RESUMO
The purpose of this study was to evaluate intrapulmonary arteriovenous shunts in patients with and without sudden unexplained infant death. We identified open intrapulmonary bronchopulmonary anastomoses as potential pathways for right-to-left shunt in a subset of infants with sudden unexplained infant death.
Assuntos
Pulmão , Morte Súbita do Lactente , Humanos , Morte Súbita do Lactente/etiologia , Morte do Lactente , Pulmão/diagnóstico por imagem , Cardiopatias Congênitas , Malformações Arteriovenosas , Masculino , Feminino , LactenteAssuntos
Insuficiência Cardíaca , Transplante de Células-Tronco Hematopoéticas , Derrame Pleural , Insuficiência Renal , Insuficiência Respiratória , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Derrame Pleural/etiologia , Insuficiência Renal/etiologia , Insuficiência Renal/terapia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapiaRESUMO
The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rß, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rß, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rß surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rß-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rß expression and signaling in T and NK cells.
Assuntos
Subunidade beta de Receptor de Interleucina-2/genética , Células Matadoras Naturais/imunologia , Mutação/genética , Linfócitos T/imunologia , Autoimunidade/genética , Compartimento Celular , Proliferação de Células/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Homozigoto , Humanos , Imunofenotipagem , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/química , Modelos Moleculares , Fenótipo , Irmãos , Transdução de Sinais , Resultado do TratamentoRESUMO
OBJECTIVES: To determine the incidence, characteristics of, and risk factors contributing to the development of pulmonary hypertension in children with Down syndrome. STUDY DESIGN: This retrospective, review of a large cohort (n = 1242) of children with Down syndrome receiving care at a specialized referral center evaluated clinical data and serial echocardiograms from a clinic database and electronic medical records. Pulmonary hypertension characteristics and comorbidities were reviewed. Pulmonary hypertension was considered transient if echocardiographic evidence of pulmonary hypertension resolved without recurrence, persistent if no resolution, and recurrent if evidence of pulmonary hypertension returned after a period of resolution. RESULTS: The incidence of pulmonary hypertension in children with Down syndrome was 28% (n = 346). Median age at initial diagnosis was 5 days (range: 0-7067 days). Pulmonary hypertension was differentiated into transient (70%), persistent (15%), and recurrent (15%) disease. Median duration of transient pulmonary hypertension was 8 months (range: 0.1-130.2 months). Median age at recurrence was 2.5 years (range 0.2-11.5 years). Initial pulmonary hypertension diagnosis was classified as World Health Organization group I disease in 82%, with 45% associated with congenital heart disease (CHD), and 38% persistent pulmonary hypertension of the newborn (PPHN). The pulmonary hypertension recurrence rate was significant and similar for both those with initial PPHN (12%) and non-PPHN (16%). A majority (87%) of patients with recurrent pulmonary hypertension were classified as World Health Organization group III. Frequently identified comorbid conditions included CHD, obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia. CONCLUSIONS: Pulmonary hypertension is common in children with Down syndrome, is typically transient, and related to CHD or PPHN but can recur in the setting of respiratory disease such as obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia.
Assuntos
Síndrome de Down/diagnóstico , Síndrome de Down/epidemiologia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Distribuição por Idade , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Síndrome de Down/terapia , Ecocardiografia Doppler/métodos , Feminino , Humanos , Hipertensão Pulmonar/terapia , Lactente , Recém-Nascido , Masculino , Monitorização Fisiológica , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Estados UnidosRESUMO
OBJECTIVE: To evaluate fibrosis and fibrosis-related gene expression in the myocardium of pediatric subjects with single ventricle with right ventricular failure. STUDY DESIGN: Real-time quantitative polymerase chain reaction was performed on explanted right ventricular myocardium of pediatric subjects with single ventricle disease and controls with nonfailing heart disease. Subjects were divided into 3 groups: single ventricle failing (right ventricular failure before or after stage I palliation), single ventricle nonfailing (infants listed for primary transplantation with normal right ventricular function), and stage III (Fontan or right ventricular failure after stage III). To evaluate subjects of similar age and right ventricular volume loading, single ventricle disease with failure was compared with single ventricle without failure and stage III was compared with nonfailing right ventricular disease. Histologic fibrosis was assessed in all hearts. Mann-Whitney tests were performed to identify differences in gene expression. RESULTS: Collagen (Col1α, Col3) expression is decreased in single ventricle congenital heart disease with failure compared with nonfailing single ventricle congenital heart disease (P = .019 and P = .035, respectively), and is equivalent in stage III compared with nonfailing right ventricular heart disease. Tissue inhibitors of metalloproteinase (TIMP-1, TIMP-3, and TIMP-4) are downregulated in stage III compared with nonfailing right ventricular heart disease (P = .0047, P = .013 and P = .013, respectively). Matrix metalloproteinases (MMP-2, MMP-9) are similar between nonfailing single ventricular heart disease and failing single ventricular heart disease, and between stage III heart disease and nonfailing right ventricular heart disease. There is no difference in the prevalence of right ventricular fibrosis by histology in subjects with single ventricular failure heart disease with right ventricular failure (18%) compared with those with normal right ventricular function (38%). CONCLUSIONS: Fibrosis is not a primary contributor to right ventricular failure in infants and young children with single ventricular heart disease. Additional studies are required to understand whether antifibrotic therapies are beneficial in this population.
Assuntos
Regulação para Baixo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/patologia , Miocárdio/patologia , Criança , Pré-Escolar , Feminino , Fibrose , Marcadores Genéticos , Insuficiência Cardíaca/congênito , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/patologia , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVES: To determine the frequency of histologic features of impaired lung vascular and alveolar development and to identify the presence of intrapulmonary bronchopulmonary anastomoses (IBA) in infants and children who died with Down syndrome. STUDY DESIGN: A retrospective review of autopsy reports and lung histology from 13 children with Down syndrome (ages: 0-8 years) was performed. Histologic features of abnormal lung development were identified and semiquantified, including the presence of IBA. Three-dimensional reconstructions of IBA were also performed. Comparisons were made with 4 age-matched patients without Down syndrome with congenital heart defects who underwent autopsies during this time period. RESULTS: Of the 13 subjects with Down syndrome, 69% died from cardiac events, 77% had a congenital heart defect, and 46% had a clinical diagnosis of pulmonary hypertension. Lung histology from all subjects with Down syndrome demonstrated alveolar simplification, and 92% had signs of persistence of a double capillary network in the distal lung. The lungs from the subjects with Down syndrome frequently had features of pulmonary arterial hypertensive remodeling (85%), and prominent bronchial vessels and IBA were observed in all subjects with Down syndrome. These features were more frequent in subjects with Down syndrome compared with control subjects. CONCLUSIONS: Children with Down syndrome who died of cardiopulmonary diseases often have histologic evidence of impaired lung alveolar and vascular development, including the presence of prominent IBA and pulmonary hypertension. We speculate that children with Down syndrome are at risk for reduced lung surface area and recruitment of IBA, which may worsen gas exchange in subjects with Down syndrome.
Assuntos
Anormalidades Múltiplas/patologia , Síndrome de Down/complicações , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Pulmão/anormalidades , Pulmão/patologia , Brônquios/anormalidades , Brônquios/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Alvéolos Pulmonares/anormalidades , Alvéolos Pulmonares/patologia , Estudos RetrospectivosRESUMO
We examined lung histology from 8 infants who died with meconium aspiration syndrome in order to determine the presence of intrapulmonary bronchopulmonary anastomotic pathways. Each infant required mechanical ventilation to treat hypoxemic respiratory distress. Lung histology from each infant shows evidence of prominent bronchopulmonary vascular connections.
Assuntos
Anastomose Arteriovenosa/patologia , Pulmão/irrigação sanguínea , Síndrome de Aspiração de Mecônio/patologia , Feminino , Humanos , Recém-Nascido , Pulmão/patologia , Masculino , Circulação Pulmonar , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To determine whether prominent intrapulmonary anastomotic vessels (IPAVs) or bronchopulmonary "shunt" vessels can be identified in lungs from infants with fatal congenital diaphragmatic hernia (CDH). STUDY DESIGN: We performed histology with immunostaining for CD31 (endothelium) and D2-40 (lymphatics), along with high-precision 3-dimensional (3D) reconstruction on lung tissue from 9 patients who died with CDH. RESULTS: Each patient with CDH required mechanical ventilation, cardiotonic support, and pulmonary hypertension (PH)-targeted drug therapy. All patients were diagnosed with severe PH by echocardiography, and 5 received extracorporeal membrane oxygenation therapy. Death occurred at a median age of 24 days (range, 10-150 days) from refractory hypoxemia with severe PH, pneumonia, or tension pneumothorax. Histology showed decreased alveolarization with pulmonary vascular disease. In each patient, prominent IPAVs were identified as engorged, thin-walled vessels that connected pulmonary veins with microvessels surrounding pulmonary arteries and airways in lungs ipsilateral and contralateral to the CDH. Prominent anastomoses between pulmonary arteries and bronchial arteries were noted as well. The 3D reconstruction studies demonstrated that IPAVs connect pulmonary vasculature to systemic (bronchial) vessels both at the arterial and venous side. CONCLUSION: Histology and 3D reconstruction identified prominent bronchopulmonary vascular anastamoses in the lungs of infants who died with severe CDH. We speculate that IPAVs connecting pulmonary and bronchial arteries contribute to refractory hypoxemia in severe CDH.
Assuntos
Anticorpos Monoclonais Murinos/metabolismo , Fístula Arteriovenosa/diagnóstico , Hérnias Diafragmáticas Congênitas/diagnóstico , Pulmão/irrigação sanguínea , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Fístula Arteriovenosa/metabolismo , Feminino , Hérnias Diafragmáticas Congênitas/metabolismo , Hérnias Diafragmáticas Congênitas/mortalidade , Humanos , Hipertensão Pulmonar/diagnóstico , Lactente , Recém-Nascido , Masculino , Artéria Pulmonar/patologia , Veias Pulmonares/patologiaRESUMO
Alveolar capillary dysplasia (ACD) with misalignment of pulmonary veins (MPV) is a lethal neonatal lung disease. Death from ACD/MPV is caused by hypoxia, but the role of the MPV is unknown. Using 3-dimensional reconstruction of ACD/MPV lung tissue, we report that the veins in MPV are intrapulmonary shunt vessels, and speculate that MPV contributes to the poor prognosis.