A structural and metabolic framework for classifying pre-clinical tuberculosis infection phenotypes using 18F-FDG PET-CT: a prospective cohort analysis following M. tuberculosis exposure.

Tuberculosis (TB) control efforts are limited by ineffective characterisation of tuberculosis infection (TBI) -a heterogeneous spectrum of pre-clinical infection states, invisible to tools of routine clinical screening, that are associated with variable risk of progression to TB disease. In this prospective study, we use positron emission tomography-CT (PET-CT) as a high-resolution imaging modality to characterise and classify structural and metabolic features observed in 16 asymptomatic household TB contacts with normal chest radiographs. We identify four feature patterns that associate with distinct clinical and microbiological outcomes, supporting potential utility of PET-CT for objective classification of TBI phenotypes.

Guideline concordance for timely chest imaging after new presentations of dyspnoea or haemoptysis in primary care: a retrospective cohort study.

BACKGROUND: Guidelines recommend urgent chest X-ray for newly presenting dyspnoea or haemoptysis but there is little evidence about their implementation. METHODS: We analysed linked primary care and hospital imaging data for patients aged 30+ years newly presenting with dyspnoea or haemoptysis in primary care during April 2012 to March 2017. We examined guideline-concordant management, defined as General Practitioner-ordered chest X-ray/CT carried out within 2 weeks of symptomatic presentation, and variation by sociodemographic characteristic and relevant medical history using logistic regression. Additionally, among patients diagnosed with cancer we described time to diagnosis, diagnostic route and stage at diagnosis by guideline-concordant status. RESULTS: In total, 22 560/162 161 (13.9%) patients with dyspnoea and 4022/8120 (49.5%) patients with haemoptysis received guideline-concordant imaging within the recommended 2-week period. Patients with recent chest imaging pre-presentation were much less likely to receive imaging (adjusted OR 0.16, 95% CI 0.14-0.18 for dyspnoea, and adjusted OR 0.09, 95% CI 0.06-0.11 for haemoptysis). History of chronic obstructive pulmonary disease/asthma was also associated with lower odds of guideline concordance (dyspnoea: OR 0.234, 95% CI 0.225-0.242 and haemoptysis: 0.88, 0.79-0.97). Guideline-concordant imaging was lower among dyspnoea presenters with prior heart failure; current or ex-smokers; and those in more socioeconomically disadvantaged groups.The likelihood of lung cancer diagnosis within 12 months was greater among the guideline-concordant imaging group (dyspnoea: 1.1% vs 0.6%; haemoptysis: 3.5% vs 2.7%). CONCLUSION: The likelihood of receiving urgent imaging concords with the risk of subsequent cancer diagnosis. Nevertheless, large proportions of dyspnoea and haemoptysis presenters do not receive prompt chest imaging despite being eligible, indicating opportunities for earlier lung cancer diagnosis.

Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches.

BACKGROUND: Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen. METHODS: Using four international lung cancer screening studies, we extracted 2060 radiomic features for each of 16 797 nodules (513 malignant) among 6865 participants. After filtering out low-quality radiomic features, 642 radiomic and 9 epidemiological features remained for model development. We used cross-validation and grid search to assess three machine learning (ML) models (eXtreme Gradient Boosted Trees, random forest, least absolute shrinkage and selection operator (LASSO)) for their ability to accurately predict risk of malignancy for pulmonary nodules. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set. RESULTS: The LASSO model yielded the best predictive performance in cross-validation and was fit in the full training set based on optimised hyperparameters. Our radiomics model had a test-set AUC of 0.93 (95% CI 0.90 to 0.96) and outperformed the established Pan-Canadian Early Detection of Lung Cancer model (AUC 0.87, 95% CI 0.85 to 0.89) for nodule assessment. Our model performed well among both solid (AUC 0.93, 95% CI 0.89 to 0.97) and subsolid nodules (AUC 0.91, 95% CI 0.85 to 0.95). CONCLUSIONS: We developed highly accurate ML models based on radiomic and epidemiological features from four international lung cancer screening studies that may be suitable for assessing indeterminate screen-detected pulmonary nodules for risk of malignancy.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Mucus clears from the trachea in a helix: a new twist to understanding airway diseases.

BACKGROUND: Mucociliary clearance (MCC) is critical to lung health and is impaired in many diseases. The path of MCC may have an important impact on clearance but has never been rigorously studied. The objective of this study is to assess the three-dimensional path of human tracheal MCC in disease and health. METHODS: Tracheal MCC was imaged in 12 ex-smokers, 3 non-smokers (1 opportunistically imaged during acute influenza and repeated after recovery) and 5 individuals with primary ciliary dyskinesia (PCD). Radiolabelled macroaggregated albumin droplets were injected into the trachea via the cricothyroid membrane. Droplet movement was tracked via scintigraphy, the path of movement mapped and helical and axial models of tracheal MCC were compared. MEASUREMENTS AND MAIN RESULTS: In 5/5 participants with PCD and 1 healthy participant with acute influenza, radiolabelled albumin coated the trachea and did not move. In all others (15/15), mucus coalesced into globules. Globule movement was negligible in 3 ex-smokers, but in all others (12/15) ascended the trachea in a helical path. Median cephalad tracheal MCC was 2.7 mm/min ex-smokers vs 8.4 mm/min non-smokers (p=0.02) and correlated strongly to helical angle (r=0.92 (p=0.00002); median 18o ex-smokers, 47o non-smokers (p=0.036)), but not to actual speed on helical path (r=0.26 (p=0.46); median 13.6 mm/min ex-smokers vs 13.9 mm/min non-smokers (p=1.0)). CONCLUSION: For the first time, we show that human tracheal MCC is helical, and impairment in ex-smokers is often caused by flattened helical transit, not slower movement. Our methodology provides a simple method to map tracheal MCC and speed in vivo.

Thoracic ultrasound influences physiotherapist's clinical decision-making in respiratory management of critical care patients: a multicentre cohort study.

BACKGROUND: The potential influence of thoracic ultrasound on clinical decision-making by physiotherapists has never been studied. The aim of this study was to assess the impact of thoracic ultrasound on clinical decision-making by physiotherapists for critical care patients. METHODS: This prospective, observational multicentre study was conducted between May 2017 and November 2020 in four intensive care units in France and Australia. All hypoxemic patients consecutively admitted were enrolled. The primary outcome was the net reclassification improvement (NRI), quantifying how well the new model (physiotherapist's clinical decision-making including thoracic ultrasound) reclassifies subjects as compared with an old model (clinical assessment). Secondary outcomes were the factors associated with diagnostic concordance and physiotherapy treatment modification. RESULTS: A total of 151 patients were included in the analysis. The NRI for the modification of physiotherapist's clinical decisions was-40% (95% CI (-56 to -22%), p=0.02). Among the cases in which treatment was changed after ultrasound, 41% of changes were major (n=38). Using a multivariate analysis, the physiotherapist's confidence in their clinical diagnosis was associated with diagnostic concordance (adjusted OR=3.28 95% CI (1.30 to 8.71); p=0.014). Clinical diagnosis involving non-parenchymal conditions and clinical signs reflecting abolished lung ventilation were associated with diagnostic discordance (adjusted OR=0.06 95% CI (0.01 to 0.26), p<0.001; adjusted OR=0.26 95% CI (0.09 to 0.69), p=0.008; respectively). CONCLUSION: Thoracic ultrasound has a high impact on the clinical decision-making process by physiotherapists for critical care patients. TRIAL REGISTRATION NUMBER: NCT02881814; https://clinicaltrials.gov.

Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities.

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=-0.7; 95%CI=-0.2 to -1.2, p=0.019), St George's Respiratory Questionnaire-score (SGRQ Δ=-6; 95% CI=-1 to -11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

Growing small solid nodules in lung cancer screening: safety and efficacy of a 200 mm3 minimum size threshold for multidisciplinary team referral.

The optimal management of small but growing nodules remains unclear. The SUMMIT study nodule management algorithm uses a specific threshold volume of 200 mm3 before referral of growing solid nodules to the multidisciplinary team for further investigation is advised, with growing nodules below this threshold kept under observation within the screening programme. Malignancy risk of growing solid nodules of size >200 mm3 at initial 3-month interval scan was 58.3% at a per-nodule level, compared with 13.3% in growing nodules of size ≤200 mm3 (relative risk 4.4, 95% CI 2.17 to 8.83). The positive predictive value of a combination of nodule growth (defined as percentage volume change of ≥25%), and size >200 mm3 was 65.9% (29/44) at a cancer-per-nodule basis, or 60.5% (23/38) on a cancer-per-participant basis. False negative rate of the protocol was 1.9% (95% CI 0.33% to 9.94%). These findings support the use of a 200 mm3 minimum volume threshold for referral as effective at reducing unnecessary multidisciplinary team referrals for small growing nodules, while maintaining early-stage lung cancer diagnosis.

Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial.

The National Optimal Lung Cancer Pathway recommends rapid progression from abnormal chest X-rays (CXRs) to CT. The impact of the more rapid reporting on the whole pathway is unknown. The aim of this study was to determine the impact of immediate reporting of CXRs requested by primary care by radiographers on the time to diagnosis of lung cancer. METHOD: People referred for CXR from primary care to a single acute district general hospital in London attended sessions that were prerandomised to either immediate radiographer (IR) reporting or standard radiographer (SR) reporting within 24 hours. CXRs were subsequently reported by radiologists blind to the radiographer reports to test the reliability of the radiographer report. Radiographer and local radiologist discordant cases were reviewed by thoracic radiologists, blinded to reporter. RESULTS: 8682 CXRs were performed between 21 June 2017 and 4 August 2018, 4096 (47.2%) for IR and 4586 (52.8%) for SR. Lung cancer was diagnosed in 49, with 27 (55.1%) for IR. The median time from CXR to diagnosis of lung cancer for IR was 32 days (IQR 19, 70) compared with 63 days (IQR 29, 78) for SR (p=0.03).8258 CXRs (95.1%) were reported by both radiographers and local radiologists. In the 1361 (16.5%) with discordance, the reviewing thoracic radiologists were equally likely to agree with local radiologist and radiographer reports. CONCLUSIONS: Immediate reporting of CXRs from primary care reduces time to diagnosis of lung cancer by half, likely due to rapid progress to CT. Radiographer reports are comparable to local radiologist reports for accuracy. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN21818068. Registered on 20 June 2017.

Differentiation of malignant from benign pleural effusions based on artificial intelligence.

INTRODUCTION: This study aimed to construct artificial intelligence models based on thoracic CT images to perform segmentation and classification of benign pleural effusion (BPE) and malignant pleural effusion (MPE). METHODS: A total of 918 patients with pleural effusion were initially included, with 607 randomly selected cases used as the training cohort and the other 311 as the internal testing cohort; another independent external testing cohort with 362 cases was used. We developed a pleural effusion segmentation model (M1) by combining 3D spatially weighted U-Net with 2D classical U-Net. Then, a classification model (M2) was built to identify BPE and MPE using a CT volume and its 3D pleural effusion mask as inputs. RESULTS: The average Dice similarity coefficient, Jaccard coefficient, precision, sensitivity, Hausdorff distance 95% (HD95) and average surface distance indicators in M1 were 87.6±5.0%, 82.2±6.2%, 99.0±1.0%, 83.0±6.6%, 6.9±3.8 and 1.6±1.1, respectively, which were better than those of the 3D U-Net and 3D spatially weighted U-Net. Regarding M2, the area under the receiver operating characteristic curve, sensitivity and specificity obtained with volume concat masks as input were 0.842 (95% CI 0.801 to 0.878), 89.4% (95% CI 84.4% to 93.2%) and 65.1% (95% CI 57.3% to 72.3%) in the external testing cohort. These performance metrics were significantly improved compared with those for the other input patterns. CONCLUSIONS: We applied a deep learning model to the segmentation of pleural effusions, and the model showed encouraging performance in the differential diagnosis of BPE and MPE.

MUC5B, telomere length and longitudinal quantitative interstitial lung changes: the MESA Lung Study.

BACKGROUND: The MUC5B promoter variant (rs35705950) and telomere length are linked to pulmonary fibrosis and CT-based qualitative assessments of interstitial abnormalities, but their associations with longitudinal quantitative changes of the lung interstitium among community-dwelling adults are unknown. METHODS: We used data from participants in the Multi-Ethnic Study of Atherosclerosis with high-attenuation areas (HAAs, Examinations 1-6 (2000-2018)) and MUC5B genotype (n=4552) and telomere length (n=4488) assessments. HAA was defined as the per cent of imaged lung with attenuation of -600 to -250 Hounsfield units. We used linear mixed-effects models to examine associations of MUC5B risk allele (T) and telomere length with longitudinal changes in HAAs. Joint models were used to examine associations of longitudinal changes in HAAs with death and interstitial lung disease (ILD). RESULTS: The MUC5B risk allele (T) was associated with an absolute change in HAAs of 2.60% (95% CI 0.36% to 4.86%) per 10 years overall. This association was stronger among those with a telomere length below an age-adjusted percentile of 5% (p value for interaction=0.008). A 1% increase in HAAs per year was associated with 7% increase in mortality risk (rate ratio (RR)=1.07, 95% CI 1.02 to 1.12) for overall death and 34% increase in ILD (RR=1.34, 95% CI 1.20 to 1.50). Longer baseline telomere length was cross-sectionally associated with less HAAs from baseline scans, but not with longitudinal changes in HAAs. CONCLUSIONS: Longitudinal increases in HAAs were associated with the MUC5B risk allele and a higher risk of death and ILD.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

CT pectoralis muscle area is associated with DXA lean mass and correlates with emphysema progression in a tobacco-exposed cohort.

INTRODUCTION: Muscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression. METHODS: Participants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (ß) with 95% CI. RESULTS: PMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: ß=0.76 (95% CI 0.65 to 0.86), p<0.001; ASMI: ß=0.76 (95% CI 0.66 to 0.86), p<0.001; BMI: ß=0.36 (95% CI 0.25 to 0.47), p<0.001) and longitudinal (ΔFFMI: ß=0.43 (95% CI 0.28 to 0.57), p<0.001; ΔASMI: ß=0.42 (95% CI 0.27 to 0.57), p<0.001; ΔBMI: ß=0.34 (95% CI 0.22 to 0.46), p<0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (ß=0.39 (95% CI 0.23 to 0.56), p<0.001) but not with 6-year change in airflow obstruction. CONCLUSIONS: PMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis.

INTRODUCTION: Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis. METHODS: Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression. RESULTS: Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (-0.036; 95% CI -0.068 to -0.004; p=0.029), associations with fibrotic sequelae did not reach significance (-0.021; 95% CI -0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864). DISCUSSION: Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity. PROSPERO REGISTRATION NUMBER: CRD42020183139.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

Subtyping emphysematous COPD by respiratory volume change distributions on CT.

BACKGROUND: There is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients. OBJECTIVE: To evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts. METHODS: Emphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions. RESULTS: Patients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT. CONCLUSION: Lower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

The relationship between interstitial lung abnormalities, mortality, and multimorbidity: a cohort study.

BACKGROUND: Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases. METHODS: We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression. RESULTS: Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik. CONCLUSIONS: ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation.

BACKGROUND: Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. METHODS: Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. RESULTS: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). CONCLUSIONS: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness.

Benign but fatal: management of endotracheal Rosai-Dorfman disease with acute onset.

Rosai-Dorfman disease (RDD) is a non-malignant condition mainly manifesting as a proliferation of histiocytes in lymph nodes. Endotracheal RDD (ERDD) with an acute onset presentation is extremely rare. There are few case reports of ERDD mainly concerning its pathology, diagnostics and bronchoscopic treatment, without providing sufficient clinical information from a comprehensive perspective. As a novel and challenging technique, tracheal resection and reconstruction (TRR) with spontaneous-ventilation video-assisted thoracoscopic surgery (SV-VATS) has been reported as feasible and safe in highly selected patients, but few centres have shared their experience with this approach. This case-based discussion includes not only practical issues in the management of a life-threatening ERDD patient, but also specialists' views on the management of acute obstructive airway, and the surgeons' reflection on TRR with SV-VATS.

Risk factors for poorer respiratory outcomes in adolescents and young adults born preterm.

RATIONALE: The respiratory outcomes for adult survivors of preterm birth in the postsurfactant era are wide-ranging with prognostic factors, especially those encountered after the neonatal period, poorly understood. OBJECTIVES: To obtain comprehensive 'peak' lung health data from survivors of very preterm birth and identify neonatal and life-course risk factors for poorer respiratory outcomes in adulthood. METHODS: 127 participants born ≤32 weeks gestation (64%, n=81 with bronchopulmonary dysplasia (BPD), initially recruited according to a 2 with-BPD:1 without-BPD strategy), and 41 term-born controls completed a lung health assessment at 16-23 years, including lung function, imaging and symptom review. Risk factors assessed against poor lung health included neonatal treatments, respiratory hospitalisation in childhood, atopy and tobacco smoke exposure. MEASUREMENTS AND MAIN RESULTS: Young adults born prematurely had greater airflow obstruction, gas trapping and ventilation inhomogeneity, in addition to abnormalities in gas transfer and respiratory mechanics, compared with term. Beyond lung function, we observed greater structural abnormalities, respiratory symptoms and inhaled medication use. A previous respiratory admission was associated with airway obstruction; mean forced expiratory volume in 1 s/forced vital capacity z-score was -0.561 lower after neonatal confounders were accounted for (95% CI -0.998 to -0.125; p=0.012). Similarly, respiratory symptom burden was increased in the preterm group with a respiratory admission, as was peribronchial thickening (6% vs 23%, p=0.010) and bronchodilator responsiveness (17% vs 35%, p=0.025). Atopy, maternal asthma and tobacco smoke exposure did not influence lung function or structure at 16-23 years in our preterm cohort. CONCLUSIONS: Even after accounting for the neonatal course, a respiratory admission during childhood remained significantly associated with reduced peak lung function in the preterm-born cohort, with the largest difference seen in those with BPD. A respiratory admission during childhood should, therefore, be considered a risk factor for long-term respiratory morbidity in those born preterm, especially for individuals with BPD.