RESUMEN
Molecular diagnosis of inborn errors of immunity (IEI) plays a critical role in determining patients' long-term prognosis, treatment options, and genetic counseling. Over the past decade, the broader utilization of next-generation sequencing (NGS) techniques in both research and clinical settings has facilitated the evaluation of a significant proportion of patients for gene variants associated with IEI. In addition to its role in diagnosing known gene defects, the application of high-throughput techniques such as targeted, exome, and genome sequencing has led to the identification of novel disease-causing genes. However, the results obtained from these different methods can vary depending on disease phenotypes or patient characteristics. In this study, we conducted whole-exome sequencing (WES) in a sizable cohort of IEI patients, consisting of 303 individuals from 21 different clinical immunology centers in Türkiye. Our analysis resulted in likely genetic diagnoses for 41.1% of the patients (122 out of 297), revealing 52 novel variants and uncovering potential new IEI genes in six patients. The significance of understanding outcomes across various IEI cohorts cannot be overstated, and we believe that our findings will make a valuable contribution to the existing literature and foster collaborative research between clinicians and basic science researchers.
Asunto(s)
Secuenciación del Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Femenino , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/inmunología , Predisposición Genética a la Enfermedad , Niño , Preescolar , Mutación/genética , Pruebas Genéticas/métodos , Lactante , Exoma/genética , AdolescenteRESUMEN
In the last 20 years, discoveries about the autoimmune regulator (AIRE) protein and its critical role in immune tolerance have provided fundamental insights into understanding the molecular basis of autoimmunity. This review provides a comprehensive overview of the effect of AIRE on immunological tolerance and the characteristics of autoimmune diseases in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is caused by biallelic AIRE mutations. A better understanding of the immunological mechanisms of AIRE deficiency may enlighten immune tolerance mechanisms and new diagnostic and treatment strategies for autoimmune diseases. Considering that not all clinical features of APECED are present in a given follow-up period, the diagnosis is not easy in a patient at the first visit. Longer follow-up and a multidisciplinary approach are essential for diagnosis. It is challenging to prevent endocrine and other organ damage compared with other diseases associated with multiple autoimmunities, such as FOXP3, LRBA, and CTLA4 deficiencies. Unfortunately, no curative therapy like haematopoietic stem cell transplantation or specific immunomodulation is present that is successful in the treatment.
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Enfermedades Autoinmunes , Trasplante de Células Madre Hematopoyéticas , Poliendocrinopatías Autoinmunes , Humanos , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/terapia , Autoinmunidad/genética , Enfermedades Autoinmunes/genética , Tolerancia Inmunológica , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Eosinophilia is common in children and may be caused by various disorders. Large-cohort studies, including mild cases, are limited in children. This study aimed to reveal underlying etiologies of childhood eosinophilia and to create a diagnostic algorithm. Children (< 18 years) with absolute eosinophil counts (AECs) ≥ 0.5 × 109/L were reviewed from medical files. Clinical characteristics and laboratory values were recorded. Patients were grouped based on the severity of eosinophilia as mild (0.5-1.5 × 109/L), moderate (≥ 1.5 × 109/L) and severe (≥ 5.0 × 109/L). An algorithm was formed to evaluate these patients. We included 1178 children with mild (80.8%), moderate (17.8%) and severe eosinophilia (1.4%). The most common reasons of eosinophilia were allergic diseases (80%), primary immunodeficiency (PID) (8.5%), infectious diseases (5.8%), malignancies (0.8%) and rheumatic diseases (0.7%). Only 0.3% of children presented with idiopatic hypereosinophilic syndrome. Allergic diseases and PIDs were the most common etiologies in mild/moderate and severe groups, respectively. The median duration of eosinophilia was 7.0 (3.0-17.0) months in the study population and was the shortest in severe cases (2.0 (2.0-5.0) months). Multiple logistic regression analysis demonstrated food allergy [OR:1.866, 95%CI:1.225-2.842, p = 0.004] and PIDs [OR:2.200, 95%CI:1.213-3.992, p = 0.009] as independent factors for childhood eosinophilia. A diagnostic algorithm including mild form was presented for childhood eosinophilia. Conclusion: Eosinophilia was frequently determined due to secondary causes; allergic diseases in mild/moderate eosinophilia, PIDs in severe group. Etiology of eosinophilia was diverse, and an algorithm concerning the severity of eosinophilia would be practical and rational. What is Known: ⢠In children, eosinophilia is common, and mild eosinophilia occurs frequently. ⢠Malignancies presents frequently with severe eosinophilia. What is New: ⢠Primary immunodeficiencies were not a rare cause of eosinophilia, especially in countries such as the Middle East and eastern Mediterranean countries, where the countries consanguineous marriages are common, and should be investigated in children with eosinophilia who do not have allergic or infectious diseases. ⢠In literature, there are many algorithms about childhood hypereosinophilia. However, mild eosinophilia is extremely important in children. Because all patients with malignancy and most of the patients with rheumatic diseases presented with mild eosinophilia. Therefore, we proposed an algorithm for childhood eosinophilia that includes mild eosinophilia besides moderate and severe cases.
Asunto(s)
Síndrome Hipereosinofílico , Hipersensibilidad , Humanos , Niño , Síndrome Hipereosinofílico/diagnóstico , Síndrome Hipereosinofílico/epidemiología , Síndrome Hipereosinofílico/etiología , Hipersensibilidad/diagnóstico , Recuento de Leucocitos , Diagnóstico Diferencial , AlgoritmosRESUMEN
BACKGROUND: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings. OBJECTIVE: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis. METHODS: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry. RESULTS: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia. CONCLUSIONS: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia.
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Agammaglobulinemia , Bronquiolitis , Neutropenia , Lactante , Masculino , Humanos , Ruidos Respiratorios/etiología , Bronquiolitis/complicaciones , Bronquiolitis/diagnóstico , Neutropenia/complicacionesRESUMEN
Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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Subunidad alfa del Receptor de Interleucina-21/deficiencia , Subunidad alfa del Receptor de Interleucina-21/genética , Adolescente , Linfocitos B/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Niño , Preescolar , Criptosporidiosis/genética , Criptosporidiosis/inmunología , Cryptosporidium/inmunología , Femenino , Genómica/métodos , Humanos , Inmunidad Humoral/genética , Inmunidad Humoral/inmunología , Lactante , Subunidad alfa del Receptor de Interleucina-21/inmunología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Células B de Memoria/inmunología , Infección Persistente/genética , Infección Persistente/inmunología , Fenotipo , Transducción de Señal/genética , Transducción de Señal/inmunología , Adulto JovenRESUMEN
BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is an effective treatment for allergic rhinitis, asthma, and venom allergy. Compliance is essential for SCIT to obtain maximal benefit as it is a long-term treatment. OBJECTIVES: This study aimed to determine the level of real-life SCIT compliance in pediatric patients and the associated factors. Additional aims were to determine how SCIT compliance was affected by the COVID-19 pandemic and why some patients dropped out SCIT. METHOD: Pediatric patients diagnosed with allergic rhinitis, allergic asthma, or venom allergy that received SCIT between September 2012 and July 2020 were analyzed. RESULTS: The study included 201 children (66.7% male) with a median (interquartile range) age of 12.8 years (9.4-15.2) at the time of the first SCIT injection. The overall compliance rate before COVID-19 pandemic was 86.1%. Short SCIT follow-up time and venom anaphylaxis were found to be risk factors for drop out. The leading causes of drop outs were moving to another city/country (32.1%), symptom improvement (17.8%), treatment ineffectiveness (14.2%), and adverse reactions (14.2%). Among the 108 patients that were still receiving SCIT during the COVID-19 pandemic, 31 (28.7%) dropped out the therapy. The most frequent reasons for drop-out were fear of being infected with COVID-19 (35.4%) and thinking that the AIT practise stopped due to COVID-19 pandemic (29%). Male gender and older age were found to be the independent risk factors for drop-out of SCIT. CONCLUSIONS: Real life compliance in children was found 13.9% and it was higher than adults. Nearly one-third of children dropped out during the CO-VID-19 pandemic. Male gender and older age are associated with SCIT drop-out during the COVID-19 pandemic.
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COVID-19 , Desensibilización Inmunológica , Hipersensibilidad Inmediata/terapia , Cooperación del Paciente/estadística & datos numéricos , Adolescente , COVID-19/prevención & control , COVID-19/psicología , Niño , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Desensibilización Inmunológica/psicología , Desensibilización Inmunológica/estadística & datos numéricos , Femenino , Humanos , Inyecciones Subcutáneas , Modelos Logísticos , Masculino , Cooperación del Paciente/psicología , Pacientes Desistentes del Tratamiento/psicología , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , TurquíaRESUMEN
Defects in the regulatory components of the complement system can lead to inflammatory diseases. We present a patient who had four episodes of demyelination in the central nervous system as the only manifestation of inherited CD59 deficiency. Relapsing encephalopathy partially responsive to intravenous immunoglobulin and steroid treatments on the background of parental consanguinity suggested an inherited immune dysregulation. Next generation sequencing revealed homozygous mutation in the CD59 gene, confirmed by lack of CD59 expression on flow cytometry. Inherited CD59 deficiency is a rare autosomal recessive condition characterized by chronic hemolysis, recurrent strokes, and relapsing peripheral demyelinating neuropathy mimicking Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Recurrent central nervous system demyelinating episodes as the only manifestation has not been reported to date in inherited CD59 deficiency. This entity should be considered in the differential diagnosis of patients with early-onset recurrent neurological diseases with central or peripheral origin.
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Anemia Hemolítica/complicaciones , Anemia Hemolítica/genética , Antígenos CD59/genética , Encefalomielitis Aguda Diseminada/etiología , Hemoglobinuria/complicaciones , Hemoglobinuria/genética , Niño , Consanguinidad , Homocigoto , Humanos , Masculino , Mutación , RecurrenciaAsunto(s)
Enfermedad de Castleman , Ectima Contagioso , Factores de Intercambio de Guanina Nucleótido , Virus del Orf , Enfermedad de Castleman/complicaciones , Enfermedad de Castleman/diagnóstico , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/genética , HumanosRESUMEN
BACKGROUND/AIMS: Inborn errors of immunity (IEI) may associate with autoimmune diseases, including autoimmune liver diseases (AILD). However, both the IEI frequency and secondary effects of immunosuppressives are unknown in patients with AILD due to the lack of data. We aimed to evaluate the ratio of IEI in AILD. MATERIALS AND METHODS: A total of 82 patients with AILD (39 autoimmune hepatitis, 32 primary biliary cholangitis, 7 variant syndromes (VS), and 4 primary sclerosing cholangitis patients) were included in this single-center, cross-sectional, and descriptive study. The patients were evaluated and classified according to diagnostic criteria for IEI. RESULTS: Out of 82 patients with AILD, female/male ratio was 3.6. Median age of diagnosis of AILD was 45 years. We diagnosed 15 (18%) patients with immunodeficiency (ID). Inborn errors of immunity ratio was highest in VS patient group (29%). Out of 15 patients with ID, 4 (4.8%) patients had common variable immunodeficiency, 4 (4.8%) had partial immunoglobulin A deficiency, 4 (4.8%) had selective immunoglobulin M deficiency, and 3 (3.6%) had combined immunodeficiency. CONCLUSION: We detect ID in about one-fifth of the patients with AILD. The present study showed a significant risk of IEI that is blurred by the shadow of immune suppressive treatments. We suggest that the AILD patients with ID will benefit from the individualized and targeted therapeutic options used in IEI. Further research with larger patient groups and long-term follow-up are desperately needed to elucidate the diagnostic, therapeutic, and prognostic impacts of IEI-related individualized therapy on AILD patients.
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Hepatitis Autoinmune , Humanos , Femenino , Masculino , Estudios Transversales , Persona de Mediana Edad , Adulto , Hepatitis Autoinmune/inmunología , Inmunosupresores/uso terapéutico , Adulto Joven , Anciano , Colangitis Esclerosante/inmunología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/complicaciones , Enfermedades Autoinmunes/inmunología , Cirrosis Hepática Biliar/inmunología , AdolescenteRESUMEN
OBJECTIVE: Bacillus Calmette-Guérin (BCG) vaccine derived from Mycobacterium bovis can cause BCG vaccine associated complications (BCG-VAC) especially in patients with primary immunodeficiencies (PID). No consensus exists for antimycobacterial prophylactic therapy for patients with PID who receive the BCG vaccine. AIM: This study aimed to define the risk factors in the development of BCG-VAC and effect of antimycobacterial prophylaxis in PID patients vaccinated with BCG. METHODS: This is a retrospective cohort study. 104 patients diagnosed with PID who received the BCG vaccination were referred to pediatric pulmonology in a single center were enrolled. The demographic characteristics, type, dosage and duration of antimycobacterial prophylaxis regimen, treatment modalities for BCG-VAC were documented. Regression analysis was performed to evaluate the effect of covariates for predicting BCG-VAC in patients with PIDs. RESULTS: Among 104 patients 21 (21.2%) developed BCG-VAC. The frequency of BCG-VAC was highest in patients with Mendelian susceptibility to mycobacterial disease (46.2%) followed by patients with severe combined immunodeficiency (22.4%) and those with chronic granulomatous disease (9.5%). Prophylactic therapy against mycobacterium was initiated for 72 patients (69.2%). Among patients who received the antimycobacterial prophylaxis, BCG-VAC developed in only four patients (5.6%), whereas 17 patients (53.1%) developed BCG-VAC in the non-prophylaxis group and this difference was statistically significant (p < 0.001). Multivariable regression analysis with age at diagnosis, type of PID, receiving antimycobacterial prophylaxis, median T cell number at the time of PID diagnosis and HSCT status showed that not receiving antimycobacterial prophylaxis and lower median T cell number were predictors, with antimycobacterial prophylaxis having the highest odds ratio for BCG-VAC prediction in patients with PIDs (p:<0.001, R2:0.64). CONCLUSION: The lower frequency of BCG-VAC in our cohort can be explained by two main reasons; relatively late BCG vaccination schedule and receiving antimycobacterial prophylaxis. It is reasonable to begin antimycobacterial prophylaxis in patients with PIDs who are susceptible to BCG-VAC.
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Vacuna BCG , Mycobacterium bovis , Tuberculosis , Antibacterianos/uso terapéutico , Vacuna BCG/efectos adversos , Niño , Humanos , Estudios Retrospectivos , Tuberculosis/tratamiento farmacológico , Vacunación/efectos adversosRESUMEN
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is the defect of one of the checkpoint inhibitory molecules and defined as a primary immunodeficiency characterized by immune dysregulation. A 26-year-old female with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, and hypogammaglobulinemia was admitted with an inability to walk, urinary hesitancy, and bowel incontinence. Neurological examination revealed mild weakness, pyramidal, and deep sensorial involvement of the left lower extremity. Brain MRI revealed periventricular, juxtacortical, and cerebellar inflammatory lesions. Thoracic spinal MRI showed a longitudinaly extensive cord lesion. Additionally, thoracal CT showed parenchymal opacities and bilateral hilar lymph nodes. The biopsy from mediastinal lymph nodes and lung parenchyma demonstrated a low-grade lymphoproliferation and grade 1 "Lymphomatoid granulomatosis". Detailed laboratory analyses indicated the diagnosis of ''common variable immunodeficiency''. Next-generation sequencing with primary immunodeficiency panel revealed a heterozygous mutation in CTLA-4 (c.436G>A(p.G146R)(p.Gly146Arg)). After molecular diagnosis, abatacept therapy was started as a targeted therapeutic approach with subcutaneous immunoglobulin therapy.
RESUMEN
BACKGROUND: Vaccination is one of the most effective public health tools to prevent a variety of infectious diseases. However, concerns about vaccine related adverse effects cause difficulties in clinical practice. METHODS: This review was prepared based on the latest literature available in the PUBMED database in English language (as of March 2021), and all articles with the keywords pediatric vaccine, allergy, hypersensitivity, adverse reaction were evaluated to prepare the article. RESULTS: Vaccine related confirmed allergic reactions are rare in children, ranging between 0,65-1.45 cases per million vaccine doses. Most of the allergic reactions are self-limited local reactions although in some cases severe anaphylaxis with multisystem involvement can be observed. Allergic reactions may occur because of either the active component (the antigen) of the vaccine, or additional components, such as preservatives, adjuvants, antimicrobials, stabilizers and other substances. Finding the culprit allergen is necessary to prevent future exposure to the allergen and to use alternative vaccines if possible. Diagnosis is largely based on a detailed history and clinical manifestation; also in vivo and in vitro tests may be helpful. CONCLUSIONS: In this review we provide information about hypersensitivity reactions to allergen components of childhood vaccines along with the diagnosis and management of vaccine allergy. Besides the tremendous benefits of vaccination for the health of children, we emphasized that the risk of adverse effects is rare and poses a negligible threat.
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Anafilaxia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Vacunas , Alérgenos , Niño , Humanos , Vacunación/efectos adversos , Vacunas/efectos adversosRESUMEN
BACKGROUND: Dedicator of cytokinesis 2 (DOCK2) deficiency is a rare autosomal recessive combined immunodeficiency presenting with very early onset, severe bacterial and viral infections. In DOCK2 deficiency; T, B and NK cell numbers are decreased and functions are impaired resulting in severe atrophy of secondary lymphoid tissues. The aim of this report is to provide information on clinical and laboratory features and hematopoietic stem cell transplantation (HSCT) outcomes of a DOCK2 deficient patient. The patient was diagnosed by using a targeted next generation sequencing primary immunodeficiency (PID) panel. Lymphocyte subsets were measured by flow-cytometry. CASE: Here, we describe a patient with DOCK2 deficiency presented with severe combined immunodeficiency. He underwent HSCT without conditioning regimen before the genetic diagnosis and developed hemophagocytic lymphohistiocytosis(HLH) due to Epstein-Barr virus (EBV) infection. CONCLUSIONS: Genetic testing is necessery for early diagnosis of DOCK2 deficiency. The curative treatment should be HSCT soon after diagnosis.