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Objectives Lymph node involvement in non-small-cell lung cancer (NSCLC) is a major factor in determining management and prognosis. We aimed to evaluate the accuracy of fluorine-18-fluorodeoxyglucose-PET/computed tomography (CT) for the assessment of nodal involvement in patients with NSCLC. Patients and methods In this retrospective study, we included 61 patients with suspected or confirmed resectable NSCLC over a 2-year period from April 2013 to April 2015. 221 nodes with pathological staging from surgery or endobronchial ultrasound-guided transbronchial needle aspiration were assessed using a nodal station-based analysis with original clinical reports and three different cut-offs: mediastinal blood pool (MBP), liver background and tumour standardized uptake value maximal (SUVmax)/2. Results Using nodal station-based analysis for activity more than tumour SUVmax/2, the sensitivity was 45%, the specificity was 89% and the negative predictive value (NPV) was 87%. For activity more than MBP, the sensitivity was 93%, the specificity was 72% and NPV was 98%. For activity more than liver background, the sensitivity was 83%, the specificity was 84% and NPV was 96%. Using a nodal staging-based analysis for accuracy at detecting N2/3 disease, for activity more than tumour SUVmax/2, the sensitivity was 59%, the specificity was 85% and NPV was 80%. For activity more than MBP, the sensitivity was 95%, the specificity was 61% and NPV was 96%. For activity more than liver background, the sensitivity was 86%, the specificity was 81% and NPV was 92%. Receiver-operating characteristic analysis showed the optimal nodal SUVmax to be more than 6.4 with a sensitivity of 45% and a specificity of 95%, with an area under the curve of 0.85. Conclusion Activity more than MBP was the most sensitive cut-off with the highest sensitivity and NPV. Activity more than primary tumour SUVmax/2 was the most specific cut-off. Nodal SUVmax more than 6.4 has a high specificity of 95%.

Human rhinovirus (HRV) infection is an important trigger of exacerbations of chronic obstructive pulmonary disease (COPD) but its role in determining exacerbation frequency phenotype or the time-course of HRV infection in naturally occurring exacerbations is unknown. Sputum samples from 77 patients were analysed by real-time quantitative PCR for both HRV (388 samples), and Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (89 samples). Patients recorded worsening of respiratory symptoms on daily diary cards, from which exacerbations were identified. HRV prevalence and load at exacerbation presentation were significantly higher than in the stable state (prevalence 53.3% versus 17.2%, respectively; p

Uncertainty exists over the ability of the exacerbations of chronic pulmonary disease tool (EXACT) patient-reported outcome diary to quantify exacerbation severity and frequency. To clarify this, we investigated the ability of the EXACT to assess severity of exacerbations and examined the relationship between exacerbations diagnosed using London chronic obstructive pulmonary disease (COPD) cohort diary cards, physician review and symptom-defined events using the EXACT. 58 patients enrolled in the London Chronic Obstructive Pulmonary Disease (COPD) cohort prospectively completed the EXACT during 128 cohort diary card-defined exacerbations between January 2010 and April 2012. Mean ± sd EXACT scores increased from 42.6 ± 8.6 at baseline to 48.0 ± 8.6 at exacerbation onset (p

Little is known about changes in physical activity during moderate (out-patient managed) exacerbations.6-min walking distance (6MWD) was measured during 50 exacerbations when the patients were stable, and at 3 and 7 days post-exacerbation presentation. At similar time points, quadriceps maximum voluntary contraction (QMVC) was measured during 47 different exacerbations. Physical activity (SenseWear; Bodymedia Inc., Pittsburgh, PA, USA) was recorded over 2 consecutive-week periods post-presentation.6MWD fell from a median 422 m when stable to 373 m on day 3 (p=0.001). Similarly, QMVC fell from 32.6 versus 29.7 kg (p=0.026). Falls in 6MWD were associated with a rise in C-reactive protein (r= −0.364; p=0.041) and increased Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) (r= −0.44; p=0.013). Light physical activity was 2.18 h·day−1 during the first week post-exacerbation and was less over week 2 (1.98 h·day−1; p=0.009). Patients who had attended pulmonary rehabilitation had smaller changes in 6MWD than those who had not attended (−35.0 versus −114.9 m; p=0.013). Falls in physical activity were correlated with higher depression scores (rho= −0.51; p=0.006).These findings indicate that exercise capacity and muscle strength fall at exacerbation in chronic obstructive pulmonary disease patients who are treated at home and are free to maintain normal activity.

Extrapulmonary comorbidities are common and significant in chronic obstructive pulmonary disease (COPD), often contributing to symptoms, exacerbations, hospital admissions and mortality. Cardiovascular, musculoskeletal and psychological conditions are among the most prevalent and important of these. In particular, ischemic heart disease is a leading cause of death in the COPD population as a whole. Here, we provide a state-of-the-art summary of key comorbidities observed in COPD patients in terms of their prevalence, impact, pathophysiology and prognosis. In addition, we review clinical, diagnostic and management strategies that may differ in COPD patients from the rest of the population.

Background: Gastro-oesophageal reflux disease (GORD) may increase the risk of exacerbations of COPD (ECOPD), but little is known about use of proton-pump inhibitors (PPI) and histamine receptor antagonists (H2RA) and ECOPD. Aim: To evaluate the relationship between self-reported history of GORD, use of PPI/H2RA and future ECOPD in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort (SCO104960, NCT00292552). Methods: Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GORD stratified by use of PPI/H2RA, and time to first moderate-severe exacerbation and hospitalized exacerbation. Results: Out of 2,135 COPD patients, GORD was reported in 547 (26%) of patients; 237 (43%) were also taking PPI/H2RA; 126 (6%) reported PPI/H2RA use in the absence of GORD. During the three year follow-up, 1,579 (74%) patients reported at least one moderate-severe exacerbation; 668 (42%) required hospitalization. When compared to patients who did not report GORD or use of PPI/H2RA, the population with GORD and also using PPI/H2RA had a significantly increased risk of exacerbation (HR=1.58, 95% CI=1.35-1.86); the risk was also increased for patients who reported GORD only or use of PPI/H2RA only (HR=1.21 [1.04-1.40] and 1.33 [1.08-1.65], respectively). Similar findings were observed for time to first hospitalized exacerbation. Conclusion: GORD in COPD is highly prevalent. Use of PPI/H2RA and self-reported history of GORD were associated with an increased risk of moderate-to-severe and hospitalized exacerbations. Funded by GSK.

Rationale Information concerning how climate and atmospheric pollutants affects physical activity in COPD patients is lacking and might be valuable in determining when physical activity should be encouraged. Methods Seventy-three stable COPD patients recorded on daily diary cards worsening of respiratory symptoms, peak expiratory flow rate, hours spent outside the home and the number of steps taken per day. Pedometry data was recorded on 16,478 days, an average of 267 days per patient (range 29-658). Daily data for atmospheric PM10 and ozone (O3) were obtained for Bloomsbury Square, Central London from the Air Quality Information Archive databases. Daily weather data were obtained for London Heathrow from the British Atmospheric Data Archive. Results Colder weather below 22.5 °C, reduced daily step count by 43.3 steps day per°C (95 % CI 2.14 to 84.4; p = 0.039) and activity was lower on rainy than dry days (p = 0.002) and on overcast compared to sunny days (p

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiovascular risk, and myocardial injury is common during severe exacerbations. Little is known about the prevalence, magnitude, and underlying mechanisms of cardiovascular risk in community-treated exacerbations. Objectives: To investigate how COPD exacerbations and exacerbation frequency impact cardiovascular risk and myocardial injury, and whether this is related to airway infection and inflammation. Methods: We prospectively measured arterial stiffness (aortic pulse wave velocity [aPWV]) and cardiac biomarkers in 98 patients with stable COPD. Fifty-five patients had paired stable and exacerbation assessments, repeated at Days 3, 7, 14, and 35 during recovery. Airway infection was identified using polymerase chain reaction. Measurements and Main Results: COPD exacerbation frequency was related to stable-state arterial stiffness (rho = 0.209; P = 0.040). Frequent exacerbators had greater aPWV than infrequent exacerbators (mean ± SD aPWV, 11.4 ± 2.1 vs. 10.3 ± 2.0 ms−1; P = 0.025). Arterial stiffness rose by an average of 1.2 ms−1 (11.1%) from stable state to exacerbation (n = 55) and fell slowly during recovery. In those with airway infection at exacerbation (n = 24) this rise was greater (1.4 ± 1.6 vs. 0.7 ± 1.3 ms−1; P = 0.048); prolonged; and related to sputum IL-6 (rho = 0.753; P < 0.001). Increases in cardiac biomarkers at exacerbation were higher in those with ischemic heart disease (n = 12) than those without (n = 43) (mean ± SD increase in troponin T, 0.011 ± 0.009 vs. 0.003 ± 0.006 μg/L, P = 0.003; N-terminal pro–brain natriuretic peptide, 38.1 ± 37.7 vs. 5.9 ± 12.3 pg/ml, P < 0.001). Conclusions: Frequent COPD exacerbators have greater arterial stiffness than infrequent exacerbators. Arterial stiffness rises acutely during COPD exacerbations, particularly with airway infection. Increases in arterial stiffness are related to inflammation, and are slow to recover. Myocardial injury is common and clinically significant during COPD exacerbations, particularly in those with underlying ischemic heart disease.

COPD is a common and important disorder that affects more than 200 million people worldwide. Its incidence is rising and by 2020 it is projected to become the fourth leading cause of death worldwide [1]. COPD is characterized by an abnormal inflammatory response in the lung to noxious particles or gases [2], but there is increasing evidence and acceptance that COPD also has important systemic manifestations. The Global Initiative for Obstructive Lung Disease (GOLD) definition includes the statement that COPD has “significant extrapulmonary effects that may contribute to the severity in individual patients” [2]. Indeed, careful analysis of data from the Towards a Revolution in COPD Health (TORCH) study found that only 40 % of deaths in patients with well-characterised moderate to very severe airflow limitation were definitely or probably related to COPD. Cause-specific mortality was: cardiovascular 27 %, respiratory 35 %, cancer 21 % (predominantly lung cancer), other 10 % and unknown 8 % [3]. In this chapter we will highlight the critical role of airway and systemic inflammation in COPD and review the impact of exacerbations on both the local and extrapulmonary manifestations of this important disease.

Background Prevalence and load of airway bacteria in stable and exacerbated chronic obstructive pulmonary disease (COPD) has been previously studied using microbiological culture. Molecular techniques, such as quantitative PCR (qPCR), may be more informative. Methods In this study, 373 sputum samples from 134 COPD outpatients were assessed for prevalence and load of typical airway bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis) by multiplex qPCR, with 176 samples analysed for atypical bacteria. Paired stable and exacerbation typical bacteria data were compared in 52 patients. We compared routine culture with qPCR in 177/373 samples. Results Typical bacteria were more prevalent in exacerbation than stable-state paired samples: 30/52 (57.7%) vs. 14/52 (26.9%); p=0.001. In patients who were bacteria-positive at both time points, mean (±1 SEM) load was significantly higher at exacerbation than stable state (108.5(±0.3) vs. 107.2(±0.5) cfu/ml), constituting a 20-fold increase (p=0.011). qPCR was more discriminatory at detecting typical bacteria than microbiological culture (prevalence 59.3% vs. 24.3%; p

The Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) is an eight-item questionnaire designed to assess and quantify the impact of COPD symptoms on health status. COPD exacerbations impair quality of life and are characterized by worsening respiratory symptoms from the stable state. We hypothesized that CAT scores at exacerbation relate to exacerbation severity as measured by exacerbation duration, lung function impairment, and systemic inflammation.To evaluate the usefulness of the CAT to assess exacerbation severity.One hundred sixty-one patients enrolled in the London COPD cohort completed the CAT at baseline (stable state), exacerbation, and during recovery between April 2010 and June 2011.Frequent exacerbators had significantly higher baseline CAT scores than infrequent exacerbators (19.5 ± 6.6 vs. 16.8 ± 8.0, P = 0.025). In 152 exacerbations, CAT scores rose from an average baseline value of 19.4 ± 6.8 to 24.1 ± 7.3 (P0.001) at exacerbation. Change in CAT score from baseline to exacerbation onset was significantly but weakly related to change in C-reactive protein (rho = 0.26, P = 0.008) but not to change in fibrinogen (rho = 0.09, P = 0.351) from baseline to exacerbation. At exacerbation, rises in CAT score were significantly associated with falls in FEV(1) (rho = -0.20, P = 0.032). Median recovery time as judged by symptom diary cards was significantly related to the time taken for the CAT score to return to baseline (rho = 0.42, P = 0.012).The CAT provides a reliable score of exacerbation severity. Baseline CAT scores are elevated in frequent exacerbators. CAT scores increase at exacerbation and reflect severity as determined by lung function and exacerbation duration.

Background The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this. Methods 40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR), oxygen saturation (SpO2) and peak-expiratory flow (PEF) over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD) observed from each patient when stable. Results In stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min-1, 1% and 10l min-1. There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise) distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003). In the presence of symptoms, a change in Score of ≥1 (average of ≥1SD change in both HR and SpO2) was 71% sensitive and 74% specific for exacerbation onset. Conclusion We have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials.

There is an unmet need in the diagnosis, phenotyping, and staging of COPD that could potentially be fulfilled by a validated molecular biomarker. Many promising candidates have been investigated, and some have been shown to be useful in certain situations. However, to date there is no outstanding disease-specific biomarker for widespread clinical application for patients in the stable state. Given the functional, social, and financial importance of exacerbations of COPD, it would be very useful to be able to employ a biomarker to aid optimal treatment and predict clinical outcome from the acute episode. Although serum C-reactive protein (CRP) is not specific to COPD, its use as a molecular biomarker in the stable state and at exacerbation has been studied extensively, and it remains the most commonly measured molecular biomarker in routine secondary care practice. Utilizing biomarkers in combinations may ultimately prove more useful. Airway-derived biomarkers and their relationships with outcome measures require further longitudinal study as well as refinement of sampling techniques to make them more broadly applicable. There is substantial ongoing investigation of many biomarkers that we are hopeful will advance the field for the benefit of our patients.

Background Exacerbations of non-cystic fibrosis bronchiectasis cause significant morbidity but there are few detailed data on their clinical course and associated physiological changes. The biology of an exacerbation has not been previously described. The purpose of this study was to describe changes in lung function, symptoms, health status and inflammation during the development and recovery from community-treated exacerbations. Methods This was a prospective observational cohort study of 32 outpatients with non-cystic fibrosis bronchiectasis conducted between August 2010 and August 2012. Patients completed a symptom diary card and measured their peak expiratory flow rate (PEFR) daily. Exacerbations were defined as oral antibiotic treatment taken for a worsening of respiratory symptoms. Symptoms and peak flow at exacerbation were analysed, and further measurements including the COPD Assessment Test (CAT) and inflammatory markers were also compared to baseline values. Results At baseline, health status was significantly related to lung function, prognostic severity and systemic inflammation. 51 exacerbations occurred in 22 patients. Exacerbation symptoms began a median (interquartile range) of 4 (2, 7) days before treatment started and the median exacerbation duration was 16 (10, 29) days. 16% had not recovered by 35 days. At exacerbation, mean PEFR dropped by 10.6% (95% confidence interval 6.9-14.2, p