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Background: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. Methods: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. Findings: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p

Summary Background Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). Methods Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. Findings Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 μg, and a therapeutic dose of 750–1500 μg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 μg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference −850 mL [SD 699], p=0·028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. Interpretation The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion. Funding Lunamed, Chur, Switzerland.

Background: The optimal choice of chest tube size for the treatment of pleural infection is unknown, with only small cohort studies reported describing the efficacy and adverse events of different tube sizes. Methods: A total of 405 patients with pleural infection were prospectively enrolled into a multicenter study investigating the utility of fibrinolytic therapy. The combined frequency of death and surgery, and secondary outcomes (hospital stay, change in chest radiograph, and lung function at 3 months) were compared in patients receiving chest tubes of differing size (χ2, t test, and logistic regression analyses as appropriate). Pain was studied in detail in 128 patients. Results: There was no significant difference in the frequency with which patients either died or required thoracic surgery in patients receiving chest tubes of varying sizes ( 20F, 30/69 [44%]; χ2trend, 1 degrees of freedom [df ] = 1.21, P = .27), nor any difference in any secondary outcome. Pain scores were substantially higher in patients receiving (mainly blunt dissection inserted) larger tubes (20F, 6 [6-8]; χ2, 3 df = 10.80, P =.013, Kruskal-Wallis; χ2trend, 1 df = 6.3, P =.014). Conclusions: Smaller, guide-wire-inserted chest tubes cause substantially less pain than blunt-dissection-inserted larger tubes, without any impairment in clinical outcome in the treatment of pleural infection. These results suggest that smaller size tubes may be the initial treatment of choice for pleural infection, and randomized studies are now required. Trial registration: MIST1 trial ISRCTN number: 39138989. © 2010 American College of Chest Physicians.

Pleural infection is responsible for significant morbidity and mortality worldwide, and its clinical management is challenging. The diagnosis of empyema and tuberculous pleurisy may be difficult, and these conditions may be confused with other causes of exudative pleural effusions. Complicated parapneumonic effusion or empyema may present with 'atypical' clinical features; delays in diagnosis are common and may contribute to the high mortality of these infections. Pleural aspiration is the key diagnostic step; pleural fluid that is purulent or that has a pH < 7.2, or organisms on Gram stain or culture, is an indication for formal intercostal drainage. In order to achieve a definitive diagnosis of tuberculous pleurisy, Mycobacterium tuberculosis must be isolated in the culture of pleural fluid, pleural tissue or sputum; demonstration of granulomas in pleural tissue is also suggestive of tuberculosis. The use of pleural fluid biochemical markers, such as adenosine deaminase, in the diagnosis of tuberculous pleurisy varies among clinicians; the diagnostic value of such markers is affected by the background prevalence of tuberculosis and the likelihood of an alternative diagnosis. Uncertainties also remain regarding the treatment of pleural infection. Treatment of complicated parapneumonic effusion and empyema involves prolonged courses of antibiotics and attention to the patient's nutritional state. The role of intrapleural fibrinolytics and the optimal timing of surgical intervention are unknown. The lack of clear predictors of clinical outcome in empyema contributes to the difficulty in treating this condition. The pharmacological treatment of tuberculous pleurisy is the same as for pulmonary tuberculosis; the precise role of steroids in the treatment of tuberculous pleurisy remains uncertain.

Recurrent, chronic pleural infection creates difficult management issues. Surgical drainage is currently recommended for patients who have failed initial "medical treatment" (ie, tube thoracostomy and antibiotic therapy), but the options for patients not fit for surgery are limited. Prolonged closed tube drainage may be an option in this group, although concerns exist regarding the efficacy and risk of catheter blockage. Long-term indwelling pleural catheters are increasingly used for the treatment of recurrent malignant pleural effusion. Pleural infection is recognized as a complication and is cited as a contraindication to insertion of an indwelling pleural drain within the product literature. We report two patients with empyema in a fixed pleural space in whom the insertion of an ambulatory catheter produced successful drainage. Long-term indwelling pleural catheters may have a role in maintaining the drainage of a chronically infected pleural space that is not readily treated in other ways.

PURPOSE OF REVIEW: Complicated parapneumonic effusion and empyema continue to account for significant morbidity and mortality, and uncertainties remain regarding their optimal management. This review describes recent advances in this field, as well as areas for future research. RECENT FINDINGS: Recent advances have addressed the pathogenesis, bacteriology, and treatment of pleural infection. Key areas for research in the development of empyema include the interplay between inflammatory and coagulation cascades and development of fibrosis within the pleural space. The varied bacteriology of empyema has been more clearly defined, and in particular the differences between community- and hospital-acquired infection highlighted. Studies of treatment have focused particularly on the roles of intrapleural fibrinolytics and surgery. SUMMARY: Increased understanding of the pathogenesis of empyema may ultimately yield novel therapeutic targets. Comprehensive descriptions of the bacteriology of empyema aids antibiotic choice, and the use of intrapleural DNase shows promise in facilitating drainage of infected pleural fluid. Uncertainties remain, such as the role of intrapleural fibrinolytics and the optimal timing of surgical intervention.

In pleural infection, medical treatment failure (chest-tube drainage and antibiotics) requires surgery and increases mortality. It would be helpful to predict which patients will fail this approach. We examined clinical predictors in 85 consecutive patients with pleural infection receiving chest drainage and intrapleural fibrinolytics, and recorded age, length of history, antibiotic delay and choice, time to drainage, blood/pleural fluid (PF) bacteriology, PF pH, lactate dehydrogenase (LDH), glucose and appearance, effusion size, pleural thickness on computed tomographic (CT) scan, and survival from time of drainage. Failures (surgery/death) were compared with successes. There were 13 (15%) medical failures. PF purulence was more frequent in medical failures (10 of 13 versus 29 of 72 successes, p < 0.02 chi-square). Absence of purulence was a useful predictor of success (positive predictive value [PPV] 93%). Purulence was not useful in predicting medical failure (PPV 26%). There was a trend for positive blood culture to predict failure (5 of 13 failures versus 11 of 72 successes, p = 0.05 chi-square), but no significant differences in other endpoints. Twelve (14%) patients died in follow-up, all with comorbidity within 400 d after drainage. Probability of survival at 4 yr was 86%. Of endpoints considered in this study, PF purulence was the only useful predictor of outcome with medical therapy in pleural infection. There is good long-term survival from pleural infection.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. METHODS: 100 men with moderate-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon gamma (IFNgamma) and anti-inflammatory adiponectin. RESULTS: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes -0.24 mg/l (95% CI -0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNgamma did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and -0.07 pg/ml (95% CI -0.72 to +1.94 and -0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI -0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNgamma and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. CONCLUSIONS: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate-severe obstructive sleep apnoea.

Objective: Pleural effusions are a frequent complication of malignancy and cause considerable morbidity from dyspnea. The drainage and control of malignant effusions relieve symptoms and maintain quality of life but these are difficult in patients with multiloculated effusions in whom drainage usually fails. This observational series reports the use of intrapleural streptokinase (IPSK) in the management of malignant multiloculated pleural effusions resistant to standard chest tube drainage. Methods: Ten consecutive patients with malignant multiloculated pleural effusions, aged 39 to 89 years, were given 250,000-IU doses of IPSK twice daily after failure to drain the effusions with a standard chest tube because of multiloculation and multiseptation, as demonstrated by CT or ultrasound scanning. Outcome was assessed by radiographic improvement and symptom control. Results: All 10 patients responded to between 500,000 and 1,500,000 IU of streptokinase. There was an increase in pleural fluid drained (mean volume 6 SD; pre-IPSK, 843 6 690 mL; post-IPSK, 2,368 6 1,051 mL; p < 0.001, paired t test), and radiographic improvement was seen in all 10 patients. All subjects tolerated the instillation of streptokinase well. One subject required opiate analgesia for transient chest pain, and there were no hemorrhagic or allergic complications. One patient died of unrelated septicemia. Conclusions: This series suggests that IPSK may be useful in the drainage of malignant multiloculated pleural effusions in patients who fail to drain adequately with a standard chest tube. Malignant pleural effusions should not be considered a contraindication to IPSK. (CHEST 1999; 115:729 ‐733)

Summary Background Mesothelioma invades the tracts made by chest instrumentation. Prophylactic radiotherapy is effective at preventing malignant seeding at these sites. Methods We assessed the use and effectiveness of radiotherapy at our centre in 39 of the 40 patients identified with mesothelioma between January 2000 and September 2003. Results Thirty-seven (95%) patients received radiotherapy to their chest instrumentation site between 6 and 42 days (median 26 days) following the diagnosis of mesothelioma. The radiotherapy field size varied, from 4 cm square to 14×10.5 cm. The radiotherapy was given as 21 Gy in 3 fractions over 1 week. In 3 patients (8%), there was already tumour invasion of the skin at the time of radiotherapy. In 2 other patients (5%), there was tumour recurrence following radiotherapy; in both this was at the edge of the previous radiotherapy fields. Further treatment was administered to an adjacent field in both. One patient with an indwelling pleural catheter developed tumour growth at the catheter insertion site. This was treated successfully with radiotherapy, with no catheter damage. Conclusions Prompt radiotherapy referral and radiotherapy field selection is important to maximise the effect of radiotherapy given to prevent chest wall tumour growth. There was no tumour growth in areas that were treated with radiotherapy. Further chest interventions outside the radiotherapy field should be followed with further radiotherapy.

Pleural procedures are commonly performed by physicians from a range of specialities. These procedures vary in complexity, from relatively straightforward pleural aspiration to more challenging procedures such as pleuroscopy. After appropriate training, even complex pleural procedures have a low risk of complications. Nevertheless, an appreciation of procedural risks is essential for physician training and forms the crux of a valid patient consent process. This review presents a systematic evaluation of the potential complications of common pleural procedures.

Background: Obstructive sleep apnoea syndrome (OSAS) has been suggested to be an independent risk factor for non-alcoholic fatty liver disease (NAFLD), possibly via intermittent hypoxia that influences blood pressure, lipid levels and insulin resistance, factors themselves known to cause NAFLD. In observational studies, OSAS has been associated with elevated levels of liver enzymes. Continuous positive airway pressure (CPAP) is the treatment for OSAS, but the effects of CPAP on liver enzymes have not been studied in a randomized controlled trial. Objective: To determine if 4 weeks of CPAP influence alanine-aminotransferase (ALT) and aspartate-aminotranferase (AST) levels. Methods: 94 patients with moderate-to-severe OSAS were randomized to therapeutic or sub-therapeutic CPAP treatment. Plasma ALT and AST were measured before and after 4 weeks of CPAP. Results: Results are means ± SD. ALT levels decreased from 39.1 ± 26.3 to 30.3 ± 16.4 IU/l in patients treated with therapeutic CPAP, but also decreased from 36.9 ± 20.7 to 31.5 ± 16.5 IU/l in patients treated with sub-therapeutic CPAP (difference between mean changes –3.4, 95% CI –7.8 to 1.0 IU/l, p = 0.13 between groups). AST levels did not change significantly with therapeutic CPAP (from 29.1 ± 14.7 to 30.2 ± 13.6 IU/l), nor with sub-therapeutic CPAP (from 28.2 ± 16.2 to 29.5 ± 12.6 IU/l; difference between mean changes –0.2, 95% CI –3.0 to 2.6 IU/l, p = 0.87 between groups). Conclusions: Four weeks of active CPAP has no beneficial effect on aminotransferase levels when compared to sub-therapeutic CPAP in patients with OSAS. Therefore, CPAP does not seem to improve biochemical markers of potential NAFLD in OSAS patients.

Conventional approaches to the analysis of sleep and sleep apnea do not describe all of the critical events that result from upper airway narrowing during sleep. The hypersomnolence that drives treatment is mainly due to microarousals, but these are poorly documented with conventional epoch-based sleep staging. The counting of apneas and hypopneas also fails to document other equally important events, such as the arousals due to increased respiratory effort in response to partial upper airway narrowing that may not cause significant hypopnea, hypoxemia, or even snoring. Modifications of conventional polysomnography, such as microarousal detection and analysis of the ribcage/abdominal paradox, may be an improvement. However, no system has been shown to be better than any other at identifying the critical events that produce symptoms of sleep-related breathing disorders, and thus be likely to respond to effective treatment. The time is right to explore innovative ways to characterize sleep-related breathing disorders, such as those derived from the cardiovascular change related to upper airway obstruction and arousal, without the shackles of conventional polysomnography. New monitoring techniques need to identify patients with events that will respond to treatment, not mimic the flawed gold standard of polysomnography.

AIM: To assess the role of contrast-enhanced computed tomography (CT) prospectively in patients with suspected malignant pleural effusions. MATERIALS AND METHODS: Forty consecutive patients referred for the investigation of a suspected malignant pleural effusion had contrast-enhanced thoracic CT, thoracoscopy, thoraco-centesis and pleural biopsy, either percutaneously or at thoracoscopy. Final diagnoses were based on histopathological or cytological analysis ( n =30), autopsy findings ( n =3) or clinical follow-up ( n =7). The pleural surfaces were classified at contrast-enhanced CT as normal or abnormal and, if abnormal, as benign or malignant in appearance using previously established CT criteria for malignant pleural thickening by two observers unaware of the pathological diagnosis. RESULTS: Pleural effusions were malignant in 32 patients and benign in eight patients. Pleural surfaces assessed at CT showed features of malignancy in 27 out of 32 patients with a malignant effusion (sensitivity 84%, specificity 100%). Overall, CT appearances indicated the presence of malignancy in 28 of 32 (87%) patients. All eight patients with benign pleural disease were correctly diagnosed by CT. CONCLUSION: Contrast-enhanced CT is of value in patients with suspected malignant pleural effusions. The previously established criteria for malignant pleural thickening of nodularity, irregularity and pleural thickness >1cm are reliable in the presence of a pleural effusion. Traill, Z. C. et al . (2001). Clinical Radiology , 56 , 193–196.

Thoracoscopy under local anaesthetic and intravenous sedation, also known as local anaesthetic thoracoscopy, medical thoracoscopy or pleuroscopy, is increasingly being performed by chest physicians in the UK. In 1999, 11 centres across the UK offered a local anaesthetic thoracoscopy service, increasing to 17 centres in May 20041 and 37 centres in 2009 (Dr N Downer, personal communication). This document, which will use the term ‘local anaesthetic thoracoscopy’, aims to consider the following issues and to make appropriate recommendations on the basis of evidence where available: Creation of this guideline followed the Appraisal of Guidelines Research and Evaluation/Scottish Intercollegiate Guidelines Network (AGREE/SIGN) methodology of evidence assessment and integration (see introduction to pleural disease guidelines). Is there a need for a physician-based local anaesthetic thoracoscopy service in the UK? The majority of local anaesthetic thoracoscopy is carried out in the context of an undiagnosed exudative pleural effusion, the commonest cause of which is malignancy.2 This section of the document will therefore focus mainly on local anaesthetic thoracoscopy in the context of malignant disease. ### The increasing burden of pleural disease Malignant pleural effusion is a common clinical problem. Although the incidence of lung cancer in the UK is falling, the incidence of other cancers is rising. With increasing life expectancy in an ageing population and at current cancer incidence rates, an additional 100 000 cases of cancer per year are expected by 2025.3 Up to 15% of patients who die with malignancy have a pleural effusion at autopsy.4 Studies suggest that exudative effusions are caused by malignancy …

BackgroundThe therapeutic and economic benefits of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnoea syndrome (OSAS) have been established in middle-aged people. In older people there is a lack of evidence.ObjectiveTo determine the clinical efficacy of CPAP in older people with OSAS and to establish its cost-effectiveness.DesignA randomised, parallel, investigator-blinded multicentre trial with within-trial and model-based cost-effectiveness analysis.MethodsTwo hundred and seventy-eight patients, aged ≥ 65 years with newly diagnosed OSAS [defined as oxygen desaturation index at ≥ 4% desaturation threshold level for > 7.5 events/hour and Epworth Sleepiness Scale (ESS) score of ≥ 9] recruited from 14 hospital-based sleep services across the UK.InterventionsCPAP with best supportive care (BSC) or BSC alone. Autotitrating CPAP was initiated using standard clinical practice. BSC was structured advice on minimising sleepiness.Coprimary outcomesSubjective sleepiness at 3 months, as measured by the ESS (ESS mean score: months 3 and 4) and cost-effectiveness over 12 months, as measured in quality-adjusted life-years (QALYs) calculated using the European Quality of Life-5 Dimensions (EQ-5D) and health-care resource use, information on which was collected monthly from patient diaries.Secondary outcomesSubjective sleepiness at 12 months (ESS mean score: months 10, 11 and 12) and objective sleepiness, disease-specific and generic quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, cardiovascular risk factors and events at 3 and 12 months.ResultsTwo hundred and seventy-eight patients were randomised to CPAP (n = 140) or BSC (n = 138) over 27 months and 231 (83%) patients completed the trial. Baseline ESS score was similar in both groups [mean (standard deviation; SD) CPAP 11.5 (3.3), BSC 11.4 (4.2)]; groups were well balanced for other characteristics. The mean (SD) in ESS score at 3 months was –3.8 (0.4) in the CPAP group and –1.6 (0.3) in the BSC group. The adjusted treatment effect of CPAP compared with BSC was –2.1 points [95% confidence interval (CI) –3.0 to –1.3 points;p p p = 0.02), increased mobility (p = 0.03) and reduced total and low-density lipoprotein cholesterol (p = 0.05,p = 0.04, respectively) at 3 months but not at 12 months. In the BSC group, there was a fall in systolic blood pressure of 3.7 mmHg at 12 months, which was not seen in the CPAP group (p = 0.04). Mood, functionality, nocturia, accidents, cognitive function and cardiovascular events were unchanged. There were no medically significant harms attributable to CPAP.ConclusionIn older people with OSAS, CPAP reduces sleepiness and is marginally more cost-effective than BSC over 12 months. Further work is required in the identification of potential biomarkers of sleepiness and those patients at increased risk of cognitive impairment. Early detection of which could be used to inform the clinician when in the disease cycle treatment is needed to avert central nervous system sequelae and to assist patients decision-making regarding treatment and compliance. Treatment adherence is also a challenge in clinical trials generally, and adherence to CPAP therapy in particular is a recognised concern in both research studies and clinical practice. Suggested research priorities would include a focus on optimisation of CPAP delivery or support and embracing the technological advances currently available. Finally, the improvements in quality of life in trials do not appear to reflect the dramatic changes noted in clinical practice. There should be a greater focus on patient centred outcomes which would better capture the symptomatic improvement with CPAP treatment and translate these improvements into outcomes which could be used in health economic analysis.Trial registrationCurrent Controlled Trials ISRCTN90464927.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 40. See the NIHR Journals Library website for further project information.

Malignant pleural effusion accounts for 22% of all pleural effusions, and affects about 300 000 patients annually (UK and USA). Approximately 50% of patients with breast cancer, 25% of those with lung cancer and >90% with pleural mesothelioma develop a symptomatic malignant pleural effusion. Thoracentesis provides effective short term symptomatic relief but most large malignant pleural effusions recur,1 and pleurodesis is then the standard treatment. A wide range of compounds have been used as pleurodesing agents, but talc is preferred by the majority of respiratory physicians worldwide.2 The Medicines and Healthcare Products Regulatory Authority (MHRA) has recently completed an urgent review of the safety of talc as a pleurodesis agent for malignant effusion, reclassifying it as a medicinal product rather than medical device.3 This review requires that from January 2008, manufacturers must submit regulatory data if they wish their talc preparation to be used for pleurodesis. This is a milestone on the path towards improved care for malignant effusion as it heralds the first time an agent for intrapleural administration will be regulated under the systems used for biologically active drugs. Talc is a magnesium silicate hydroxide (Mg3(Si2O5)2(OH)2) and is mined, milled and sterilised prior to clinical use, although these processes still sometimes leave behind mineral or organic contaminants. The MHRA review was a response to evidence that some of the preparations produced by these processes, and considered safe for pleurodesis in the UK and USA for over 50 …

Summary Background Over 200 000 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.

The pharyngeal airway narrows when pharyngeal muscle tone decreases. During sleep, partial collapse at this level leads to snoring, and complete collapse to obstructive sleep apnoea [25], Such upper airway incompetence is relatively common: 17% of randomly selected normal British men snore [60]; one in 300 have severe obstructive sleep apnoea and cannot maintain a patent airway in any sleeping posture [60]. In hospital inpatient cohorts the prevalence is greater still. In one middle-aged group with ischaemic heart disease, significant obstructive sleep apnoea affected 14% of the sample [30]. Obstructive sleep apnoea has a range of undesirable acute effects which may be avoided by appropriate management. This review considers the causes of upper airway collapse, its consequences and treatment for the patient in hospital. Aetiology of upper airway collapse during sleep The patency of the muscular pharynx depends on the balance of forces acting across the pharyngeal wall. Muscle tone widens the airway, while external pressure from the peripharyngeal tissues, combined with intraluminal negative inspiratory pressures, narrow it. Any factor which adversely affects this balance tends to provoke airway collapse. Increased peripharyngeal soft tissue reduces sleeping airway calibre, probably through a simple mass effect [38]. In adults, neck fat deposition is the commonest factor predisposing to obstructive sleep apnoea; the circumference of the neck is a simple predictor of those at risk [13]. Internal airway narrowing as a result of retrognathia [49], adenotonsillar hypertrophy [61], craniofacial abnormalities [5, 33], nasal obstruction [29] and pharyngeal masses [66] also has a role. In children, large tonsils and adenoids are the usual reason for sleep apnoea, and among children awaiting tonsillectomy more than 50% have some respiratory disturbance during sleep [61]. Finally, a reduction in upper airway muscle tone caused by neuromuscular blocking drugs, sedatives [19,44] and some antihypertensive drugs [41] exacerbates airway incompetence. This reduction in tone also underlies the widely recognized association between alcohol intake, snoring and obstructive sleep apnoea [31, 54, 63]. Similar effects have been shown for

For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven.To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion.A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013.Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]).Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%).Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20).Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy.isrctn.org Identifier: ISRCTN33288337.

Although empyema affects more than 65,000 people each year in the United States and in the United Kingdom, there are limited data on the pathogenesis of pleural infection. We investigated the pathogenesis of empyema using animal and cell culture models of Streptococcus pneumoniae infection. The pathological processes during the development of empyema associated with murine pneumonia due to S. pneumoniae (strain D39) were investigated. Lungs were examined using histology, and pleural fluid and blood bacterial colony-forming units, cytokine levels, and cellular infiltrate were determined over time. Bacterial migration across mesothelial monolayers was investigated using cell culture techniques, flow cytometry, and confocal microscopy. After intranasal inoculation with 10(7) S. pneumoniae D39 strain, mice developed pneumonia associated with rapid bacterial invasion of the pleural space; raised intrapleural IL-8, VEGF, MCP-1, and TNF-α levels; and caused significant intrapleural neutrophilia followed by the development of fibrinous pleural adhesions. Bacterial clearance from the pleural space was poor, and in vitro assays demonstrated that S. pneumoniae crossed mesothelial layers by translocation through cells rather than by a paracellular route. This study describes key events during the development of S. pneumoniae empyema using a novel murine model of pneumonia-associated empyema that closely mimics human disease. The model allows for future assessment of molecular mechanisms involved in the development of empyema and evaluation of potential new therapies. The data suggest that transmigration of bacteria through mesothelial cells could be important in empyema development. Furthermore, upon entry the pleural cavity offers a protected compartment for the bacteria.

Clinical trials are an essential in advancing our knowledge and treatment of patients with respiratory disease. Conducting well-designed clinical studies which accurately and reliably answer important clinical questions is challenging. The expertise required to deliver such studies is increasingly concentrated in clinical trials units. This article will describe some of the challenges associated with clinical studies and the methods and personnel involved in a clinical trials unit.

BACKGROUND Thoracic ultrasound-guided pleural procedures are associated with fewer adverse events than 'blind' procedures for patients with pleural effusion. Ultrasound is increasingly practised by respiratory physicians but there has been no prospective assessment of its safety and diagnostic accuracy when delivered by respiratory physicians. METHODS The activity level, safety and diagnostic accuracy of thoracic ultrasound delivered by respiratory physicians were prospectively assessed. Diagnostic accuracy was assessed using a stepwise pragmatic approach (recording if pleural fluid was obtained or effusion was present on another radiological modality). In the absence of the above, ultrasound clips were reviewed by a blinded radiologist. The number of ultrasounds referred to radiologists and adverse events within 1 week were recorded. The complication rate was compared with the published literature. RESULTS 960 ultrasound scans occurred over a 3 year period. The activity of the service increased over time, as a result of increased use of interventional ultrasound. The referral rate to radiology remained constant over the study period (mean proportion 4.0%). Physician-delivered ultrasound correctly identified the presence/absence of pleural fluid in 951 of 955 evaluable scans (99.6% CI 98.9% to 99.9%). The major complication rate was 3/558=0.5% (95% CI 0.1% to 1.6%), which compared favourably with the identified published literature. CONCLUSION Respiratory physician-delivered thoracic ultrasound appears to be safe and effective in the diagnosis/intervention of pleural effusion, and is associated with a major complication rate comparable with that of published studies. Continued liaison with the radiology service has here been demonstrated as a requirement for a physician-based service.

Pseudochylothorax (cholesterol pleurisy or chyliform effusion) is a cholesterol-rich pleural effusion that is commonly associated with chronic inflammatory disorders such as tuberculosis or rheumatoid arthritis. Until now, there were only 15 published cases of arthritis-associated pseudochylothorax in the English language literature. Previous literature has suggested that pleural fluid cholesterol enrichment occurs in the context of grossly thickened (fibrotic) pleura over a prolonged period, usually > 5 years. We present six well-characterized cases of arthritis-associated pseudochylothorax, each notable due to their minimal pleural thickening. The median duration of symptoms (or arthritis, in the case of asymptomatic effusions) was 15 months. Such findings cast significant doubt on the conventional concepts of the pathogenesis of rheumatoid-associated pseudochylothorax. Clinicians should consider pseudochylothorax even in short-duration nonfibrotic pleural effusions.

Copyright © 2009 by the American Thoracic Society. Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS. Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Oxford Biomedical Research Centre, Wellcome Trust, and AFTBVAC.

OBSTRUCTIVE SLEEP APNEA (OSA) IS CHARACTERIZED BY REPETITIVE APNEAS AND HYPOPNEAS DURING SLEEP ASSOCIATED WITH OXYGEN DESATURATION, leading to sleep disruption and excessive daytime sleepiness. It has been estimated that OSA is present in 9% to 24%1 of adults, being clinically significant in 2% to 4%,1 and becoming more prevalent as the average population body weight rises.2 Excessive daytime sleepiness related to increased sleep fragmentation and impaired sleep quality clearly has an adverse impact on quality of life and health status.3 Nasal continuous positive airways pressure (CPAP) is considered to be the treatment of choice for OSA. Excessive daytime sleepiness remains the main indication for CPAP treatment in OSA,4 although cardiovascular benefits are thought to result as well. Results from previous studies, including a randomized double-blind controlled parallel trial of therapeutic versus subtherapeutic CPAP showed that CPAP has beneficial effects on excessive daytime sleepiness and on self-reported functioning and well-being, affecting quality of life of OSA patients.4–8 The cost-effectiveness of this treatment has also been demonstrated.9 Despite an increasing amount of information on the efficacy of CPAP treatment in OSA patients, data from randomized double-blind controlled trials on treatment outcome measures that included quality of life assessment have been reported in only 2 previous studies.4,7 Particularly, it remains unclear which aspects of symptomatic improvement are the most sensitive to CPAP treatment and carry independent information in predicting response to CPAP. To address this uncertainty we investigated, using data from a randomized double-blind controlled trial, which outcome measures best identify the effect of real CPAP compared to nonspecific placebo effects. The overall aim of this study is to improve the current knowledge about the efficacy of CPAP treatment on symptoms and health status. This issue may be relevant in clinical practice and for future treatment trials.

Pneumothorax is a common clinical entity that may present to a wide variety of medical specialties. Primary pneumothorax (in the presence of no known underlying lung disease) and secondary pneumothorax (in known lung disease) are distinct entities with varied etiology, treatment, and prognosis. Diagnosis is usually based on clinical history and basic radiology, but more advanced radiological techniques may be required in certain circumstances. There is relatively little evidence on which to base management decisions in patients with pneumothoraces, and many important aspects of management (e.g., aspiration vs intercostal drainage, chest drain size, use of suction) are often based on best practice and expert opinion. The etiology of pneumothorax will often inform the clinician whether a more conservative or more invasive approach is required. Radiological intervention techniques are valuable in the treatment of complicated pneumothoraces and in certain clinical situations.

Parapneumonic effusion is a common clinical problem, and those that go on to develop pleural infection have high morbidity and mortality. The process of pleural infection evolution involves changes in pleural physiology that are increasingly being elucidated and understood. The microbiology of pleural infection has changed over recent years, with clear differences emerging between hospital- and community-acquired infections. Using biochemical surrogates of infection, chest drainage can be undertaken rationally for those who do not respond to antibiotics alone. Recent data suggest that fibrinolytics do not influence outcomes in pleural infection. The optimal type and timing of surgery remain controversial.

The accumulation of fluid in the pleural space is a common manifestation of a wide range of disease. This review provides a structured approach to the investigation of the patient with a pleural effusion. This should allow an accurate diagnosis to be made with the minimum number of invasive and time-consuming investigations.

Background Pleurodesis is important in the management of malignant pleural effusions, but no consensus exists on the optimal agent or methods of pleurodesis. How pleurodesis is practiced worldwide has not been studied. Objectives To identify variations in the clinical practice of pleurodesis in major English-speaking countries, and to quantify the experience of pulmonologists on the effectiveness and adverse effects of different pleurodesis agents worldwide. Methods Eight hundred fifty-nine pulmonologists practicing in the United States, United Kingdom, Canada, Australia, and New Zealand participated in a Web-based survey. Results The respondents collectively perform > 8,300 pleurodesis annually. Talc was the preferred agent by most respondents (slurry, 56%; poudrage, 12%), followed by tetracycline derivatives (26%), and bleomycin (7%). Differences were seen in pleurodesis practice patterns among practitioners among and within the surveyed countries. Physicians' overall satisfaction with the available pleurodesis agents was modest (5.0 out of 8), and the reported success rate averaged only 66%. Talc (both poudrage and slurry) was perceived as significantly more effective, but was associated with significantly more pain, nausea, and fever (p Conclusions Significant variations exist in how pleurodesis is performed worldwide. Pleurodesis agents currently available are perceived as suboptimal. Talc poudrage and slurry were perceived to be more effective, but were associated with more complications, including respiratory failure.

Study objectives: Pleural fluid cytology and non–image-guided Abrams or Cope biopsies have sensitivities of approximately 30% for detecting malignant mesothelioma, and thoracoscopic biopsy has a sensitivity of approximately 90%. The difference between these two probably relates to obtaining adequate tissue. The use of immunohistochemical stains allows a firm diagnosis to be made from relatively small samples. This study explores whether percutaneous image-guided cutting needle biopsy (CNB) combined with immunohistochemistry is accurate in diagnosing pleural thickening due to mesothelioma. Design: Retrospective review of image-guided CNB of pleural thickening performed on consecutive patients over 7 years by a single radiologist. Setting: Teaching hospital chest radiology department. Patients: Twenty-one adult patients with a final diagnosis of malignant mesothelioma were identified from 53 consecutive patients who underwent percutaneous image-guided CNB. All 21 patients had pleural thickening identified on contrast-enhanced CT, and all had a final histologic diagnosis of mesothelioma confirmed by postmortem examination or thoracoscopy. Interventions: Fourteen-gauge and 18-gauge cutting needles were used. Biopsy guidance was by ultrasound in 6 patients and by CT in 15 patients. Measurements and results: A correct histologic diagnosis of malignant mesothelioma was made by CNB in 18 patients (86% sensitivity and 100% specificity). Complications included one chest wall hematoma and a small hemoptysis. Four patients with a pleural thickness of < 5 mm underwent biopsy, and all specimens were diagnostic for mesothelioma. Conclusions: Image-guided percutaneous CNB of pleural thickening is a safe procedure, with 86% sensitivity for detecting malignant mesothelioma. Pleural thickening of < 5 mm may be successfully sampled. (CHEST 2001; 120:1798 –1802)

Patients with obstructive sleep apnoea (OSA) are reported to have an increased risk of road traffic accidents. This study examines the nature of the impairment during simulated steering in patients with OSA, compared to normal subjects following either sleep deprivation or alcohol ingestion. Twenty-six patients with OSA and 12 normal subjects, either deprived of one night's sleep or following alcohol ingestion [mean (SD) alcohol blood level 71.6 mg dl(-1) (19.6)], performed a simulated steering task for a total of 90 min. Performance was measured using the tendency to wander (SD), deterioration across the task, number of 'off-road' events and the reaction time to peripheral events. Control data for OSA, sleep deprivation and alcohol were obtained following treatment with nasal continuous positive airway pressure (nCPAP), after a normal night of sleep, and following no alcohol, respectively. Patients with untreated OSA, and sleep-deprived or alcohol-intoxicated normal subjects performed significantly less well, compared to their respective controls (P

A well designed and delivered clinical trial is the main tool to define whether medical interventions ‘work’, and how well. As such, they are potent weapons in the armoury of medical progress—and like all potent weapons need to be used with care. In this month's Thorax, Koegelenberg et al ( see page 857 ) report the findings of a trial comparing the diagnostic accuracy of closed pleural biopsy (Abrams needle) and cutting needle pleural biopsy after thoracic ultrasound, for the diagnosis of pleural tuberculosis (TB).1 This question is clearly important given the global significance of TB, and the key role of pleural biopsy in the diagnosis and microbiological assessment of its pleural presentations. To date, there are no published studies assessing ultrasound-guided pleural biopsy for the diagnosis of TB-related pleural effusions. This study is a continuation of this group's research programme which has a track record of delivering valuable evidence in the diagnosis of pleural TB, not least their previous study showing that thoracoscopy is superior to closed pleural biopsy in this disease.2 Their studies are conducted in an area with a high prevalence of TB, with all the recruited subjects receiving the compared diagnostic tests, allowing the comparison of diagnostic results. In this new study, all patients underwent both Abrams biopsy and cutting needle biopsy, performed in random order. The design is simple, logical and efficient, with the diagnostic accuracy for TB assessed against accepted ‘gold standards’. Given the biology of pleural TB, which manifests as diffuse pleural involvement, it is reasonable to propose that …

Eleven mild atopic asthmatic patients were exposed for 6 h, in randomized order, to air, 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2, followed immediately by bronchial allergen challenge. Subsequently 10 of these patients were exposed for 3 h to air, 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2, followed immediately by bronchial allergen challenge. All exposures were carried out in an environmental chamber, with intermittent moderate exercise, and a minimal interval of 2 wk. Exposure for 6 h to 100 ppb O3, 200 ppb NO2, and 100 ppb O3 + 200 ppb NO2 did not lead to any significant increase in the airway response of these individuals to inhaled allergen, when compared with exposure for 6 h to air. In contrast, exposure for 3 h to 200 ppb O3, 400 ppb NO2, and 200 ppb O3 + 400 ppb NO2 significantly decreased the dose of allergen (in log cumulative breath units [CBU]) required to decrease FEV1 by 20% (allergen PD20FEV1), compared with exposure to air (geometric mean CBU: 3.0 for air versus 2.66 for O3 [p = 0.002]; 2.78 for NO2 [p = 0. 018]; 2.65 for O3 + NO2 [p = 0.002]). These results suggest that the pollutant-induced changes in airway response of mild atopic asthmatics to allergen may be dependent on a threshold concentration rather than the total amount of pollutant inhaled over a period of time.

Although studies have suggested that exposure to cigarette smoke (CS) may be associated with the development of atopy, the mechanisms underlying this are not clearly understood. It has been suggested that CS impairs the barrier function of the airway epithelium, leading to increased access of allergens such as those of the house dust mite (HDM) Dermatophagoides pteronyssinus (Der p) to antigen-presenting cells, with subsequent allergic sensitization. In order to test this hypothesis, we established primary explant cultures of human bronchial epithelial cells (HBEC) in cell culture inserts, and exposed these for 20 min, 1 h, 3 h, and 6 h to CS or air in the absence or presence of 300 ng/ml Der p, and then further incubated the cultures over a period of 24 h. The HBEC cultures were assessed for changes in permeability as measured by changes in: (1) electrical resistance (ER); and (2) passage of 14C-labeled bovine serum albumin (14C-BSA) and Der p allergens across the HBEC cultures. We also assessed the effects of protease inhibitors and the antioxidant glutathione (GSH) in this experimental system. Damage to HBEC cultures was assessed by the release of [51Cr]sodium chromate from prelabeled cells, and by release of lactate dehydrogenase (LDH). Twenty minutes of exposure to CS as compared with exposure to air did not significantly alter either the ER or passage of 14C-BSA across the HBEC cultures. In contrast, incubation with Der p led to a significant increase in the permeability of HBEC cultures, an effect that was enhanced by exposure to CS but was abrogated by the specific protease inhibitors and GSH. Passage of Der p was also increased by exposure to CS. Exposure of HBEC cultures to CS led to a significant release of 51Cr and LDH from these cells as compared with cells exposed to air. This effect was augmented further when HBEC cultures were incubated with Der p. Exposure of HBEC cultures for 1 h, 3 h, and 6 h to CS led to a markedly significant dose- and time-dependent increase in the permeability of these cells. These results suggest that exposure to CS significantly enhances Der p-induced decreases in electrical resistance and the increased passage across HBEC cultures of 14C-BSA and of the Der p allergen itself.

Background: Recent studies have suggested that asthmatic patients may be more susceptible to the adverse effects of air pollutants, including diesel exhaust particles (DEP). The underlying mechanisms, however, are not clear. Methods: We cultured bronchial epithelial cells from bronchial biopsy specimens of well-characterized groups of nonatopic, nonasthmatic individuals and atopic patients with mild asthma and compared the ciliary beat frequency (CBF) and release of IL-8, GM-CSF, regulated on activation, normal T-cell expressed and secreted (RANTES), and soluble intercellular adhesion molecule-1 (sICAM-1) from these cells both before and after exposure for 24 hours to 10 to 100 μg/mL DEP in vitro. Results: The baseline CBF was not found to be significantly different in the bronchial epithelial cell cultures of nonasthmatic and asthmatic individuals. Incubation with DEP significantly attenuated the CBF of both the nonasthmatic and asthmatic bronchial epithelial cell cultures at all concentrations of DEP investigated and were maximal (55.5% and 45.2%, respectively) after incubation with 100 μg/mL DEP. The bronchial epithelial cell cultures of asthmatic patients constitutively released significantly greater amounts of IL-8, GM-CSF, and sICAM-1 than bronchial epithelial cell cultures of nonasthmatic subjects. The cultures of only asthmatic patients additionally released RANTES. Incubation of the asthmatic cultures with 10 μg/mL DEP significantly increased the release of IL-8 (from 102.0 to 167.8 pg/μg cellular protein; P < .01), GM-CSF (from 0.43 to 1.87 pg/μg cellular protein; P < .01), and sICAM-1 (from 14.7 to 38.1 pg/μg cellular protein; P < .02) after 24 hours. Incubation with 50 to 100 μg/mL DEP, however, significantly decreased the release of IL-8 and RANTES from these cultures. In contrast, only the higher concentrations of 50 to 100 μg/mL DEP significantly increased release of IL-8 (from 37.9 to 71.5 pg/μg cellular protein; P < .05) and GM-CSF (from 0.06 to 0.34 pg/μg cellular protein; P < .05) from the bronchial epithelial cells of nonasthmatic individuals. Conclusions: These results suggest that bronchial epithelial cells of asthmatic subjects are different from bronchial epithelial cells of nonasthmatic subjects with regard to the amounts and types of proinflammatory mediators they can release and that the increased sensitivity of bronchial epithelial cells of asthmatic subjects to DEP may possibly result in exacerbation of their disease symptoms. (J Allergy Clin Immunol 1998;102:771-82.)

Sleep fragmentation and respiratory disturbance measures are used in the assessment of obstructive sleep apnea (OSA) but have proved to be disappointingly poor correlates of daytime sleepiness. This study investigates the ability of electroencephalograph (EEG) and non-EEG sleep fragmentation indices to predict both presenting sleepiness and the improvement in sleepiness with subsequent nasal continuous positive airway pressure (nCPAP) therapy (nCPAP responsive sleepiness). Forty-one patients (36 men, 5 women), ranging from nonsnorers to severe OSA (> 4% O2 dip rate, median 11.1, range 0.4 to 76.5), had polysomnography with microarousal scoring, computerized EEG analysis, autonomic arousal detection, and body movement analysis. All patients received a trial of nCPAP regardless of sleep study outcome. Spearman's correlation analysis showed significant and similar associations between all sleep fragmentation indices with both pretreatment and nCPAP responsive sleepiness. There was no deterioration in sleepiness on nCPAP in the nonsnorers. Using stepwise multiple regression analysis, the best predictor of nCPAP responsive subjective and objective sleepiness was body movement index, explaining 38% and 43% of the variance, respectively. Variability in EEG sleep depth, quantified from computerized EEG analysis, was the only other index to contribute to these models. Together these indices explained 44% and 51% of the subjective and objective response to nCPAP, respectively. These results suggest that sleep fragmentation indices are useful for identifying OSA patients with sleepiness likely to respond to nCPAP.

Background: Recent studies have suggested that airway epithelial cells of atopic and nonatopic individuals may differ in their ability to produce proinflammatory cytokines. Methods : We have cultured human nasal epithelial cells (NECs) as confluent explant cultures from nasal biopsy specimens of well-characterized nonatopic normal volunteers without rhinitis ( n =8), atopic volunteers without rhinitis ( n =9), and atopic patient volunteers with rhinitis ( n =10) and measured the amounts of IL-1β, IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and RANTES released spontaneously into the culture medium by these cells in vitro. NECs from patients with allergic rhinitis were cultured from biopsy specimens obtained on two different occasions, during and after the pollen season. Results : In general, NECs from atopic individuals released significantly greater amounts ofIL-1β, IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and RANTES than NECs from nonatopic individuals. IL-8 was released in greatest quantity and IL-1β in lowest quantity, regardless of whether the NECs were derived from atopic or nonatopic volunteers. Of the atopic individuals, NECs of atopic patients with rhinitis naturally exposed to pollen released greater quantities of all these cytokines, compared with NECs of atopic patients with rhinitis and atopic patients without rhinitis who were not exposed to allergen. Conclusions : These results suggest that NECs of atopic individuals, who are geneticallypredisposed to upper airway disease, release increased amounts of proinflammatory cytokines and that natural exposure to allergen enhances the release of these cytokines, exacerbating the symptoms of allergic disease.

Parapneumonic effusion and empyema are still an important medical problem since they remain a significant cause of morbidity and mortality (Davies et al. 1999; Farjah et al. 2007). Risk factors for the development of empyema include alcohol abuse, aspiration and poor dental hygiene, chronic lung disease, diabetes mellitus, gastroesophageal reflux, rheumatoid arthritis, and intravenous drug abuse (Ferguson et al. 1996). About one third of cases occur without any identified risk factors (Ferguson et al. 1996; Davies et al. 2003), suggesting that the host immune defense system or modification in bacterial virulence may also play important roles.

We conducted a series of studies investigating the antiinflammatory effects of nedocromil sodium, with particular reference to its effects on human bronchial epithelial cells and eosinophils in vitro and on eosinophils in vivo. Nedocromil sodium produced a dose-related inhibition of ozone-induced IL-8 release from human bronchial epithelial cells and also attenuated the release of granulocyte macrophage colony-stimulating factor, tumor necrosis factor-alpha, and soluble intercellular adhesion molecule 1. The culture medium from human bronchial epithelial cell cultures, containing the proinflammatory cytokines IL-8, granulocyte macrophage colony-stimulating factor, "regulated on activation, normal T expressed and secreted," IL-1 beta, and tumor necrosis factor-alpha, increased eosinophil chemotaxis and eosinophil adhesion to cultured human endothelial cells. The chemotaxis and increased adhesion were blocked in the presence of nedocromil sodium. The drug also abrogated the epithelial cell dysfunction (assessed as ciliary beat frequency) induced by the presence of activated eosinophils and blocked the release of eosinophil cationic protein from the eosinophils. We also conducted a double-blind placebo-controlled study of the effects of regular albuterol 200 micrograms or nedocromil sodium 4 mg, both given four times daily for 16 weeks, on inflammatory cell numbers in bronchial biopsy and bronchoalveolar lavage samples. Assessed in terms of total and activated eosinophils in biopsy samples, inflammation decreased with nedocromil sodium and was significantly different from a deterioration with albuterol, although neither of these changes was significantly different from that with placebo treatment. Levels of eosinophil cationic protein in bronchoalveolar lavage samples showed a similar trend.

This review focuses on bacterial induction and release of inflammatory cytokines and adhesion molecules by human bronchial epithelial cells, with special reference to Haemophilus influenzae, a pathogen commonly associated with chronic bronchitis. Studies investigating the mechanisms underlying bacterial colonization of the airways and bacterial-induced chronic airway inflammation have suggested that these are likely to involve localization of bacteria to the site(s) of infection in the respiratory tract and induction of a local airway inflammation resulting in the initiation of epithelial damage. We have hypothesized that the gross airway epithelial damage observed in chronic infective lung disease is an indirect consequence of proteolytic enzymes and toxic oxygen radicals generated by large numbers of neutrophils infiltrating the airways. Furthermore, the infiltration and activation of the neutrophils is a consequence of increased release of proinflammatory mediators from the host respiratory epithelium, induced by bacterial products, such as endotoxin. This hypothesis is based on studies which have demonstrated that the concentrations of circulating cytokines, such as interleukin (IL)-8 and tumour necrosis factor-alpha (TNF-alpha), which have profound effects on neutrophil activity, are increased in endotoxaemia and that airway epithelial cells are a rich source of these cytokines. Support for this hypothesis is provided by studies of cultured human bronchial epithelial cells incubated either in the absence or presence of purified endotoxin preparations from nontypable and type b H. influenzae strains which have demonstrated that these endotoxins lead to significantly increased expression and/or release of proinflammatory mediators, including IL-6, IL-8, TNF-alpha and intercellular adhesion molecule-1 (ICAM-1). Treatment of the cells with steroids can downregulate the expression and/or release of these inflammatory mediators. Additionally, these studies have demonstrated that culture medium collected from endotoxin-treated cultures, 24 h after treatment, significantly increases neutrophil chemotaxis and adhesion to human endothelial cells in vitro.

Recent studies have demonstrated that RANTES, a member of the CC chemokine family affecting monocytes, T cells, basophils, and eosinophils, is expressed by several cell types. To investigate whether human bronchial epithelial cells can also express this chemokine, we investigated human bronchial epithelial cells for their ability to synthesize RANTES, both in vitro and in vivo. Additionally, we investigated the effect of treatment for 4 mo with inhaled corticosteroids on the expression of RANTES in these cells in vivo. Human bronchial epithelial cells cultured from surgical tissue expressed the mRNA for RANTES and synthesized RANTES, as demonstrated by polymerase chain reaction and immunocytochemical staining and enzyme-linked immunosorbent assay, respectively. Incubation of the cultures with 50 ng/ml of tumor necrosis factor-alpha (TNF-alpha) significantly increased the release of RANTES into culture medium after 18 to 48 h of incubation, an effect that was abolished by treatment of the cultures with anti-TNF-alpha antibody. RANTES was also expressed in the bronchial epithelium in vivo, as indicated by positive immunocytochemical staining of bronchial biopsy tissues obtained from mild asthmatic patients before and after treatment with 500 micrograms of inhaled beclomethasone dipropionate (BDP) twice daily or matched placebo for 4 mo. Quantitation, by color image analysis, of the percentage of epithelium staining for RANTES showed that treatment with BDP decreased the expression of RANTES in the bronchial epithelium from 17.12% to 4.22% (P < 0.05). The numbers of EG2-staining cells in the epithelium were also reduced, from 790.1/mm2 to 203.3/mm2 (geometric mean; P < 0.01), after BDP treatment. These results suggest that human bronchial epithelial cells are capable of synthesizing RANTES and may therefore play an important role in the development of inflammation in allergic airways disease. Furthermore, corticosteroids may prevent airway inflammation by downregulating the expression of proinflammatory cytokines in the bronchial epithelium.

BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p