RESUMO
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.
Assuntos
Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
Assuntos
Imunodeficiência de Variável Comum , Qualidade de Vida , Inquéritos e Questionários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
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.
Assuntos
Hemorragia , Fatores Imunológicos/uso terapêutico , Pneumopatias , Lúpus Eritematoso Sistêmico , Radiografia Torácica , Adolescente , Assistência ao Convalescente/métodos , Assistência ao Convalescente/estatística & dados numéricos , Idade de Início , Transfusão de Sangue/métodos , Feminino , Hemorragia/diagnóstico , Hemorragia/etnologia , Hemorragia/fisiopatologia , Hemorragia/terapia , Humanos , Testes Imunológicos/estatística & dados numéricos , Pneumopatias/diagnóstico , Pneumopatias/etnologia , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Registros Médicos Orientados a Problemas , Radiografia Torácica/métodos , Radiografia Torácica/estatística & dados numéricos , Avaliação de Sintomas/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: "Copa syndrome". Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1ß and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.
Assuntos
Proteína Coatomer/genética , Síndromes de Imunodeficiência , Artrite/genética , Artrite/imunologia , Artrite/patologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Nefropatias/genética , Nefropatias/imunologia , Nefropatias/patologia , Pneumopatias/genética , Pneumopatias/imunologia , Pneumopatias/patologiaRESUMO
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.
Assuntos
Granulomatose com Poliangiite/fisiopatologia , Hemorragia/fisiopatologia , Falência Renal Crônica/fisiopatologia , Pneumopatias/fisiopatologia , Poliangiite Microscópica/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Distribuição por Idade , Anticorpos Anticitoplasma de Neutrófilos , Ásia/epidemiologia , Azatioprina/uso terapêutico , Canadá/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Europa (Continente)/epidemiologia , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/terapia , Hemorragia/etiologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Pneumopatias/etiologia , Masculino , Metotrexato/uso terapêutico , Poliangiite Microscópica/complicações , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/terapia , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/etiologia , Oxigenoterapia , Plasmaferese , Proteinúria/etiologia , Diálise Renal , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Rituximab/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND/AIMS: There is a critical need for more noninvasive biomarkers to identify nephritis in patients with systemic lupus erythematosus (SLE). Recent studies in a model mouse and an adult SLE patient cohort suggest that anti-basement membrane antibody levels correlate well with lupus activity and kidney injury. The purpose of this study was to assess the anti-basement membrane reactivity in pediatric SLE (pSLE) patients with or without nephritis. METHODS: Auto-antibodies to basement membrane antigens were assessed using an anti-matrigel ELISA. Endpoint titers were measured in pSLE patients and healthy children, as well as in autoimmune and non-immune mice, with good reproducing capabilities. Findings were also analyzed with respect to the presence or absence of nephritis, dsDNA antibodies, and other manifestations of pSLE. RESULTS: MRL/lpr mice developed high-titer anti-matrigel antibodies, whereas C57BL/6 mice did not. In a cohort of 21 pSLE patients and 22 pediatric controls, high-titer anti-matrigel IgG, IgM and IgA antibody levels were specific for pSLE. High-titer anti-matrigel IgG3 levels could distinguish with good sensitivity the 13 pSLE patients with a history of nephritis from the 8 non-renal pSLE patients. High-titer anti-matrigel IgG, IgA, IgM or IgG3 did not correlate with positive anti-double stranded DNA, but defined an overlapping subset of patients. CONCLUSION: The addition of anti-basement membrane antibody testing to serologic testing in pSLE may help to monitor disease activity or to define important subsets of patients with risks for specific disease manifestations.
Assuntos
Autoanticorpos/sangue , Membrana Basal/imunologia , Biomarcadores/sangue , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/sangue , Adolescente , Animais , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Antinucleares/sangue , Estudos de Casos e Controles , Criança , DNA/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lprRESUMO
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.
Assuntos
Artrite/genética , Doenças Autoimunes/genética , Proteína Coatomer/genética , Complexo de Golgi/metabolismo , Doenças Pulmonares Intersticiais/genética , Sequência de Aminoácidos , Pré-Escolar , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Transporte ProteicoRESUMO
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 Assuntos
Aterosclerose/complicações
, Aterosclerose/terapia
, Doenças Cardiovasculares/epidemiologia
, Conhecimentos, Atitudes e Prática em Saúde
, Doenças Vasculares Periféricas/complicações
, Doenças Vasculares Periféricas/terapia
, Veteranos
, Idoso
, Idoso de 80 Anos ou mais
, Aterosclerose/etnologia
, População Negra
, Doenças Cardiovasculares/etnologia
, Estudos de Coortes
, Doença da Artéria Coronariana/epidemiologia
, Doença da Artéria Coronariana/etnologia
, Estudos Transversais
, Feminino
, Hispânico ou Latino
, Humanos
, Pessoa de Meia-Idade
, Educação de Pacientes como Assunto
, Doenças Vasculares Periféricas/etnologia
, Fatores de Risco
, Acidente Vascular Cerebral/epidemiologia
, Acidente Vascular Cerebral/etnologia
, Texas/epidemiologia
, Túnica Íntima/patologia
, Túnica Média/patologia
, População Branca