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2.
Pediatr Pulmonol ; 53(1): E4-E5, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29193836

RESUMO

Continuous vancomycin has been previously reported to maximize antimicrobial activity while avoiding toxicities associated with dose escalation, but the efficacy of this dosing strategy has not been reported. This case report describes the successful use of continuous vancomycin, including improvement in lung function and avoidance of nephrotoxicity, demonstrated in a pediatric cystic fibrosis (CF) patient with MRSA.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/uso terapêutico , Criança , Feminino , Humanos
4.
J Allergy Clin Immunol ; 139(1): 232-245, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27577878

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 Jovem
5.
Hosp Pediatr ; 6(8): 496-500, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27390368

RESUMO

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/epidemiologia
6.
Chest ; 149(6): 1579-80, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27287578
7.
J Clin Immunol ; 36(4): 377-387, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27048656

RESUMO

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/patologia
8.
Pediatr Surg Int ; 32(4): 417-24, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26790674

RESUMO

Tracheobronchial mucoepidermoid carcinomas (MEC) are rare in the pediatric population with literature limited primarily to case reports. Here we present our institutional experience treating MEC in three patients and review the literature of 142 pediatric cases previously published from 1968 to 2013. Although rare, tracheobronchial MEC should be included in the differential diagnosis in a child with recurrent respiratory symptoms. Conservative surgical management is often sufficient to achieve complete resection and good outcomes.


Assuntos
Neoplasias Brônquicas/diagnóstico , Carcinoma Mucoepidermoide/diagnóstico , Neoplasias da Traqueia/diagnóstico , Adolescente , Neoplasias Brônquicas/complicações , Neoplasias Brônquicas/cirurgia , Broncoscopia , Carcinoma Mucoepidermoide/complicações , Carcinoma Mucoepidermoide/cirurgia , Criança , Humanos , Masculino , Pneumonectomia , Pneumonia/etiologia , Tomografia Computadorizada por Raios X , Neoplasias da Traqueia/complicações , Neoplasias da Traqueia/cirurgia
9.
Pediatr Emerg Care ; 32(4): 237-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26414632

RESUMO

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by the triad of hemoptysis, pulmonary infiltrates on chest radiograph, and anemia. Its diagnosis should be considered in any child presenting with moderate to severe anemia and failure to thrive of unclear etiology. Consideration of the differential diagnosis in such a child should include the review of both extravascular and intravascular causes of hemolysis. Systemic treatment of IPH with glucocorticoids has been shown to decrease morbidity, mortality, and disease progression to pulmonary fibrosis. Thus, diagnostic delays can impact prognosis. Here, we present a case of a 15-month-old boy with IPH who presented with anemia, jaundice, and failure to thrive, as well as a history of hemoptysis that was not initially elicited.


Assuntos
Anemia/diagnóstico , Insuficiência de Crescimento/diagnóstico , Hemossiderose/diagnóstico , Icterícia/diagnóstico , Pneumopatias/diagnóstico , Diagnóstico Diferencial , Glucocorticoides/uso terapêutico , Hemossiderose/complicações , Hemossiderose/tratamento farmacológico , Humanos , Lactente , Pneumopatias/complicações , Pneumopatias/tratamento farmacológico , Masculino , Metilprednisolona/uso terapêutico
10.
Chest ; 149(3): 836-45, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26502226

RESUMO

Diffuse lung diseases in children, also called children's interstitial lung disease, are a diverse group of rare disorders that cause disturbances of gas exchange in the lungs. Although individually rare, there are many different forms of diffuse lung disease in children, and collectively these disorders are associated with significant morbidity and mortality, as well as health-care resource utilization. Over the past several years, there have been many significant advances in the field, including genetic discoveries and the development of clinical practice guidelines. This review summarizes recent advances in the understanding, diagnosis, and treatment of diffuse lung diseases in children.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Criança , Humanos , Hiperplasia/diagnóstico , Hiperplasia/genética , Hiperplasia/terapia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/terapia , Mutação , Células Neuroendócrinas/patologia , Doenças Raras , Vasculite/complicações , Vasculite/diagnóstico , Vasculite/terapia
12.
Ital J Pediatr ; 41: 93, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26606984

RESUMO

BACKGROUND: Surfactant metabolism disorders may result in diffuse lung disease in children. CASE PRESENTATION: We report a 3-years-old boy with dry cough, progressive hypoxemia, dyspnea and bilateral ground glass opacities at chest high-resolution computed tomography (HRCT) who had no variants in genes encoding surfactant proteins or transcription factors. Lung histology strongly suggested an abnormality of surfactant protein. A 7-month course of pulse intravenous high-dose methylprednisolone plus oral hydroxychloroquine and azithromycin led to gradual weaning from oxygen and oral steroids, and to improvement of cough and dyspnea. Over the follow-up period, hydroxychloroquine and azithromycin were not withdrawn as cough and dyspnea re-appeared at each attempt and disappeared at re-start. At 6 years of age chest HRCT still appeared unchanged, but clinical symptoms or signs were absent. CONCLUSIONS: In children suspected of inborn errors of pulmonary surfactant metabolism who do not have a recognized genetic mutation, lung biopsy with consistent histology may help physicians to address the definitive diagnosis.


Assuntos
DNA/genética , Doenças Pulmonares Intersticiais/genética , Mutação , Proteína C Associada a Surfactante Pulmonar/genética , Biópsia , Pré-Escolar , Análise Mutacional de DNA , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Proteína C Associada a Surfactante Pulmonar/metabolismo , Tomografia Computadorizada por Raios X
13.
Allergy Asthma Proc ; 36(5): 407-11, 2015 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26314823

RESUMO

Hematopoietic stem cell transplantation (HSCT) outcomes in X-linked severe combined immune deficiency are most effective when performed with patients <3 months of age and without coexisting morbidity, and with donor cells from a matched sibling. Even under such favorable circumstances, outcomes can be suboptimal, and full cellular engraftment may not be complete, which results in poor B or natural killer cell function. Protein losing enteropathies can accompany persistent immune deficiency disorders with resultant low serum globulins (immunoglobulin A [IgA], IgG, IgM) and lymphopenia. Patients with immune disorders acquire infections that can be predicted by their immune dysfunction. Fungal infections are typically noted in neutropenic (congenital or acquired) and T-cell deficient individuals. Coexisting fungal infections are rare, even in hosts who are immunocompromised, and they require careful evaluation. Antifungal treatment may result in drug-drug interactions with significant complications.


Assuntos
Bronquiectasia/diagnóstico , Budesonida/uso terapêutico , Síndrome de Cushing/diagnóstico , Combinação Fluticasona-Salmeterol/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Histoplasma/imunologia , Histoplasmose/diagnóstico , Itraconazol/uso terapêutico , Enteropatias Perdedoras de Proteínas/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Adolescente , Bronquiectasia/etiologia , Bronquiectasia/terapia , Budesonida/efeitos adversos , Criança , Quimerismo/induzido quimicamente , Síndrome de Cushing/imunologia , Interações de Medicamentos , Combinação Fluticasona-Salmeterol/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histoplasma/efeitos dos fármacos , Histoplasmose/etiologia , Histoplasmose/terapia , Humanos , Doença Iatrogênica , Imunossupressão , Recém-Nascido , Itraconazol/efeitos adversos , Masculino , Linhagem , Enteropatias Perdedoras de Proteínas/etiologia , Enteropatias Perdedoras de Proteínas/terapia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Ganho de Peso/imunologia
14.
Nat Genet ; 47(6): 654-60, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25894502

RESUMO

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 Proteico
15.
J Pediatr ; 160(4): 700-702.e3, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240110

RESUMO

Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family.


Assuntos
Distúrbios no Reparo do DNA/complicações , Fibrose Pulmonar/genética , Progressão da Doença , Humanos , Recém-Nascido , Masculino , Fatores de Tempo
16.
Paediatr Respir Rev ; 12(4): 238-42, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22018037

RESUMO

Diffuse lung disease [DLD] in children comprises a group of heterogeneous, rare disorders. Despite the rarity of these diseases there has been a considerable increase in our knowledge of DLD in children including their diagnosis and management. Diagnosis of these diseases requires a detailed history and physical examination, diagnostic imaging, pulmonary function testing, selected and directed laboratory testing, bronchoalveolar lavage and in most cases an open lung biopsy. Once a diagnosis is made, treatment is centred on supportive care including nutritional and supplemental oxygen therapy when needed. Medications including corticosteroids and other immunomodulatory medications are often used. Lung transplantation has been used for final treatment in some cases of DLD. Formation of research collaborations will continue to further our understanding of these diseases.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Criança , Humanos
17.
Pediatr Allergy Immunol Pulmonol ; 23(1): 33-41, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22332030

RESUMO

The spectrum of childhood interstitial lung diseases (chILD) encompasses a group of heterogeneous, rare disorders in children characterized by diffuse pulmonary infiltrates and disordered gas exchange. Whereas the disorders that present in early life are unique to children, those that present in older children are also seen in adults. This review will concentrate on chILD presenting in children older than 2 years of age with a focus on the idiopathic interstitial pneumonias, connective tissue diseases, alveolar hemorrhage, and hypersensitivity pneumonitis. A systematic approach to diagnosis that includes a careful history and physical, computed tomography of the chest, bronchoalveolar lavage, and lung biopsy can be very helpful in establishing the correct diagnosis. Treatment approaches are described, including general supportive measures, indications for a trial of systemic corticosteroids, or other immunomodulating therapies, and when lung transplantation reserved for those with end-stage lung disease should be considered.

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