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1.
Thorax ; 79(3): 245-249, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38216317

RESUMEN

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may be at risk of hypoxaemia at altitude, such as during air travel. We have performed preflight hypoxic challenge testing (HCT) since 2006, incorporating British Thoracic Society (BTS) guidance since 2011, to determine which children may require oxygen during air travel. AIMS: We aimed to compare the outcome of HCTs in children with a history of BPD who met the 2011 BTS criteria and those who did not and, in addition to this, to interrogate the data for factors that may predict the outcome of HCT in this population. METHODS: We performed a retrospective analysis of data from HCTs of children with a history of BPD referred 2006-2020. Cases were excluded if the patient had a respiratory comorbidity, was still on oxygen therapy, if the test was a repeat or if the clinical record was incomplete. Descriptive and univariate analysis of the data was performed, and a binary logistic regression model was fitted. RESULTS: There were 79 HCTs, of which 24/79 (30%) did not meet BTS 2011 guidelines referral criteria. The analysis showed a greater proportion of desaturation in the group that did not meet criteria: 46% vs 27% (no statistical significance). Baseline oxygen saturations were higher in those who did not require oxygen during HCT and this variable was significant when adjusted for confounders. CONCLUSIONS: This study found that the current criteria for referral for preflight testing may incorrectly identify those most at risk and highlights the need for further investigation to ensure those most at risk are being assessed prior to air travel.


Asunto(s)
Displasia Broncopulmonar , Trastornos Respiratorios , Recién Nacido , Niño , Humanos , Estudios Retrospectivos , Hipoxia/diagnóstico , Hipoxia/etiología , Oxígeno , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/terapia
2.
Perfusion ; 38(7): 1530-1533, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-35840547

RESUMEN

BACKGROUND: Sensitised patients undergoing Human Leukocyte Antigen-incompatible transplantation are at increased risk of hyperacute rejection and may be predisposed to antibody-mediated rejection, chronic lung allograft dysfunction and higher mortality. CASE: We present a case of primary lung transplantation in the setting of late identification of donor specific antibodies treated with intraoperative target plasma exchange. The patient was treated with fresh human plasma to a final volume of 1.5 times the patient's systemic circulation. From a pre-transplant mean fluorescence intensity of 5002, donor-specific antibodies were undetectable following plasma exchange on single antigen bead assay. CONCLUSIONS: This method represents a potential desensitisation technique for use in the intraoperative period.


Asunto(s)
Trasplante de Pulmón , Intercambio Plasmático , Humanos , Lactante , Antígenos HLA , Donantes de Tejidos , Trasplante Homólogo
3.
Am J Hum Genet ; 103(6): 984-994, 2018 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-30471717

RESUMEN

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.


Asunto(s)
Dineínas Axonemales/genética , Cilios/genética , Dineínas/genética , Mutación/genética , Situs Inversus/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Trastornos de la Motilidad Ciliar/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Sistema Respiratorio/patología , Alineación de Secuencia
4.
J Med Genet ; 57(5): 322-330, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31879361

RESUMEN

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.


Asunto(s)
Cilios/genética , Trastornos de la Motilidad Ciliar/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Pueblo Asiatico/genética , Cilios/patología , Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/patología , Estudios de Cohortes , Etnicidad/genética , Femenino , Homocigoto , Humanos , Masculino , Mutación/genética , Fenotipo
5.
Thorax ; 75(2): 172-175, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31748256

RESUMEN

We performed a prospective, observational, cohort study of children newly diagnosed with children's interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3-7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88-96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8-12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.


Asunto(s)
Corticoesteroides/administración & dosificación , Azitromicina/administración & dosificación , Hidroxicloroquina/administración & dosificación , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Adolescente , Causas de Muerte , Niño , Preescolar , Estudios de Cohortes , Quimioterapia Combinada , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Lactante , Estimación de Kaplan-Meier , Estudios Longitudinales , Enfermedades Pulmonares Intersticiales/epidemiología , Masculino , Monitoreo Fisiológico/métodos , Estudios Prospectivos , Sistema de Registros , Pruebas de Función Respiratoria , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Factores de Tiempo
6.
Transpl Infect Dis ; 22(3): e13274, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32129923

RESUMEN

BACKGROUND: Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M abscessus comprises three subspecies (M abscessus subsp abscessus, M abscessus subsp massiliense, and M abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single center was related to the M abscessus subspecies and genetic cluster. METHODS: CF patients with chronic M abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M abscessus isolates were identified to subspecies level by polymerase chain reaction and sequencing. Genetic cluster was determined by variable number tandem repeat profiling and whole-genome sequencing (WGS), and sequence type inferred from WGS. RESULTS: Thirteen patients with chronic M abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n = 1 with M abscessus bolletii, n = 5 with M abscessus massiliense, and n = 7 with M abscessus abscessus infection. Eight (62%) patients (one with M abscessus massiliense and seven with M abscessus abscessus) died post-lung transplant. The patient with M abscessus bolletii and three patients with M abscessus massiliense did well post-transplant. One patient with M abscessus massiliense is receiving ongoing treatment. CONCLUSIONS: Dramatically worse outcomes are observed in patients infected with M abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M abcsessus strains can have acceptable outcomes.


Asunto(s)
Fibrosis Quística/complicaciones , Trasplante de Pulmón/efectos adversos , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium abscessus/clasificación , Adolescente , Niño , Fibrosis Quística/microbiología , Fibrosis Quística/cirugía , ADN Bacteriano/genética , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/fisiopatología , Mycobacterium abscessus/patogenicidad , Evaluación de Procesos y Resultados en Atención de Salud , Filogenia , Estudios Retrospectivos , Análisis de Secuencia de ADN , Secuenciación Completa del Genoma
7.
Am J Respir Crit Care Med ; 197(5): e1-e19, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29493315

RESUMEN

BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.


Asunto(s)
Pruebas Respiratorias/métodos , Diagnóstico Precoz , Enfermedades Pulmonares/diagnóstico , Niño , Preescolar , Femenino , Humanos , Pulmón/fisiopatología , Enfermedades Pulmonares/fisiopatología , Masculino , Pruebas de Función Respiratoria/métodos , Sociedades Médicas , Estados Unidos
8.
Thorax ; 73(3): 231-239, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29056600

RESUMEN

BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.


Asunto(s)
Enfermedades Pulmonares Intersticiales/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Sistema de Registros , Reproducibilidad de los Resultados , Adulto Joven
9.
Eur Respir J ; 50(5)2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29122914

RESUMEN

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.


Asunto(s)
Fibrosis Quística/diagnóstico , Fibrosis Quística/fisiopatología , Pulmón/fisiopatología , Tamizaje Neonatal , Estudios de Casos y Controles , Femenino , Volumen Espiratorio Forzado , Capacidad Residual Funcional , Humanos , Lactante , Recién Nacido , Masculino , Análisis de Regresión , Reino Unido
11.
Clin Infect Dis ; 60(7): 1007-16, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25452595

RESUMEN

BACKGROUND: Mycobacterium abscessus has emerged as a major pathogen in cystic fibrosis (CF) patients and has been associated with poor clinical outcomes, particularly following lung transplant. We investigated the acquisition of this bacterium in a cohort of pediatric CF patients. METHODS: Demographic and patient location data were used to uncover epidemiological links between patients with genetically related strains of M. abscessus that had been previously typed by variable-number tandem repeat profiling. Whole-genome sequencing was applied to 27 M. abscessus isolates from the 20 patients in this cohort to provide definitive data on the genetic relatedness of strains. RESULTS: Whole-genome sequencing data demonstrated that M. abscessus isolates from 16 patients were unrelated, differing by at least 34 single-nucleotide polymorphisms (SNPs) from any other isolate, suggesting that independent acquisition events have occurred. Only 2 clusters of very closely related (<25 SNPs) isolates from different patients were seen. The first cluster contained 8 isolates, differing by a maximum of 17 SNPs, from a sibling pair who had intense exposure to each other both inside and outside the hospital. The second cluster contained 3 isolates, differing by a maximum of 24 SNPs, from 2 individuals with no apparent epidemiological links. CONCLUSIONS: We have not demonstrated cross-transmission of M. abscessus within our hospital, except between 1 sibling pair. Alternative routes of acquisition of M. abscessus infection, in particular the environment, require further investigation.


Asunto(s)
Fibrosis Quística/complicaciones , Métodos Epidemiológicos , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/transmisión , Mycobacterium/clasificación , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/transmisión , Adolescente , Niño , Preescolar , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Hospitales Pediátricos , Humanos , Masculino , Tipificación Molecular , Mycobacterium/genética , Mycobacterium/aislamiento & purificación , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones del Sistema Respiratorio/microbiología , Homología de Secuencia
12.
Eur Respir J ; 46(4): 1055-64, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26160868

RESUMEN

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.


Asunto(s)
Antibacterianos/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Pulmón/fisiopatología , Adolescente , Adulto , Pruebas Respiratorias/métodos , Niño , Preescolar , Análisis por Conglomerados , Femenino , Volumen Espiratorio Forzado , Humanos , Infusiones Intravenosas , Pulmón/microbiología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Observacionales como Asunto , Estudios Prospectivos , Pruebas de Función Respiratoria , Estudios Retrospectivos , Espirometría/métodos , Adulto Joven
14.
Respiration ; 90(4): 332-51, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26352941

RESUMEN

This statement summarizes the information available on specific exercise test protocols and outcome parameters used in patients with cystic fibrosis (CF) and provides expert consensus recommendations for protocol and performance of exercise tests and basic interpretation of results for clinicians. The conclusions were reached employing consensus meetings and a wide-band Delphi process. Although data on utility are currently limited, standardized exercise testing provides detailed information on physiological health, allows screening for exercise-related adverse reactions and enables exercise counselling. The Godfrey Cycle Ergometer Protocol with monitoring of oxygen saturation and ventilatory gas exchange is recommended for exercise testing in people 10 years and older. Cycle ergometry only with pulse oximetry using the Godfrey protocol or treadmill exercise with pulse oximetry - preferably with measurement of gas exchange - are second best options. Peak oxygen uptake, if assessed, and maximal work rate should be reported as the primary measure of exercise capacity. The final statement was reviewed by the European Cystic Fibrosis society and revised based on the comments received. The document was endorsed by the European Respiratory Society.


Asunto(s)
Fibrosis Quística , Prueba de Esfuerzo , Humanos
15.
Thorax ; 69(10): 910-7, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24072358

RESUMEN

RATIONALE: Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants. OBJECTIVE: To assess changes in pulmonary function during the first year of life in CF NBS infants. METHODS: Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV0.5) were measured at 3 months and 1 year of age. MAIN RESULTS: Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year. CONCLUSIONS: This is the first study reporting improvements in FEV0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.


Asunto(s)
Fibrosis Quística/fisiopatología , Flujo Espiratorio Medio Máximo/fisiología , Tamizaje Neonatal/métodos , Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Edad Gestacional , Humanos , Lactante , Recién Nacido , Mediciones del Volumen Pulmonar , Masculino , Valor Predictivo de las Pruebas , Prevalencia , Pruebas de Función Respiratoria , Estudios Retrospectivos , Factores de Tiempo , Reino Unido/epidemiología
16.
Eur Respir J ; 44(6): 1479-503, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25359357

RESUMEN

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention.


Asunto(s)
Corticoesteroides/uso terapéutico , Bronquiolitis Obliterante/terapia , Inmunosupresores/uso terapéutico , Trasplante de Pulmón , Pulmón/patología , Tacrolimus/uso terapéutico , Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Biopsia , Bronquiolitis Obliterante/diagnóstico , Ciclosporina/uso terapéutico , Manejo de la Enfermedad , Volumen Espiratorio Forzado , Reflujo Gastroesofágico/epidemiología , Reflujo Gastroesofágico/cirugía , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Reoperación , Factores de Riesgo , Tomografía Computarizada por Rayos X
17.
J Med Genet ; 50(3): 174-86, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23315542

RESUMEN

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.


Asunto(s)
Enfermedades del Oído/genética , Oído/anomalías , Mutación , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Oído/patología , Enfermedades del Oído/patología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Linaje , Fosfolipasa C beta/genética , Reacción en Cadena de la Polimerasa
18.
Pediatr Pulmonol ; 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39031489

RESUMEN

The multiple breath washout (MBW) test is widely reported in the context of Lung Clearance Index (LCI). LCI reflects global ventilation inhomogeneity but does not provide information regarding the localization of disease along the respiratory tree. The MBW-derived normalized phase III slope (SnIII) indices (Scond and Sacin), instead, can distinguish between convective-dependent and diffusion-convection-dependent ventilation inhomogeneity considered to occur within the conductive and acinar airways, respectively. In cystic fibrosis, Scond tends to become abnormal even earlier than LCI and spirometry. The value of Scond and Sacin in clinical practice has been recently explored in other respiratory conditions, including asthma, primary ciliary dyskinesia, bronchopulmonary dysplasia, bronchiolitis obliterans, and sickle cell disease. In this narrative review we offer an overview on the theoretical background, potentialities, and limitations of SnIII analysis in children, including challenges and feasibility aspects. Moreover, we summarize current evidence on the use of SnIII-derived indices across different groups of pediatric chronic respiratory disease and we highlight the gaps in knowledge that need to be addressed in future studies.

19.
Eur Respir J ; 42(1): 116-24, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23222876

RESUMEN

Knowledge of short- and longer-term repeatability of lung function in health and disease is essential to determine bronchodilator reversibility thresholds and to recognise if changes in lung function represent disease progression, therapeutic intervention or normal variability. Multiple-breath washout indices (lung clearance index, conductive ventilation inhomogeneity (Scond)) and specific airway resistance (sRaw) were measured in healthy children and stable wheezers. Measurements were performed at baseline and after 20 min without intervention to assess repeatability and determine bronchodilator reversibility thresholds. Bronchodilator reversibility was assessed by repeating baseline measurements 20 min after inhaled salbutamol. 28 healthy controls, mean±sd age 6.1±0.7 years and 62 wheezers 5.4±0.6 years were tested. Baseline variability in multiple-breath washout indices and sRaw was not significantly different between wheezers and healthy controls. Significant bronchodilator reversibility was only observed in wheezers for Scond (16%), but in both wheezers (37%) and healthy controls (20%) for sRaw. Some wheezers and healthy controls demonstrated increases in multiple-breath washout indices post-bronchodilator. Lung clearance index and sRaw demonstrate low baseline variability in healthy and diseased subjects. Neither multiple-breath washout indices nor sRaw are ideal for assessing bronchodilator reversibility in young children with stable wheeze. These findings will help to interpret the effect of therapeutic interventions in children with respiratory diseases.


Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Broncodilatadores/uso terapéutico , Antropometría , Asma/tratamiento farmacológico , Asma/fisiopatología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Estudios Prospectivos , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria , Fenómenos Fisiológicos Respiratorios , Ruidos Respiratorios/diagnóstico , Ruidos Respiratorios/fisiopatología , Resultado del Tratamiento
20.
Eur Respir J ; 42(2): 527-38, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23520316

RESUMEN

Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed; both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review; chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.


Asunto(s)
Fibrosis Quística/terapia , Lavado Broncoalveolar , Preescolar , Humanos , Lactante , Inflamación , Pulmón/fisiología , Enfermedades Pulmonares/terapia , Respiración , Pruebas de Función Respiratoria , Espirometría , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
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