infections. These patients can also develop chronic gastrointestinal infections caused by norovirus with persistent viral dissemination, which can be detect ed months after primoinfection. Additionally, a proportion of CVID patients show a typical severe enteropathy presenting with recurrent diarrhoea, intestinal malabsorption, inflammatory lesions, and villous atrophy. Some studies have related this enteropathy with chronic intestinal infection caused by norovirus. (AU)

Raised Serum Markers of T Cell Activation and Exhaustion in Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

PURPOSE: About 20-30% of patients with common variable immunodeficiency (CVID) develop granulomatous-lymphocytic interstitial lung disease (GLILD) as one of several non-infectious complications to their immunodeficiency. The purpose of this study was to identify biomarkers that could distinguish GLILD from other non-infectious complications in CVID. METHODS: We analyzed serum biomarkers related to inflammation, pulmonary epithelium injury, fibrogenesis, and extracellular matrix (ECM) remodeling, and compared three subgroups of CVID: GLILD patients (n = 16), patients with other non-infectious complications (n = 37), and patients with infections only (n = 20). RESULTS: We found that GLILD patients had higher levels of sCD25, sTIM-3, IFN-γ, and TNF, reflecting T cell activation and exhaustion, compared to both CVID patients with other inflammatory complications and CVID with infections only. GLILD patients also had higher levels of SP-D and CC16, proteins related to pulmonary epithelium injury, as well as the ECM remodeling marker MMP-7, than patients with other non-infectious complications. CONCLUSION: GLILD patients have elevated serum markers of T cell activation and exhaustion, pulmonary epithelium injury, and ECM remodeling, pointing to potentially important pathways in GLILD pathogenesis, novel targets for therapy, and promising biomarkers for clinical evaluation of these patients.

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.

Functions of NK and iNKT cells in pediatric and adult CVID, ataxia telangiectasia and agammaglobulinemia patients.

Primary immune deficiencies (PID) are known to be more than 400 genetic defects caused by the impairment in development and/or functions of the immune system. Common Variable Immunodeficiency (CVID), Ataxia Telangiectasia (AT) and Agammaglobulinemia (AG) are examples of the most common immunodeficiency syndrome. Natural killer (NK) cells are a component of innate immune system and play a major role in the host-rejection of both tumors and virally infected cells. iNKT cells have a role in autoimmune and infectious diseases and controlling of tumor rejection. In this study, NK and iNKT cells and their functions, and intracellular cytokine amount are aimed to determine in patients that suffer CVID, AT and AG. NKp30, NKp46, NKG2D, perforin and granzyme mRNA expression levels were analyzed using RT-PCR. Receptors, cytokine amount of NK cell subset and iNKT were analyzed by flow cytometry. Decreased CD3+ T and elevated NK cell subset in pediatric AT were found. Expression of NKp44 was decreased in adult AG, but not in pediatric patients. Low NKp44 expression in CD3-CD16+CD56dim NK cell subset was found in pediatric AT patients. High HLA-DR, perforin and granzyme expression were found in CD3-CD16+CD56dim NK cell subset of pediatric CVID and AT patients. Alteration of the number of NK subsets, NK receptor expression and cytokine production were observed in pediatric patients compared to healthy subjects.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The "variable" aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren's syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better "autoimmune" association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

Pulmonary Hypertension in Patients with Common Variable Immunodeficiency.

PURPOSE: Common variable immunodeficiency (CVID) is known to cause infectious, inflammatory, and autoimmune manifestations. Pulmonary hypertension (PH) is an unusual complication of CVID with largely unknown characteristics and mechanisms. METHODS: We report the clinical, functional, hemodynamics, radiologic and histologic characteristics, and outcomes of CVID-associated PH patients from the French PH Network. RESULTS: Ten patients were identified. The median (range) age at CVID diagnosis was 36.5 (4-49) years and the median delay between CVID and PH diagnosis was 12 (0-30) years. CVID-associated PH affected predominantly women (female-to-male ratio 9:1). Most patients were New York Heart Association functional class III with a severe hemodynamic profile and frequent portal hypertension (n = 6). Pulmonary function tests were almost normal in 70% of patients and showed a mild restrictive syndrome in 30% of patients while the diffusing capacity for carbon monoxide was decreased in all but one patient. High-resolution computed tomography found enlarged mediastinal nodes, mild interstitial infiltration with reticulations and nodules. Two patients had a CIVD-interstitial lung disease, and one presented with bronchiectasis. Pathologic assessment of lymph nodes performed in 5 patients revealed the presence of granulomas (n = 5) and follicular lymphoid hyperplasia (n = 3). At last follow-up (median 24.5 months), 9 patients were alive, and one patient died of Hodgkin disease. CONCLUSION: PH is a possible complication of CVID whose pathophysiological mechanisms, while still unclear, would be due to the inflammatory nature of CVID. CVID-associated PH presents as precapillary PH with multiple possible causes, acting in concert in some patients: a portal hypertension, a pulmonary vascular remodeling, sometimes a pulmonary parenchymal involvement and occasionally an extrinsic compression by mediastinal lymphadenopathies, which would be consistent with its classification in group 5 of the current PH classification.

Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge.

Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.

Effect of Selenium on Quantitative Structural Changes in Dexamethasone-Induced Immunodeficiency Rat Models.

Background: One of the major indices of immunodeficiency is lymphoid organ atrophy. Some trace elements are candidates for the treatment of this defect. These conditions may induce structural changes in the sub-components of lymphoid organs. Therefore, this study evaluated the effect of selenium on volumetric changes in dexamethasone (DEX)-induced lymphoid organ atrophy in an animal model. Methods: This study was conducted at Histomorphometry and Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran, in September 2016 to September 2017. Thirty-two male rats were divided into four groups: Group I; control (normal saline, 0.5 mL/kg, intraperitoneally), Group II; DEX (0.4 mg/kg; intraperitoneally), Group III; selenium plus DEX (similar to Group II and Group IV), and Group IV; selenium (0.1 mg/kg; orally). At the end of the experiment, the rats' thymus, spleen, and lymph nodes were removed, processed, and stained by hematoxylin and eosin (H&E). The volume and volume density of theses organs were estimated by stereology. The results were analyzed using the Mann-Whitney U-test and the Kruskal-Wallis test. Results: The volume of the thymus as well as its cortex and medulla; the volume of the spleen as well as the volume density of its white pulp, periarterial lymphatic sheath zone, and follicles; and the volume of the lymph nodes as well as their inner (P=0.001) and outer (P=0.007) cortices showed a significant reduction in the DEX-treated animals in comparison with the controls. In the DEX plus selenium-treated animals, maximum effects were observed on the increment in the thymic cortex (P=0.001), the outer cortex of the lymph nodes (P=0.012), and the splenic follicles (P=0.018) in comparison with the DEX group. There was no significant difference between the animals receiving selenium treatment and the controls in terms of lymphoid organs. Conclusion: Selenium may improve lymphoid organ structures in an immunodeficiency rat model but has no effect on normal lymphoid tissues.

Evaluation of B-cell intracellular signaling by monitoring the PI3K-Akt axis in patients with common variable immunodeficiency and activated phosphoinositide 3-kinase delta syndrome.

BACKGROUND: Primary antibody deficiencies (PADs) are characterized by hypogammaglobulinemia and impaired B-cell differentiation. Patients with common variable immunodeficiency (CVID) present severe reductions in at least 2 serum immunoglobulins and impaired terminal differentiation of B cells. Most patients with CVID do not appear to present monogenic defects. Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by gain-of-function mutations in the PIK3CD gene (p110δ), can present in patients with a CVID-like phenotype. Memory B-cell differentiation requires the orchestrated activation of numerous intracellular signaling pathways, which promote transcriptional programs required for long-term B-cell survival. The aim of this study was to develop a flow cytometry assay to trace the PI3K-Akt-mTOR pathway, a critical component of B-cell homeostasis, and analyze its status in PADs. METHODS: We analyzed the intracellular expression of Akt and S6 by flow cytometry and their phosphorylation status in both baseline conditions and upon B-cell receptor activation with anti-IgM in various primary B-cell subsets of patients with CVID and APDS. RESULTS: B cells from CVID patients showed reduced phosphorylation in Akt and S6 proteins after anti-IgM stimulation. Constitutive high baseline B-cell levels of Akt and S6 phosphorylation in a patient with APDS were reduced once m-TOR inhibition therapy was initiated. CONCLUSIONS: Intracellular flow cytometry can be routinely employed to explore alterations in the PI3K-Akt-mTOR pathway in B cells from patients with PADs. AKT and S6 phosphorylation levels are informative biomarkers that could be employed as mTOR inhibitors for monitoring therapies targeting this pathway.

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

INTRODUCTION AND OBJECTIVES: Common 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 METHODS: Clinical 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). RESULTS: The 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). CONCLUSIONS: CVID 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

No disponible

Lung disease in patients with common variable immunodeficiency

BACKGROUND: Common Variable Immunodeficiency (CVID) is characterized by an impaired antibody production and a higher susceptibility to encapsulated bacterial infections. Lung disease is considered to be the most important cause of morbidity and mortality. METHODS: We analyzed clinical, radiological and functional characteristics in 80 patients with CVID assisted in the Unidad Inmunologia e Histocompatibilidad at Durand Hospital from 1982 to 2018. RESULTS: Of the 80 patients, 55 showed pathologic lung Computed Tomography (CT). Twenty of them (36.4%) showed bronchiectasis; 26 (47.3%) interstitial involvement associated with nodules and adenopathies called GLILD (granulomatous-lymphocytic interstitial lung disease); and nine patients (16.3%) showed other lesions. Nine percent of patients with lung disease showed CT progression; none of them had spirometry worsening. GLILD patients had normal and restrictive patterns in lung function tests, in equal proportions. Two patients - one with GLILD and the other one with bronchiectasis - had an increase in spirometric pattern severity without CT progression. Lung biopsy was performed in 19% of GLILD patients, all of whom had histopathologic diagnosis of Lymphoid Interstitial Pneumonia (LIP). CONCLUSIONS: GLILD is the major cause of lung disease in CVID. Computed tomography is useful for diagnosis but not necessary in follow-up, in which functional tests should have better correlation with clinical evolution, reducing radiation exposure. Biopsy should be indicated when the clinical diagnosis is unclear. Treatment should be considered whenever there is clear evidence of disease progression

No disponible

Involvement of miR-142 and miR-155 in Non-Infectious Complications of CVID.

BACKGROUND AND OBJECTIVES: Common variable immunodeficiency (CVID) is the most prevalent antibody impairment. It is characterized by failure in immunoglobulin and protective antibody generation and defined by an increased tendency toward bacterial infections, autoimmunity, and malignancy. Most CVID diagnoses do not follow a classical Mendelian pattern of inheritance. In recent years, CVID has been considered an epigenetic phenomenon in the majority of cases, overtaking previous monogenetic and/or polygenetic theories. The aim of this study was to review the role of microRNAs (miRNAs) in CVID, focusing on the involvement of the same miRNAs in various non-infectious clinical complications of CVID, mainly autoimmunity and/or cancer. MATERIALS AND METHODS: A bibliographic search of the scientific literature was carried out independently by two researchers in scientific databases and search engines. The MeSH terms "microRNAs" and "common variable immunodeficiency" were used. All research articles from inception to May 2020 were considered. RESULTS: The literature data showed the involvement of two miRNAs in primary immunodeficiency: miR-142 and miR-155. Both of these miRNAs have been investigated through mice models, in which miR-142 and miR-155 were deleted. These knock-out (KO) mice models showed phenotypic analogies to CVID patients with hypogammaglobulinemia, adaptive immunodeficiency, polyclonal proliferation, lung disease, and enteric inflammation. miR-142 and miR-155 have been found to be involved in the following autoimmune and neoplastic clinical complications of CVID: Gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, natural killer/Tcell lymphoma (NKTCL), and immune thrombocytopenia. CONCLUSIONS: miR-142 and miR-155 deregulation leads to similar CVID phenotypesin KO mice models. Although no data are available on the involvement of these miRNAs in human CVID, their dysregulation has been detected in human CVID comorbidities. The literature data show that miRNA sequences in murine models are comparable to those in humans; therefore, miR-142 and miR-155 involvement in human CVID could be hypothesized.

Aplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency.

Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a pathogenic variant in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-κB signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.

Pathogenesis of immune thrombocytopenia in common variable immunodeficiency.

Immune Thrombocitopenic Purpura (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and variable reduced platelet production. Besides antibody-mediated platelet destruction, new pathogenic mechanisms have been reported to be involved in reducing platelet count. Among these, desialylation is one of the most recent and innovative mechanisms that has been found to be implied, at least in part, in non-antibody mediated platelet clearance. Common Variable Immunodeficiency (CVID) is the most common Primary Immunodeficiency seen in clinical practice. About 25-30% of CVID patients are affected by autoimmune manifestation, among which ITP is the most common. Little is know about pathophysiological mechanisms that lead to ITP in CVID. Given the poor antibody production typical of CVID patients, we aimed at verifying whether platelet desialylation could be responsible for CVID associated thrombocytopenia. According to our results, we may suggest that in CVID patients, ITP is due to a decreased bone marrow platelets production, rather than an increased peripheral platelet destruction, which is more common in patients with primary ITP. An increased platelet desialylation does not appear to be implicated in the thrombocytopenia secondary to CVID, while it is implicated in the pathogenesis of primary ITP. Nevertheless an intriguing aspect has emerged from this study: regardless the presence of thrombocytopenia, the majority of CVID patients present a double platelet population as far as desialylation concerns, whilst no one of the healthy donors and of the patients with primary ITP shows a similar characteristic.