The Economic Impact of Exacerbations of Chronic Obstructive Pulmonary Disease and Exacerbation Definition: A Review

ABSTRACT

Chronic obstructive pulmonary disease (COPD) poses a significant economic burden on society, and a substantial portion is related to exacerbations of COPD. A literature review of the direct and indirect costs of COPD exacerbations was performed. A systematic search of the MEDLINE database from 1998–2008 was conducted and supplemented with searches of conference abstracts and article bibliographies. Articles that contained cost data related to COPD exacerbations were selected for in-depth review. Eleven studies examining healthcare costs associated with COPD exacerbations were identified. The estimated costs of exacerbations vary widely across studies: $88 to $7,757 per exacerbation (2007 US dollars). The largest component of the total costs of COPD exacerbations was typically hospitalization. Costs were highly correlated with exacerbation severity. Indirect costs have rarely been measured. The wide variability in the cost estimates reflected cross-study differences in geographic locations, treatment patterns, and patient populations. Important methodological differences also existed across studies. Researchers have used different definitions of exacerbation (e.g., symptom- versus event-based definitions), different tools to identify and measure exacerbations, and different classification systems to define exacerbation severity. Unreported exacerbations are common and may influence the long-term costs of exacerbations. Measurement of indirect costs will provide a more comprehensive picture of the burden of exacerbations. Evaluation of pharmacoeconomic analyses would be aided by the use of more consistent and comprehensive approaches to defining and measuring COPD exacerbations.

Keywords: :

• COPD
• Exacerbation
• Cost
• Economic
• Definition
• Unreported

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a common disease that has considerable health and economic consequences. In the United States during 2000, COPD was the cause of 8 million physician office and hospital outpatient visits, 1.5 million emergency department visits, 726,000 hospitalizations, and 119,000 deaths (1). COPD in the United States is estimated to result in direct costs of $29.5 billion and indirect costs of $20.4 billion in 2010 (2).

A significant portion of the economic burden of COPD is associated with exacerbations of COPD. Exacerbations are estimated to account for 50%–75% of the cost of healthcare services for COPD (3). Exacerbations often lead to hospital stays, physician visits, additional medication, and can have serious consequences with respect to quality of life, lung function, and mortality. The Global Initiative on Chronic Obstructive Lung Disease (GOLD) stated that the prevention and treatment of exacerbations should be a key goal of COPD management (4).

Generally, an exacerbation of COPD is a “sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations that is acute in onset and may warrant additional treatment in a patient with underlying COPD”(5). This definition is broad and reflects the fact that exacerbations have varied effects and symptoms. Currently, there is no universally agreed upon method to identify exacerbations. Investigators have used definitions based on the types of additional healthcare resources used (event-based definitions), the presence of various reported symptoms (symptom-based definitions), or combinations of these two approaches (combined definitions). The variation in criteria and methods used by investigators to identify exacerbations complicates the comparison of study results. In the words of one investigator, “Unfortunately, many definitions [for exacerbations] exist, many authors employ substantively different criteria, and many studies poorly describe their inclusion criteria”(6). This paper reviews the recent literature on economic costs of COPD exacerbations. Special attention is given to the methodological approaches used to define and identify exacerbations in cost studies.

MATERIALS AND METHODS

A systematic review of the literature was conducted to identify studies on the direct and indirect costs of COPD exacerbations. The MEDLINE database was used to identify articles published between May 1998 and May 2008. The search criteria consisted of a title and/or abstract that contained the terms COPD/chronic obstructive pulmonary disease, exacerbation(s), and cost(s)/economic; only English language journals were searched.

Studies that satisfied these criteria were examined to identify a smaller set of articles that warranted in-depth review and analysis. This computerized search was supplemented by searching meeting abstracts obtained from organizations and conference websites offering free and searchable abstracts (e.g., American Thoracic Society (ATS) and CHEST), examining article bibliographies, and expert opinion. The selected studies had to have a primary focus on empirical measurement of the direct and/or indirect costs of COPD exacerbations. The selected studies had to contain data on the monetary cost per exacerbation; studies that reported only changes in healthcare utilization or that dealt exclusively with the costs of COPD in general were not included.

Information extracted from these studies included data on cost, the location of the sample population, patient selection criteria and characteristics, and the definitions of exacerbation and exacerbation severity. Cost data were converted to 2007 U.S. dollars using currency exchange rates and inflation indices for health/medical goods based on the region of the study. To aid our critical analysis of this literature, we also reviewed additional literature related to topics such as the definition of exacerbations and the methods to measure and identify exacerbations.

RESULTS

The initial search of the MEDLINE database yielded 184 studies. The abstracts for these studies were read, and 33 of the full articles were examined, as most of these studies did not focus on the cost of exacerbations. Cost-of-illness studies that examined all COPD-related costs were not included in this review unless they specifically addressed exacerbations. A total of 11 original research articles on the costs of COPD exacerbations were selected for in-depth review and included as part of this review (7–17).

Eight of the eleven studies were identified in the initial search of the MEDLINE database (7, 8, 10–12, 14). Three additional studies were selected after additional review of conference abstracts (13), bibliographies of reviewed studies (17), and expert opinion (9). All 11 studies (7–17) calculated the mean or median direct cost of an exacerbation, four studies (10–13) calculated the direct cost of exacerbations based on exacerbation severity, and 3 studies (8, 16, 17) investigated the cost of exacerbations based on patients’ underlying severity of COPD. One study reported the indirect cost of lost work days per exacerbation (9).

The estimated cost per exacerbation varies substantially, ranging from $88 to $7,757 (2007 U.S. dollars). The magnitude of costs depends on the severity of the exacerbation (e.g., whether a hospitalization was involved), and a variety of approaches were used to define an exacerbation. Table 1 presents details of the reviewed studies. Cost estimates are reported both in the year and currency used in the original articles as well as 2007 US dollars (in parentheses).

Mean cost and cost categories

Eleven studies (7–17) investigated the overall mean direct cost related to exacerbations. Categories of exacerbation-related costs often considered in these studies included hospitalization, medication, diagnostic and laboratory testing, outpatient and general practitioner visits, and transportation. Most researchers concluded that hospitalizations accounted for a majority of the costs. Figure 1 shows the mean cost per exacerbation and cost-type breakdown.

Simoens et al. (7) studied patients suffering from an exacerbation as defined by the symptom-based definition of increase in sputum purulence, increase in sputum volume, and worsening of dyspnea. The median direct cost of exacerbation treatment was €5,514 ($7,757) with hospital stays accounting for 75% of total costs, diagnostic and laboratory tests for 20%, and medications for the remaining 5%. Many of the patients in the study were suffering from severe COPD, as inclusion in the study required admission to a hospital and 69 of the 267 participants died during the study period.

In a 12-month study, O’Reilly et al. (8) followed 149 British patients who were admitted to a hospital and diagnosed as experiencing an exacerbation. The mean direct cost of an exacerbation was £ 2,130 ($4,659) with 72%, 23%, and 5% being attributable to bed costs, other services and investigation costs, and medication costs, respectively. No specific definition for an exacerbation was used in this study; rather, exacerbations were diagnosed by physicians or respiratory nurses. The study sample was suffering from severe COPD as patients required hospital admission for study inclusion.

Figure 1.  Mean Cost per COPD Exacerbation and Cost Type Breakdown

Jahnz-Różyk et al. (9) analyzed the direct and indirect costs of exacerbations in 73 patients treated for exacerbations in hospital pulmonary departments or in ambulatory care. This study evaluated the economic value of lost work days associated with exacerbations; it was the only study that we found to estimate indirect costs of exacerbations. The overall mean cost of an exacerbation was €1,397 ($1,953). The largest cost category was in-hospital direct costs, while indirect costs accounted for 14% of the total cost.

Mittmann et al. (10) studied the direct costs of moderate and severe exacerbations from a Canadian perspective in a year-long prospective, observational study. The authors identified exacerbations as a complex of COPD-related symptoms including one or more of cough, wheeze, dyspnea, or sputum production lasting three or more days. Exacerbations were then classified based on level of health care use. We calculated a weighted average cost per exacerbation of CAD 1,951 ($1,850) using the cost data presented in the study. Hospitalization costs comprised approximately 87% of total costs. Because the authors excluded patients with mild exacerbations, this study reflects a study population suffering more severe exacerbations.

Oostenbrink et al. (11) found that the overall mean direct cost of exacerbations suffered by patients over the age of 40 was €720 ($1,257). The major costs included €454 ($793) for general/pulmonary wards, €101 ($176) for intensive care units, €53 ($93) for diagnostic testing, €54 ($94) for medications, and €38 ($66) for healthcare professional visits. General/pulmonary ward and intensive care unit costs accounted for approximately 77% of the total costs of treating an exacerbation. The authors found that a small number of the total exacerbations accounted for a large portion of the total costs. The 16% of exacerbations that were associated with hospitalization accounted for approximately 90% of the total costs of all exacerbations. The authors used a symptom-based exacerbation definition that relied on patients’ evaluation of the severity of their symptoms. The study data were collected in a clinical trial setting where patients were monitored daily. Therefore, it is possible that results may differ from data collected in a typical setting where patients are not followed as closely.

Andersson et al. (12) studied 61 patients who reported additional respiratory problems or influenza during the previous winter. These exacerbations were categorized by severity based on resource use, ranging from increased self-medication to hospital admission. The authors determined the mean direct costs of an exacerbation to be SEK 3,163 ($604), computed as the weighted average of all exacerbation severities. The largest component of these costs was attributable to hospitalizations (67%). Costs associated with visits to an emergency department and contacts with nurses or doctors (at a GP or hospital) accounted for 24% of total costs, and smaller fractions were attributable to drugs (6%) and transportation (3%). The study stated that 35%–45% of total per capita healthcare costs for COPD were attributable to exacerbations. This study was subject to recall bias related to interviewing patients about their healthcare use during the previous winter. Also, the study has a small sample size and is subject to seasonality variation because data were only collected for the winter.

In the United Kingdom, Price et al. (13) collected data on healthcare utilization as part of a clinical trial. The authors classified 194 exacerbations as mild, moderate, or severe depending on level of healthcare utilization. We calculated a weighted average direct cost per exacerbation of £ 214 ($556) using the cost data presented. A detailed breakdown of costs categories was not reported by the authors.

Miravitlles et al. (14) determined the direct costs of managing exacerbations of chronic bronchitis and COPD in an ambulatory setting in Spain. Exacerbations were identified using a combined definition: increased dyspnea and increased production and purulence of sputum that led to a change or increase in medication. The follow-up period was one month following the initial visit to the general practitioner. The average direct cost of treating all patients with acute exacerbations of chronic bronchitis and COPD was $159 ($168) per exacerbation with hospitalizations accounting for 58%, drug acquisition costs for 32%, clinic visits for 5%, and emergency department visits for 4% of the total costs. Laboratory and diagnostic tests were included in the costs of emergency department visits and hospitalizations. The authors note that the overall costs are lower in this study than in other studies because prices of medicines and medical fees in Spain are generally among the lowest in Europe. Additionally, the recruitment of patients from an ambulatory setting, as opposed to a hospital, results in a study population suffering less severe exacerbations.

Llor et al. (15) compiled data on 1,656 patients with chronic bronchitis and COPD that visited one of 252 participating physicians at primary health care centers. A symptom-based definition for exacerbation was used, whereby at least two of the following symptoms were observed: increase in the usual dyspnea, increase in the sputum volume, and/or an increase of the purulence of the sputum. The average cost of an exacerbation was €119 ($168). Patients that required attendance in emergency wards and hospitalization accounted for only 6.3% and 2% of the patients in the sample, respectively. The in-patient cost accounted for 38% of the average cost per exacerbation.

In a study of 286 patients, Schermer et al. (16) relied on general practitioners to identify exacerbations using a standardized data extraction form that collected data on drug use and other healthcare utilization (e.g., referrals to respiratory consultants and emergency room (ER) visits). The mean direct cost per exacerbation was €66 ($116), with 16% of the costs associated with hospitalizations. Out of 507 exacerbations, one exacerbation resulted in a hospital admission and one exacerbation necessitated an ER visit. The cost of the hospital admission and ER visit were €2,237 ($3,906) and €161 ($281), respectively. Based on the study inclusion criteria, there was an underrepresentation of patients suffering from severe exacerbations.

Masa et al. (17) retrospectively analyzed 363 patients with COPD in Spain, identified from a representative sample of the general population aged 40–69 years. This study estimated the costs associated generally with COPD, but it reported exacerbation-specific costs associated with the direct cost of medication in an ambulatory setting. As a result, the estimated costs reflect exacerbations that were mild in nature, did not capture the cost of professional services, and did not require hospitalization. They estimated cost per exacerbation at €54 ($88). This study was based on interviews with patients who recalled their experiences in the previous 12 months, which make these estimates relatively uncertain.

Cost by exacerbation severity

Four studies have broken down the cost of exacerbations by exacerbation severity (10–13). The studies uniformly show that the more severe an exacerbation, the greater the healthcare utilization and cost. Given the fact that the definition of exacerbation varies across studies, it is not surprising that studies also use different definitions and approaches for classifying the severity of exacerbations. Figure 2 shows the cost per exacerbation by severity.

Figure 2.  Cost per COPD Exacerbation by Severity

Mittmann et al. (10) classified moderate and severe exacerbations based on health care use: moderate exacerbations required visits to an outpatient facility or emergency department and a change in medication while severe exacerbations were those that required hospitalization. The average costs of treating moderate exacerbations were CAD 641 ($608), while the overall mean costs of treating a severe exacerbation were CAD 9,557 ($9,060), or 15 times higher than a moderate exacerbation. Including both moderate and severe exacerbations, hospital-related costs (hospital stay and hospital laboratory and diagnostic tests) accounted for 87% of total mean costs.

Oostenbrink et al. (11) categorized awareness of tolerable signs/symptoms as mild exacerbations, signs causing discomfort with normal activity as moderate exacerbations, and incapacitating exacerbations as severe. The authors’ reasoning for this approach was an attempt to negate different criteria for hospitalization across countries. The average costs per exacerbation of mild, moderate, and severe exacerbations were €86 ($150), €579 ($1,011), and €4,007 ($6,996), respectively. Costs of severe exacerbations were 7 and 47 times higher than those of mild and moderate exacerbations. About 86% of costs of severe exacerbations resulted from inpatient hospital days and 6% from diagnostic tests.

Andersson et al. (12) classified exacerbations into four severity categories. Mild exacerbations were self-managed by the patient, mild/moderate exacerbations required telephone contact with a healthcare institution and/or treatment with antibiotics or systemic corticosteroids, moderate exacerbations required a visit to a GP or clinic, and severe exacerbations required visits to an ER department or hospital admission. The average healthcare costs per exacerbation were SEK 120 ($23), SEK 354 ($68), SEK 2,111 ($403), and SEK 21,852 ($4,172) for mild, mild/moderate, moderate, and severe exacerbations, respectively. On average, severe exacerbations were 10 times more expensive than moderate exacerbations, 62 times more expensive than mild/moderate exacerbations, and 182 times more expensive than mild exacerbations. The median length of hospitalization was 6 days (mean 6.6 days) for severe exacerbations (by definition, hospitalizations occurred only in severe exacerbations). Of the total direct costs of treating severe exacerbations of SEK 21,852 ($4,172), hospitalization costs amounted to SEK 20,352 ($3,886), 93% of total costs.

Price et al. (13) classified exacerbations as mild, moderate, or severe, depending on whether the exacerbation was self-managed by the patient, treated by a family physician or outpatient clinic, or required hospital admission, respectively. Mild, moderate, and severe exacerbations cost, on average, £ 15 ($39), £ 95 ($248), and £ 1,659 ($4,313), respectively. For severe exacerbations, inpatient care accounted for 92% of total costs. For moderate exacerbations, outpatient and general practitioner costs accounted for over 70% of total costs.

Cost by COPD severity

Three studies calculated the cost of exacerbations in relation to the severity of COPD (as opposed to severity of the exacerbation) (8, 16, 17). COPD severity was typically categorized based on measurements of FEV₁ % predicted, a measure of lung function. The studies varied in how they defined COPD severity.

O’Reilly et al. (8) concluded that total mean costs per exacerbation for patients with FEV₁ % predicted < 50% were £ 2,234 ($4,886), or about 13% higher than for patients with FEV₁ % predicted ≥ 50% (£ 1,979 ($4,329)).

Schermer et al. (16) categorized patients suffering from exacerbations by severity of airflow obstruction based on European Respiratory Society criteria (no obstruction: FEV₁ % predicted ≥ 80%; mild: between 70% and 80%; moderate: between 50% and 70%; severe: less than 50%). Mean annual exacerbation costs per patient were €40 ($70), €53 ($93), €61 ($107), and €92 ($161) for the no, mild, moderate, and severe airflow obstruction subgroups. The study did not find any relationship between exacerbation occurrence rate and severity of airflow obstruction. The increase in costs with severity was due to more physician consultations, diagnostic procedures, and prescription of reliever medication.

Masa et al. (17) used the same COPD severity scale as Schermer et al. (16). Restricting their analysis to the direct cost of medications used to treat exacerbations in an ambulatory setting, they found that the cost of moderate and severe exacerbations per patient per year were 28% and 63% greater than the cost of mild exacerbations, respectively.

DISCUSSION

COPD is the fourth-leading cause of chronic morbidity and mortality in the United States and imposes a considerable economic burden (1). Exacerbations of COPD are a significant contributor to the cost-of-illness. The American Thoracic Society and European Respiratory Society (ATS/ERS) estimate that exacerbations account for 50%–75% of COPD-related costs (3), while other studies have estimated that fraction to range from 35%–84% (12, 18, 19).

This study reviewed the literature on the direct and indirect costs of COPD exacerbations. Despite the importance of exacerbations, we found relatively few cost studies that have focused specifically on exacerbations. There is substantial variability in the findings reported in these studies. The range of estimated costs per exacerbation was $88 to $7,757; these estimates differ by a factor of 88. Hospitalization was identified as the largest cost category, accounting for 38%–93% of exacerbation-related costs (excluding the cost estimates of Schermer et al. (16) and Masa et al. (17), which focused almost entirely on exacerbations that did not involve hospitalizations). The two studies with the lowest percentages in this range (58% and 38%) were Miravitlles et al. (14) and Llor et al. (15), where patients were only enrolled in the studies if they were initially treated as outpatients, and thus had exacerbations that were less severe than the other studies. The studies also found that severe exacerbations were substantially more expensive than mild or moderate exacerbations.

It is not surprising that the literature contains cost estimates that vary substantially. The studies were conducted in different countries: Belgium (7, 11), United Kingdom (8, 13), Poland (9), Canada (10), Netherlands (11, 16), Sweden (12), and Spain (14, 15, 17), which may have different types of health care systems and different treatment patterns. It should be noted that the Burden of Lung Disease Initiative (BOLD) is currently being implemented in an effort standardize the collection of COPD prevalence and resource utilization data across countries (20, 21).

In addition to cross-country differences, the study populations differed with respect to the severity of their conditions. For example, the two studies that reported the highest cost per exacerbation (7, 8) included only those patients who were hospitalized for an exacerbation. On the low-cost end of the spectrum (see Figure 1), only one exacerbation in the Schermer et al. (16) study necessitated a hospital admission, while the exacerbation costs reported by Masa et al. (17) were associated strictly with medications used in an ambulatory setting. The other studies in Figure 1 reflected exacerbations that were treated in both hospital and outpatient settings.

Another reason why such variability exists in the cost estimates is that these studies use different methods to define and identify exacerbations. This is a fundamental methodological issue that must be considered in interpreting study results and must be critically examined by researchers undertaking studies of exacerbation-related outcomes (e.g., health economics and outcomes research on new pharmaceuticals).

ATS/ERS define a COPD exacerbation as “an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management” (3). This definition is broad and reflects the fact that exacerbations have varied effects and symptoms. As a result, researchers must wrestle with the fact that this definition does not translate easily into a uniform method of analyzing exacerbations in a research setting. In response, clinical investigators have employed various criteria to identify an exacerbation. Definitions broadly fall into three groups: event-based, symptom-based, and a combination of the two.

Event-based exacerbation definitions are contingent on the use of additional healthcare resources (12, 13, 16). For example, the Andersson et al. (12) and Price et al. (13) studies identify exacerbations by whether a patient self-managed the exacerbation (e.g., increasing the dose of current medication), visited a general practitioner or outpatient clinic, or required a visit to an emergency room or hospital admission.

Event-based definitions have the advantage of being based on objective data that can sometimes be collected with relative ease (e.g., retrospective administrative claims data are generated in the normal course of care). However, a variety of specific criteria have been used to identify exacerbations; as one researcher noted, “Without a consistent and standardized definition of an outcome, it is impossible to compare one trial with another—or even one medication against another—to determine the relative efficacy of different therapies in reducing the rate of COPD exacerbations” (22). In addition, event-based definitions do not capture the exacerbations for which patients do not (or cannot) seek additional healthcare resources. Approaches to accounting for so-called unreported exacerbations are discussed below.

Symptom-based definitions were used in four of the reviewed cost studies. For example, the Simoens et al. (7), Jahnz-Różyk et al. (9), Oostenbrink et al. (11), and Llor et al. (15) studies used definitions that are variations on the most commonly used symptom-based definition developed by Anthonisen et al. (23), which centers on worsening of dyspnea, increase in sputum purulence, and increase in sputum volume. Anthonisen categorized exacerbation severity as follows: patients with type 1 (severe) exacerbations have all 3 of the above symptoms, patients with type 2 (moderate) exacerbations have 2 of 3 of the symptoms, and patients with type 3 (mild) exacerbations have one of these symptoms, as well as one of the following clinical criteria: an upper respiratory tract infection in the past 5 days, fever without another apparent cause, increased wheezing, increased cough, or increase in respiratory rate or heart rate by 20% above baseline.

An important drawback of symptom-based definitions is the subjectivity related to patient reporting (i.e., how large must a symptom change be for it to “matter” to a patient and for the patient to report a change in condition?). Symptom-based definitions have not been validated in terms of reliability and responsiveness. (24) Additionally, not only are reporting inconsistencies possible, but the patient may suffer from a co-morbid condition that has similar symptoms to COPD or may contribute to COPD symptoms. (25) In this case, reporting symptoms solely attributable to COPD is not possible.

In view of these shortcomings of symptom-based definitions, researchers are developing a symptom-based method of measuring exacerbations that possesses better characterized measurement properties. The EXACT-PRO initiative is developing, validating, and disseminating a patient-reported outcome measure to evaluate exacerbation frequency, severity, and duration in a standardized manner. It is based on a 3-minute, 14-item daily diary completed by the patient on a personal digital assistant (PDA) (26–28).

Combined definitions of exacerbations rely on event- and symptom-based elements. Miravitlles et al. (14) identified exacerbations using symptom changes that led to a change in treatment. The combined definitions used in clinical studies generally incorporate a worsening of the symptoms used in the Anthonisen definition and an event-based measure such as an increase in medication. Mittmann et al. (10) defined exacerbations using symptoms of cough, wheeze, dyspnea, or sputum production lasting three or more days and then categorized exacerbation severity based on whether the patient sought treatment at an outpatient facility or was hospitalized.

It is unlikely that there is a necessary correlation between the type of definition used and the magnitude of the assessed costs. Indeed, the severity of the exacerbation and whether it involves a hospitalization are likely to be the major driver of costs. Nevertheless, the estimated cost of an exacerbation would be affected by the definitional approach because of differences in what is considered an exacerbation. Calverly et al. (24) followed 796 patients in 11 countries over a one-year period. Using an event-based approach, exacerbations were defined as “the use of oral corticosteroids and/or antibiotics and/or hospitalization….”

They used a variety of criteria based on symptoms of dyspnea, cough, chest tightness, and night-time awakenings as the basis for identifying a symptom-based exacerbation. The authors analyzed the extent to which there was overlap or “concurrence” between symptom- and event-based exacerbations. They concluded that there was “poor” concurrence between the two approaches. For example, concurrence ranged from 32% to 70.5%, depending on the criteria used for a symptom-based definition.

O’Reilly et al. (29) also investigated the impact of different exacerbation definitions. The study observed 127 patients from a primary care facility for 12 months. An event-based exacerbation was identified by considering a patient's use of antibiotics, oral corticosteroids, or call or visit to a nurse or physician. A symptom-based exacerbation was based on a scoring system developed by the authors. The study found that 41% of event-based exacerbations were identified using the symptom-based definition. Approximately 54% of symptom-based exacerbations were identified using the event-based definition. These two studies illustrate how the analyses of exacerbations, and the associated conclusions, can be highly sensitive to the manner in which an exacerbation is defined.

Researchers have also noted that patients with COPD likely experience exacerbations that are “unreported.” Researchers have found that unreported exacerbations comprise 40%–68% of total exacerbations (30–36). An unreported exacerbation may not entail the use of healthcare resources in the short-term but may lead to increased healthcare utilization in the long-term. For example, Wilkinson et al. (34) concluded that patients who reported a higher percentage of their exacerbations to their physician had a better health-related quality of life (as measured at time of recruitment and during the first annual review) and were less likely to be hospitalized for the management of an exacerbation. Other studies that assessed the health status of patients based on whether they reported an exacerbation had findings that were not consistent with those of Wilkinson (30–33, 35, 36).

Our study reveals that there is very little information on the indirect cost of an exacerbation, and this is an area where more research is needed to fully understand the burden of exacerbations. Due to the nature of COPD and COPD exacerbations, where many patients may no longer be in the workforce, it is essential to assess not only the cost of reduced work productivity—both absenteeism (days missed from work) and presenteeism (productivity at work)—but also the cost of restricted activity and burden on informal caregivers.

This review of the literature is subject to several limitations. The quality of the reviewed studies varies significantly. A number of studies are retrospective in nature, are based on small samples sizes, and are based on patient recall of historical events. In addition, it is possible that our search method did not capture all relevant studies in the literature. For example, our computerized search of the literature was restricted to English-language journals.

CONCLUSION

The literature provides widely diverging estimates of the cost of COPD exacerbations. Nevertheless, several generalizations can be made. First, hospitalizations are a primary driver of the overall cost related to exacerbations. Second, costs are closely related to exacerbation severity (which is related to whether a hospitalization is necessary). Finally, the mean costs of exacerbations vary widely across studies due to geographic differences, patients, and methods for defining exacerbations.

In particular, the definition of an exacerbation is a fundamental aspect of clinical and pharmacoeconomic research, yet there is no universally accepted approach. The available evidence indicates that use of symptom- and event-based approaches can lead to substantially different conclusions regarding whether an exacerbation has occurred. This obviously creates difficulty in interpreting results across multiple studies. In this era of growing interest and use of comparative effectiveness research, our review highlights the potential differences and biases that may exist in studies of COPD exacerbations. A coherent and uniform definition may be necessary.

Declaration of interest

Toy, Gallagher, and Duh are employees of Analysis Group, Inc., which has received funding from Novartis Pharmaceuticals Corporation for the preparation of this manuscript. Stanley and Swensen are employees of Novartis, which develops products in the area of COPD; they also own stock in Novartis. The authors alone are responsible for the content and writing of the paper.