A systematic review and meta-analysis of the adequacy of endobronchial ultrasound transbronchial needle aspiration for next-generation sequencing in patients with non-small cell lung cancer.

OBJECTIVES: Next-generation sequencing (NGS) is able to identify targetable mutations to guide therapy and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) offers a potential route to routinely obtain specimens for analysis. However, the suitability of EBUS-TBNA samples for NGS remains uncertain. MATERIALS & METHODS: A search was conducted from inception till 28th August 2020. Pooled proportion of adequate EBUS-TBNA samples for NGS was obtained based on binomial distribution with Freeman-Tukey double-arcsine transformation. meta-analysis of means was conducted to determine mean weight of DNA extracted from EBUS-TBNA samples. meta-regression was performed to explore sources of heterogeneity. The random-effects model was used for all analyses to account for variation between studies. RESULTS: Twenty-one studies comprising 1,175 patients were included. The pooled proportion of adequate EBUS-TBNA samples for NGS (yield) was 86.5% (95%-CI: 80.9% to 91.4%). Pooled mean weight of DNA extracted from EBUS-TBNA samples was 868.7 ng (95%-CI: 446.3 ng to 1291.1 ng). However, considerable heterogeneity (I2 = 84.0%, 97.1%) was found. Meta-regression with a mixed-effects negative exponential model showed an increased proportion of adequate EBUS-TBNA samples for NGS as mean number of passes increases (ß = 0.495, 95%-CI 0.313 to 0.676, P < 0.001). Modelled yield rates were 77.3%, 86.2%, 91.6% and 94.9% at mean passes of 3, 4, 5 & 6 respectively. CONCLUSION: EBUS-TBNA was associated with a high yield for NGS and the success of EBUS-TBNA sampling for NGS was proportional to the number of passes.

Eosinophilic endotype of chronic obstructive pulmonary disease: similarities and differences from asthma.

Approximately 25% to 40% of patients with chronic obstructive pulmonary disease (COPD) have the eosinophilic endotype. It is important to identify this group accurately because they are more symptomatic and are at increased risk for exacerbations and accelerated decline in forced expiratory volume in the 1st second. Importantly, this endotype is a marker of treat ment responsiveness to inhaled corticosteroid (ICS), resulting in decreased mortality risk. In this review, we highlight differences in the biology of eosinophils in COPD compared to asthma and the different definitions of the COPD eosinophilic endotype based on sputum and blood eosinophil count (BEC) with the corresponding limitations. Although BEC is useful as a biomarker for eosinophilic COPD endotype, optimal BEC cut-offs can be combined with clinical characteristics to improve its sensitivity and specificity. A targeted approach comprising airway eosinophilia and appropriate clinical and physiological features may improve identification of subgroups of patients who would benefit from biologic therapy or early use of ICS for disease modification.

Transitioning to Combined EBUS EUS-B FNA for Experienced EBUS Bronchoscopist.

Endobronchial ultrasound (EBUS) combined with trans-esophageal endoscopic ultrasound bronchoscope guided fine need aspirate (EUS-B FNA) of mediastinal lymph nodes is an established procedure for diagnosis. The main barrier to a combined EBUS EUS-B FNA approach is availability of trained and accredited pulmonologist who can perform procedure safely and confidently. To address this gap, we undertook a training program for experienced EBUS bronchoscopists to train, learn, and incorporate combined EBUS EUS-B FNA into their procedural practice. Thirty-two patients were selected based on CT and or PET findings. Four experienced bronchoscopists participated by reading through learning material, observing 5 cases before performing EUS-B FNA under direct supervision. Forty-one lymph nodes and 6 non-nodal lesions were sampled. EUSAT assessment was performed by supervisor. Learning curves were derived from assessment scores. We observed that learning curve tends to plateau when participant can perform 3 or more consecutive cases with EUSAT score above 50. There were no complications. Our experience suggests that there is relative ease in transition to combined EBUS EUS-B TBNA procedures for mediastinal lymphadenopathy and lung cancer diagnosis and staging for experienced bronchoscopist using a program which incorporates direct supervision, EUSAT assessment, and extension of EUS B FNA training into daily real-world practice.

Procalcitonin and antibiotics in moderate-severe acute exacerbation of chronic obstructive pulmonary disease: to use or not to use.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Acute exacerbations of COPD (AECOPD) are major driver for healthcare utilization with each exacerbation begetting the next exacerbation. It is, therefore, important to treat each episode effectively to prevent the next. However, this can be challenging as AECOPD result from complex interactions between host, environment and infective agents. The benefits of starting antibiotics in AECOPD, which are not life-threatening (e.g. not requiring mechanical ventilation) or not complicated by pneumonia remain controversial. RECENT FINDINGS: The use of procalcitonin to guide antibiotic therapy in AECOPD has gained interest in recent years. The main advantage of this approach is a safe reduction in antibiotic use in a large group of patients, which may potentially translate to several other benefits. These include reduced antibiotic-related side-effects, reduced risk of developing antibiotic-resistant organisms and cost savings. This approach is associated with no increase in mortality or morbidity such as treatment failure, re-admission, admission to ICU. SUMMARY: Procalcitonin-guided antibiotic therapy in AECOPD is a promising and safe approach, which may be ready for the prime time.

Role of BMI, airflow obstruction, St George's Respiratory Questionnaire and age index in prognostication of Asian COPD.

BACKGROUND AND OBJECTIVE: COPD is a complex condition with a heavy burden of disease. Many multidimensional tools have been studied for their prognostic utility but none has been universally adopted as each has its own limitations. We hypothesize that a multidimensional tool examining four domains, health-related quality of life, disease severity, systemic effects of disease and patient factors, would better categorize and prognosticate these patients. METHODS: We first evaluated 300 patients and found four factors that predicted mortality: BMI, airflow obstruction, St George's Respiratory Questionnaire and age (BOSA). A 10-point index (BOSA index) was constructed and prospectively validated in a cohort of 772 patients with all-cause mortality as the primary outcome. Patients were categorized into their respective BOSA quartile group based on their BOSA score. Multivariate survival analyses and receiver operator characteristic (ROC) curves were used to assess the BOSA index. RESULTS: Patients in BOSA Group 4 were at higher risk of death compared with their counterparts in Group 1 (hazard ratio (HR): 0.29, 95% CI: 0.16-0.51, P < 0.001) and Group 2 (HR: 0.53, 95% CI: 0.34-0.82, P = 0.005). Race and gender did not affect mortality. The area under the ROC curve for BOSA index was 0.690 ± 0.025 while that for Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 was 0.641 ± 0.025 (P = 0.17). CONCLUSION: The BOSA index predicts mortality well and it has at least similar prognostic utility as GOLD 2011 in Asian patients. The BOSA index is a simple tool that does not require complex equipment or testing. It has the potential to be used widely.

Prognostic utility of the 2011 GOLD classification and other multidimensional tools in Asian COPD patients: a prospective cohort study.

BACKGROUND: How well the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification prognosticates for Asian patients with COPD is unknown. OBJECTIVE: The authors aimed to study the predictive utility of the GOLD 2011 classification for exacerbations and mortality as compared with other multidimensional tools in an Asian population. METHODS: In all, 1,110 COPD patients were prospectively followed between March 2008 and March 2013. They were classified using the 2011 and 2007 GOLD guidelines, modified Medical Research Council score, St. George's Respiratory Questionnaire (SGRQ), and Body mass index, Obstruction, Dyspnea (BOD) index. Outcome measures were exacerbations and mortality. Multivariable survival analyses and receiver operating characteristic (ROC) curves were used to assess the different classification systems. RESULTS: Time-to-event analyses demonstrated earlier exacerbations in 2011's GOLD D when compared with GOLD A (hazard ratio [HR] 0.54, 95% confidence interval [CI]: 0.31-0.95, P=0.032) and GOLD B (HR 0.62, 95% CI: 0.45-0.85, P=0.003) and higher mortality when compared with GOLD A (HR 0.37, 95% CI: 0.16-0.88, P=0.025) and GOLD B (HR 0.46, 95% CI: 0.31-0.70, P<0.001). The areas under the ROC curve for GOLD 2011, GOLD 2007, modified Medical Research Council, St. George's Respiratory Questionnaire, and BOD index were 0.62, 0.59, 0.61, 0.60, and 0.61, respectively, for the prediction of exacerbations and 0.71, 0.70, 0.71, 0.71, and 0.72, respectively, for the prediction of mortality (ROC comparator, P>0.05). CONCLUSION: The 2011 GOLD classification predicts exacerbations and mortality moderately well in Asian COPD patients. Its prognostic utility is similar to that of other multidimensional systems.

Mediastinal Lymphadenopathy: Melioidosis Mimicking Tuberculosis.

Melioidosis has protean manifestations and often mimics other disease processes. We present a case of a gentleman presenting with chronic cough whose initial radiographic findings of a cavitatory lung lesion and mediastinal lymphadenopathy were suggestive of tuberculosis. This case highlights the important role that bronchoscopy and endobronchial ultrasound can play in the diagnosis of melioidosis in patients presenting with mediastinal lymphadenopathy whose initial microbiological findings from sputum are negative for tuberculosis.

Oxidative stress and exhaled breath analysis: a promising tool for detection of lung cancer.

Lung cancer is one of the few neoplasia in which the principal aetiology is known, with cigarette smoke donating a considerable oxidative burden to the lungs. This may be part of the aetiology of lung cancer, but the neoplastic process is also associated with increased oxidative stress. Nonetheless, it is difficult to study the mechanisms behind the induction of lung cancer in smokers, but newer techniques of breath analysis targeting markers of oxidative stress and anti-oxidant capacity show promise in unravelling some of the pathways. This review highlights recent developments in the assessment of oxidative stress by non-invasive methods of breath analysis which are becoming powerful research techniques with possible clinical applications.

Elevated levels of oxidative stress markers in exhaled breath condensate.

INTRODUCTION: Lung cancer is the leading cause of cancer death and oxidative stress secondary to carcinogens such as cigarette smoke has been implicated in its pathogenesis. Therefore, lung cancer patients were hypothesized to have higher levels of oxidative stress markers in their exhaled breath compared with controls. METHODS: Exhaled breath condensate (EBC) was collected from newly diagnosed subjects with non-small cell lung cancer (NSCLC) and control subjects in a cross-sectional observational study. The samples were then analyzed for hydrogen peroxide (H(2)O(2)), pH, 8-isoprostane, and antioxidant capacity. RESULTS: A total of 71 subjects (21 NSCLC patients, 21 nonsmokers, 13 exsmokers, and 16 smokers) were recruited. NSCLC patients had significantly higher EBC H(2)O(2) concentration (NSCLC subjects versus smokers, 10.28 microM, 95% confidence interval [CI]: 4.74-22.30 and 2.29 microM, 95% CI: 1.23-4.25, respectively, p = 0.003) and lower antioxidant capacity (NSCLC versus smokers, 0.051 mM, 95% CI: 0.042-0.063 and 0.110 mM, 95% CI: 0.059-0.206, p = 0.023; NSCLC versus all controls as a group, 0.051 mM, 95% CI: 0.042-0.063 and 0.087 mM, 95% CI: 0.067-0.112, p = 0.001). They also had significantly lower pH (5.9, 3.3-7.3) compared with exsmokers (6.7, 5.8-7, p = 0.009). CONCLUSION: The significant increase of H(2)O(2) and reduction in antioxidant capacity in the EBC of lung cancer patients further support the concept of the disequilibrium between levels of oxidants and antioxidants in lung cancer, which leads to increased oxidative stress. These findings suggest oxidative stress is implicated in the development of lung cancer and may be an early marker of the disease.

Exhaled breath analysis: novel approach for early detection of lung cancer.

Lung cancer is a leading cause of cancer death, with the prognosis adversely affected by late diagnosis. Early diagnosis of lung cancer is desirable, but current evidence does not support the application of screening with techniques such as chest radiography, sputum cytology or computed tomography. Breath analysis, which includes gaseous phase analysis that measures volatile organic compounds using electronic noses, exhaled nitric oxide, and exhaled breath condensate (EBC), has been proposed as a non-invasive and simple technique to investigate neoplastic processes in the airways. EBC can be easily collected by breathing into a cooling system that condenses the water vapour in the breath. EBC has already been demonstrated to be useful in investigating inflammatory and oxidative stress changes in various respiratory conditions as it contains measurable mediators of airway inflammation and oxidative stress markers. Furthermore, EBC has also been shown to be a useful method to monitor severity of diseases such as asthma and to act as a surrogate measure of compliance to medical therapy. Presently, there still remains a relative paucity of lung cancer research involving EBC. However, since EBC is a simple, non-invasive technique that can be easily performed, even in ill patients, it has the potential to be validated for use in screening for the early diagnosis of lung cancer.

Effect of hydrofluoroalkane-ethanol inhalers on estimated alcohol levels in asthmatic subjects.

BACKGROUND AND OBJECTIVE: Inhaled medication administered via a metered dose inhaler (MDI) is often used to treat asthma. Hydrofluoroalkane (HFA) has replaced chlorofluorocarbons (CFC) as the propellant and these new MDI may contain alcohol. This raises concerns that their use may transiently increase breath ethanol concentration (BEC), thereby interfering with random breath testing. It was hypothesized that HFA-ethanol MDI may contribute to raising BEC above the legal limit. METHODS: The effect of a HFA-ethanol MDI on BEC was compared with that of CFC and placebo MDI and the effect of ingesting a standard amount of alcohol was also investigated. Asthmatic (n = 16) and normal control subjects (n = 15) were recruited for the double-blind, placebo-controlled study. Each subject used the three MDI in random sequence. BEC was measured at baseline and at 2, 5 and 15 min after inhalation of each MDI, using the Lion Alcometer SD-400TM. Spirometry was performed at baseline and 20 min after the last inhalation. An identical procedure was followed after alcohol consumption. RESULTS: Use of the HFA-ethanol MDI resulted in a significant increase in BEC from 0.002 to 0.0138 mg/100 mL (28 mg/100 mL of blood, P = 0.001) in asthmatics, and from 0.001 mg/100 mL to 0.016 mg/100 mL (33 mg/100 mL of blood, P = 0.002) in normal subjects. By 5 min, there were no significant differences in BEC of asthmatics (0.0031 mg/100 mL) and normal subjects (0.003 mg/100 mL), when compared with baseline (P > 0.2). CONCLUSIONS: BEC are transiently elevated after inhalation of HFA-ethanol MDI; however, by 5 min, BEC had already returned to baseline levels. Thus the effect of HFA-ethanol MDI on BEC is transient and would be negligible after 5 min.