Patient-Reported Outcomes (PROs) in COPD Clinical Trials: Trends and Gaps.

Key characteristics of chronic obstructive pulmonary disease (COPD) that significantly affect health-related quality of life (HRQoL) include chest symptoms, dyspnea, cough, sputum production, and exacerbations. Additional areas of impact are sleep, fatigue, emotional well-being, social functioning, and coping. Patient-reported outcomes (PROs) are essential to evaluate symptoms, impact of symptoms on activities of daily living, and treatment response. This review summarizes COPD-specific PRO endpoints from randomized controlled trials of approved and commonly used COPD drugs. A search conducted in "ClinicalTrials.gov" to identify COPD clinical trials (only completed Phase III and IV) incorporating PRO endpoints yielded a total of 104 clinical trials for inclusion in this analysis. Both symptom-based and HRQoL-specific PRO measures were reported. Several COPD-specific PRO measures are available; however, the St. George's Respiratory Questionnaire (SGRQ) and the Baseline and Transition Dyspnea Indexes (BDI/TDI) were reported in the majority of the studies. Results reflected a gap in terms of full coverage of key impacted areas from a patient's perspective. Methodological issues identified in this review related to scoring of instruments require careful consideration, as these challenges may limit the complete assessment of drug benefits. Selection of PRO measures aligned with the expected treatment benefit of a drug in a clinical trial should reflect patients' perspective holistically.

Increased Chronic Obstructive Pulmonary Disease Exacerbations of Likely Viral Etiology Follow Elevated Ambient Nitrogen Oxides.

RATIONALE: Epidemiologic research strongly supports an association between air pollution and chronic obstructive pulmonary disease exacerbations. Numerous mechanisms may underlie any association because pollutants are toxic to pulmonary cells and may increase susceptibility to respiratory infections. The relationship between ambient pollution and exacerbation etiology has not been studied. OBJECTIVES: To evaluate the characteristics of pollution-associated exacerbations and whether the association is specific to exacerbations of infective or noninfective etiology. METHODS: We analyzed the effect of preceding ambient particulate matter less than or equal to 10 µm in aerodynamic diameter, oxides of nitrogen (NOx), and ozone on characterized chronic obstructive pulmonary disease exacerbations in a regression model adjusted for temperature, seasonality, and long-term trend. We specifically examined associations with exacerbations of suspected viral and/or bacterial, or noninfective etiology. For the associations identified we further examined the characteristics of pollution-associated exacerbations. MEASUREMENTS AND MAIN RESULTS: A total of 4,173 exacerbations occurred over the 20-year study period. Higher ambient NOx was consistently associated with increased viral-type exacerbations at 2-4 days lag (P = 0.010). Recovery for viral-type exacerbations after higher ambient NOx was significantly prolonged. These findings were consistent in the subset of 2,841 exacerbations treated with oral corticosteroids or antibiotics, with recovery 1.29 (95% confidence interval, 1.17-1.42; P < 0.001) times longer with viral-type exacerbations of onset 3 days after above- versus below-median ambient NOx. A likely bimodal association of particulate matter less than or equal to 10 µm in aerodynamic diameter with infective exacerbations was also evident and supported by a daily time-series analysis. CONCLUSIONS: Higher levels of ambient NOx are associated with prolonged exacerbations of likely viral etiology, supporting toxicologic effects of air pollution that increase susceptibility to, and severity of, infection.

Patient-reported Outcomes for the Detection, Quantification, and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations.

An exacerbation of chronic obstructive pulmonary disease (COPD) is an acute worsening of respiratory symptoms accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients, and thus patient-reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical industry- and large academy-sponsored studies have used a healthcare resource use definition alone, which is based on sustained worsening of a patient's condition from the stable state that requires a change in regular medication. This Review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD e-Diary, Exacerbations of Chronic Obstructive Pulmonary Disease Tool, COPD Assessment Test, and Chronic Respiratory Disease Questionnaire, highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting; quantify exacerbation characteristics, including the frequency, duration, and severity of events; and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches.

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.

Influence of weather and atmospheric pollution on physical activity in patients with COPD.

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 < 0.001). Daily step count was 434 steps per day lower on Sunday than Saturday (p < 0.001) and 353 steps per day lower on Saturday than Friday (p < 0.001). After allowance for these effects, higher O3 levels decreased activity during the whole week (-8 steps/ug/m3; p = 0.005) and at weekends (-7.8 steps/ug/m3; p = 0.032). Whilst, during the week PM10 reduced activity (p = 0.018) but not during the weekend. CONCLUSIONS: Inactivity of COPD patients is greatest on cold, wet and overcast days and at the weekends. This study also provides evidence of an independent effect of atmospheric pollution at high levels.

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.

Sputum-to-serum hydrogen sulfide ratio in COPD.

OBJECTIVES: Hydrogen sulfide (H2S) is a gas produced by respiratory cells including smooth muscle cells and may play a role as a cellular gasotransmitter. We evaluated whether H2S levels in serum or sputum could represent a new biomarker of COPD in a cross-sectional study. METHODS: H2S levels in sputum and serum samples were measured using a sulfide-sensitive electrode in 64 patients with stable COPD (S-COPD), 29 COPD subjects during acute exacerbation (AE-COPD), 14 healthy smokers and 21 healthy non-smokers. RESULTS: Sputum H2S levels in AE-COPD subjects were higher than those in S-COPD, healthy smoking and non-smoking subjects (p<0.001), but serum H2S levels in AE-COPD were lower than those in S-COPD (p<0.001). Thus, the sputum-to-serum ratio of H2S (H2S ratio) in AE-COPD subjects were higher than those in stable COPD, healthy smoking and non-smoking subjects (p<0.001). In 14 COPD subjects whose H2S ratios were measured during and after an exacerbation, the mean ratio was increased during exacerbation (p<0.05). H2S ratio was positively correlated with St. George's Respiratory Questionnaire score, sputum neutrophils and IL-6 and IL-8 levels in sputum and serum (p<0.01) but inversely correlated with sputum macrophages (%), FEV1%predicted and FEV1/FVC (p<0.01). The cut-off level of H2S ratio to indicate an exacerbation was ≥0.44 (sensitivity of 93.1% and specificity of 84.5%). CONCLUSIONS: The ratio of sputum-to-serum levels of H2S may provide a useful marker of COPD indicative of obstructive neutrophilic inflammation and of potential ongoing exacerbation.

Daily activity during stability and exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: During most COPD exacerbations, patients continue to live in the community but there is little information on changes in activity during exacerbations due to the difficulties of obtaining recent, prospective baseline data. METHODS: Patients recorded on daily diary cards any worsening in respiratory symptoms, peak expiratory flow (PEF) and the number of steps taken per day measured with a Yamax Digi-walker pedometer. Exacerbations were defined by increased respiratory symptoms and the number of exacerbations experienced in the 12 months preceding the recording of daily step count used to divide patients into frequent (> = 2/year) or infrequent exacerbators. RESULTS: The 73 COPD patients (88% male) had a mean (±SD) age 71(±8) years and FEV1 53(±16)% predicted. They recorded pedometer data on a median 198 days (IQR 134-353). At exacerbation onset, symptom count rose by 1.9(±1.3) and PEF fell by 7(±13) l/min. Mean daily step count fell from 4154(±2586) steps/day during a preceding baseline week to 3673(±2258) step/day during the initial 7 days of exacerbation (p = 0.045). Patients with larger falls in activity at exacerbation took longer to recover to stable level (rho = -0.56; p < 0.001). Recovery in daily step count was faster (median 3.5 days) than for exacerbation symptoms (median 11 days; p < 0.001). Recovery in step count was also faster in untreated compared to treated exacerbation (p = 0.030).Daily step count fell faster over time in the 40 frequent exacerbators, by 708 steps/year, compared to 338 steps/year in 33 infrequent exacerbators (p = 0.002). CONCLUSIONS: COPD exacerbations reduced physical activity and frequent exacerbations accelerate decline in activity over time.

Acute COPD exacerbations.

Exacerbations are important events for patients with chronic obstructive pulmonary disease (COPD) and key outcomes in COPD studies and trials. Exacerbations have an impact on health status and contribute to disease progression, and exacerbation prevention is a key goal of therapy in COPD. A majority of COPD exacerbations are triggered by respiratory viral infections and/or bacterial infections. Several pharmacologic therapies can prevent COPD exacerbations and reduce hospital admissions. Nonpharmacologic interventions for exacerbation prevention include pulmonary rehabilitation, long-term oxygen therapy, and home noninvasive ventilator support. Improved management of acute exacerbations also prolongs the time to the next exacerbation event.

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.

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.

COPD exacerbations: causes, prevention, and treatment.

The mechanisms of chronic obstructive pulmonary disease exacerbation are complex. Respiratory viruses (in particular rhinovirus) and bacteria play a major role in the cause of these events. A distinct group of patients seems susceptible to frequent exacerbations, irrespective of disease severity, and this phenotype is stable over time. Many current therapeutic strategies help reduce exacerbation frequency. Further work is required to develop novel anti-inflammatory therapies for exacerbation prevention and treatment. This article focuses on the cause of chronic obstructive pulmonary disease exacerbations, and the current preventative and acute interventions available.

COPD exacerbations: causes, prevention, and treatment.

The mechanisms of COPD exacerbation are complex. Respiratory viruses (in particular rhinovirus) and bacteria play a major role in the causative etiology of COPD exacerbations. In some patients, noninfective environmental factors may also be important. Data recently published from a large observational study identified a phenotype of patients more susceptible to frequent exacerbations. Many current therapeutic strategies can reduce exacerbation frequency. Future studies may target the frequent exacerbator phenotype, or those patients colonized with potential bacterial pathogens, for such therapies as long-term antibiotics, thus preventing exacerbations by decreasing bacterial load or preventing new strain acquisition in the stable state. Respiratory viral infections are also an important therapeutic target for COPD. Further work is required to develop new anti-inflammatory agents for exacerbation prevention, and novel acute treatments to improve outcomes at exacerbation.

Usefulness of the Chronic Obstructive Pulmonary Disease Assessment Test to evaluate severity of COPD exacerbations.

RATIONALE: 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. OBJECTIVES: To evaluate the usefulness of the CAT to assess exacerbation severity. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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 (P < 0.001) 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). CONCLUSIONS: 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.

The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD.

BACKGROUND: Comorbid ischemic heart disease (IHD) is a common and important cause of morbidity and mortality in patients with COPD. The impact of IHD on COPD in terms of a patient's health status, exercise capacity, and symptoms is not well understood. METHODS: We analyzed stable-state data of 386 patients from the London COPD cohort between 1995 and 2009 and prospectively collected exacerbation data in those who had completed symptom diaries for ≥ 1 year. RESULTS: Sixty-four patients (16.6%) with IHD had significantly worse health status as measured by the St. George Respiratory Questionnaire (56.9 ± 18.5 vs 49.1 ± 19.0, P = .003), and a larger proportion of this group reported more severe breathlessness in the stable state, with a Medical Research Council dyspnea score of ≥ 4 (50.9% vs 35.1%, P = .029). In subsets of the sample, stable patients with COPD with IHD had a higher median (interquartile range [IQR]) serum N-terminal pro-brain natriuretic peptide concentration than those without IHD (38 [15, 107] pg/mL vs 12 [6, 21] pg/mL, P = .004) and a lower exercise capacity (6-min walk distance, 225 ± 89 m vs 317 ± 85 m; P = .002). COPD exacerbations were not more frequent in patients with IHD (median, 1.95 [IQR, 1.20, 3.12] vs 1.86 (IQR, 0.75, 3.96) per year; P = .294), but the median symptom recovery time was 5 days longer (17.0 [IQR, 9.8, 24.2] vs 12.0 [IQR, 8.0, 18.0]; P = .009), resulting in significantly more days per year reporting exacerbation symptoms (median, 35.4 [IQR, 13.4, 60.7] vs 22.2 [IQR, 5.7, 42.6]; P = .028). These findings were replicated in multivariate analyses allowing for age, sex, FEV(1), and exacerbation frequency where applicable. CONCLUSIONS: Comorbid IHD is associated with worse health status, lower exercise capacity, and more dyspnea in stable patients with COPD as well as with longer exacerbations but not with an increased exacerbation frequency.