The association between frailty and survival in patients with pleural disease: a retrospective cohort study.

BACKGROUND: There are currently no data on the relationship between frailty and mortality in pleural disease. Understanding the relationship between frailty and outcomes is increasingly important for clinicians to guide decisions regarding investigation and management. This study aims to explore the relationship between all-cause mortality and frailty status in patients with pleural disease. METHODS: In this retrospective analysis of a prospectively collected observational cohort study, outpatients presenting to the pleural service at a tertiary centre in Bristol, UK with a radiologically confirmed, undiagnosed pleural effusion underwent comprehensive assessment and were assigned a final diagnosis at 12 months. The modified frailty index (mFI) was calculated and participants classified as frail (mFI ≥ 0.4) or not frail (mFI ≤ 0.2). RESULTS: 676 participants were included from 3rd March 2008 to 29th December 2020. The median time to mortality was 490 days (IQR 161-1595). A positive association was found between 12-month mortality and frailty (aHR = 1.72, 95% CI 1.02-2.76, p = 0.025) and age ≥ 80 (aHR = 1.80, 95% CI 1.24-2.62, p = 0.002). Subgroup analyses found a stronger association between 12-month mortality and frailty in benign disease (aHR = 4.36, 95% CI 2.17-8.77, p < 0.0001) than in all pleural disease. Malignancy irrespective of frailty status was associated with an increase in all-cause mortality (aHR = 10.40, 95% CI 6.01-18.01, p < 0.0001). CONCLUSION: This is the first study evaluating the relationship between frailty and outcomes in pleural disease. Our data demonstrates a strong association between frailty and 12-month mortality in this cohort. A malignant diagnosis is an independent predictor of 12-month mortality, irrespective of frailty status. Frailty was also strongly associated with 12-month mortality in patients with a benign underlying cause for their pleural disease. This has clinical relevance for pleural physicians; evaluating patients' frailty status and its impact on mortality can guide clinicians in assessing suitability for invasive investigation and management. TRIAL REGISTRATION: This study is registered with the Health Research Authority (REC reference 08/H0102/11) and the NIHR Portfolio (Study ID 8960).

A role for cardiopulmonary exercise testing in detecting physiological changes underlying health status in Idiopathic pulmonary fibrosis: a feasibility study.

INTRODUCTION: There is limited data available on the use of CPET as a predictive tool for disease outcomes in the setting of IPF. We investigated the feasibility of undertaking CPET and the relationship between CPET and quality of life measurements in a well-defined population of mild and moderate IPF patients. METHODS: A prospective, single-centre observational study. RESULTS: Thirty-two IPF patients (mild n = 23, moderate n = 9) participated in the study, n = 13 mild patients attended for repeat CPET testing at 12 months. At baseline, total K-BILD scores and total IPF-PROM scores significantly correlated with 6MWT distance, but not with baseline FVC % predicted, TLco % predicted, baseline or minimum SpO2. VO2 peak/kg at AT positively correlated with total scores, breathlessness/activity and chest domains of the K-BILD questionnaire (p < 0.05). VO2 peak significantly correlated with total IPF PROM scores and wellbeing domains (p < 0.05), with a trend towards statistical significance for total IPF-PROM and VO2 peak/kg at anaerobic threshold (p = 0.06). There was a statistically significant reduction in FVC% predicted at 12 months follow up, although the mean absolute decline was < 10% (p < 0.05). During this period VO2 peak significantly reduced (21.6 ml/kg/min ± 2.9 vs 19.1 ± 2.8; p = 0.017), with corresponding reductions in total K-BILD and breathlessness/activity domains that exceeded the MCID for responsiveness. Lower baseline VO2 peak/kg at anaerobic threshold correlated with greater declines in total K-BILD scores (r = - 0.62, 0.024) at 12 months. Whilst baseline FVC% predicted or TLco % predicted did not predict change in health status, CONCLUSION: We have shown that it is feasible to undertake CPET in patients with mild to moderate IPF. CPET measures of VO2 peak correlated with both baseline and change in K-BILD measurements at 1 year, despite relatively stable standard lung function (declines of < 10% in FVC), suggesting its potential sensitivity to detect physiological changes underlying health status.

The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

VEGF and sVEGFR-1 in malignant pleural effusions: association with survival and pleurodesis outcomes.

VEGF is a key mediator of tumour growth and metastasis and is considered central to the formation of exudative pleural effusions. This study examined the relationship between levels of VEGF and its soluble receptor, sVEGFR-1 in the pleural fluid and plasma of patients with malignant pleural effusions and their association with pleurodesis outcomes and survival. 103 patients with malignant pleural effusions were recruited at their first presentation. Follow-up was to 6 months or death. Survival and pleurodesis outcomes were robustly ascertained. VEGF and sVEGFR-1 were measured in pleural fluid and plasma by ELISA. VEGF and sVEGFR-1 were present in significantly higher concentrations in pleural fluid than plasma. There was no significant correlation between mediators within or between sample types. There was no association between baseline pleural fluid VEGF or sVEGFR-1 levels and pleurodesis failure. In both sample types, survival was inversely associated with sVEGFR-1 and within the non-small cell lung cancer sub-group (n=26), a highly significant association between increased pleural fluid VEGF and sVEGFR-1 and reduced survival was demonstrated (p=0.02 and 0.004 respectively). In conclusion, we have shown for the first time that sVEGFR-1 can be reproducibly measured in pleural fluid from malignant effusions. High levels at presentation in those with non-small cell carcinoma are strongly associated with poor outcomes.

Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study.

BACKGROUND: The opportunistic fungus Pneumocystis jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy. METHODS: A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P jiroveci. Polymerase chain reaction for detection of P jiroveci specific DNA was also performed. RESULTS: Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P jiroveci DNA. In contrast, P jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher's exact test). CONCLUSIONS: P jiroveci colonisation, as determined by detection of P jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.

Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial.

BACKGROUND: Over 200000 pleural effusions are attributable to cancer in the UK and USA every year. Cytological examination of pleural fluid classifies about 60% of malignant effusions. Pleural biopsy needs to be done in the remaining cases. We aimed to assess whether CT-guided biopsy is an improvement over standard pleural biopsy in this setting. METHODS: 50 consecutive patients with cytologically negative suspected malignant pleural effusions were recruited. All had a contrast-enhanced thoracic CT scan to assess pleural thickening. Patients were randomly allocated, stratified by baseline pleural thickening, to either Abrams' pleural biopsy (standard care; n=25) or CT-guided cutting needle biopsy (n=25). Sensitivity for pleural malignancy from the biopsy specimen was the primary endpoint, with the patient's clinical outcome after 1 year being the diagnostic gold standard. Analysis was per protocol. FINDINGS: Three patients did not undergo biopsy. Abrams' biopsy correctly diagnosed malignancy in eight of 17 patients (sensitivity 47%, specificity 100%, negative predictive value 44%, positive predictive value 100%). CT-guided biopsy correctly diagnosed malignancy in 13 of 15 (sensitivity 87%, specificity 100%, negative predictive value 80%, positive predictive value 100%; difference in sensitivity between Abrams' and CT-guided 40%, 95% CI 10-69, p=0.02). Diagnostic advantage was similar in patients proving to have mesothelioma. INTERPRETATION: Primary use of CT-guided biopsy would avoid doing at least one Abrams' biopsy for every 2.5 CT-guided biopsies undertaken. In cytology-negative suspected malignant pleural effusions, CT-guided pleural biopsy is a better diagnostic test than Abrams' pleural biopsy.