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BACKGROUND AND AIMS: Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. METHODS: A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. RESULTS: Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. CONCLUSIONS: This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.
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Cardiopatías , Hipertensión Pulmonar , Enfermedades Vasculares , Humanos , Estudios Retrospectivos , Hemodinámica , Resistencia Vascular , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.
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Asma , Transcriptoma , Humanos , Asma/tratamiento farmacológico , Asma/genética , Asma/diagnóstico , Perfilación de la Expresión Génica , Biomarcadores , Corticoesteroides/uso terapéuticoRESUMEN
Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 × 10-6). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response.
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Hipertensión Arterial Pulmonar , Área Bajo la Curva , Biomarcadores , Hipertensión Pulmonar Primaria Familiar , Humanos , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Pronóstico , ProteomaRESUMEN
Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).
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Antiasmáticos , Asma , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Biomarcadores , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Fenotipo , Factores de RiesgoRESUMEN
Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.
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Autoinmunidad , Hipertensión Pulmonar , Autoanticuerpos , Estudios Transversales , Hipertensión Pulmonar Primaria Familiar , Humanos , Hipertensión Pulmonar/genéticaRESUMEN
BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.
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Asma , Etnicidad , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Humanos , Grupos Minoritarios , Método Simple CiegoRESUMEN
INTRODUCTION: There is no gold standard criterion for the diagnosis of cystic fibrosis-related liver disease (CFRLD) and there is uncertainty over its impact on the outcome of lung transplantation. METHOD: Lung recipients (n = 238) were divided into two groups-CFRLD and non-CFRLD based on a modified aspartate aminotransferase-to-platelet ratio index (APRI) score (mAPRI) to diagnose CFRLD and predict severity of liver disease. Groups were compared to assess validity of the diagnosis and survival outcomes. RESULT: The new diagnostic criterion was effective at differentiating CFRLD from non-CFRLD. There was no significant difference in the survival between two groups at short, medium, or long term demonstrated by the Kaplan-Meier plot with survival of 85%, 73%, 47%, 18.6%, and 4.7% at 1, 2, 5, 10, and 15 years respectively. A mAPRI score of greater than .2 had a sensitivity of 43.0% but a specificity of 82.5 % for diagnosis of CFRLD and 46.5% sensitivity but 100% specificity in predicting an ultrasound/biopsy proven hepatic abnormality associated with CFRLD. CONCLUSION: A mAPRI sore is a highly specific non-invasive tool for diagnosis of CFRLD. Recipients with CFRLD but grossly preserved hepatocellular function have a similar outcome to patients without CFRLD.
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Fibrosis Quística , Hepatopatías , Trasplante de Pulmón , Aspartato Aminotransferasas , Biomarcadores , Biopsia , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/cirugía , Humanos , Hígado/patología , Cirrosis Hepática/patología , Hepatopatías/diagnóstico , Hepatopatías/etiología , Hepatopatías/cirugía , Trasplante de Pulmón/efectos adversos , Recuento de Plaquetas , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.
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Consenso , Testimonio de Experto/normas , Hipertensión Pulmonar/cirugía , Atención Perioperativa/normas , Complicaciones Posoperatorias/prevención & control , Testimonio de Experto/métodos , Humanos , Hipertensión Pulmonar/diagnóstico , Atención Perioperativa/métodos , Complicaciones Posoperatorias/diagnósticoRESUMEN
BACKGROUND AND OBJECTIVE: Non-adherence is an important issue within severe asthma. Prednisolone and cortisol assays have been proposed as an inexpensive, objective measure of adherence for oral corticosteroid (OCS)-dependent asthmatics, however, little is known about the reliability of these tests. METHODS: 41 severe OCS-dependent asthmatics had their prednisolone and cortisol measured during six study visits over a three month time period. Subjects were classed as non-adherent/variably-adherent if they had undetectable prednisolone and/or cortisol >100 nmol/L. Intraclass correlation coefficients (ICCs) were used to assess the test-retest reliability of prednisolone and cortisol, and Gwets AC1 kappa was used to assess the reliability of the adherence classification. Mean change in blood eosinophils for adherent and variably/non-adherent visits were calculated and linear regression with cluster-robust standard errors was used to test for differences. RESULTS: 30 subjects were included in the analysis. Reliability was poor for prednisolone (ICC: 0.43; 95% CI: 0.27, 0.59), and moderate for cortisol (ICC: 0.60; 95% CI: 0.44, 0.74). Using the combined rule, subjects were classified as adherent during 141 (88%) visits, with 21 subjects (70%) adherent during all study visits. The adherence classification had almost perfect reliability (Kappa: 0.84; 95% CI: 0.74, 0.95). Blood eosinophils were decreased by 47 cells/µl (95% CI: 11, 84) during adherent visits but increased by 65 cells/µl (95% CI: 4, 134; Pdifference = 0.03) during variably/non-adherent visits. CONCLUSIONS: Assessing adherence to maintenance OCS using a simple rule based on prednisolone and cortisol assays is highly reliable and correlated with blood eosinophil changes. Clinicians should have confidence in the results of this rule.
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Asma , Hidrocortisona , Administración Oral , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Humanos , Hidrocortisona/uso terapéutico , Prednisolona/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The demand for lung transplantation vastly exceeds the availability of donor organs. This translates into long waiting times and high waiting list mortality. We set out to examine factors influencing patient outcomes from the time of listing for lung transplantation in the UK, examining for differences by patient characteristics, lung disease category and transplant centre. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant for adult lung-only registrations between 1January 2004 and 31 March 2014. Pretransplant and post-transplant outcomes were evaluated against lung disease category, blood group and height. RESULTS: Of the 2213 patient registrations, COPD comprised 28.4%, pulmonary fibrosis (PF) 26.2%, cystic fibrosis (CF) 25.4% and other lung pathologies 20.1%. The chance of transplantation after listing differed by the combined effect of disease category and centre (p<0.001). At 3 years postregistration, 78% of patients with COPD were transplanted followed by 61% of patients with CF, 59% of other lung pathology patients and 48% of patients with PF, who also had the highest waiting list mortality (37%). The chance of transplantation also differed by height with taller patients having a greater chance of transplant (HR: 1.03, 95% CI: 1.02 to 1.04, p<0.001). Patients with blood group O had the highest waiting mortality at 3 years postregistration compared with all other blood groups (27% vs 20%, p<0.001). CONCLUSIONS: The way donor lungs were allocated in the UK resulted in discrepancies between the risk profile and probability of lung transplantation. A new donor lung allocation scheme was introduced in 2017 to try to address these shortcomings.
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Sistema del Grupo Sanguíneo ABO , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón/estadística & datos numéricos , Listas de Espera , Aloinjertos/provisión & distribución , Estatura , Fibrosis Quística/sangre , Fibrosis Quística/cirugía , Asignación de Recursos para la Atención de Salud/métodos , Instituciones de Salud/estadística & datos numéricos , Humanos , Periodo Posoperatorio , Periodo Preoperatorio , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/cirugía , Sistema de Registros , Tasa de Supervivencia , Tiempo de Tratamiento , Reino Unido/epidemiología , Listas de Espera/mortalidadRESUMEN
Type-2 biomarkers and related cytokines (IL-5, IL-13), lung function and asthma symptoms were measured in 44 poorly-controlled severe oral corticosteroid (OCS)-dependent asthmatics for up to 88 days after a 7-day prednisolone boost (0.5 mg/kg). High-dose OCS reduced median blood eosinophils (-60 cells/µl; 95% CI -140 to 10), periostin (-8.4 ng/mL; -11.6 to -2.8), FeNO (-19.0 ppb; -28.5 to -4.0), IL-5 (-0.17 pg/mL; -0.28 to -0.08) and IL-13 (-0.15 pg/mL; -0.27 to -0.03). There were small improvements in mean FEV1 (0.16 L; 0.05 to 0.27) and (Asthma Control Questionnaire) ACQ-7 score (0.3; 0.0 to 0.7). Study measures returned to baseline 1-month postintervention. Following rescue OCS, 1 month is sufficient before using type-2 biomarkers to guide long-term treatment. TRIAL REGISTRATION NUMBER: NCT01948401.
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Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Eosinófilos , Interleucina-13/sangre , Interleucina-5/sangre , Prednisolona/uso terapéutico , Administración Oral , Adulto , Antiinflamatorios/administración & dosificación , Asma/sangre , Biomarcadores/sangre , Pruebas Respiratorias , Moléculas de Adhesión Celular/sangre , Femenino , Volumen Espiratorio Forzado , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Óxido Nítrico/análisis , Prednisolona/administración & dosificación , Capacidad VitalRESUMEN
While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5â µm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a prioriHigher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3â µg·m-3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3â µg·m-3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000â m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.
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Contaminación del Aire/efectos adversos , Hipertensión Arterial Pulmonar/epidemiología , Contaminación por Tráfico Vehicular/efectos adversos , Adulto , Anciano , Contaminación del Aire/análisis , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Dióxido de Nitrógeno/efectos adversos , Dióxido de Nitrógeno/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Estudios Prospectivos , Hipertensión Arterial Pulmonar/etiología , Contaminación por Tráfico Vehicular/análisis , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Lung transplantation is a well-established treatment for end-stage non-cystic fibrosis bronchiectasis (BR), though information regarding outcomes of transplantation remains limited. Our results of lung transplantation for Br are reported here. METHODS: A retrospective review of case notes and transplantation databases was conducted for patients that had underwent lung transplantation for bronchiectasis at the Freeman Hospital between 1990 and 2013. RESULTS: Fourty two BR patients underwent lung transplantation, the majority (39) having bilateral sequential lung transplantation. Mean age at transplantation was 47.1 years. Pre-transplantation osteoporosis was a significant non-pulmonary morbidity (48%). Polymicrobial infection was common, with Pseudomonas aeruginosa infection frequently but not universally observed (67%). Forced expiratory volume in 1 second (% predicted) improved from a pre-transplantation mean of 0.71 L (22% predicted) to 2.56 L (79 % predicted) at 1-year post-transplantation. Our survival results were 74% at 1 year, 64% at 3 years, 61% at 5 years and 48% at 10 years. Sepsis was a common cause of early post-transplantation deaths. CONCLUSIONS: Lung transplantation for end-stage BR is a useful therapeutic option, with good survival and lung function outcomes. Survival values were similar to other bilateral lung transplants at our centre. Pre-transplantation Pseudomonas infection is common.
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Bronquiectasia/microbiología , Bronquiectasia/cirugía , Trasplante de Pulmón , Adulto , Bronquiectasia/mortalidad , Bases de Datos Factuales , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Infecciones por Pseudomonas/epidemiología , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA. METHODS AND RESULTS: Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s(-1)·cm(-5) at reassessment correlated with worse long-term survival. CONCLUSIONS: Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patients postsurgery.
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Endarterectomía/tendencias , Hipertensión Pulmonar/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Endarterectomía/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo/métodos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto JovenRESUMEN
Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the 'most common' emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis ('CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate.
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Cuidados Críticos , Hipertensión Pulmonar/terapia , Rol del Médico , Arritmias Cardíacas/etiología , Bacteriemia/microbiología , Dolor en el Pecho/etiología , Ensayos Clínicos como Asunto , Medicina Basada en la Evidencia , Hemoptisis/etiología , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/mortalidad , Irlanda , Guías de Práctica Clínica como Asunto , Pronóstico , Factores de Riesgo , Resultado del Tratamiento , Reino Unido , Disfunción Ventricular Derecha/etiologíaRESUMEN
Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10â µm (PM10) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM10 (hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500â m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.
Asunto(s)
Contaminación del Aire/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Trasplante de Pulmón/mortalidad , Disfunción Primaria del Injerto/fisiopatología , Adulto , Contaminantes Atmosféricos/análisis , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Supervivencia de Injerto , Humanos , Macrólidos/uso terapéutico , Masculino , Persona de Mediana Edad , Material Particulado/análisis , Modelos de Riesgos Proporcionales , Análisis de RegresiónRESUMEN
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/epidemiología , Investigación Biomédica/métodos , Manejo de la Enfermedad , Cooperación del Paciente , Medición de Riesgo , Humanos , Reino UnidoRESUMEN
BACKGROUND: We conducted a placebo-controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. METHODS: We compared azithromycin (250â mg alternate days, 12â weeks) with placebo. Primary outcome was FEV1 change at 12â weeks. RESULTS: 48 patients were randomised; (25 azithromycin, 23 placebo). It was established, post randomisation that two did not have BOS. 46 patients were analysed as intention to treat (ITT) with 33 'Completers'. ITT analysis included placebo patients treated with open-label azithromycin after study withdrawal. OUTCOME: The ITT analysis (n=46, 177 observations) estimated mean difference in FEV1 between treatments (azithromycin minus placebo) was 0.035â L, with a 95% CI of -0.112â L to 0.182â L (p=0.6). Five withdrawals, who were identified at the end of the study as having been randomised to placebo (four with rapid loss in FEV1, one withdrawn consent) had received rescue open-label azithromycin, with improvement in subsequent FEV1 at 12â weeks. Study Completers showed an estimated mean difference in FEV1 between treatment groups (azithromycin minus placebo) of 0.278â L, with 95% CI for the mean difference: 0.170â L to 0.386â L (p=<0.001). Nine of 23 ITT patients in the azithromycin group had ≥10% gain in FEV1 from baseline. No patients in the placebo group had ≥10% gain in FEV1 from baseline while on placebo (p=0.002). Seven serious adverse events, three azithromycin, four in the placebo group, were deemed unrelated to study medication. CONCLUSIONS: Azithromycin therapy improves FEV1 in patients with BOS and appears superior to placebo. This study strengthens evidence for clinical practice of initiating azithromycin therapy in BOS. TRIAL REGISTRATION NUMBER: EU-CTR, 2006-000485-36/GB.
Asunto(s)
Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Bronquiolitis Obliterante/tratamiento farmacológico , Trasplante de Pulmón/efectos adversos , Adulto , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/etiología , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Síndrome , Resultado del TratamientoRESUMEN
BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing. METHODS: Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata. RESULTS: 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was -7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP. CONCLUSIONS: Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.