Beverly Kowlessar

Cardiovascular Risk, Myocardial Injury, and Exacerbations of Chronic Obstructive Pulmonary Disease

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.

Impact of Prolonged Exacerbation Recovery in Chronic Obstructive Pulmonary Disease

RATIONALE Exacerbations are important and heterogeneous events in the natural history of chronic obstructive pulmonary disease (COPD). OBJECTIVES To examine the consequences of prolonged exacerbation recovery in patients with COPD. METHODS A cohort of 384 patients with COPD (FEV1 % predicted 45.8 [SD, 16.6] and a median exacerbation rate of 2.13 per year [interquartile range, 1.0-3.2]) were followed for 1,039 days (interquartile range, 660-1,814) between October 1995 and January 2013. Patients recorded daily worsening of respiratory symptoms and peak expiratory flow (PEF), and when stable underwent spirometry every 3 months, and completed the St. Georges Respiratory Questionnaire annually. Exacerbations were diagnosed as 2 consecutive days with one major symptom plus another respiratory symptom. Exacerbation duration was defined as the time from onset to the day preceding 2 consecutive symptom-free days and recovery in PEF as return to preexacerbation levels. MEASUREMENTS AND MAIN RESULTS A total of 351 patients had one or more exacerbations. Patients with a longer symptom duration (mean, 14.5 d) had a worse St. Georges Respiratory Questionnaire total score (0.2 units per 1 day; P = 0.040). A longer symptomatic duration was associated with a shorter interval between exacerbation recovery and onset of the next exacerbation (hazard ratio, 1.004; P = 0.013). For 257 (7.3%) exacerbations, PEF did not recover within 99 days. These exacerbations were associated with symptoms of a viral infection (cold and sore throat). Patients with these nonrecovered exacerbations showed a 10.8 ml/yr (P < 0.001) faster decline in FEV1. CONCLUSIONS Prolonged exacerbation symptomatic duration is associated with poorer health status and a greater risk of a new event. Exacerbations where lung function does not recover are associated with symptoms of viral infections and accelerated decline in FEV1.

Detection and severity grading of COPD exacerbations using the exacerbations of chronic pulmonary disease tool (EXACT)

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<0.001), and rose further to a maximum score of 54.1±8.9. Maximum EXACT scores were significantly higher in treated than untreated events. Time taken for EXACT scores to return to baseline was significantly related to symptom recovery time as judged by London COPD cohort diary cards, and to peak expiratory flow rate recovery. ∼50% of both diary card-defined and healthcare utilisation exacerbations crossed the EXACT event threshold. However, only 27.9% of diary card-defined and 34.6% of healthcare utilisation exacerbations fully met the criteria for an EXACT event. Patients exhibited smaller rises in the EXACT score at exacerbation as baseline disease severity increased. The EXACT is an effective method of evaluating chronic obstructive pulmonary disease exacerbation severity. However, concerns remain about the ability of the EXACT to accurately detect exacerbations. The EXACT is an effective method to assess exacerbation severity but uncertainty remains over its ability to detect exacerbations http://ow.ly/rHg1P

Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease

BackgroundThere has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients. We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort.MethodsWe prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012. Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test.ResultsAirway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p < 0.001, p = 0.049 and p = 0.261, respectively). Increasing total bacterial load was associated with increasing airway (p < 0.01) but not systemic inflammation (p > 0.05). Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads. Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p < 0.05), and was significantly greater than with other PPMs. No association was observed between inflammation and health status (p > 0.05).ConclusionsAirway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique. The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae. However, discordance between inflammation and health status was observed.

Physical activity and exercise capacity in patients with moderate COPD exacerbations.

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. Falls in physical capacity and muscle strength during COPD exacerbations managed in the community http://ow.ly/ZtU45

Upper Respiratory Symptoms Worsen over Time and Relate to Clinical Phenotype in Chronic Obstructive Pulmonary Disease

RATIONALE How nasal symptoms in patients with chronic obstructive pulmonary disease (COPD) change over time and resolve during naturally occurring exacerbations has not been described previously. OBJECTIVES To evaluate the evolution and impact of upper airway symptoms in a well-defined COPD cohort when stable and at exacerbation. METHODS Patients in the London COPD cohort were asked about the presence of nasal symptoms (nasal discharge, sneezing, postnasal drip, blocked nose, and anosmia) over an 8-year period (2005-2013) every 3 months at routine clinic visits while in a stable state and daily during exacerbations with the use of diary cards. Data were prospectively collected, and, in a subgroup of patients, COPD Assessment Test scores and human rhinovirus identification by polymerase chain reaction were available. Patients were also defined as having infrequent or frequent exacerbations (<2 or ≥2 exacerbations/yr, respectively). MEASUREMENTS AND MAIN RESULTS At an aggregate of 4,368 visits, 209 patients with COPD were asked about their nasal symptoms. At 2,033 visits when the patients were stable, the odds ratio (OR) for nasal discharge increased by 1.32% per year (95% confidence interval [CI], 1.19-1.45; P < 0.001); the OR for sneezing increased by 1.16% (95% CI, 1.05-1.29; P = 0.005); the OR for postnasal drip increased by 1.18% (95% CI, 1.03-1.36; P = 0.016); and the OR for anosmia increased by 1.19% (95% CI, 1.03-1.37; P = 0.015). At visits when the patients were having exacerbations, nasal discharge was present for 7 days and blocked nose, sneezing, and postnasal drip increased for just 3 days. Anosmia did not change. Nasal discharge was more likely in patients with frequent exacerbations (OR, 1.96; 95% CI, 1.17-3.28; P = 0.011), and COPD Assessment Test scores were higher by 1.06 units (95% CI, 0.32-1.80; P = 0.005) when patients were stable and higher by 1.30 units (95% CI, 0.05-2.57; P = 0.042) during exacerbations. CONCLUSIONS Upper airway symptoms increase over time in patients with COPD and are related to the frequent exacerbation phenotype. These longitudinal changes may be due to increasing airway inflammation or to progression of COPD.

P47 The impact of comorbid ischaemic heart disease on exercise capacity in COPD patients

Introduction Comorbid ischaemic heart disease (IHD) is associated with an adverse impact on health status, symptoms (ARJCCM 2011;183:A2614) and exacerbation recovery in COPD patients (ERJ 2010;954s:E5209). Any impact on exercise capacity is poorly understood. We aimed to assess and quantify differences in exercise capacity in stable COPD patients with and without IHD. Methods We assessed 6-min walking distance (6MWD) in accordance with ATS guidance (AJRCCM 2002;166:111–117) in patients from the London COPD cohort. All assessments were performed in the stable state with no symptom-defined exacerbations recorded on daily diary cards for 6 weeks prior and 2 weeks following the visit. Dyspnoea and fatigue were measured before and after the test using the Borg scale, as were saturations from a pulse oximeter. Data were analysed using unpaired t-tests, Mann–Whitney U, χ2 tests and multiple regression techniques. Results 115 patients had a 6MWD assessment, 19 (17%) had IHD (Abstract P47 table 1). COPD patients with IHD had a lower mean ± SD 6MWD than those without (310±138 vs 354±107 m) although this was not statistically significant (p=0.119). Following adjustment for age, gender, FEV1 % predicted, BMI and smoking pack year history, IHD was found to be independently related with a 66 m reduction in 6MWD (95% CI 5 to 127 m), p=0.035. Median (IQR) dyspnoea on the Borg scale before the test was not higher in those with IHD (1(1,2) vs 1(0,3), p=0.135), this increased more in those with IHD compared to those without during the test (2(1,3) vs 1(0,3), p=0.043). Fatigue measured on the Borg scale was higher at the start of the test in those with IHD (1.5(0,3) vs 0(0,2), p=0.038), however, the increase after the test was not different between the groups (0(0,2) vs 0(0,2), p=0.831). The mean ± SD pre-test oxygen saturations and post-test change were similar in those with and without IHD (93.8±2.6% vs 94.1±2.4%, p=0.684; −0.9±4.4% vs −1.4±3.2%, p=0.595).Abstract P47 Table 1 Clinical characteristics of COPD patients with and without comorbid ischaemic heart disease (IHD) All COPD patients (n=115) COPD without IHD† (n=96) COPD with IHD‡ (n=19) p Value† vs ‡ Age (years) 69.7±8.7 68.9±8.9 74.0±5.9 0.019 Male gender 67% 65% 79% 0.224 FEV1 (% predicted) 51.9±18.6 52.3±19.2 49.5±15.5 0.550 FEV1 (L) 1.36±0.61 1.37±0.64 1.29±0.46 0.583 BMI (kg/m2) 26.8±5.8 27.1±6.0 25.8±4.8 0.390 Current smoker 28% 28% 26% 0.872 Smoking (pack years) 46 (30,72) 44 (30,72) 57 (40,79) 0.110 Data are presented as percentage, mean ± SD or median (IQR) as appropriate. Conclusions Comorbid IHD is independently associated with a clinically significant lower exercise capacity in COPD patients. Such patients may have a higher level of fatigue before exercise and develop more dyspnoea during exercise. Such patients may be an appropriate target for further intervention such as tailored pulmonary rehabilitation.