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Patient Reported Outcomes for the Detection, Quantification and Evaluation of Chronic Obstructive Pulmonary Disease ExacerbationsAuthorsAlex J Mackay1,2, Konstantinos Kostikas3, Lindsey Murray4, Fernando J Martinez5, Marc Miravitlles6, Gavin Donaldson1, Donald Banerji7, Francesco Patalano3, Jadwiga A. Wedzicha1Affiliations1National Heart and Lung Institute, Imperial College, United Kingdom; 2European Respiratory Society Fellowship in Industry, Novartis Campus, Basel, Switzerland; 3Novartis Pharma AG, Basel, Switzerland; 4Evidera, Bethesda, MD, USA; 5Weill Cornell Medical College of Cornell University, New York, NY, USA; 6Pneumology Dept, Hospital Universitari Vall d'Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, United StatesWord Count: 4629Key Words: COPD; Exacerbations; Patient-reported outcomes; EXACT; Health-care resource useRunning Title: Use of PROs at COPD ExacerbationAuthor Contributions: AJM, KK, FP, DB and JAW developed the concept of the paper; AJM and KK wrote the first draft, LM, FJM, MM, GD, DB, FP, JAW provided critical analysis and discussions. All authors reviewed and approved the final manuscript.Abstract (249 words)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 directly 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 and large academic-sponsored studies have used a healthcare resource utilization definition alone 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 (ESCO) e-Diary, EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT?), COPD Assessment TestTM (CAT) and Chronic Respiratory Disease Questionnaire (CRQ), 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.IntroductionAn exacerbation of COPD is an acute worsening of respiratory symptoms, accompanied by a variable degree of physiological deterioration (1). The pivotal Anthonisen study defined exacerbations symptomatically with a particular focus on increased dyspnea, sputum volume and sputum purulence (2). However, most pharmaceutical studies, and many large academic-sponsored studies (3, 4), have used a healthcare resource utilization (HCRU) definition based on a sustained worsening of the patient’s condition from the stable state requiring a change in regular medication (5), frequently resulting in the use of antibiotics or oral steroids, unscheduled physician visits, emergency department visits and/or hospital admission. This is reflected in the Global Initiative for chronic Obstructive Lung Disease (GOLD) strategy, which defines an exacerbation as “an acute worsening of respiratory symptoms that results in additional therapy” (6). This review will explore the use of different methods for the detection, quantification, and evaluation of COPD exacerbations, including HCRU and patient-reported outcomes (PROs).The many faces of Healthcare Resource Utilization defined exacerbationsAn HCRU definition of exacerbations has certain challenges. Treatment decisions at exacerbation are a complex interplay of psychological, behavioral, and physical factors that in combination with challenges relating to differing treatment models and resource allocation vary greatly between patients and healthcare systems. Even within healthcare systems, significant variability exists between physicians in both diagnostic practices and prescribing habits at exacerbation (7, 8) and the utility of biomarkers to guide clinicians in exacerbation diagnosis and treatment is currently limited (9-11).In addition to physician-managed events, self-management is a common practice in some settings for COPD exacerbations (12); however, some patients may have difficulty recognizing exacerbation symptoms and perceive symptom severity differently (13). It has been reported that patients who experience frequent COPD exacerbations have an enhanced perception of dyspnea and infrequent exacerbators display a blunted perception of breathlessness during carbon dioxide (CO2) rebreathing (14). Therefore, patients may over- or underestimate the need to seek care or medical assessment, and also the necessity for treatment with antibiotics and/or oral corticosteroids according to what is medically appropriate (15). Patients also have different thresholds to commence treatment and will frequently rely on their own experiential knowledge of previous episodes of symptom deterioration, making an assessment of whether symptoms are serious enough to justify the potential adverse effects of medication prior to initiating therapy (15). Fear and anxiety often increase at exacerbation, thus may limit patients’ ability to perform self-management and further impact health care resource use (13). Patients with high levels of anxiety and depression have higher rates of COPD exacerbation and hospitalization (16-19). If uncertain about their condition and the need for therapy, patients (particularly those with high levels of anxiety) frequently consult a healthcare professional, whereas some others may hesitate to seek help for fear of being burdensome to their physician (15). Physiological comorbidities, such as cardiovascular disease, are also extremely prevalent in patients with COPD (20) and are a particular challenge that impacts clinician decision making at COPD exacerbation (21). Comorbidities cause diagnostic uncertainty and alter prescribing thresholds for both oral corticosteroids and antibiotics, the mainstays of current acute exacerbation therapy (6, 22), particularly if comorbid conditions such as diabetes or drug levels for concomitant medications (such as warfarin) will be significantly worsened by such therapies (21, 23). Comorbidities also play a large role in determining the likelihood of admission for exacerbation. COPD patients with comorbid ischemic heart disease are more likely to be hospitalized (24) and thresholds for admission are naturally reduced in patients with additional severe comorbidities and less physiological reserve (21, 25). Hospitalization for exacerbations is associated with lung function decline (26), increased mortality, and repeated admissions (27, 28). An important factor in physician decision-making relating to hospitalization of COPD exacerbations is the assessment of a patient’s social support (21). Patients who are socially isolated may be less capable of performing activities of daily living whilst unwell and so struggle to cope during exacerbations when managed out of hospital (21). This is particularly relevant to resource variability between healthcare systems. There are considerable differences in hospitalization rates for COPD between countries (29). Hospital at home and admission avoidance schemes are designed to reduce admission and when available can help to manage patients in their own home during exacerbation (30, 31), however provision of such services is sporadic, resulting in a lack of generalizability across different healthcare systems. Furthermore, patient and carer preference for location of management is variable (32). Therefore defining exacerbation severity by treatment setting (inpatient or outpatient) is complicated by variability and heterogeneity within and between patients and systems.Regulatory GuidanceIn an attempt to improve the evaluation of patient experience for use in clinical trials, the Food and Drug Administration (FDA) published guidance on the development and use of PRO instruments to measure treatment benefit in medical product development trials (33).?The FDA defines a PRO as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. The outcome can be measured in absolute terms (e.g., severity of a symptom, sign, or state of a disease) or as a change from a previous measure”. Historically, regulatory agencies have stipulated that the assessment of the presence and severity of exacerbations in drug development trials be evaluated using the HCRU definition, based on physician’s interpretation of the symptoms described by patients in combination with physical examination findings, with severity defined by magnitude of care (clinic visit with pharmacologic treatment or hospitalization) and duration defined by treatment duration (days of drug or length of admission). However, the importance and value of PRO measures in COPD efficacy studies has been specifically highlighted by the FDA (34). The European Medicines Agency (EMA) has also advised that definitions of exacerbation and severity of the exacerbation should be standardized to allow comparisons between different interventions in different settings (35). More recently, the “Patient-Focused Drug Development” section of the 21st Century Cures Act (36, 37) emphasizes the need for patient engagement in drug development, including the standardization of patient experience data in regulatory programs.In the future, therefore, it would be extremely valuable to include information gathered directly from patients in the detection and quantification of exacerbation frequency and severity, and thus standardized instruments such as PROs are well-suited to the assessment of COPD exacerbations, in combination with physician verification of events. Since PRO scores are directly acquired from patients they may also be less susceptible to some of the challenges of HCRU events described previously. The combination of a validated PRO measure during an HCRU event offers a powerful method for quantifying HCRU exacerbations in clinical trials, incorporating standardized numerical measurement of exacerbation symptom severity and duration, and clinical data on the patient’s health status and treatment. It should be noted that PROs are not interchangeable and the specific research question should drive the selection of the optimal tool for use in a particular study, including the measure best representing the content of interest and data requirements. The EMA 2012 guideline on clinical investigation of medicinal products in the treatment of COPD specifically recommends the use of questionnaires or daily diary cards to enable the capture of both reported and unreported exacerbations, and evaluate symptoms, to provide patient relevant outcomes (35). Key instruments that may fulfil this purpose are described in the subsequent part of this review. Symptom Diary CardsOne of the earliest iterations of PROs are daily symptom diary cards. Daily diary cards are extremely sensitive to change in symptom burden (38) and can determine the precise onset and resolution of exacerbations (1). This enables the accurate calculation of exacerbation duration, an important clinical outcome and modifiable therapeutic target (39), in addition to generating the total number of exacerbation days per patient during a study (40). Importantly, such instruments can identify unreported exacerbations and so can be used to generate an accurate exacerbation frequency (41). However, traditional symptom diaries have predominantly used binary responses to determine the presence or absence of any worsening above the patient’s usual daily level of symptoms and therefore have been limited in their ability to determine the severity of individual exacerbation events, with assessments restricted to summation of individual symptoms, sometimes with increased weighting given to “major” symptoms (usually dyspnea, sputum purulence and sputum volume) (Figure 1) (42). Further iterations of symptom diaries have also included a graded symptom score for Anthonisen criteria (dyspnea, sputum color and sputum volume), in addition to well-being, and have provided valuable insights, including a potential difference in intensity of dyspnea between treated and untreated episodes (43), again suggesting that dyspnea perception may play a key role in exacerbation reporting and treatment. An important disadvantage of paper-based methods, compared to electronic diaries, is the inability to prompt users at regular intervals to record data. This lack of prompting may lead to delays in entering symptoms (diary hoarding), thus reducing data accuracy (44), though this can be ameliorated by collecting other information such as daily peak flow that necessitates daily recording.Electronic Symptom Diary (e-Diary) toolsSymptom diary cards have been transitioning from paper-based methods to electronic approaches. The major advantage of e-Diary approaches is the potential for contemporaneous recording and transmission of data to healthcare and research teams. In addition, and according to the trial design, feedback may be provided to patients in order to prompt appropriate actions (45, 46). Incorporated alerts to overcome missing diary transmissions may result in more complete data sets. Smartphone-based collection of COPD symptom diaries has been shown to enable near-complete identification of exacerbations, detecting both treated and untreated events (47, 48). Separate dedicated devices are often used in drug development trials rather than app-based tools on the patients’ personal device for increased standardization (49). The Exacerbations and Symptoms in COPD (ESCO) e-DiaryA specific e-Diary developed to monitor exacerbations and symptoms in COPD, henceforth referred to as the Exacerbations and Symptoms in COPD (ESCO) e-Diary, has shown high completion rates when used in pivotal clinical trials to evaluate exacerbations (49, 50). In both the SPARK and FLAME studies exacerbations were defined using symptom-based criteria: a worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence) or a worsening of any 1 major symptom together with an increase in any one minor symptom (sore throat, cold, fever without other cause, cough, wheeze), for at least 2 consecutive days compared to symptoms recorded at baseline during the study run-in period. The type of treatment determined the severity of the exacerbation, with a worsening of symptoms that met the above symptom definition but not treated with systemic corticosteroids and/or antibiotics considered a mild exacerbation. A COPD exacerbation was considered of moderate severity if treated with systemic corticosteroids, antibiotics, or both, and severe if hospitalization was required (49, 50). The ESCO e-Diary also provides the means to capture accurately the onset, peak, recovery, symptom burden and duration of exacerbations (Figure 2).In both SPARK and FLAME, use of the ESCO e-Diary enabled a significant difference to be seen in HCRU exacerbation rates between a long-acting β2-agonist/long-acting muscarinic antagonist (LABA/LAMA) and LAMA or LABA/inhaled corticosteroid (ICS), respectively (49, 50). In order to ensure accurate capture of exacerbations, when patients experienced a deterioration in symptoms that met the criteria of a COPD exacerbation, the diary triggered an alarm and patients were advised to contact their study site. This approach has been criticized due to concerns that use of an alert that notifies patients when they have recorded symptoms compatible with a possible exacerbation on the ESCO e-Diary could lead to symptom variation being registered as exacerbations (51), or that patient awareness of the notification process could affect symptom recording behavior. However, in both studies, all exacerbations (including mild events) were confirmed by the study investigators and it is unlikely that both patients and physicians would mistake day-to-day variability for an exacerbation. EXAcerbations of Chronic Obstructive Pulmonary Disease ToolAn important instrument used for exacerbation recognition is the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) (52). The EXACT is a daily symptom diary developed in-line with the FDA PRO Guidance (33) which captures the frequency, severity, and duration of exacerbations in clinical trials of COPD (53). During the initial development of the EXACT, COPD patients were asked to describe key exacerbation symptoms, indicators of progression and recovery, cues for self-diagnosis and care-seeking triggers (54). Experts in questionnaire development and clinicians reviewed the resulting information and generated a preliminary 23-item framework.Following this initial assessment, a large observational study was performed to enable item reduction, resulting in a final tool consisting of 14 items addressing 8 concepts: cough, sputum, chest tightness, breathlessness, breathlessness with activity, tiredness, sleep and worry/concern (53). EXACT scores are calculated from the responses to these 14 items. Scores range from 0 to 100, with higher scores indicating a more severe condition. Validation studies confirmed that the EXACT reliably assesses symptom severity and that EXACT scores are significantly elevated at exacerbation compared to baseline, stable state values (53, 55). Independent studies have also confirmed that EXACT scores increase at COPD exacerbation, the magnitude of which reflects the severity of the event in terms of treatment, systemic inflammation, airflow limitation and symptom recovery time (56). Furthermore, because the EXACT generates an interval-level score on a large dynamic range (from 0-100), it may have the potential to discriminate subtle relative efficacies of novel therapies in absolute numerical values. A symptom-defined event identified using the EXACT, hereafter referred to as symptom (EXACT)-defined event, is defined as a persistent increase from baseline in total EXACT score of ≥9 points for 3 days or ≥12 points for 2 days (53). One of the strengths of the EXACT is its ability to recognize unreported events, where patients experience a deterioration in their symptoms but do not seek or receive additional therapy, and studies using the EXACT have confirmed the high prevalence and clinical significance of these events. In the ATTAIN study, comparing a LAMA with placebo, unreported (untreated) symptom (EXACT)-defined events had the same medium-term health consequences as reported (treated) HCRU exacerbations and importantly, in this study, the trial intervention reduced the rate of both symptom (EXACT)-defined and HCRU events (57), suggesting that symptom (EXACT)-defined events may be a valuable metric, even when unreported. The EXACT has also been qualified for use as an exploratory endpoint in clinical trials by both the FDA (58) and EMA (59). Therefore, the EXACT may be a useful outcome measure in clinical trials of acute exacerbation therapies (56).Health Status MeasuresThe COPD Assessment Test (CAT)The COPD Assessment Test (CAT) is an 8-item questionnaire that generates a measure of health status, including symptoms and disease impact (). The CAT is designed for periodic administration to capture how the patient is feeling, with a recall period reflecting current experience. It has excellent measurement properties (60) and is short and simple for patients to complete, with development in-line with the FDA PRO guidance (33). CAT scores indicate disease impact and range from 0 to 40, with higher scores indicating greater severity. CAT scores are responsive to pulmonary rehabilitation (61) and correlate closely with St. George’s Respiratory Questionnaire (SGRQ) scores when patients are stable (60).Stable state CAT scores may also help to evaluate future exacerbation risk. Baseline CAT scores are significantly elevated in patients with stable COPD with a history of frequent exacerbations (62). Furthermore, patients with higher baseline CAT scores are associated with significantly shorter time to first exacerbation and greater future exacerbation risk than patients with lower scores (63). In the outpatient setting, CAT scores rise significantly at exacerbation from paired baseline values, and reflect exacerbation severity, measured by lung function reduction and exacerbation duration. A weak relationship has also been seen between exacerbation CAT scores and systemic inflammatory markers (62). Exacerbation CAT scores are also elevated in hospitalized patients compared to convalescent levels and are significantly worse in admitted compared with ambulatory patients (64). The CAT has also shown promise in monitoring recovery of and predicting outcomes following hospitalized events. Patients who recover from acute hospitalized exacerbations exhibit a highly significant improvement in CAT scores (64). Also, in a study of 45 patients admitted for an exacerbation of COPD, those who required a new hospitalization during the 3-month follow-up had higher scores during the first days of admission and a higher area under the curve (AUC) of CAT scores during the first 5 days of hospitalization (65).Smaller improvements in CAT score from admission to discharge, and higher convalescent levels, also appear to predict a higher risk of recurrence, readmission and death (Figure 3) (66-68). Therefore, the CAT may have the potential to aid discharge planning in clinical practice and to assess risk of future events.Chronic Respiratory Disease Questionnaire (CRQ)The CRQ is a 20-item instrument that measures health related quality of life in COPD patients by assessing four domains: a patient’s perception of mastery, fatigue, emotional function, and dyspnea experienced during certain activities in the 2 weeks prior to its administration (69). It is reproducible and responsive when administered in the stable state and changes in CRQ score correlate with changes in spirometry, exercise capacity, and patients and physicians' global ratings (69). CRQ scores also improve in response to pulmonary rehabilitation in patients with moderate COPD (70) and improvements are sustained over time (71).The CRQ has also been used in a small observational study of patients presenting to the emergency department at exacerbation by Aaron and colleagues (72). In this study, changes in CRQ from presentation to 10 days thereafter correlated with changes in breathlessness (as measured by TDI) and changes in FEV1. When assessed at follow-up (day 10 or day of relapse), changes in CRQ also appeared to differentiate patients experiencing a relapse from those with an uncomplicated recovery. Amongst non-relapsing patients, scores across each of the four domains of the CRQ improved markedly. In contrast, those patients who had a clinical relapse did not improve on any domain of the CRQ (72). The authors interpreted the observed results as indicating that the CRQ became responsive to short-term improvements in quality of life and that this study validated the use of the CRQ at exacerbation. However patients who relapsed during recovery did not show a significant deterioration in their CRQ scores from initial exacerbation values, raising the possibility that either the study was underpowered to detect such changes or the ability of the tool to discriminate further deteriorations during exacerbation recovery is limited (72). The CRQ has been used in a trial examining etanercept as an alternative therapy to prednisolone in patients presenting to a physician or the emergency department during an exacerbation of COPD. No significant differences were seen in CRQ scores between treatment groups at 14 days and 90 days after randomization, except for the mastery domain at 14 days, although the study was also negative in its primary outcome (change in FEV1 from baseline, measured from the day of randomization to 14 days after randomization) (73). However, there is limited validation data using the CRQ at exacerbation, and uncertainty exists regarding the ability of this tool to accurately discriminate subtle health status changes during exacerbation recovery (72). The standard CRQ has a 2-week recall period, limiting its ability to track the subtleties of exacerbation severity at the time of treatment (reflecting back 2 weeks, before the event began, may dilute the score) and recovery (again, measuring 2 weeks later during recovery asks patients to “average” their responses over a time of change). The previously described observational study using the CRQ at exacerbation attempted to mitigate this effect by replacing “2 weeks” with “2 to 3 days” in all questions to assess changes over a 2-day to 3-day recall period rather than a 2-week recall period (72). Nonetheless, daily diaries, such as the EXACT or ESCO, are more suitable choices to measure symptomatic changes in future studies of novel acute exacerbation treatments. The CAT is also more suited, administered at the time of the event and at frequent intervals during the recovery period.Interpreting HCRU and PRO DataAn important conceptual issue is the complex relationship between symptom-defined and HCRU events. Up to two-thirds of COPD exacerbations are not reported to health-care professionals (41, 74, 75) and are either untreated or self-treated and thus may not be identified by HCRU definitions. Unreported exacerbations impair health-related quality of life (41, 74, 75) and are important events to recognize and quantify with a symptom-diary. Failure to report exacerbations is associated with increased risk of emergency hospitalization (76) and data from the ATTAIN study has suggested that unreported events may lead to a poorer prognosis than treated HCRU exacerbations (57). When compared to patients who experienced an HCRU event, patients who experienced unreported exacerbations recovered more slowly, had greater deterioration in FEV1 and worse absolute SGRQ scores.However, a challenge of using both HCRU and symptom-defined events has been how to interpret the data. One of the first large pharmaceutical studies to use the EXACT instrument was the FORWARD study, a randomized, double-blind trial that compared the efficacy and safety of a LABA/ICS vs. a LABA in severe COPD patients with a history of exacerbations (52). In this study HCRU exacerbations was a co-primary outcome (pre-dose morning FEV1 at 12 weeks was the other co-primary outcome), and the EXACT was used to enhance the detection of exacerbation events. A predefined aim of the FORWARD study was also to perform exploratory analyses to inform on the utility of the EXACT to detect exacerbations (77). In-line with other symptom-diaries, the EXACT captured a greater number of symptom-defined events compared to HCRU events. Whilst these data have not been fully published, preliminary results showed discordance between HCRU exacerbations and symptom (EXACT)-defined events, with 23% of events in the trial treated as exacerbations by physicians in the absence of a deterioration in EXACT score (78). This discrepancy has been replicated in both observational studies (56) and clinical trials (57). In the ATTAIN study only 34.8% of all HCRU events met the threshold for a symptom-defined event using the EXACT (Figure 4) (57). However, as discussed previously, HCRU events are susceptible to patient and physician attitudes, as well as variation in healthcare provision. This view is corroborated by evidence of differential geographic variation in HCRU exacerbation frequency, compared with relatively consistent rates of symptom (EXACT)-defined events across different locations in the ATTAIN trial (57). Furthermore, studies using the EXACT have provided additional evidence that baseline disease severity plays a role in patient health seeking behavior and physician prescribing habits. Patients who experienced symptom (EXACT)-defined events accompanied by HCRU (reported) had a worse EXACT score when stable compared with patients with unreported (not accompanied by HCRU) symptom (EXACT)-defined events (55, 57), and the maximum EXACT score recorded during an exacerbation has been shown to be higher in treated compared to untreated events (56). Patients with only HCRU events had lower predicted FEV1 at baseline than patients with symptom (EXACT)-defined events only (57), and at exacerbation, patients exhibit smaller rises in EXACT score as baseline EXACT score increases (56). This suggests that as disease severity increases, patients are more likely to report and receive additional therapy at exacerbations associated with smaller increases in symptom intensity. More severe patients may also be more sensitive to changes in symptoms and be encouraged by clinicians to report any deterioration in symptoms earlier (56). This finding has also been replicated, in part, using CAT scores to measure exacerbation severity where not all patients experienced a significant rise in CAT scores at exacerbation (62). Symptom (EXACT)-defined exacerbations, like alternative symptom-defined events, are characterized by sustained symptom worsening that exceeds a pre-defined threshold for symptom deterioration and are therefore a standardized metric, providing an objective measurement of symptomatic change at exacerbation. As previously described, HCRU events are frequently driven by symptom tolerance and the patient’s decision to seek care, and therefore the symptom severity associated with HCRU events is highly variable. Hence, the low concordance between symptom (EXACT)-defined events and HCRU exacerbations is not a failure of the EXACT instrument (57). Instead, it must be appreciated that symptom-defined exacerbations, defined using the EXACT or other symptom diaries, and HCRU exacerbations are distinct and complementary entities, to be recorded and reported separately or in combination, as outcome measures in clinical trials. Future developmentsIncreasingly it is recognized that treatments should be targeted to appropriate patient groups to maximize clinical benefits whilst reducing adverse event risk and costs (79). Recent studies have shown that biologic therapies may be beneficial in a subgroup of COPD patients (80), although current biomarkers may be limited in their ability to identify these individuals (81). Established therapies have also shown benefit only when used in patients with key clinical characteristics, such as roflumilast in COPD patients with a bronchitic phenotype (82). Therefore, future studies should utilize PROs to identify specific symptomatic patient populations for recruitment to clinical trials and to target therapy appropriately. As novel anti-inflammatory and biologic therapies become widely explored as a method to reduce COPD exacerbations, it is likely that their benefits will be most pronounced not only in specific patient groups, but also against specific exacerbation phenotypes. PROs may be useful to provide additional outcome measures, and enhance treatment targeting, by phenotyping exacerbation events according to their symptomatic presentation. Digital instruments and wearable technologies may also provide supplementary endpoints in future trials to detect symptom and activity changes at exacerbation and increase sensitivity in combination with PROs (83). In a small non-interventional study of 17 patients where subjects were monitored using both the EXACT and an accelerometer, physical activity was found to decrease significantly at symptom (EXACT)-defined exacerbation, the reduction in activity being greatest during the first week of the event and remaining low for approximately 2 weeks after symptomatic resolution (84). Importantly, the combination of the EXACT and an objective monitor enabled activity changes during both reported and unreported exacerbations to be measured, providing evidence that the combination of PROs and wearable technologies can provide additional endpoints in COPD exacerbation studies by demonstrating both subjective and objective improvement in outcomes that are clinically relevant to patients (34). ConclusionsAn HCRU definition of exacerbations has certain challenges with considerable heterogeneity between patient and clinician behavior, variability between healthcare systems, and inability to detect unreported events. The inclusion of PROs, often combined with investigator assessment, should therefore be increasingly used to evaluate COPD exacerbations during clinical trials. The most extensively validated PRO in exacerbation studies is EXACT, which appears valuable to assess exacerbation frequency, duration, and severity, and has been qualified as an exploratory endpoint by both the FDA and EMA. Alternative e-Diaries may also represent a sensitive way of identifying exacerbations and providing information for the time course, recovery and characteristics of different types of events. We therefore advocate the use of standardized validated measures in prospective clinical studies to facilitate meta-analyses, advance our understanding of exacerbation frequency, duration, and severity phenotypes, and enable better understanding of patient treatment-seeking and physician prescribing behaviors. HCRU exacerbations are associated with lung function decline and mortality (26, 28). Furthermore, patients with a history of frequent (>2.92 per year) symptom-defined exacerbations, of which approximately 50% involve HCRU (reported), have been shown to have faster lung function decline compared to patients with a history of infrequent (<2.92) symptom-defined exacerbations (85). However, at present data relating unreported symptom-defined exacerbations alone and such long-term outcomes is limited. The relationship between symptom-defined events and these key endpoints is an important area for future study that should be explored as validated PROs become increasingly used to evaluate exacerbations in clinical trials. The combination of PRO and HCRU data should ultimately enhance evaluation of the effects of new interventions to prevent or treat exacerbations of COPD, thus supporting the transition to more personalized, patient-focused therapy.References1.Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-13.2.Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204.3.Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Jr., Criner GJ, et al. 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Respiratory Medicine. 2015;109(12):1546-52; DOI: 10.1016/j.rmed.2015.10.011 (66).Figure 4. Number of patients with HCRU and/or EXACT-identified, symptom-defined events in the ATTAIN trial. Reproduced with permission from the ? ERS 2014. European Respiratory Journal Nov 2014, 44 (5) 1156-1165; DOI: 10.1183/09031936.00038814 (57). ................
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