Royal Brompton Hospital Research Articles

June Podcast: The natural history of progressive fibrosing ILD.

As part of the June issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief Editor Martin Kolb interviews Kevin K. Brown (National Jewish Health, Denver, CO, USA) and Athol U. Wells (Royal Brompton Hospital, London, UK) about analyses of data from the INBUILD and INPULSIS trials suggesting that progressive fibrosing interstitial lung diseases other than idiopathic pulmonary fibrosis have a clinical course similar to IPF.

Correlation Between Echocardiographic and Hemodynamic Variables in Cardiothoracic Intensive Care Unit

The echocardiographic indices have not been validated in critically ill population. The authors investigated the correlation between some echocardiographic and hemodynamic parameters. Prospective, spontaneous, noninterventional observational study. Adult cardiothoracic intensive care unit, single center (Royal Brompton Hospital, London, United Kingdom). Consecutive adult patients admitted to the cardiothoracic intensive care unit for severe respiratory failure, primary cardiocirculatory failure, and post-aortic surgery. Clinical hemodynamic parameters (stroke volume [SV], cardiac output [CO], mean arterial pressure [MAP], and cardiac power index [CPI]) and echocardiographic indices of ventricular function (left ventricular total isovolumic time [t-IVT], mitral annular plane systolic excursion [MAPSE], and left ventricular fraction [LVEF]) were evaluated offline. The study comprised 117 patients (age 57.2 ± 19; 60.6% male). The t-IVT showed an inverse correlation with SV, CO, MAP, and CPI (r -67%; -38%; -45%; -51%, respectively). MAPSE exhibited a positive correlation with SV, CO, MAP, and CPI (r 43%; 44%; 34%; 31%, respectively). LVEF did not show any correlation. In the multivariate analysis the association between t-IVT and hemodynamics was confirmed for SV, CO, MAP, and CPI, with the highest partial correlation between t-IVT and MAP (R = -58%). MAPSE and t-IVT are 2 reproducible and reliable echocardiographic indices of systolic function and ventricular efficacy associated with hemodynamic variables in cardiothoracic critically ill patients, whereas LVEF did not show any correlation.

Research Day of the Royal Brompton and Harefield Hospitals, Royal Society of Medicine, London

Research Day of the Royal Brompton and Harefield Hospitals, Royal Society of Medicine, London

A model based on clinical parameters to identify myocardial late gadolinium enhancement by magnetic resonance in patients with aortic stenosis: An observational study.

ObjectiveWith increasing age, the prevalence of aortic stenosis grows exponentially, increasing left heart pressures and potentially leading to myocardial hypertrophy, myocardial fibrosis and adverse outcomes. To identify patients who are at greatest risk, an outpatient model for risk stratification would be of value to better direct patient imaging, frequency of monitoring and expeditious management of aortic stenosis with possible earlier surgical intervention. In this study, a relatively simple model is proposed to identify myocardial fibrosis in patients with a diagnosis of moderate or severe aortic stenosis.DesignPatients with moderate to severe aortic stenosis were enrolled into the study; patient characteristics, blood work, medications as well as transthoracic echocardiography and cardiovascular magnetic resonance were used to determine potential identifiers of myocardial fibrosis.SettingThe Royal Brompton Hospital, London, UKParticipantsOne hundred and thirteen patients in derivation cohort and 26 patients in validation cohort.Main outcome measuresIdentification of myocardial fibrosis.ResultsThree blood biomarkers (serum platelets, serum urea, N-terminal pro-B-type natriuretic peptide) and left ventricular ejection fraction were shown to be capable of identifying myocardial fibrosis. The model was validated in a separate cohort of 26 patients.ConclusionsAlthough further external validation of the model is necessary prior to its use in clinical practice, the proposed clinical model may direct patient care with respect to earlier magnetic resonance imagining, frequency of monitoring and may help in risk stratification for surgical intervention for myocardial fibrosis in patients with aortic stenosis.

An approach to the management of children with problematic severe asthma.

Children with poor asthma control despite high levels of prescribed treatment are described as having problematic severe asthma. Most of these children have steroid sensitive disease which improves with adherence to daily inhaled corticosteroids and after having removed modifiable factors like poor inhalation technique, persistent adverse environmental exposures and psychosocial factors. These children are described as having “difficult-to-treat asthma” while children with persistent symptoms despite above-mentioned factors having been addressed are described as having “severe therapy-resistant asthma”. In this review, we will describe the 6-step approach to the diagnosis and management of a child with problematic severe asthma adopted by The Royal Brompton Hospital (London, UK). The role of a multidisciplinary team is crucial for identification and treatment of modifiable factors and comorbidities in order to avoid invasive examinations and useless pharmacological treatments. The current knowledge on add-on therapies will be discussed.

The Fungal Airway Microbiome in Cystic Fibrosis and Bronchiectasis

Background: The prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and bronchiectasis. Methods: Next generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls. Findings: ITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20·4%), whereas in bronchiectasis sputum Candida albicans (21·8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp. This study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases. Funding Statement: The project was supported by the Asmarley Trust, the Wellcome Trust and the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust, Imperial College London. IF was supported by an NIHR PhD studentship. Declaration of Interests: The authors have no conflicts of interests to disclose. Ethics Approval Statement: The study was approved by the Royal Brompton and Harefield Hospital Biomedical Research Unit Ethics Committee (Advanced Lung Disease Biobank Study Number: 10/H0504/9).

Familial lung disease presenting in reverse

A 52-year-old man presents with rapidly progressive dyspnoea and cough. His teenage son suffers from aplastic anaemia. What is the relevance of his son's haematological condition to his respiratory disease? Test your knowledge on a case that was investigated and managed at the Royal Brompton Hospital highlighting an emerging concept in interstitial lung disease.

Kenneth Michael Citron

Kenneth Michael Citron studied medicine at Guy’s Hospital, London, where he won the Golding Bird medal in bacteriology and the Leonard Lubbock prize in clinical pathology. After house appointments at...

Right Ventricular to Left Ventricular Ratio at CT Pulmonary Angiogram Predicts Mortality in Interstitial Lung Disease

Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to the severity of the ILD. The right ventricular to left ventricular diameter (RV:LV) ratio measured at CT pulmonary angiogram (CTPA) has been shown to provide valuable information in patients with pulmonary arterial hypertension and to predict death or deterioration in acute pulmonary embolism. Demographic characteristics, ILD subtype, echocardiography, and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterization at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored according to CT criteria. The RV:LV ratio at CTPA was evaluated by using three different methods. Cox proportional hazards analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. A total of 92 patients were included (64%male; mean age 65 ± 11 years) with an FVC 57 ± 20%predicted, corrected transfer factor of the lung for carbon monoxide 22 ± 8%predicted, and corrected transfer coefficient of the lung for carbon monoxide 51 ± 17%predicted. PH was confirmed at right heart catheterization in 78%. Of all the CTPA-derived measures, an RV:LV ratio≥ 1.0 strongly predicted mortality or transplantation at univariate analysis (hazard ratio, 3.26; 95%CI, 1.49-7.13; P= .003), whereas invasive hemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (hazard ratio, 3.19; 95%CI, 1.44-7.10; P= .004), adjusting for an ILD diagnosis of idiopathic pulmonary fibrosis and CT imaging-derived ILD severity. An increased RV:LV ratio measured at CTPA provides a simple, noninvasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow-up, more aggressive treatment, and consideration of lung transplantation.

Transition to adult care in young people with neuromuscular disease on non-invasive ventilation

BackgroundLong-term mechanical ventilation (LTV) with non-invasive ventilation (NIV) prolongs survival in patients with Neuromuscular Diseases (NMDs). Transition from paediatric to adult healthcare system is an undervalued and challenging issue for children with chronic conditions on mechanical ventilation.Methodsthis retrospective study aims to compare issues of young adults in age to transition to adult care (≥ 15 years old) affected by NMDs on NIV in two different Paediatric Respiratory Units in two different countries: Bambino Gesù Children’s Hospital, Research Institute, (Rome, Italy) (BGCH) and the Paediatric Respiratory Unit of the Royal Brompton Hospital (London, UK) (RBHT).ResultsThe median (min-max) age at starting ventilation was significantly different in the two groups (16 years old vs 12, p = 0.0006). We found significant difference in terms of median age at the time of observation (18 (15–22) vs 17 (15–19) years, p = 0.0294) and of type of referral (all the patients from the BGCH group were referred to paediatric services (n = 15, 100%), median age 18 (15–22); only 6 patients, in the RBHT group, with a median age 15.50 (15–17) years, were entirely referred to paediatric service). We found different sleep-disordered breathing assessments 6 full Polysomnographies, 7 Cardio-Respiratory Polygraphies and 2 oximetry with capnography (SpO2-tcCO2) studies in the BCGH group, while all patients of RBHT group were assessed with an SpO2-tcCO2 study. All patients from both groups underwent multidisciplinary assessment.ConclusionsIn conclusion, patients with NMDs on NIV in age to transition to adult require complex multidisciplinary management: significant efforts are needed to achieve the proper transition to adult care.

ERJ July Podcast: Nontuberculous mycobacteria.

As part of the July issue, the European Respiratory Journal presents the latest in its series of podcasts. Deputy Chief Editor James Chalmers interviews Michael Loebinger (Royal Brompton Hospital and Imperial College London, UK) and Jakko van Ingen (Radboud University Medical Center, Nijmegen, the Netherlands) about five articles on the subject on nontuberculous mycobacteria published in this issue.

Aortic Valve Function at Medium-term Follow-up after Resuspension During Repair of Acute Type A Aortic Dissection. Royal Brompton and Harefield Hospitals, Experience

Objective: Aortic Valve Resuspension (AVS) at the time of dissection repair is a technique with excellent early outcomes in terms of aortic valve (AV) function. However, limited data is available w...

New guidelines for home oxygen therapy in children

New guidelines for home oxygen therapy in children

ERJ March Podcast: Novel therapies in idiopathic pulmonary fibrosis.

As part of the March issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief Editor Martin Kolb interviews Toby Maher (Royal Brompton Hospital and Imperial College London, UK) about two articles in this issue reporting the results of randomised controlled trials in idiopathic pulmonary fibrosis.

Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze

Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze

Electronic Monitoring of Adherence to Inhaled Corticosteroids: An Essential Tool in Identifying Severe Asthma in Children

To study if electronic monitoring could be used to separate patients with severe asthma with poor control. In addition, the purpose was to observe if electronic monitoring would lead to the optimization of standard asthma therapy.This was a prospective observational cohort of children aged 5 to 17 years. The study included 108 children with asthma recruited from the outpatient department of Royal Brompton Hospital in London, United Kingdom.All children had an asthma diagnosis by standard protocols. Children were classified into 3 groups: severe therapy-resistant asthma, difficult asthma, and mild-to-moderate asthma. Baseline and end–of–monitoring period assessments included an asthma control test, lung function, fractional exhaled nitric oxide, asthma-related quality of life, and medication adherence using a smart inhaler.Data for 93 children who completed the study were analyzed. The median days of monitoring was 92. Good adherence was found in 42% of patients who took ≥80% of medications. Suboptimal adherence was noted in 58% of patients (27% took 60%–79% of medications, and 31% took <60% of medications). No significant differences were seen between the adherence groups for the asthma control test, fractional exhaled nitric oxide, forced expiratory volume in 1 second, the exacerbation rate, or oral corticosteroid use. Four groups were identified after the data analysis: (1) good adherence with improved control (24%; likely previous poor adherence), (2) good adherence with poor control (18%; severe therapy-resistant asthma), (3) poor adherence with good control (26%; likely overtreated), and (4) poor adherence with poor control (32%).This study revealed the importance of accurate adherence monitoring in children with asthma. Suboptimal adherence was noted in 58% of patients despite knowing that adherence was being monitored. The authors of this study identified patients with true severe asthma despite good adherence to therapy, suggesting that patients would merit further phenotyping of their asthma. In the study, researchers also confirmed the inadequacy of self-reported adherence and the limitation of prescription records.Not surprisingly, 58% of the study patients had suboptimal adherence. This represents real-world data and the difficulty with asthma adherence despite education, monitoring, and routine follow-up. This study also reveals that electronic monitoring could be helpful in identifying poor adherence as a cause of asthma poor control. Therefore, for some, improved education may be more beneficial than prescribing more medications.

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial

SummaryBackgroundPatients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown.MethodsWe did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.FindingsBetween April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5–67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6–57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure.InterpretationMany patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely.FundingBritish Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Predicting Outcomes in Idiopathic Pulmonary Fibrosis Using Automated Computed Tomographic Analysis.

Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials. To determine whether computer-derived CT measures, specifically measures of pulmonary vessel-related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations. Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER [Computer-Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria. In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%. Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria-the VRS score-that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.

Editorial introductions

Editorial introductions

The Clinical Significance of Body Weight Loss in Idiopathic Pulmonary Fibrosis Patients

Background: The significance of the nutritional status in idiopathic pulmonary fibrosis (IPF) is largely unknown. Temporal body weight (BW) change, a dynamic index of nutrition status, can detect the malnutrition more accurately than the conventional single-point body mass index evaluation. Objective: To investigate how the temporal BW change influences the clinical courses of IPF. Methods: This multicenter study enrolled IPF patients from four referral hospitals of interstitial lung diseases in Japan (the Japanese cohort, the derivation cohort) and the Royal Brompton Hospital (the UK cohort, the validation cohort). The annual rate of BW change from the initial presentation was evaluated. A > 5% decrease of BW was defined as a significant BW loss. Results: Twenty-seven out of 124 patients in the Japanese cohort and 13 out of 86 patients in the UK cohort showed significant BW loss. Patients with BW loss showed significantly worse survival in both cohorts. Multivariate analyses revealed that BW loss was an independent factor for decreased survival (Japanese cohort: p = 0.047, UK cohort: p = 0.013). A 6.1% loss of BW was chosen as the optimal cutoff value to predict the 2-year mortality from the initial presentation. The stratified analysis revealed that a 6.1% or greater BW loss could predict worse survival specifically in cases without a greater than 10% decline in forced vital capacity (FVC). Conclusions: BW loss is independently associated with the survival of IPF patients, particularly when a decline in the FVC was not observed. Further studies are needed to understand the mechanisms underlying BW loss in IPF.