Neurological involvement in patients with primary immunodeficiency

Introduction: Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions. Materials and method: We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study. Results: The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%) (AU)

Atopic Manifestations Are Underestimated Clinical Features in Various Primary Immunodeficiency Disease Phenotypes

Background: Atopic manifestations are described as a clinical feature of various primary immunodeficiency disease (PID) phenotypes and are frequently reported in combined immunodeficiencies. The prevalence of atopic manifestations in other PIDs remains largely unknown. Objective: To evaluate the prevalence of atopic manifestations in PIDs other than combined immunodeficiencies and to identify in which PIDs atopic manifestations are most common with the aim of improving patient care. Methods: A partner-controlled, questionnaire-based study was performed in pediatric and adult PID patients. Data from diagnostic tests to assess atopic manifestations (ie, diagnostic criteria for atopic dermatitis, spirometry, specific IgE against food and inhalant allergens) were collected from adult patients to confirm patient-reported atopic manifestations. Results: Forty-seven children and 206 adults with PIDs and 56 partner-controls completed the questionnaire. Thirty-five pediatric patients (74.5%) and 164 adult patients (79.6%) reported having experienced 1 or more atopic manifestations compared with 28 partner-controls (50.0%). In the comparison of adult patients with partner-controls, prevalence values were as follows: atopic dermatitis, 49.5% vs 27.3% (P=.003); food allergy, 10.7% vs 1.9% (P=.031); asthma, 55.7% vs 14.8% (P<.001); and allergic rhinitis, 49.8% vs 21.8% (P<.001). The frequency of current atopic manifestations reported by patients was higher than the prevalence based on diagnostic tests (atopic dermatitis, 11.2%; food allergy, 1.9%; asthma 16.4%; and allergic rhinitis, 11.5%). Conclusion: Atopic manifestations are prevalent clinical features across a broad spectrum of PIDs and, in our cohort, frequently present in patients with combined immunodeficiencies and predominant antibody deficiencies. Atopic manifestations should be evaluated in patients with PIDs (AU)

Antecedentes: En varios de los fenotipos asociados a las inmunodeficiencias primarias (PID), se describen, frecuentemente, diversas manifestaciones atópicas, en particular, en la inmunodeficiencia combinada. Sin embargo, la prevalencia de las manifestaciones atópicas en otras PID sigue siendo desconocida. Objetivo: Calcular la prevalencia de las manifestaciones atópicas en otras PID e identificar en cuáles de éstas son las más frecuentes con el fin de mejorar la atención a los pacientes. Métodos: Se realizó un estudio basado en un cuestionario validado, tanto en pacientes pediátricos como en adultos diagnosticados de PID. Posteriormente, se recopilaron los resultados de diferentes pruebas diagnósticas para enfermedades atópicas con el fin de corroborar los síntomas notificados por los pacientes adultos; es decir, criterios de diagnóstico para la dermatitis atópica, espirometría e IgE específica contra alérgenos alimentarios e inhalados. Resultados: El cuestionario se completó por 47 niños y 206 adultos con PID, y por 56 controles. Treinta y cinco pacientes pediátricos (74,5%) y 164 adultos (79,6%) informaron haber experimentado alguna vez una o más manifestaciones atópicas en comparación con 28 controles (50,0%). En los pacientes adultos, al comparar la prevalencia con sus controles, se observaron los siguientes resultados, respectivamente: dermatitis atópica 49,5% vs. 27,3% (p = 0,003); alergia alimentaria 10,7% vs. 1,9% (p = 0,031); asma 55,7% vs. 14,8% (p <0,001); y rinitis alérgica 49,8% frente a 21,8% (p <0,001). La frecuencia de manifestaciones atópicas objetivadas en los pacientes fue superior a la prevalencia basada en las pruebas diagnósticas (dermatitis atópica 11,2%, alergia alimentaria 1,9%, asma 16,4% y rinitis alérgica 11,5%) (AU)

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)

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

Introduction: Common variable immunodeficiency (CVID) is the most prevalent symptom-atic humoral deficiency; however, its heterogeneous presentation makes the diagnosis diffi-cult. 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. Methods: Information was collected from their medical records and when needed, lymphocyte subpopulations in peripheral blood (PB) were performed by flow cytometry. Results: 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 respon-sive. 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. Conclusions: 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 (AU)

Easy approach to detect cell immunity to COVID vaccines in common variable immunodeficiency patients

Background Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function.Methods Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test.Results Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR.Conclusions The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID.Clinical Implications There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations.Capsule Summary Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning (AU)

Enfermedad pulmonar intersticial linfocítica granulomatosa: descripción de una serie de 9 casos / Granulomatous lymphocytic interstitial lung disease: description of a series of 9 cases

Introducción: La enfermedad pulmonar intersticial linfocítica granulomatosa (GLILD) es una de las complicaciones no infecciosas más graves de los pacientes con inmunodeficiencia común variable (IDCV). Su diagnóstico y tratamiento suponen un reto.ObjetivoAnalizar las características de los pacientes con IDCV y GLILD del Hospital General Universitario de Alicante.Material y métodosEstudio descriptivo de los pacientes con IDCV y GLILD diagnosticados desde 2000 a 2020.ResultadosDe los 42 pacientes con IDCV 9 presentaban GLILD (21%). La edad media al diagnóstico fue de 39 años. El 66% de IDCV fue de tipo MB0. El 55% tenía los linfocitos LB disminuidos. Se observó una disminución de la capacidad de transferencia del monóxido de carbono en un 89%. La biopsia pulmonar quirúrgica (BPQ) se realizó en el 78%. La manifestación extrapulmonar más frecuente fue adenopatías (78%). Una paciente presentó mutación patológica en heterocigosis en el gen CTLA4. El 67% de los pacientes recibió tratamiento combinado de corticoides con rituximab.ConclusionesLa GLILD es una complicación infrecuente de las IDCV cuyo diagnóstico y tratamiento es un reto. Su diagnóstico requiere un alto índice de sospecha, por lo que el enfoque diagnóstico multidisciplinar y el tratamiento combinado podrían proporcionar un buen resultado en la población adulta. (AU)

Introduction: Granulomatous-lymphocytic interstitial lung disease (GLILD) is one of the most serious non-infectious complications in patients with common variable immunodeficiency (CVID). Its diagnosis and treatment are challenging.ObjectiveTo analyse the characteristics of Hospital General Universitario de Alicante patients with CVID and GLILD.Material and methodsDescriptive study of patients with CVID and GLILD diagnosed from 2000 to 2020.ResultsOf the 42 patients with CVID, 9 had GLILD (21%). Mean age at diagnosis of 39 years. Sixty-six percent of the CVID was type MB0. Fifty-five percent had decreased BLs. There was a decrease in DLCO by 89%. Surgical lung biopsy (SLB) was performed in 78%. The most frequent extrapulmonary manifestation was adenopathy (78%). One patient had a heterozygous pathological mutation in the CTLA4 gene. Of the patients, 67% received combined corticosteroid treatment with Rituximab.ConclusionsGLILD is a rare complication of CVID whose diagnosis and treatment are a challenge. Its diagnosis requires a high index of suspicion, therefore a multidisciplinary diagnostic approach and combined treatment could provide a good result in the adult population. (AU)

Evaluation of miR-210 expression in common variable immunodeficiency: patients with unsolved genetic defect

Background Common variable immunodeficiency (CVID) is one of the most prevalent forms of primary immunodeficiency diseases (PID). CVID is characterized by failure in the final differentiation of B lymphocytes and impaired antibody production but the pathogenesis is not known in the majority of patients. We postulated that the expression pattern of miRNAs in unsolved CVID patients might be the underlying epigenetic cause of the disease. Therefore, we aimed to assess the expression of hsa-miR-210-5p and FOXP3 transcription factor in CVID cases in comparison with healthy individuals. Methods Eleven CVID cases with no genetic defects (all PID known genes excluded) and 10 sex and age-matched healthy individuals were enrolled in the study. T lymphocytes were purified from PBMC, and expression levels of miR-210-5p and FOXP3 mRNA were evaluated by real-time PCR. Results We demonstrated that miR-210 expression in patients was significantly higher than the control group (P = 0.03). FOXP3 expression was slightly lower in patients compared with healthy controls (P = 0.86). There was a negative correlation between miR and gene expression (r: −0.11, P = 0.73). Among various clinical complications, autoimmunity showed a considerable rate in high-miR patients (P = 0.12, 42.8%), while autoimmunity was not observed in normal miR-210 patients. Conclusions Our results suggest a role for miR-210 in the pathogenesis of autoimmunity in CVID patients. Further studies would better elucidate epigenetic roles in CVID patients with no genetic defects (AU)

The CXCR5 T follicular helper cell compartment in children with antibody deficiencies—in search of a prognostic marker of childhood hypogammaglobulinemia

Background Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hypermutations, and affinity maturation. Objective To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. Methods We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. Results In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. Conclusions A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency (AU)

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

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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

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Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management

La inmunodeficiencia variable común (CVID) es un trastorno heterogéneo caracterizado por una hipogammaglobulinemia y por una mayor susceptibilidad a infecciones bacterianas recurrentes. Se trata de la inmunodeficiencia humoral sintomática más frecuente y cursa con una extensa variedad de complicaciones infecciosas y no infecciosas. En la patogenia de la CVID están involucrados diferentes defectos inmunológicos y genéticos. Sin embargo, en la mayoría de los casos, el fondo genético de la enfermedad permanece sin identificar. Esta revisión tiene como objetivo discutir diferentes aspectos de la CVID, incluyendo epidemiología, patogenia, síntomas, diagnóstico, clasificaciones y tratamiento de la enfermedad

Success with multidisciplinary team work: experience of a primary immunodeficiency unit

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