RESUMEN
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
Asunto(s)
Síndromes de Inmunodeficiencia/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVES: Cardiovascular disease (CVD) is the leading cause of death in women. Aggressive management of atherosclerotic risk factors can prevent or delay the onset of CVD. Treatment of modifiable risk factors provides an important opportunity to reduce the burden of CVD in women and decrease future adverse event rates. The aims of this study were to assess current treatment of atherosclerotic risk factors in women found to be at moderate or high-risk for CVD and to examine levels of CVD knowledge and awareness among women found to be at moderate or high-risk for CVD METHODS: In a cross-sectional study, we screened ambulatory female veterans aged 40 to 85 y for the prevalence of peripheral vascular disease (PVD) and associated atherosclerotic risk factors, and administered a survey to assess the participants' knowledge and awareness of CVD, risk factors, and consequences. Medical records, pharmacy data, and clinician encounter notes were reviewed for documented evidence of CVD risk factors, comorbidities, and corresponding treatment. From a total cohort of 162 women, 108 (66.7%) were categorized as having an increased risk of cardiovascular disease based on a modification of the Framingham cardiovascular risk score, which took into account the presence of carotid intimal-medial thickness (cIMT) > 1.0 mm or ankle-brachial index Asunto(s)
Aterosclerosis/complicaciones
, Aterosclerosis/terapia
, Enfermedades Cardiovasculares/epidemiología
, Conocimientos, Actitudes y Práctica en Salud
, Enfermedades Vasculares Periféricas/complicaciones
, Enfermedades Vasculares Periféricas/terapia
, Veteranos
, Anciano
, Anciano de 80 o más Años
, Aterosclerosis/etnología
, Población Negra
, Enfermedades Cardiovasculares/etnología
, Estudios de Cohortes
, Enfermedad de la Arteria Coronaria/epidemiología
, Enfermedad de la Arteria Coronaria/etnología
, Estudios Transversales
, Femenino
, Hispánicos o Latinos
, Humanos
, Persona de Mediana Edad
, Educación del Paciente como Asunto
, Enfermedades Vasculares Periféricas/etnología
, Factores de Riesgo
, Accidente Cerebrovascular/epidemiología
, Accidente Cerebrovascular/etnología
, Texas/epidemiología
, Túnica Íntima/patología
, Túnica Media/patología
, Población Blanca
RESUMEN
BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a devastating clinical syndrome characterized by a falling hematocrit, respiratory insufficiency, and radiographic evidence of pulmonary infiltrates. Literature regarding management of DAH in childhood-onset SLE (cSLE) is limited. METHODS: We reviewed the presentation, management, and outcome of DAH in a pediatric tertiary medical center with one of the largest cSLE cohorts in North America. During a 10 year period 7 of 410 children with cSLE had DAH. RESULTS: The majority of cSLE patients with DAH were male (71%) and Hispanic (57%). The median age at the time of DAH diagnosis was 14 years (range 3 -15 years). DAH was the presenting manifestation of cSLE in 29% of children; 71% presented with DAH within 3 months of their diagnosis. All patients had cough, 86% had dyspnea, and 29% had hemoptysis. All patients had anemia and 71% had thrombocytopenia. Eighty-six percent had hematuria/proteinuria, and a positive anti-double stranded DNA antibody. Chest imaging showed diffuse ground glass opacities in all events. All patients developed respiratory insufficiency (29% supplemental oxygenation and 71% mechanical ventilation). Transfusions were required in 57% of cases. All patients received corticosteroids and additional immunomodulation to achieve disease control. Eighty-six percent of our DAH/cSLE cohort survived their initial event (median follow-up 2.5 years). No survivor required supplemental oxygen or had a DAH recurrence. CONCLUSIONS: SLE should be in the hospitalist's differential diagnosis for any child with respiratory insufficiency, cytopenias, and/or urinary abnormalities. Once cSLE is identified, initiation of aggressive immune suppression with multiple agents may enhance outcomes.
Asunto(s)
Hemorragia , Factores Inmunológicos/uso terapéutico , Enfermedades Pulmonares , Lupus Eritematoso Sistémico , Radiografía Torácica , Adolescente , Cuidados Posteriores/métodos , Cuidados Posteriores/estadística & datos numéricos , Edad de Inicio , Transfusión Sanguínea/métodos , Femenino , Hemorragia/diagnóstico , Hemorragia/etnología , Hemorragia/fisiopatología , Hemorragia/terapia , Humanos , Pruebas Inmunológicas/estadística & datos numéricos , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/etnología , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/terapia , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Registros Médicos Orientados a Problemas , Radiografía Torácica/métodos , Radiografía Torácica/estadística & datos numéricos , Evaluación de Síntomas/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Generic health status quality of life (QoL) instruments have been used in patients with common variable immune deficiency (CVID). However, by their nature, these tools may over- or underestimate the impact of diseases on an individual's QoL. OBJECTIVE: The objective of this study was to develop and validate a questionnaire to measure specific-health-related QoL for adults with CVID (CVID_QoL). METHODS: The 32-item content of the CVID_QoL questionnaire was developed using focus groups and individual patient interviews. Validation studies included 118 adults with CVID who completed Short Form-36, Saint George Respiratory Questionnaire, General Health Questionnaire-12, and EuroQol-5D questionnaire in a single session. Principal component and factor analysis solutions identified 3 scores to be similar in number and content for each solution. Validation of 3 factor scores was performed by construct validity. Reproducibility, reliability, convergent validity, and discriminant validity were evaluated. Matrices consisting of correlations between the 32 items in the CVID_QOL were calculated. RESULTS: Factor analysis identified 3 dimensions: emotional functioning (EF), relational functioning (RF), and gastrointestinal and skin symptoms (GSS). The instrument had good internal consistency (Cronbach's alpha, min. 0.74 for GSS, max. 0.84 for RF, n = 118) and high reproducibility (intraclass correlation coefficient, min. 0.79 for RF, max 0.90 for EF, n = 27). EF and RF scores showed good convergent validity correlating with conceptually similar dimensions of other study scales. Acute and relapsing infections had a significant impact on EF and RF. CONCLUSIONS: This study provides evidence of the reliability and construct validity of the CVID_QoL to identify QoL issues in patients with CVID that may not be addressed by generic instruments.
Asunto(s)
Inmunodeficiencia Variable Común , Calidad de Vida , Encuestas y Cuestionarios , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.
Asunto(s)
Granulomatosis con Poliangitis/fisiopatología , Hemorragia/fisiopatología , Fallo Renal Crónico/fisiopatología , Enfermedades Pulmonares/fisiopatología , Poliangitis Microscópica/fisiopatología , Síndrome Nefrótico/fisiopatología , Insuficiencia Respiratoria/fisiopatología , Adolescente , Corticoesteroides/uso terapéutico , Distribución por Edad , Anticuerpos Anticitoplasma de Neutrófilos , Asia/epidemiología , Azatioprina/uso terapéutico , Canadá/epidemiología , Niño , Preescolar , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada , Europa (Continente)/epidemiología , Femenino , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/epidemiología , Granulomatosis con Poliangitis/terapia , Hemorragia/etiología , Humanos , Inmunosupresores/uso terapéutico , Lactante , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Enfermedades Pulmonares/etiología , Masculino , Metotrexato/uso terapéutico , Poliangitis Microscópica/complicaciones , Poliangitis Microscópica/epidemiología , Poliangitis Microscópica/terapia , Ácido Micofenólico/uso terapéutico , Síndrome Nefrótico/etiología , Terapia por Inhalación de Oxígeno , Plasmaféresis , Proteinuria/etiología , Diálisis Renal , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Rituximab/uso terapéutico , Estados Unidos/epidemiologíaRESUMEN
Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.