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  • Impact of respiratory muscle training on respiratory muscle strength, respiratory function and quality of life in individuals with tetraplegia: a randomised clinical trial
    Thorax (IF 9.640) Pub Date : 2020-01-14
    Claire L Boswell-Ruys; Chaminda R H Lewis; Nirupama S Wijeysuriya; Rachel A McBain; Bonsan Bonne Lee; David K McKenzie; Simon C Gandevia; Jane E Butler

    Background Respiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health. Methods Sixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes. Results After 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH2O (95% CI 5.6 to 17.4), p<0.001) and respiratory symptoms were reduced (St George Respiratory Questionnaire mean difference 10.3 points (0.01–20.65), p=0.046). Significant improvements were observed in quality of life (EuroQol-Five Dimensional Visual Analogue Scale 14.9 points (1.9–27.9), p=0.023) and perceived breathlessness (Borg score 0.64 (0.11–1.17), p=0.021). There were no significant improvements in other measures of respiratory function (p=0.126–0.979). Conclusions Progressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia. Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN 12612000929808).

    更新日期:2020-01-15
  • RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock
    Thorax (IF 9.640) Pub Date : 2020-01-14
    Kai Zhang; Yue Jin; Dengming Lai; Jieyan Wang; Yang Wang; Xiaoliang Wu; Melanie Scott; Yuehua Li; Jinchao Hou; Timothy Billiar; Mark Wilson; Qiang Shu; Xiangming Fang; Jie Fan

    Background Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. Objective To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. Methods Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. Results The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. Conclusions These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.

    更新日期:2020-01-15
  • Integrated proteogenomic approach identifying a protein signature of COPD and a new splice variant of SORBS1
    Thorax (IF 9.640) Pub Date : 2020-01-14
    Corry-Anke Brandsma; Victor Guryev; Wim Timens; Ana Ciconelle; Dirkje S Postma; Rainer Bischoff; Maria Johansson; Ekaterina S Ovchinnikova; Johan Malm; Gyorgy Marko-Varga; Thomas E Fehniger; Maarten van den Berge; Peter Horvatovich

    Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD.

    更新日期:2020-01-15
  • Mendelian randomisation supports causal link between obesity and asthma
    Thorax (IF 9.640) Pub Date : 2020-01-08
    Diana A van der Plaat

    Over the last few decades the prevalence of both obesity and asthma has increased substantially in many parts of the world. A clear link between obesity and asthma incidence and severity has been shown in both children and adults in observational studies.1 2 The biological mechanisms underlying this relationship are not fully understood. Hypotheses to explain the association include mechanisms related to one or more factors, including systemic inflammation, endocrine factors, oxidative stress, decreased lung volumes and comorbidities (type 2 diabetes, obstructive sleep apnoea and gastro-oesophageal reflux disease).3–6 The systemic inflammation pathway has gained particular traction, as both obese subjects and asthmatics have high inflammatory burdens. In addition, obese patients with asthma present with a different type of airway inflammation, tending to be more neutrophilic than eosinophilic.3 Controversy exists over whether obesity has a different effect on asthma in males and females, as studies in children show mixed results while some studies in adults suggest stronger effects in females.4 5 Furthermore, there has been a concern that the body mass index (BMI)–asthma association is due to reverse causation; that is, that people with asthma become obese due to the impact of asthma on their ability to remain active or perhaps even due to medications. Overall, findings by observational studies are susceptible to bias (confounding) and cannot elucidate the directionality of the relationship between obesity and asthma. The Mendelian randomisation (MR) approach is increasingly used to assess causal relationships and can be regarded as a ‘natural’ randomised controlled trial. MR uses genetic variants (single nucleotide polymorphisms; SNP), which were randomly assigned at conception, as proxies (‘instrumental variables’) for an exposure of interest.7 Indirect evidence of a causal effect of the exposure on the outcome is provided when the SNPs that are known to modify the exposure …

    更新日期:2020-01-08
  • Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility)
    Thorax (IF 9.640) Pub Date : 2020-01-08
    Irene J Higginson; Andrew Wilcock; Miriam J Johnson; Sabrina Bajwah; Natasha Lovell; Deokhee Yi; Simon P Hart; Vincent Crosby; Heather Poad; David Currow; Emma Best; Sarah Brown

    New treatments are required for severe breathlessness in advanced disease. We conducted a randomised feasibility trial of mirtazapine over 28 days in adults with a modified medical research council breathlessness scale score ≥3. Sixty-four patients were randomised (409 screened), achieving our primary feasibility endpoint of recruitment. Most patients had COPD or interstitial lung disease; 52 (81%) completed the trial. There were no differences between placebo and mirtazapine in tolerability or safety, and blinding was maintained. Worst breathlessness ratings at day 28 (primary clinical activity endpoint) were, 7.1 (SD 2.3, placebo) and 6.3 (SD 1.8, mirtazapine). A phase III trial of mirtazapine is indicated. Trial registration: [ISRCTN 32236160][1]; European Clinical Trials Database (EudraCT no: 2015-004064-11). [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN32236160

    更新日期:2020-01-08
  • Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity
    Thorax (IF 9.640) Pub Date : 2020-01-08
    Inga Wessels; Johanna Theresa Pupke; Klaus-Thilo von Trotha; Alexander Gombert; Anika Himmelsbach; Henrike Josephine Fischer; Michael J Jacobs; Lothar Rink; Jochen Grommes

    Introduction Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. Methods 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. Results Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. Conclusion Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

    更新日期:2020-01-08
  • Unusual case of preoperative hypoxaemia
    Thorax (IF 9.640) Pub Date : 2020-01-06
    Padraic C Ridge; Sarah Cullivan; Christina D Campbell; Anthony O'Regan; Robert M Rutherford

    An 82-year-old woman was admitted electively for surgical stabilisation of a persistently painful osteoporotic fracture of T12 vertebra She had a history of kyphosis with two previous osteoporotic fractures at T8 and T9 treated by kyphoplasty. She was noted to be persistently hypoxic with saturations of 80% on room air. She required 4 L/min of oxygen to maintain her saturations at >94%. There was no platypneoa-orthodeoxia. She had no history of significant cardiorespiratory disease, was an ex-20 pack year smoker and denied breathlessness. Cardiorespiratory examination was normal apart from moderate kyphosis. Figure 1 Colour flow doppler revealing shunt from right to left atria across a patent foramen ovale (white arrow); Left atrium= LA, Right atrium= RA and interatrial septum= IAS Chest radiograph was normal as was spirometry with a forced expiratory volume (FEV1) of 132% predicted, forced vital capacity (FVC) of 145% predicted with an FEV …

    更新日期:2020-01-07
  • Diffuse granulomatous disease: looking inside and outside the lungs
    Thorax (IF 9.640) Pub Date : 2020-01-06
    Alan Williams; W Peter Kelleher; Andrew G Nicholson; Anand Devaraj; Carlos Pavesio; Felix Chua

    A 39-year-old woman presented with a 6-month history of breathlessness, productive cough and painful lumps on her lower legs. She had suffered with recurrent rhinosinusitis and frequent infections of the ears, throat and chest since childhood, as well as cutaneous herpes zoster in her 20s. There was no documented history of pneumonia, invasive or deep-seated infections. She had smoked lightly, was allergic to penicillin and worked as a commercial tea buyer. Examination showed a slim female with a normal breathing pattern. Chest expansion was reduced and fine inspiratory crackles were detected over the lower lung zones. Pulmonary function tests showed ventilatory restriction with decreased gas transfer. Forced expiratory volume in one second (FEV1) 2.10 L, 71% predicted; forced vital capacity (FVC) 2.22 L, 65% predicted; spirometric ratio 0.93; total lung capacity 3.04 L, 62% predicted; haemoglobin (Hb)-adjusted carbon monoxide transfer factor/TLco 45% predicted and its coefficient/Kco 81% predicted. Indices related to small airway function were normal, maximal expiratory flow (MEF)75/50/25 all above 80% predicted and air-trapping was absent. Bloods tests showed normal full blood count, C-reactive protein as well as kidney, bone and liver biochemistry. Serum ACE was elevated at 93 ACEU (ref: 12–68). Elispot assay and HIV serology were negative. A prereferral chest radiograph revealed widening of the superior mediastinum and ill-defined nodular opacities in the middle and lower zones. Despite the history of possible erythema nodosum and raised serum ACE, the account of recurrent infections suggested a differential diagnosis broader than typical sarcoidosis. Demonstration of ventilatory restriction and impaired gas transfer factor hinted towards an interstitial or diffuse lung pathology. The Kco, at nearly twice the TLco in %-predicted terms, indicated a low likelihood of major pulmonary vasculopathy and the absence of airflow limitation or small airway dysfunction steered the diagnosis away from primary bronchiolar disorders. CT with contiguous …

    更新日期:2020-01-07
  • Comparing treatment effects of a convenient vibratory positional device to CPAP in positional OSA: a crossover randomised controlled trial
    Thorax (IF 9.640) Pub Date : 2020-01-02
    Yingjuan Mok; Alvin Tan; Pon Poh Hsu; Audrey Seow; Yiong Huak Chan; Hang Siang Wong; Yvonne Poh; Keith K H Wong

    Objectives Up to 77% of patients with obstructive sleep apnoea (OSA) have positional OSA (POSA) but traditional positional therapy (PT) methods have failed as they were poorly tolerated. New convenient vibratory PT devices have been invented but while recent studies suggest high treatment efficacy and adherence, there are no published data comparing these devices directly with continuous positive airway pressure (CPAP). Our objective is to evaluate if a convenient vibratory PT device is non-inferior to CPAP in POSA treatment. Methods In this crossover randomised controlled trial, we enrolled patients with POSA with significant daytime sleepiness (Epworth Sleepiness Scale (ESS)≥10). POSA diagnosis was based on: (1) total Apnoea/Hypopnoea Index (AHI)>10/hour and non-supine AHI<10/hour (2) supine AHI≥2 × non-supine AHI. Patients used their initial allocated devices (PT or CPAP) for 8 weeks before crossing to the alternative intervention after a 1 week washout. The primary aim is to measure changes in ESS between the two treatments. Secondary outcomes include sleep study parameters and patient treatment preference (ClinicalTrials.gov: [NCT03125512][1]). Results 40 patients completed the trial between April 2017 and December 2018. Difference in ESS after 8 weeks of device use (PT minus CPAP) was 2.0 (95% CI 0.68 to 3.32), exceeding our predetermined non-inferiority margin of 1.5. AHI on CPAP was lower than with PT (4.0±3.2 vs 13.0±13.8 events/hour, respectively, p=0.001), although both were lower than at baseline. Time spent supine was significantly lower with PT than CPAP (p<0.001). 60% of patients preferred CPAP, 20% preferred PT, while 20% preferred neither device. Conclusions The non-inferiority ESS endpoint for PT compared with CPAP was not met and the results were inconclusive. Future trials with larger sample sizes or in less symptomatic patients are warranted to provide further insight into the role of these new vibratory PT devices. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03125512&atom=%2Fthoraxjnl%2Fearly%2F2020%2F01%2F02%2Fthoraxjnl-2019-213547.atom

    更新日期:2020-01-02
  • Asthma reviews in children: what have we learned?
    Thorax (IF 9.640) Pub Date : 2020-01-02
    Mark L Levy; Louise Fleming

    Asthma is a complex chronic disease, characterised by intermittent respiratory symptoms, airway inflammation and reversible airflow obstruction, without the availability of a single confirmatory diagnostic test. Management of this disease involves many challenges for primary care physicians. These include diagnosis, monitoring, identifying risk and chronic as well as acute management; furthermore, it is challenging to maintain up to date knowledge of asthma to facilitate good quality patient education. Primary care clinicians with their limited availability of routine appointments, plus the vast spectrum of medical conditions they manage, are generalists and cannot be experts in every clinical condition. Although these health professionals develop skills in quickly assessing patients and making decisions for urgent or delayed management, the initial challenge is to accurately diagnose chronic diseases and second having the confidence and knowledge to manage these complex diseases in the community. In the case of asthma, diagnosis and monitoring are frequently based on reporting of symptoms, which are limited by their lack of specificity and patient recall. Considerable controversy1 2 surrounds the recent UK recommendations3 that primary care physicians should include spirometry and fractional exhaled nitric oxide (FeNO) in diagnosing asthma in the UK. Neither quality assured spirometry nor FeNO is widely available in primary care. This is further complicated because asthma patients may have normal spirometry when tested and this would potentially need to be repeated on a number of occasions to demonstrate reversible airflow obstruction, which is totally impractical in primary (or secondary) care settings. Peak flow diaries are a practical alternative in these cases.4 5 In their prospective …

    更新日期:2020-01-02
  • Per cent low attenuation volume and fractal dimension of low attenuation clusters on CT predict different long-term outcomes in COPD
    Thorax (IF 9.640) Pub Date : 2020-01-02
    Kaoruko Shimizu; Naoya Tanabe; Nguyen Van Tho; Masaru Suzuki; Hironi Makita; Susumu Sato; Shigeo Muro; Michiaki Mishima; Toyohiro Hirai; Emiko Ogawa; Yasutaka Nakano; Satoshi Konno; Masaharu Nishimura

    Background Fractal dimension ( D ) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. Methods Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). Results In the Hokkaido COPD cohort, higher %LAV, but not D , was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D , but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. Conclusion These well-established cohorts clarify the different prognostic roles of %LAV and D , whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

    更新日期:2020-01-02
  • Heparan sulfate chains contribute to the anticoagulant milieu in malignant pleural effusion
    Thorax (IF 9.640) Pub Date : 2019-12-31
    Emilia Hardak; Eli Peled; Yonatan Crispel; Shourouk Ghanem; Judith Attias; Keren Asayag; Inna Kogan; Yona Nadir

    Background While malignant pleural effusion (MPE) is a common and significant cause of morbidity in patients with cancer, current treatment options are limited. Human heparanase, involved in angiogenesis and metastasis, cleaves heparan sulfate (HS) side chains on the cell surface. Aims To explore the coagulation milieu in MPE and infectious pleural effusion (IPE) focusing on the involvement of heparanase. Methods Samples of 30 patients with MPE and 44 patients with IPE were evaluated in comparison to those of 33 patients with transudate pleural effusions, using heparanase ELISA, heparanase procoagulant activity assay, thrombin and factor Xa chromogenic assays and thromboelastography. A cell proliferation assay was performed. EMT-6 breast cancer cells were injected to the pleural cavity of mice. A peptide inhibiting heparanase activity was administered subcutaneously. Results Levels of heparanase, factor Xa and thrombin were significantly higher in exudate than transudate. Thromboelastography detected almost no thrombus formation in the whole blood, mainly on MPE addition. This effect was completely reversed by bacterial heparinase. Direct measurement revealed high levels of HS chains in pleural effusions. Higher proliferation was observed in tumour cell lines incubated with exudate than with transudate and it was reduced when bacterial heparinase was added. The tumour size in the pleural cavity of mice treated with the heparanase inhibitor were significantly smaller compared with control (p=0.005). Conclusions HS chains released by heparanase form an anticoagulant milieu in MPE, preventing local thrombosis and enabling tumour cell proliferation. Inhibition of heparanase might provide a therapeutic option for patients with recurrent MPE.

    更新日期:2019-12-31
  • Post-treatment survival difference between lobectomy and stereotactic ablative radiotherapy in stage I non-small cell lung cancer in England
    Thorax (IF 9.640) Pub Date : 2019-12-26
    Aamir Khakwani; Susan Harden; Paul Beckett; David Baldwin; Neal Navani; Doug West; Richard Hubbard

    Background Approximately 15%–20% of all non-small cell lung cancer (NSCLC) cases present with stage I disease. Surgical resection traditionally offers the best chance of a cure but some patients will not have this treatment due to older age, comorbidities or personal choice. Stereotactic ablative radiotherapy (SABR) has become an established curative intent treatment option for patients who are not selected for or do not choose surgery. The aim of this study is to compare survival at 90 days, 6 months, 1 year and 2 years for patients who received either lobectomy or SABR. Methods We used data from the 2015 National Lung Cancer Audit database and linked with Hospital Episode Statistics and the radiotherapy dataset to identify patients with NSCLC stage IA-IB and performance status (PS) 0–2 who underwent surgery or SABR treatment. We assessed the likelihood of death at 90 days, 6 months, 1 year and 2 year after diagnosis and procedure date to observe survival between two patient groups. Results We identified 2373 patients in our cohort, 476 of whom had SABR. The median difference between date of diagnosis and date of treatment for surgery patients was 17 days while for SABR patients it was 73 days. Increasing age and worsening PS were associated with having SABR rather than surgery. Survival between the two treatment modalities was similar early on but by 1-year people who had surgery did better than those who had SABR (adjusted ORs 2.12, 95% CI 1.35 to 2.31). This difference persisted at 2 years and when the analysis was restricted to patients aged <80 years and with PS 0 or 1 and stage IA only. Conclusion Our analysis suggests that patients who have lobectomy have a better survival compared with SABR patients; however, we found considerable delays in patients receiving SABR which may contribute to poorer long-term outcomes with this treatment option. Reducing these delays should be a key focus in development and reorganisation of services.

    更新日期:2019-12-27
  • Inhalers: to switch or not to switch? That is the question
    Thorax (IF 9.640) Pub Date : 2019-12-26
    Anna Claire Murphy

    We know that there is an increasing prevalence of asthma and COPD worldwide, leading to increased inhaler use. Chapter 3 of the British National Formulary1 has grown significantly over the years in terms of the number of inhaler options. There are currently, in the UK, more than 20 different inhaler devices available, with over 118 possible combinations of drug and device to prescribe. The inhaler market has become very crowded, with patents expiring for some of the most widely used inhaled drugs. Several analogues of branded inhaled corticosteroids/long-acting β2-adrenoceptor agonists (ICS/LABA) fixed-dose combinations have entered the market with different inhaler devices, and longer-acting ‘me-too’ formulations have appeared. Incorrect or suboptimal patient technique in using inhalers has led to yet further inhaler devices being developed, and combination/triple inhalers have been launched to support patients. Current clinical evidence suggests that, although existing inhaled therapy has the potential to control disease in most patients with asthma, control is often not achieved in practice.2 Suboptimal inhaler technique is the prominent reason for the lack of efficacy; no matter how good a drug or device is, it cannot be effective if the drug does not reach the targeted airways. Inhaler errors are associated with worsening in disease control, increased rate of exacerbations, increased healthcare resource consumption, and consequently increased healthcare expenditure.3–5 A recent systematic literature review and meta-analysis found that incorrect inhaler technique is common across devices, with up to 100% of patients demonstrating at least one error. Moreover, up to 92% of patients experience critical errors, that is, one that may impact the effectiveness of the delivered drug.6 While Chrystyn et al ’s3 team found high critical error rates reported across all devices, their meta-analysis and systematic review highlighted significant gaps in knowledge regarding different inhalers and associated error …

    更新日期:2019-12-27
  • One-year outcomes in a multicentre cohort study of incident rare diffuse parenchymal lung disease in children (ChILD)
    Thorax (IF 9.640) Pub Date : 2019-12-24
    Steve Cunningham; Catriona Graham; Morag MacLean; Paul Aurora; Michael Ashworth; Angelo Barbato; Alistair Calder; Julia Carlens; Annick Clement; Meike Hengst; Birgit Kammer; Nural Kiper; Katarzyna Krenke; Kai Kronfeld; Joanna Lange; Julia Ley-Zaporozhan; Andrew G Nicholson; Simone Reu; Traudl Wesselak; Martin Wetzke; Andrew Bush; Nicolaus Schwerk; Matthias Griese

    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.

    更新日期:2019-12-25
  • Highlights from this issue
    Thorax (IF 9.640) Pub Date : 2020-01-01
    The Triumvirate

    “I’ve got 20:20 vision and that’s all I need: enough to keep my baby for company.” The words of blues legend Rory Gallagher: “Ireland’s Jimi Hendrix”. At Thorax , we would like to keep you, our readership, for company in 2020. To do so, we bring you our new impact factor of 10.307 and a clutch of original and impactful manuscripts in this month’s issue! Global deaths from TB were estimated to be 1.3 million in 2016. Annually, 700 000 people receive treatment for recurrent TB and 480 000 for multidrug-resistant TB. Both involve administering injectable drugs for at least 60 days. The problem persists into the third decade of the 21st century. In this month’s journal, Cohen and colleagues (see page 64) describe a randomised controlled, non-inferiority trial of hospital administration of injectable drugs versus home administration by a lay “guardian”, conducted in Malawi. Recruitment proved difficult. The recruitment target was 268 patients and recruitment was stopped at 204 patients for futility. Non-inferiority could not be demonstrated. However no difference was found, between regimens, in the number of patients alive and on treatment at 60 days. Home treatment was …

    更新日期:2019-12-13
  • Palliative treatment of chronic breathlessness syndrome: the need for P5 medicine
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Daisy J A Janssen; Miriam J Johnson

    To the editor, Breathlessness is the most frequently reported symptom by patients with advanced chronic lung disease or chronic heart failure and has widespread consequences.1 Despite optimal treatment for the underlying disease, disabling breathlessness persists for many—recently named chronic breathlessness syndrome.2 Patients, and their families, may live with chronic breathlessness for years, with serious functional and social limitations, care dependency and anxiety.3 Clinical practice guidelines and policy statements now highlight pharmacological and non-pharmacological interventions for the palliative management of breathlessness as a cornerstone of care.4 5 Despite this, many clinicians still feel ill-equipped and under-resourced to manage breathlessness, which remains a neglected symptom.1 6 Although the evidence base for breathlessness interventions is growing, important questions concerning optimal palliative management of breathlessness remain.7 Studies of opioids are mostly small and of cross-over design. The most recent Cochrane review8 found a smaller effect size and lower precision than other authors, although a repeat analysis9 of the same studies accounting for the cross-over design of most showed a larger effect size with improved precision and benefit consistent with a clinically relevant improvement.10 Safety concerns appear unfounded with oral low-dose opioid. Indeed, national cohorts of oxygen-dependent COPD and advanced interstitial lung disease found no association with excess hospital admission or mortality.11 12 Another very large cohort of people with COPD showed a statistically significant, small absolute excess mortality but data regarding reason for prescribing (eg, pain or breathlessness) was not available making clinical interpretation difficult.13 A systematic review …

    更新日期:2019-12-13
  • The association of sleep disturbances measures with blood pressure: is the time to explore novel measurements?
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Bharati Prasad; Manuel Sánchez-de-la-Torre

    Obstructive sleep apnea (OSA) is a chronic disease that affects more than 15% of the adult population and becomes more prevalent with age.1 Although multiple observational studies show that OSA is an independent risk factor for cardiovascular disease (CVD), the treatment of OSA with continuous positive airway pressure (CPAP) does not uniformly prevent CVD. Recent randomised clinical trials failed to demonstrate a role for CPAP treatment in secondary CVD prevention.2 3 Nevertheless, CPAP treatment affects cardiovascular outcomes positively in specific groups of OSA patients. For example, patients with resistant hypertension experience a significant reduction in 24-hour blood pressure with CPAP treatment.4 Notably, a secondary analysis of this study showed that CPAP treatment did not decrease blood pressure in at least 30% of patients with resistant hypertension, demonstrating that a more precise approach to patient selection is needed to improve the effectiveness of OSA treatment(s) in CVD prevention. Previous studies have explored novel approaches to identify OSA patients where CPAP treatment has significant antihypertensive effects. These studies have demonstrated a combination of specific biomarkers together with the clinical characterisation of circadian blood pressure patterns to be informative.5–7 In this context, the identification of new clinical variables that go beyond the apnea-hypopnea index (AHI), which fails to capture the complexity of OSA pathophysiology, may allow precise CVD risk stratification. The results of a cross-sectional analysis of the Multi-Ethnic …

    更新日期:2019-12-13
  • Pneumococcal pneumonia
    Thorax (IF 9.640) Pub Date : 2020-01-01
    David Goldblatt; Elizabeth Miller

    Pneumococcal conjugate vaccines (PCV) were first licensed in 2000 and have been introduced into national immunisation programme in more than 145 countries. They have had a profound effect on reducing invasive pneumococcal disease (IPD) caused by serotypes in the vaccine. These reductions have been seen both in infants immunised directly with PCV and in the general population protected indirectly by reduced transmission of pneumococci from immunised infants in whom the vaccine prevented nasopharyngeal carriage. PCV7 (Prevenar7, Pfizer, New York, NY, USA) was first introduced in the UK in 2006 followed by PCV13 (Prevenar13, Pfizer, New York, NY, USA) in 2010. Both vaccines have had a striking impact on vaccine serotype IPD although a trend, seen first following PCV7, for an increase in IPD caused by serotypes not included in the vaccine(s) has been reported.1 Surveillance of the impact of PCVs is focused on IPD, defined as isolation of pneumococcus from an otherwise sterile site, and has been the bedrock of monitoring the serotype-specific impact of vaccination at a population level for many years. It is however, well understood that from a numerical point of view, IPD is only the tip of the iceberg, with pneumonia and otitis media caused by Streptococcus pneumoniae responsible for a much larger burden of disease. In this edition of the journal, Pick and colleagues2 describe the outcome of their prospective population-based study of adult community acquired pneumonia (CAP) in two teaching hospitals in Nottingham, England. They focus on trends in pneumococcal serotype contribution to the burden of adult CAP over 5 years (2013–2018), a period associated with sustained high coverage of PCV13 in the infant schedule.1 Attributing an episode of pneumonia to the pneumococcus is complicated as blood cultures are only positive in approximately 10% of clinical episodes of pneumonia and the …

    更新日期:2019-12-13
  • Resistome analyses of sputum from COPD and healthy subjects reveals bacterial load-related prevalence of target genes
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Mohammadali Yavari Ramsheh; Koirobi Haldar; Mona Bafadhel; Leena George; Robert C Free; Catherine John; Nicola F Reeve; Loems Ziegler-Heitbrock; Ivo Gut; Dave Singh; Vijay Mistry; Martin D Tobin; Marco R Oggioni; Chris Brightling; Michael R Barer

    Background Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups. Objective To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers. Methods Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study). Results ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; p<0.001). Prevalence of ARG positive signals in individuals was not related to COPD symptoms, lung function or their changes at exacerbation. In the COPD subgroups designated High γProteobacteria and High Firmicutes, ARG prevalence was not different at stable state but significantly declined from stable through exacerbation to recovery in the former (p=0.011) without changes in total bacterial abundance. The ARG patterns were similar in COPD versus health, COPD microbiome-subgroups and between sputum and bronchoscopic samples independent of antibiotic exposure in the last 12 months. Conclusions ARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation.

    更新日期:2019-12-13
  • Return to work after critical illness: a systematic review and meta-analysis
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Biren B Kamdar; Rajat Suri; Mary R Suchyta; Kyle F Digrande; Kyla D Sherwood; Elizabeth Colantuoni; Victor D Dinglas; Dale M Needham; Ramona O Hopkins

    Background Survivors of critical illness often experience poor outcomes after hospitalisation, including delayed return to work, which carries substantial economic consequences. Objective To conduct a systematic review and meta-analysis of return to work after critical illness. Methods We searched PubMed, Embase, PsycINFO, CINAHL and Cochrane Library from 1970 to February 2018. Data were extracted, in duplicate, and random-effects meta-regression used to obtain pooled estimates. Results Fifty-two studies evaluated return to work in 10 015 previously employed survivors of critical illness, over a median (IQR) follow-up of 12 (6.25–38.5) months. By 1–3, 12 and 42–60 months’ follow-up, pooled return to work prevalence (95% CI) was 36% (23% to 49%), 60% (50% to 69%) and 68% (51% to 85%), respectively ( τ 2=0.55, I2=87%, p=0.03). No significant difference was observed based on diagnosis (acute respiratory distress syndrome (ARDS) vs non-ARDS) or region (Europe vs North America vs Australia/New Zealand), but was observed when comparing mode of employment evaluation (in-person vs telephone vs mail). Following return to work, 20%–36% of survivors experienced job loss, 17%–66% occupation change and 5%–84% worsening employment status (eg, fewer work hours). Potential risk factors for delayed return to work include pre-existing comorbidities and post-hospital impairments (eg, mental health). Conclusion Approximately two-thirds, two-fifths and one-third of previously employed intensive care unit survivors are jobless up to 3, 12 and 60 months following hospital discharge. Survivors returning to work often experience job loss, occupation change or worse employment status. Interventions should be designed and evaluated to reduce the burden of this common and important problem for survivors of critical illness. Trial registration number PROSPERO CRD42018093135.

    更新日期:2019-12-13
  • Childhood pneumonia, pleurisy and lung function: a cohort study from the first to sixth decade of life
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Jennifer L Perret; Caroline J Lodge; Adrian J Lowe; David P Johns; Bruce R Thompson; Dinh S Bui; Lyle C Gurrin; Melanie C Matheson; Christine F McDonald; Richard Wood-Baker; Cecilie Svanes; Paul S Thomas; Graham G Giles; Anne B Chang; Michael J Abramson; E Haydn Walters; Shyamali C Dharmage

    Introduction Adult spirometry following community-acquired childhood pneumonia has variably been reported as showing obstructive or non-obstructive deficits. We analysed associations between doctor-diagnosed childhood pneumonia/pleurisy and more comprehensive lung function in a middle-aged general population cohort born in 1961. Methods Data were from the prospective population-based Tasmanian Longitudinal Health Study cohort. Analysed lung function was from ages 7 years (prebronchodilator spirometry only, n=7097), 45 years (postbronchodilator spirometry, carbon monoxide transfer factor and static lung volumes, n=1220) and 53 years (postbronchodilator spirometry and transfer factor, n=2485). Parent-recalled histories of doctor-diagnosed childhood pneumonia and/or pleurisy were recorded at age 7. Multivariable linear and logistic regression were used. Results At age 7, compared with no episodes, childhood pneumonia/pleurisy-ever was associated with reduced FEV1:FVC for only those with current asthma (beta-coefficient or change in z-score=−0.20 SD, 95% CI −0.38 to –0.02, p=0.028, p interaction=0.036). At age 45, for all participants, childhood pneumonia/pleurisy-ever was associated with a restrictive pattern: OR 3.02 (1.5 to 6.0), p=0.002 for spirometric restriction (FVC less than the lower limit of normal plus FEV1:FVC greater than the lower limit of normal); total lung capacity z-score −0.26 SD (95% CI −0.38 to –0.13), p<0.001; functional residual capacity −0.16 SD (−0.34 to –0.08), p=0.001; and residual volume −0.18 SD (−0.31 to –0.05), p=0.008. Reduced lung volumes were accompanied by increased carbon monoxide transfer coefficient at both time points (z-score +0.29 SD (0.11 to 0.49), p=0.001 and +0.17 SD (0.04 to 0.29), p=0.008, respectively). Discussion For this community-based population, doctor-diagnosed childhood pneumonia and/or pleurisy were associated with obstructed lung function at age 7 for children who had current asthma symptoms, but with evidence of ‘smaller lungs’ when in middle age.

    更新日期:2019-12-13
  • Pneumococcal serotype trends, surveillance and risk factors in UK adult pneumonia, 2013–18
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Harry Pick; Priya Daniel; Chamira Rodrigo; Thomas Bewick; Deborah Ashton; Hannah Lawrence; Vadsala Baskaran; Rochelle C Edwards-Pritchard; Carmen Sheppard; Seyi D Eletu; Samuel Rose; David Litt; Norman K Fry; Shamez Ladhani; Meera Chand; Caroline Trotter; Tricia M McKeever; Wei Shen Lim

    Background Changes over the last 5 years (2013–18) in the serotypes implicated in adult pneumococcal pneumonia and the patient groups associated with vaccine-type disease are largely unknown. Methods We conducted a population-based prospective cohort study of adults admitted to two large university hospitals with community-acquired pneumonia (CAP) between September 2013 and August 2018. Pneumococcal serotypes were identified using a novel 24-valent urinary monoclonal antibody assay and from blood cultures. Trends in incidence rates were compared against national invasive pneumococcal disease (IPD) data. Persons at risk of vaccine-type pneumonia (pneumococcal conjugate vaccine (PCV)13 and pneumococcal polysaccharide vaccine (PPV)23) were determined from multivariate analyses. Findings Of 2934 adults hospitalised with CAP, 1075 (36.6%) had pneumococcal pneumonia. The annual incidence of pneumococcal pneumonia increased from 32.2 to 48.2 per 100 000 population (2013–18), predominantly due to increases in PCV13non7-serotype and non-vaccine type (NVT)-serotype pneumonia (annual incidence rate ratio 1.12, 95% CI 1.04 to 1.21 and 1.19, 95% CI 1.10 to 1.28, respectively). Incidence trends were broadly similar to IPD data. PCV13non7 (56.9% serotype 3) and PPV23non13 (44.1% serotype 8) serotypes were identified in 349 (32.5%) and 431 (40.1%) patients with pneumococcal pneumonia, respectively. PCV13-serotype pneumonia (dominated by serotype 3) was more likely in patients in the UK pneumococcal vaccination clinical risk group (adjusted OR (aOR) 1.73, 95% CI 1.31 to 2.28) while PPV23-serotype pneumonia was more likely in patients outside the clinical risk group (aOR 1.54, 95% CI 1.13 to 2.10). Interpretation The incidence of pneumococcal CAP is increasing, predominantly due to NVT serotypes and serotype 3. PPV23-serotype pneumonia is more likely in adults outside currently identified clinical risk groups.

    更新日期:2019-12-13
  • Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial
    Thorax (IF 9.640) Pub Date : 2020-01-01
    David Currow; Sandra Louw; Philip McCloud; Belinda Fazekas; John Plummer; Christine F McDonald; Meera Agar; Katherine Clark; Nikki McCaffery; Magnus Pär Ekström

    Introduction Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness. Methods Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, ‘ as needed ’, immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0–100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst , best and average breathlessness ; unpleasantness of breathlessness now , fatigue; quality of life; function; and harms. Results Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference −0.15 mm (95% CI −4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation. Conclusion No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine. Trial registration number ACTRN12609000806268.

    更新日期:2019-12-13
  • Association of novel measures of sleep disturbances with blood pressure: the Multi-Ethnic Study of Atherosclerosis
    Thorax (IF 9.640) Pub Date : 2020-01-01
    John S. Kim; Ali Azarbarzin; Rui Wang; Ina E. Djonlagic; Naresh M. Punjabi; Phyllis C. Zee; Brian B. Koo; Elsayed Z. Soliman; Magdy Younes; Susan Redline

    Background Mechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden. Methods This cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010–2013. Sleep depth was assessed using the ‘OR product’, a continuous measure of arousability. Airflow limitation was assessed by duty cycle (Ti/Tt) and % of breaths with flow limitation, and hypoxia by ‘hypoxic burden’. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances. Results The sample had a mean age of 68.4 years and apnoea–hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications. Conclusions Higher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.

    更新日期:2019-12-13
  • Delivery of long-term-injectable agents for TB by lay carers: pragmatic randomised trial
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Danielle B Cohen; Kuzani Mbendera; Hendramoorthy Maheswaran; Mavuto Mukaka; Helen Mangochi; Linna Phiri; Jason Madan; Geraint Davies; Elizabeth Corbett; Bertel Squire

    Background People with recurrent or drug-resistant TB require long courses of intramuscular injections. We evaluate a novel system in which patient-nominated lay carers were trained to deliver intramuscular injections to patients in their own homes. Methods A pragmatic, individually randomised non-inferiority trial was conducted at two hospitals in Malawi. Adults starting TB retreatment were recruited. Patients randomised to the intervention received home-based care from patient-nominated lay people trained to deliver intramuscular streptomycin. Patients receiving standard care were admitted to hospital for 2 months of streptomycin. The primary outcome was successful treatment (alive and on treatment) at the end of the intervention. Results Of 456 patients screened, 204 participants were randomised. The trial was terminated early due to futility. At the end of the intervention, 97/101 (96.0%) in the hospital arm were still alive and on treatment compared with 96/103 (93.2%) in the home-based arm (risk difference −0.03 (95% CI −0.09 to 0.03); p value 0.538). There were no differences in the proportion completing 8 months of anti-TB treatment; or the proportion experiencing 2-month sputum culture conversion. The mean cost of hospital-based management was US$1546.3 per person, compared to US$729.2 for home-based management. Home-based care reduced risk of catastrophic household costs by 84%. Conclusions Although this trial failed to meet target recruitment, the available data demonstrate that training patient-nominated lay people has potential to provide a feasible solution to the operational challenges associated with delivering long-term-injectable drugs to people with recurrent or drug-resistant TB in resource-limited settings, and substantially reduce costs. Further data under operational conditions are required. Trial registration number [ISRCTN05815615][1]. [1]: http://ISRCTN05815615

    更新日期:2019-12-13
  • Using digital technology for home monitoring, adherence and self-management in cystic fibrosis: a state-of-the-art review
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Rebecca Jane Calthorpe; Sherie Smith; Katie Gathercole; Alan Robert Smyth

    Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media.

    更新日期:2019-12-13
  • Risk factors for disease progression in idiopathic pulmonary fibrosis
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Ganesh Raghu; Brett Ley; Kevin K Brown; Vincent Cottin; Kevin F Gibson; Robert J Kaner; David J Lederer; Paul W Noble; Jin Woo Song; Athol U Wells; Timothy P Whelan; David A Lynch; Stephen M Humphries; Emmanuel Moreau; Krista Goodman; Scott D Patterson; Victoria Smith; Qi Gong; John S Sundy; Thomas G O'Riordan; Fernando J Martinez

    In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.

    更新日期:2019-12-13
  • Carbon footprint impact of the choice of inhalers for asthma and COPD
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Christer Janson; Richard Henderson; Magnus Löfdahl; Martin Hedberg; Raj Sharma; Alexander J K Wilkinson

    In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

    更新日期:2019-12-13
  • Association between particulate matter air pollution and lung cancer
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Zhenyu Zhang; Dawei Zhu; Bin Cui; Ruoxi Ding; Xuefeng Shi; Ping He

    Long-term exposure to particulate matter 2.5 μm (PM2.5) air pollution is associated with an increased risk of lung cancer. However, the evidence is limited in low-income and middle-income countries. We estimated the association between the incidence of lung cancer and PM2.5 air pollution exposure in the Urban Employee Basic Medical Insurance (UEBMI) beneficiaries in China. A total of 16 483 new lung cancer cases diagnosed from 12 966 137 UEBMI beneficiaries from 36 cities between 2013 and 2016. The relative risk for lung cancer associated with a 10 µg/m3 increase in 3-year PM2.5 exposure was 1.12 (95% CI 1.00 to 1.26). The population attributable risk estimated for a reduction in PM2.5 concentration to 35 µg/m3 corresponded to a decrease of 14% in cases of lung cancer. Reducing PM2.5 air pollution has a significant public health benefit.

    更新日期:2019-12-13
  • Burkholderia cenocepacia ET12 transmission in adults with cystic fibrosis
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Ana C Blanchard; Lin Tang; Manal Tadros; Matthew Muller; Theodore Spilker; Valerie J Waters; John J LiPuma; Elizabeth Tullis

    This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.

    更新日期:2019-12-13
  • Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Marie-Louise Frémond; Marie Legendre; Michael Fayon; Annick Clement; Emilie Filhol-Blin; Nicolas Richard; Laura Berdah; Sylvie Roullaud; Gillian I Rice; Vincent Bondet; Darragh Duffy; Chiara Sileo; Hubert Ducou le Pointe; Hugues Begueret; Aurore Coulomb; Bénédicte Neven; Serge Amselem; Yanick Crow; Nadia Nathan

    COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA . Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for COPA screening. Functional tests can help to personalise patient therapy.

    更新日期:2019-12-13
  • What’s hot that the other lot got
    Thorax (IF 9.640) Pub Date : 2020-01-01
    Daryl Cheng

    Current bronchiectasis guidelines recommend that long-term macrolide antibiotics should be given to patients with frequent exacerbations and those without Pseudomonas aeruginosa infection. This study attempts to address the calls from the European Respiratory Society and the Cochrane Collaboration for further work in identifying the subgroups of patients with bronchiectasis who will benefit most from macrolide treatment (Chalmers et al , Lancet Respir Med 2019;7;845). This systematic review and meta-analysis addresses this using individual patient data from three randomised controlled trials providing data on 173 subjects on macrolide therapy and 168 on placebo. Consistent with the individual trials, the analysis found that macrolide therapy was associated with a significant reduction in the frequency of exacerbations over 6–12 months (adjusted incidence rate ratio 0.49, 95% CI 0.36 to 0.66; p<0.0001). The authors examined prespecified subgroups and found no significant interaction effects of these subgroups except for the cause of bronchiectasis (pinteraction=0.034). Notably, there was similar efficacy of therapy in patients with and without P. aeruginosa in baseline sputum culture (incident rate ratio (IRR) 0.36, 95% CI 0.18 to 0.72, p=0.004, and IRR …

    更新日期:2019-12-13
  • GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation
    Thorax (IF 9.640) Pub Date : 2019-12-10
    Soo Jung Cho, Jong-Seok Moon, Kiichi Nikahira, Ha Seon Yun, Rebecca Harris, Kyung Sook Hong, Huarong Huang, Augustine M K Choi, Heather Stout-Delgado

    Background Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive, fatal lung disease that affects older adults. One of the detrimental natural histories of IPF is acute exacerbation of IPF (AE-IPF), of which bacterial infection is reported to play an important role. However, the mechanism by which bacterial infection modulates the fibrotic response remains unclear. Objectives Altered glucose metabolism has been implicated in the pathogenesis of fibrotic lung diseases. We have previously demonstrated that glucose transporter 1 (GLUT1)-dependent glycolysis regulates fibrogenesis in a murine fibrosis model. To expand on these findings, we hypothesised that GLUT1-dependent glycolysis regulates acute exacerbation of lung fibrogenesis during bacterial infection via AIM2 inflammasome activation. Results In our current study, using a murine model of Streptococcus pneumoniae ( S. pneumoniae ) infection, we investigated the potential role of GLUT1 on mediating fibrotic responses to an acute exacerbation during bleomycin-induced fibrosis. The results of our current study illustrate that GLUT1 deficiency ameliorates S. pneumoniae -mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/ S. pneumoniae , n=3; WT/Bleomycin, n=5 ; WT/Bleomycin+ S. pneumoniae , n=7; LysM-Cre-Glut1fl/f /PBS, n=3; LysM-Cre-Glut1fl/fl / S. pneumoniae , n=3; LysM-Cre-Glut1fl/fl /Bleomycin, n=6; LysM-Cre-Glut1fl/fl /Bleomycin+ S. pneumoniae , n=9, p=0.041). Further, the AIM2 inflammasome, a multiprotein complex essential for sensing cytosolic bacterial DNA as a danger signal, is an important regulator of this GLUT1-mediated fibrosis and genetic deficiency of AIM2 reduced bleomycin-induced fibrosis after S. pneumoniae infection (WT/PBS, n=6; WT/Bleomycin+ S. pneumoniae , n=15; Aim2−/−/PBS, n=6, Aim2−/−/Bleomycin+ S. pneumoniae , n=11, p=0.034). GLUT1 deficiency reduced expression and function of the AIM2 inflammasome, and AIM2-deficient mice showed substantial reduction of lung fibrosis after S. pneumoniae infection. Conclusion Our results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during S. pneumoniae infection via AIM2 inflammasome activation.

    更新日期:2019-12-11
  • MUC1 intracellular bioactivation mediates lung fibrosis
    Thorax (IF 9.640) Pub Date : 2019-12-04
    Javier Milara, Beatriz Ballester, Paula Montero, Juan Escriva, Enrique Artigues, Manuel Alós, Alfonso Pastor-Clerigues, Esteban Morcillo, Julio Cortijo

    Background Serum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown. Objective To characterise MUC1 intracellular bioactivation in IPF. Methods and results The expression and phosphorylation of Thr41 and Tyr46 on the intracellular MUC1-cytoplasmic tail (CT) was increased in patients with IPF (n=22) compared with healthy subjects (n=21) and localised to fibroblasts and hyperplastic alveolar type II cells. Transforming growth factor (TGF)-β1 phosphorylated SMAD3 and thereby increased the phosphorylation of MUC1-CT Thr41 and Tyr46 in lung fibroblasts and alveolar type II cells, activating β-catenin to form a phospho-Smad3/MUC1-CT and MUC1-CT/β-catenin nuclear complex. This nuclear complex promoted alveolar epithelial type II and fibroblast to myofibroblast transitions, as well as cell senescence and fibroblast proliferation. The inhibition of MUC1-CT nuclear translocation using the inhibitor, GO-201 or silencing MUC1 by siRNA, reduced myofibroblast transition, senescence and proliferation in vitro. Bleomycin-induced lung fibrosis was reduced in mice treated with GO-201 and in MUC1-knockout mice. The profibrotic lectin, galectin-3, directly activated MUC1-CT and served as a bridge between the TGF-β receptor and the MUC1-C domain, indicating TGF-β1-dependent and TGF-β1-independent intracellular bioactivation of MUC1. Conclusions MUC1 intracellular bioactivation is enhanced in IPF and promotes fibrotic processes that could represent potential druggable targets for IPF.

    更新日期:2019-12-04
  • Impact of newborn screening on outcomes and social inequalities in cystic fibrosis: a UK CF registry-based study
    Thorax (IF 9.640) Pub Date : 2019-11-26
    Daniela K Schlüter, Kevin W Southern, Carol Dryden, Peter Diggle, David Taylor-Robinson

    Background Newborn bloodspot screening (NBS) for cystic fibrosis (CF) was introduced across the UK in 2007 but the impact on clinical outcomes and health inequalities for children with CF is unclear. Methods We undertook longitudinal analyses of UK CF registry data on over 3000 children with CF born between 2000 and 2015. Clinical outcomes were the trajectories of percent predicted forced expiratory volume in one second (%FEV1) from age 5, weight for age and body mass index (BMI) SD-scores from age one, and time to chronic Pseudomonas aeruginosa (cPA) infection. Using mixed effects and time-to-event models we assessed the association of NBS with outcomes and potential interactions with childhood socioeconomic conditions, while adjusting for confounders. Results NBS was associated with higher average lung function trajectory (+1.56 FEV1 percentage points 95% CI 0.1 to 3.02, n=2216), delayed onset of cPA, and higher average weight trajectory intercept at age one (+0.16 SD; 95% CI 0.07 to 0.26, n=3267) but negative rate of weight change thereafter (−0.02 SD per year; 95% CI −0.03 to −0.00). We found no significant association of NBS with BMI or rate of change of lung function. There was no clear evidence of an impact of NBS on health inequalities early in life. Conclusions Children diagnosed with CF by NBS in the UK have better lung function and increased early weight but NBS does not appear to have narrowed early health inequalities.

    更新日期:2019-11-27
  • Timing of secondhand smoke, pet, dampness or mould exposure and lung function in adolescence
    Thorax (IF 9.640) Pub Date : 2019-11-20
    Edith B Milanzi, Gerard H Koppelman, Henriette A Smit, Alet H Wijga, Judith M Vonk, Bert Brunekreef, Ulrike Gehring

    Background The relevance of timing of exposure in the associations of secondhand tobacco smoke (SHS), pets, and dampness or mould exposure with lung function is unclear. We investigated the relevance of timing of these exposures for lung function in adolescence. Methods We used data from participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort with spirometric measurements at ages 12 and 16 years (n=552). Data on residential exposure to SHS, pets, and dampness or mould were obtained by repeated parental questionnaires. We characterised timing of exposure through longitudinal patterns using latent class growth modelling and assessed associations of these patterns with FEV1 and FVC at ages 12 and 16 and FEV1 and FVC growth between ages 12 and 16 using linear regression models. Results Childhood SHS exposure was associated with reduced FEV1 growth/year (95% CI) (−0.34% (−0.64% to −0.04%)). Late childhood and early life pet exposure was associated with increased FEV1 growth (0.41% (0.14% to 0.67%)) and reduced FVC growth (−0.28% (−0.53% to −0.03%)), respectively, compared with very low exposure. Early life dampness or mould exposure was associated with reduced lung function growth. All time windows of SHS exposure tended to be associated with lower attained lung function and pet exposure tended to be associated with higher FEV1. Conclusion SHS exposure during childhood could lead to reduced lung function growth and lower attained lung function in adolescence. While pet exposure in late childhood may not adversely affect lung function, early childhood pet exposure may slow down FVC growth in adolescence.

    更新日期:2019-11-21
  • Altered relaxation times in MRI indicate bronchopulmonary dysplasia
    Thorax (IF 9.640) Pub Date : 2019-05-02
    Kai Förster, Birgit Ertl-Wagner, Harald Ehrhardt, Hannah Busen, Steffen Sass, Andreas Pomschar, Lutz Naehrlich, Andreas Schulze, Andreas W Flemmer, Christoph Hübener, Oliver Eickelberg, Fabian Theis, Olaf Dietrich, Anne Hilgendorff

    We developed a MRI protocol using transverse (T2) and longitudinal (T1) mapping sequences to characterise lung structural changes in preterm infants with bronchopulmonary dysplasia (BPD). We prospectively enrolled 61 infants to perform 3-Tesla MRI of the lung in quiet sleep. Statistical analysis was performed using logistic Group Lasso regression and logistic regression. Increased lung T2 relaxation time and decreased lung T1 relaxation time indicated BPD yielding an area under the curve (AUC) of 0.80. Results were confirmed in an independent study cohort (AUC 0.75) and mirrored by lung function testing, indicating the high potential for MRI in future BPD diagnostics. Trial registration DRKS00004600.

    更新日期:2019-11-18
  • Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age
    Thorax (IF 9.640) Pub Date : 2019-11-15
    Frances Susanna Grudzinska, Malcolm Brodlie, Barnaby R Scholefield, Thomas Jackson, Aaron Scott, David R Thickett, Elizabeth Sapey

    "Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.

    更新日期:2019-11-17
  • Highlights from this issue
    Thorax (IF 9.640) Pub Date : 2019-12-01
    The Triumvirate

    This month’s airwaves has a festive flavour… “If they would rather die, they had better do it, and decrease the surplus population.” So said Ebenezer Scrooge in Charles Dickens’ “A Christmas Carol”. His views may be a fictional reflection of those of the political economist Thomas Malthus. A different kind of economics is presented in this month’s Thorax . Chen and colleagues ( see page 1113 ) consider the economic burden of severe asthma – particularly multimorbidity. Using data from British Columbia, which cover a 20 year period, they conclude that the incremental cost of severe asthma (compared with no asthma) is $2779 per person-year. The authors attribute more than half incremental cost to co-morbidities – mainly respiratory co-morbidities. The incremental cost of severe asthma was comprised of: hospitalisations for comorbidities; medications for asthma and medication for comorbidities. Scrooge was very aware of incremental costs and paid his clerk, Bob Cratchit only 15 shillings a week. He paid this derisory salary while knowing that Cratchit’s son, Tiny Tim, suffered multimorbidity. “Bah Humbug!” In “A Christmas Carol” Scrooge is visited by the ghosts of Christmas past, present and Christmas yet to come. The ghost of Christmas yet to come shows Scrooge his likely prognosis: …

    更新日期:2019-11-14
  • Is targeted lung cancer screening an opportune time to address cardiovascular risk?
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Marie Fisk, Charlotte E Bolton

    Lung cancer and cardiovascular disease (CVD) are both leading causes of mortality and morbidity in the UK and worldwide.1 2 Every day in the UK, approximately 130 people learn that they have lung cancer, and nearly 100 die because of it.3 For CVD, the numbers are even greater; on average, 460 people die each day due to it.4 These are pause for thought statistics that are a call to action for evidence-based public health initiatives that make a difference. In early 2019, NHS England rolled out its targeted screening programme for lung cancer with low-radiation dose CT. At an estimated cost of £70 million, 10 regional community lung health check projects are planned, starting in areas with greatest lung cancer death rates and targeting high-risk individuals.5 6 Central to this initiative was the Macmillan funded Manchester study, which targeted these hard to reach individuals in the community as opposed to established healthcare settings. Health economics analysis indicated this approach was cost-effective, with high rates of early-stage lung cancer detection, which were amenable to radical treatments.7 8 There is ongoing debate, however, about the relative merits of a national targeted lung cancer screening project, particularly in the setting of an already overstretched NHS.9 To this end, rigorous audit and governance of the programme are crucial.5 Interestingly, alongside lung cancer detection, several lung cancer screening studies have also shown their study cohorts are at high risk of CVD.10–12 In this issue of the journal, …

    更新日期:2019-11-14
  • Should we shift the paradigm of preclinical models for ARDS therapies?
    Thorax (IF 9.640) Pub Date : 2019-12-01
    William Bain, Gustavo Matute-Bello

    The acute respiratory distress syndrome (ARDS) is characterised by diffuse impairment in gas exchange that can result from heterogenous aetiologies. ARDS causes 10% of intensive care unit admissions worldwide with inpatient mortality rates ranging from 35% for mild cases to 46% for severe cases.1 Despite being a common and frequently fatal process, there are no widely accepted pharmacological therapies available to treat ARDS, the management of which primarily rests on appropriate mechanical ventilation and supportive care.2 Unfortunately, numerous promising pharmacological therapies that demonstrated benefit in preclinical models or early clinical investigation have failed to demonstrate reliable improvement in clinical outcomes.3–7 In the context of a persistent clinical problem that has vexed state-of-the art investigative therapies, there have been thoughtful proposals on how to improve the investigation of potential ARDS therapies in experimental animal models of acute lung injury (ALI).8–10 A 2011 American Thoracic Society (ATS) statement defined experimental ALI as an acute process (ie, sequelae develop within 24 hours of exposure) with increased permeability of the alveolar-capillary membrane, frequently with histopathological correlation, leading to impairments in lung physiology.8 Building on these earlier proposals, Oakley and colleagues11 propose in this issue of Thorax two broad, fundamental changes in the philosophical framework for the investigation of novel therapeutics in preclinical ARDS models. The first fundamental change to the 2011 ATS definition proposed by Oakley et al 11 is that experimental animal models used to assess the clinical efficacy of proposed ARDS therapeutics should be clinically relevant. Specifically, the authors highlight three criteria to define an effective model based on the notion that the clinical conditions of animal models should reflect as best as possible the clinical conditions of human patients that would receive the experimental therapy. First, ARDS therapies should be tested in lungs with pre-existing injury …

    更新日期:2019-11-14
  • MUC5B promoter variant: genomic fingerprint for early identification of undiagnosed pulmonary fibrosis
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Ayodeji Adegunsoye

    The rising prevalence of pulmonary fibrosis and its attendant morbidity and mortality burden have spurred a renewed interest in the search for radiographical biomarkers predictive of early and clinically inconspicuous disease.1 The pressing need to identify such biomarkers becomes increasingly important as these abnormalities may herald the onset of pulmonary fibrosis, which could be rapidly progressive, necessitating clinical intervention. Antifibrotic therapies have been recently demonstrated to slow the progression of pulmonary fibrosis across diverse forms of interstitial lung disease (ILD), providing some hope in those individuals shown to be at risk.2 In this regard, high-resolution CT (HRCT) scans of the chest hold a broad appeal as a non-invasive radiological tool that is clinically accessible and rapidly performed with near-instantaneous results. Thus, a great deal of emphasis is currently placed on the recognition of radiological abnormalities that possibly signify pulmonary fibrosis in its early stages.3 These subclinical bilateral interstitial densities, often termed interstitial lung abnormalities (ILAs) or early ILD, are frequently observed on chest HRCTs and are associated with increased risk of hospitalisation and death.3 4 However, substantial inter-reader variability in radiologist interpretations of these fibrotic indices has led to increased reliance on deep learning algorithms and artificial intelligence to identify and accurately quantify the extent of lung parenchymal fibrosis in a more objective manner.5 In tandem with the rapid pace of radiological biomarker advancements is the increasing recognition of the predictive and prognostic value of genomic biomarkers associated with pulmonary fibrosis.6 Of prime importance among the genomic biomarkers that predict risk of pulmonary fibrosis are the polymorphisms in the promoter region of the gene encoding mucin 5B ( MUC5B ) ( rs35705950 ) and gene variants in the …

    更新日期:2019-11-14
  • Economic burden of multimorbidity in patients with severe asthma: a 20-year population-based study
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Wenjia Chen, Abdollah Safari, J Mark FitzGerald, Don D Sin, Hamid Tavakoli, Mohsen Sadatsafavi

    Background The economic impact of multimorbidity in severe or difficult-to-treat asthma has not been comprehensively investigated. Aims To estimate the incremental healthcare costs of coexisting chronic conditions (comorbidities) in patients with severe asthma, compared with non-severe asthma and no asthma. Methods Using health administrative data in British Columbia, Canada (1996–2016), we identified, based on the intensity of drug use and occurrence of exacerbations, individuals who experienced severe asthma in an incident year. We also constructed matched cohorts of individuals without an asthma diagnosis and those who had mild/dormant or moderate asthma (non-severe asthma) throughout their follow-up. Health service use records during follow-up were categorised into 16 major disease categories based on the International Classification of Diseases. Incremental costs (in 2016 Canadian Dollars, CAD$1=US$0.75=₤0.56=€0.68) were estimated as the adjusted difference in healthcare costs between individuals with severe asthma compared with those with non-severe asthma and non-asthma. Results Relative to no asthma, incremental costs of severe asthma were $2779 per person-year (95% CI 2514 to 3045), with 54% ($1508) being attributed to comorbidities. Relative to non-severe asthma, severe asthma was associated with incremental costs of $1922 per person-year (95% CI 1670 to 2174), with 52% ($1003) being attributed to comorbidities. In both cases, the most costly comorbidity was respiratory conditions other than asthma ($468 (17%) and $451 (23%), respectively). Conclusions Comorbidities accounted for more than half of the incremental medical costs in patients with severe asthma. This highlights the importance of considering the burden of multimorbidity in evidence-informed decision making for patients with severe asthma.

    更新日期:2019-11-14
  • Ventilation following established ARDS: a preclinical model framework to improve predictive power
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Charlotte Oakley, Marissa Koh, Rhianna Baldi, Sanooj Soni, Kieran O'Dea, Masao Takata, Michael Wilson

    Background Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of β-agonist treatment, which is effective in simple models but not clinically. Methods Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI). Results Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable. Conclusions We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.

    更新日期:2019-11-14
  • MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Susan K Mathai, Stephen Humphries, Jonathan A Kropski, Timothy S Blackwell, Julia Powers, Avram D Walts, Cheryl Markin, Julia Woodward, Jonathan H Chung, Kevin K Brown, Mark P Steele, James E Loyd, Marvin I Schwarz, Tasha Fingerlin, Ivana V Yang, David A Lynch, David A Schwartz

    Background Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT. Methods First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed. Findings In 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex. Interpretation PrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

    更新日期:2019-11-14
  • Evaluation of cardiovascular risk in a lung cancer screening cohort
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Mamta Ruparel, Samantha L Quaife, Jennifer L Dickson, Carolyn Horst, Stephen Burke, Magali Taylor, Asia Ahmed, Penny Shaw, May-Jan Soo, Arjun Nair, Anand Devaraj, Emma Louise O'Dowd, Angshu Bhowmik, Neal Navani, Karen Sennett, Stephen W Duffy, David R Baldwin, Reecha Sofat, Riyaz S Patel, Aroon Hingorani, Sam M Janes

    Introduction Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT). Methods In this cross-sectional study, current and ex-smokers aged 60–75 were invited to a ‘lung health check’. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented. Results Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%–20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes. Conclusions LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies.

    更新日期:2019-11-14
  • Airway obstruction in young adults born extremely preterm or extremely low birth weight in the postsurfactant era
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Lex William Doyle, Louis Irving, Anjali Haikerwal, Katherine Lee, Sarath Ranganathan, Jeanie Cheong

    Background It is unknown if adults born <28 weeks or <1000 g since surfactant has been available are reaching their full airway growth potential. Objective To compare expiratory airflow at 25 years and from 8 to 25 years of participants born <28 weeks or <1000 g with controls, and within the preterm group to compare those who had bronchopulmonary dysplasia with those who did not. Methods All survivors born <28 weeks or <1000 g in 1991–1992 in Victoria, Australia, were eligible. Controls were born contemporaneously, weighing >2499 g. At 8, 18 and 25 years, expiratory airflows were measured and the results converted to z-scores. Outcomes were compared between groups at age 25 years, and trajectories (change in z-scores per year) from childhood were contrasted between groups. Results Expiratory airflows were measured at 25 years on 164 of 297 (55%) preterm survivors and 130 of 260 (50%) controls. Preterm participants had substantially reduced airflow compared with controls at age 25 years (eg, zFEV1; mean difference −0.97, 95% CI −1.23 to –0.71; p<0.001). Preterm participants had lower airflow trajectories than controls between 8 and 18 years, but not between 18 and 25 years. Within the preterm group, those who had bronchopulmonary dysplasia had worse airflows and trajectories than those who did not. Conclusions Young adults born <28 weeks or <1000 g in the surfactant era, particularly those who had bronchopulmonary dysplasia, have substantially reduced airway function compared with controls. Some are destined to develop COPD in later adult life.

    更新日期:2019-11-14
  • Differences in lung function between children with sickle cell anaemia from West Africa and Europe
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Michele Arigliani, Luigi Castriotta, Ramatu Zubair, Livingstone Gayus Dogara, Chiara Zuiani, Emma Raywood, Katy Vecchiato, Enrico Petoello, Ashel Dache Sunday, Sharon Ndoro, Mario Canciano Canciani, Atul Gupta, Paola Cogo, Baba Inusa

    Introduction Lung function abnormalities are common in sickle cell anaemia (SCA) but data from sub-Saharan Africa are limited. We hypothesised that children with SCA from West Africa had worse lung function than their counterparts from Europe. Methods This prospective cross-sectional study evaluated spirometry and anthropometry in black African individuals with SCA (haemoglobin phenotype SS) aged 6–18 years from Nigeria and the UK, when clinically stable. Age-matched controls were also included in Nigeria to validate the Global Lung Initiative spirometry reference values. Results Nigerian SCA patients (n=154) had significant reductions in both FEV1 and FVC of ~1 z-score compared with local controls (n=364) and ~0.5 z-scores compared with the UK patients (n=101). Wasting (body mass index z-score<−2) had a prevalence of 27% in Nigerian patients and 7% in the UK ones (p<0.001). Among children with SCA, being resident in Nigeria (OR 2.4, 95% CI 1.1 to 4.9), wasting (OR 2.3, 95% CI 1.1 to 5.0) and each additional year of age (OR 1.2, 95% CI 1.1 to 1.4) were independently associated with increased risk of restrictive spirometry (FVC z-score<−1.64+FEV1/FVC≥−1.64). Conclusions This study showed that chronic respiratory impairment is more severe in children with SCA from West Africa than Europe. Our findings suggest the utility of implementing respiratory assessment in African children with SCA to early identify those with chronic lung injury, eligible for closer follow-up and more aggressive therapies.

    更新日期:2019-11-14
  • Biomarkers of iron metabolism facilitate clinical diagnosis in M ycobacterium tuberculosis infection
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Youchao Dai, Wanshui Shan, Qianting Yang, Jiubiao Guo, Rihong Zhai, Xiaoping Tang, Lu Tang, Yaoju Tan, Yi Cai, Xinchun Chen

    Background Perturbed iron homeostasis is a risk factor for tuberculosis (TB) progression and an indicator of TB treatment failure and mortality. Few studies have evaluated iron homeostasis as a TB diagnostic biomarker. Methods We recruited participants with TB, latent TB infection (LTBI), cured TB (RxTB), pneumonia (PN) and healthy controls (HCs). We measured serum levels of three iron biomarkers including serum iron, ferritin and transferrin, then established and validated our prediction model. Results We observed and verified that the three iron biomarker levels correlated with patient status (TB, HC, LTBI, RxTB or PN) and with the degree of lung damage and bacillary load in patients with TB. We then built a TB prediction model, neural network (NNET), incorporating the data of the three iron biomarkers. The model showed good performance for diagnosis of TB, with 83% (95% CI 77 to 87) sensitivity and 86% (95% CI 83 to 89) specificity in the training data set (n=663) and 70% (95% CI 58 to 79) sensitivity and 92% (95% CI 86 to 96) specificity in the test data set (n=220). The area under the curves (AUCs) of the NNET model to discriminate TB from HC, LTBI, RxTB and PN were all >0.83. Independent validation of the NNET model in a separate cohort (n=967) produced an AUC of 0.88 (95% CI 0.85 to 0.91) with 74% (95% CI 71 to 77) sensitivity and 92% (95% CI 87 to 96) specificity. Conclusions The established NNET TB prediction model discriminated TB from HC, LTBI, RxTB and PN in a large cohort of patients. This diagnostic assay may augment current TB diagnostics.

    更新日期:2019-11-14
  • Review of the British Thoracic Society Winter Meeting 2018, 5–7 December 2018, London, UK
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Amanda T Goodwin, Aran Singanayagam, Gisli Jenkins

    Introduction The Winter Meeting of the British Thoracic Society (BTS) is a platform for the latest clinical and scientific research in respiratory medicine. This review summarises some key symposia and presentations from the BTS Winter Meeting 2018. Methods Key symposia and research presentations from the BTS Winter Meeting 2018 were attended and reviewed by the authors. Results The seminal messages from the latest clinical and scientific research covering a range of respiratory diseases, including asthma, interstitial lung disease, infection, cystic fibrosis, pulmonary vascular disease, pleural disease and occupational lung disease were summarised in this review. Discussion The BTS Winter Meeting 2018 brought the very best of respiratory research to an audience of scientists, physicians, nurses and allied health professionals. The Winter Meeting continues to be a highlight of the UK respiratory research calendar, and we look forward to the next meeting in December 2019.

    更新日期:2019-11-14
  • Changes in asthma mortality in England and Wales since 2001
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Dominick E Shaw, Catherine M Gaynor, Andrew W Fogarty

    The number of deaths from asthma in England and Wales has not changed significantly over the last decade. This lack of improvement has received attention from both national asthma guidelines and the media. We examined asthma death data from the Office for National Statistics, stratified by age band. Every 5-year age band below the age of 80 years has seen a large reduction in mortality between 2001 and 2017, whereas numbers of asthma deaths have increased by 81% for people aged 80 years or above. This increase in older people dying from asthma requires explanation.

    更新日期:2019-11-14
  • Attendees of Manchester’s Lung Health Check pilot express a preference for community-based lung cancer screening
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Haval Balata, Janet Tonge, Phil V Barber, Denis Colligan, Peter Elton, Matthew Evison, Marie Kirwan, Juliette Novasio, Anna Sharman, Kathryn Slevin, Sarah Taylor, Sara Waplington, Richard Booton, Phil A Crosbie

    Manchester’s ‘Lung Health Check’ pilot utilised mobile CT scanners in convenient retail locations to deliver lung cancer screening to socioeconomically disadvantaged communities. We assessed whether screening location was an important factor for those attending the service. Location was important for 74.7% (n=701/938) and 23% (n=216/938) reported being less likely to attend an equivalent hospital-based programme. This preference was most common in current smokers (27% current smokers vs 19% former smokers; AdjOR 1.46, 95% CI 1.03 to 2.08, p=0.036) and those in the lowest deprivation quartile (25% lowest quartile vs 17.6% highest quartile; AdjOR 2.0, 95% CI 1.24 to 3.24, p=0.005). Practical issues related to travel were most important in those less willing to attend a hospital-based service, with 83.3% citing at least one travel related barrier to non-attendance. A convenient community-based screening programme may reduce inequalities in screening adherence especially in those at high risk of lung cancer in deprived areas.

    更新日期:2019-11-14
  • Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Alain Combes, Tommaso Tonetti, Vito Fanelli, Tai Pham, Antonio Pesenti, Jordi Mancebo, Daniel Brodie, V Marco Ranieri

    Retrospective analysis of the SUPERNOVA trial exploring the hypothesis that efficacy and safety of extracorporeal carbon dioxide removal (ECCO2R) to facilitate reduction of tidal volume (VT) to 4 mL/kg in patients with acute respiratory distress syndrome (ARDS) may differ between systems with lower (area of membrane length 0.59 m2; blood flow 300–500 mL/min) and higher (membrane area 1.30 m2; blood flow between 800 and 1000 mL/min) CO2 extraction capacity. Ninety-five patients with moderate ARDS were included (33 patients treated with lower and 62 patients treated with higher CO2 extraction devices). We found that (1) VT of 4 mL/kg was reached by 55% and 64% of patients with the lower extraction versus 90% and 92% of patients with higher extraction devices at 8 and 24 hours from baseline, respectively (p<0.001), and (2) percentage of patients experiencing episodes of ECCO2R-related haemolysis and bleeding was higher with lower than with higher extraction devices (21% vs 6%, p=0.045% and 27% vs 6%, p=0.010, respectively). Although V T of 4 mL/kg could have been obtained with all devices, this was achieved frequently and with a lower rate of adverse events by devices with higher CO2 extraction capacity.

    更新日期:2019-11-14
  • Low serum IgA and airway injury in World Trade Center-exposed firefighters: a 17-year longitudinal study
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Barbara Putman, Lies Lahousse, Rachel Zeig-Owens, Ankura Singh, Charles B Hall, Yang Liu, Theresa Schwartz, David Goldfarb, Mayris P Webber, David J Prezant, Michael D Weiden

    Serum IgA ≤70 mg/dL (low IgA) is associated with exacerbations of chronic obstructive pulmonary disease. The association of low IgA with longitudinal lung function is poorly defined. This study included 917 World Trade Center (WTC)-exposed firefighters with longitudinal spirometry measured between September 2001 and September 2018 and IgA measured between October 2001 and March 2002. Low IgA, compared with IgA >70 mg/dL, was associated with lower forced expiratory volume in 1 s (FEV1) % predicted in the year following 11 September 2001 (94.1% vs 98.6%, p<0.001), increased risk of FEV1/FVC <0.70 (HR 3.8, 95% CI 1.6 to 8.8) and increased antibiotic treatment (22.5/100 vs 11.6/100 person-years, p=0.002). Following WTC exposure, early IgA ≤70 mg/dL was associated with worse lung function and increased antibiotic treatment.

    更新日期:2019-11-14
  • What’s hot that the other lot got
    Thorax (IF 9.640) Pub Date : 2019-12-01
    Conor Walsh

    There are an increasing number of maintenance therapies available for COPD. Adherence to Global initiative on chronic Obstructive Lung Disease (GOLD) guidelines by physicians has been shown to be poor but it is not clear if this variance can be explained by the clinical characteristics of the patient. Roche and colleagues (Respiratory Research 2019;20:189) investigated how clinical characteristics may influence physician choice of COPD treatment using an observational cohort design. The French COLIBRI project database was used to identify 1171 COPD patients with complete datasets from a total of 4160 available records. Patient’s maintenance COPD treatment was divided into A: no COPD treatment or short-acting bronchodilator(s) only; B: one long-acting bronchodilator (long-acting β agonist; LABA or long-acting muscarinic antagonist; LAMA); C: LABA+LAMA; D: LABA or LAMA+inhaled corticosteroid (ICS); E: triple therapy (LABA+LAMA+ICS). There were discrepancies in treatment choice with surprisingly few patients prescribed a short-acting bronchodilator (34% of the total cohort: 15.4% of GOLD A, 29.5% of GOLD B, 17.9% of GOLD C, 51.4% of GOLD D), and 15% of patients having no inhaled treatments (short-acting or long-acting). ICSs were given in 24.5% of GOLD …

    更新日期:2019-11-14
  • Correction: Can’t see the wood for the trees: confounders, colliders and causal inference- a statistician’s approach
    Thorax (IF 9.640) Pub Date : 2019-12-01
    BMJ Publishing Group Ltd and British Thoracic Society

    Huang B, Szczesniak R. Can’t see the wood for the trees: …

    更新日期:2019-11-14
  • Healthcare system encounters before COPD diagnosis: a registry-based longitudinal cohort study
    Thorax (IF 9.640) Pub Date : 2019-11-08
    Kate M Johnson, Amir Khakban, Stirling Bryan, Don D Sin, Mohsen Sadatsafavi

    Background There is high interest in strategies for improving early detection of chronic obstructive pulmonary disease (COPD). These strategies often rely on opportunistic encounters between patients with undiagnosed COPD and the healthcare system; however, the frequency of these encounters is currently unknown. Methods We used administrative health data for the province of British Columbia, Canada, from 1996 to 2015. We identified patients with COPD using a validated case definition, and assessed their visits to pharmacists, primary care and specialist physicians in the 5 years prior to the initial diagnosis of COPD. We used generalised linear models to compare the rate of outpatient visits between COPD and non-COPD comparator subjects matched on age, sex and socioeconomic status. Results We assessed 112 635 COPD and non-COPD pairs (mean 68.6 years, 51.0% male). Patients with COPD interacted with pharmacists most frequently in the 5 years before diagnosis (mean 14.09, IQR 4–17 visits/year), followed by primary care (10.29, IQR 4–13 visits/year) and specialist (8.11, IQR 2–11 visits/year) physicians. In the 2 years prior to diagnosis, 72.1% of patients with COPD had a respiratory-related primary care visit that did not result in a COPD diagnosis. Compared with non-COPD subjects, patients with COPD had higher rates of primary care (rate ratio (RR) 1.40, 95% CI 1.39 to 1.41), specialist (RR 1.35, 95% CI 1.34 to 1.37) and pharmacist (RR 1.62, 95% CI 1.60 to 1.63) encounters. Conclusions Patients with COPD used higher rates of outpatient services before diagnosis than non-COPD subjects. Case detection technologies implemented in pharmacy or primary care settings have opportunities to diagnose COPD earlier.

    更新日期:2019-11-08
  • Lung function and asthma control in school-age children managed in UK primary care: a cohort study
    Thorax (IF 9.640) Pub Date : 2019-10-30
    David KH Lo, Caroline S Beardsmore, Damian Roland, Mathew Richardson, Yaling Yang, Lesley Danvers, Andrew Wilson, Erol A Gaillard

    Background Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. Objectives To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). Methods Prospective observational cohort study in children aged 5–16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. Results Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children’s ACT from 21 to 23 (p<0.0001). Conclusions Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks.

    更新日期:2019-11-01
  • Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study
    Thorax (IF 9.640) Pub Date : 2019-10-14
    Yi-Qian Sun, Ben Michael Brumpton, Arnulf Langhammer, Yue Chen, Kirsti Kvaløy, Xiao-Mei Mai

    Background We aimed to investigate the potential causal associations of adiposity with asthma overall, asthma by atopic status or by levels of symptom control in a large adult population and stratified by sex. We also investigated the potential for reverse causation between asthma and risk of adiposity. Methods We performed a bidirectional one-sample Mendelian randomisation (MR) study using the Norwegian Nord-Trøndelag Health Study population including 56 105 adults. 73 and 47 genetic variants were included as instrumental variables for body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Asthma was defined as ever asthma, doctor-diagnosed asthma and doctor-diagnosed active asthma, and was further classified by atopic status or levels of symptom control. Causal OR was calculated with the Wald method. Results The ORs per 1 SD (4.1 kg/m2) increase in genetically determined BMI were ranged from 1.36 to 1.49 for the three asthma definitions and similar for women and men. The corresponding ORs for non-atopic asthma (range 1.42–1.72) appeared stronger than those for the atopic asthma (range 1.18–1.26), but they were similar for controlled versus partly controlled doctor-diagnosed active asthma (1.43 vs 1.44). There was no clear association between genetically predicted WHR and asthma risk or between genetically predicted asthma and the adiposity markers. Conclusions Our MR study provided evidence of a causal association of BMI with asthma in adults, particularly with non-atopic asthma. There was no clear evidence of a causal link between WHR and asthma or of reverse causation.

    更新日期:2019-11-01
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