Introduction
============

COPD, a progressive respiratory condition, is among the leading causes of death in the West.[@b1-copd-12-529] COPD becomes more common with age[@b2-copd-12-529] and has been shown to have a substantial impact on health outcomes such as health status and health-related quality of life,[@b3-copd-12-529],[@b4-copd-12-529] health care resource use,[@b5-copd-12-529] and work productivity.[@b5-copd-12-529]--[@b7-copd-12-529] Indeed, the total cost of COPD in the US alone is nearly 50 billion dollars annually.[@b8-copd-12-529] Although forced expiratory volume in 1 second (FEV~1~) has been a standard marker for physiological change in COPD, research has suggested only a modest association between FEV~1~ and a patient's symptoms, which primarily include dyspnea, cough, and sputum production.[@b9-copd-12-529] As a result, understanding the symptom experience is an important part of proper COPD management as symptoms may relate more strongly to certain patient outcomes than standard clinical markers.[@b9-copd-12-529] Past research has suggested significant relationships between symptoms and health outcomes.[@b10-copd-12-529]--[@b13-copd-12-529] For example, an Internet survey conducted by Partridge et al[@b11-copd-12-529] found that dyspnea was among the most common symptoms and adversely affected patients' ability to perform their normal daily activities. However, these studies have generally focused on a broad COPD sample and may have included those not receiving proper treatment. As a result, the aim of this study was to examine the prevalence of symptoms and their association with health outcomes among patients receiving the appropriate standard of care (SOC) based on their modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014 group classification ("modified" due to lack of spirometry data).[@b14-copd-12-529]

Methods
=======

Data source
-----------

This study included data from the 2013 US National Health and Wellness Survey (NHWS) and the combined 2011 and 2013 5EU NHWS (including France, Germany, Italy, Spain, and UK; no 2012 5EU NHWS data were collected). Two 5EU surveys were used to maximize sample size and statistical power. The method for each region is described in more detail later.

In the US (N=75,000; response rate =13.53%), the NHWS is fielded separately in each of the first three quarters in each year (first quarter: January through March; second quarter: April through June; third quarter: July through September). Potential respondents for the NHWS were identified through the general panel of Lightspeed Research (LSR), a company which maintains various online respondent panels. All adults (aged 18 years and older) are eligible to join these respondent panels and do so by responding to advertisements in e-newsletters and online banner advertisements.[@b15-copd-12-529] Panel recruitment is not done purely by convenience, as an attempt to match the demographics of each country is made.[@b16-copd-12-529] Members of the panel receive periodic (no more than 12 per year) invitations to participate in a variety of online surveys (eg, consumer package goods, automotive, health, etc).

The NHWS uses these panels as its sample source but imposes a stratified random sample framework. Each year, data from the Current Population Survey of the US Census[@b17-copd-12-529] were used to identify the relative proportions of age, sex, and race/ethnicity groups in the US; these proportions were then mimicked during the recruiting of panel members to ensure that the final NHWS sample matched the demographic proportion of the US. Several peer-reviewed publications have previously compared demographic distributions and prevalence figures from the NHWS with other governmental sources.[@b18-copd-12-529]--[@b20-copd-12-529] For example, Bolge et al[@b18-copd-12-529] found that the prevalence rates between the NHWS and the National Health Interview Survey were within 3% of one another for 10 of the 12 conditions assessed (exceptions were with high cholesterol and depression).

The 2011 5EU (N=57,512; response rate =19.69%) and 2013 5EU NHWS (N=62,000; response rate =15.95%) methods are largely the same as described for the US. Aside from slightly different response choices being used where required (eg, health insurance, household income, etc), the survey questions are identical to that of the US version. Respondents were recruited online using the same panel and in the same manner as the US NHWS. A stratified random sample is also used in the 5EU, but only age and sex are the strata of interest (race/ethnicity data were not collected). The source used for designing the sample frame was the International Database of the United States Census,[@b21-copd-12-529] which reports age by sex distributions of each country in the world. For each country, the age and sex distributions of the adult population were mimicked during recruitment. Written (electronic) consent was obtained from all study respondents. The protocols and surveys associated with the 2013 US NHWS, 2011 5EU NHWS, and 2013 5EU NHWS were all reviewed and approved by an independent institutional review board (Essex IRB, Lebanon, NJ; Protocol numbers: KH-NHWS-US13, KH-NHWS-EU11, and KH-NHWS-EU13, respectively).

Sample
------

Only patients who are using the appropriate SOC based on the modified GOLD 2014 guidelines were included in the analyses. The SOC depends upon the patient's modified GOLD 2014 group classification,[@b14-copd-12-529] which was defined by a combination of symptoms (assessed using the modified Medical Research Council Dyspnea scale \[mMRC\]) and exacerbation history ([Figure 1](#f1-copd-12-529){ref-type="fig"}). Based on their modified GOLD 2014 group classification and self-reported medication use ([Table 1](#t1-copd-12-529){ref-type="table"}), patients were further classified as whether or not they were using the appropriate SOC based on the modified GOLD 2014 guidelines.[@b14-copd-12-529] A total of 2,006 in the 5EU and 1,666 in the US met the criteria and were included in the analyses.

Measures
--------

### Symptoms

For those who self-reported being diagnosed by a physician with COPD, emphysema, or chronic bronchitis, all patients reported the frequency (on a five-point Likert-type scale of "always", "often", "sometimes", "rarely", and "never") of the following symptoms: dyspnea, fits of coughing, infection, mucous production, and wheezing.

### Demographics

Demographic variables assessed in the NHWS included country (5EU only), sex, age, race/ethnicity (US only), marital status, employment, annual household income, education, and health insurance.

### Health history

Health history variables included smoking habits, alcohol consumption, exercise, and body mass index (BMI) category (which was calculated based on self-reported height and weight). The Charlson comorbidity index (CCI), which represents a weighted sum of multiple self-reported comorbid conditions predictive of mortality, was also included.[@b22-copd-12-529] Individual comorbidities of particular relevance to COPD were also assessed separately outside the CCI. These included asthma, allergic rhinitis, cardiovascular disease (defined by having any one of the following: congestive heart failure, myocardial infarction, arrhythmia, atrial fibrillation, transient ischemia attack, or stroke), and depression.

### Disease history

The following information on a patient's COPD history was also included: number of years they have been diagnosed, presence of exacerbations, duration of exacerbations in the past 6 months, and main cause of COPD episodes. A self-reported adherence measure, the 8-item Morisky Medication Adherence Scale (MMAS-8),[@b23-copd-12-529] was asked of the NHWS 2013 respondents about their COPD medications specifically. The MMAS-8 contains eight items, which each represents a non-adherent behavior (eg, stopping medication when you feel worse; forgetting medication when traveling, etc). Patients are categorized into high adherence, medium adherence, or low adherence according to the established scoring algorithm.

### Health outcomes

Health status was assessed using the Short Form-36 version 2 (SF-36v2) (in the US and the 2013 5EU data) and the Short Form-12 version 2 (SF-12v2) (in the 2011 5EU data).[@b24-copd-12-529],[@b25-copd-12-529] The physical component summary (PCS) and mental component summary (MCS) scores (range 0--100) were included along with health state utilities (range 0--1). Work productivity and activity impairment (WPAI) was assessed using the WPAI questionnaire (WPAI-GH) (range 0%--100%).[@b26-copd-12-529] Patients self-reported the number of traditional health care provider visits (eg, general internist, pulmonologist, gynecologist, psychologist, etc), the number of emergency room (ER) visits, and the number of times hospitalized in the past 6 months.

Statistical analysis
--------------------

The distribution of COPD symptoms was reported descriptively, using frequencies, percentages, mean, and standard deviations (SDs). Differences between patients who reported experiencing at least one symptom "always" versus patients who did not report experiencing any symptom "always" were examined with respect to demographics, health history, and disease history variables using chi-square tests and one-way analysis of variance (ANOVA). The intent of this analysis was to identify variables that differ by symptom frequency in order to include them as covariates in the regression modeling described later.

A symptom score was then developed by summing the frequency ratings of each of the five symptoms assessed. This symptom score was then used as a primary predictor of health outcomes in a series of generalized linear models. The distribution and link function varied depending upon the outcome being assessed (normal and identity, respectively, for health status variables; negative binomial and log, respectively, for work productivity and health care resource use variables). Covariates including all variables were significantly different between symptom presence (eg, at least one symptom appearing "always") and symptom absence groups in the abovementioned bivariate analysis at *P*\<0.25 (age and sex were included as covariates regardless of significance).

Since the symptom experience may be a function of the degree to which patients are adherent to their medication, we also reported the level of self-reported medication use. Further, we also examined the relationship between non-adherence and health outcomes among these patients.

Results
=======

A total of 2,006 patients in the 5EU and 1,666 patients in the US were included in the analyses ([Table 2](#t2-copd-12-529){ref-type="table"}). Most patients were male (54.3% and 58.8% in the 5EU and US, respectively) with a mean age of 57.6 years (SD =13.2) in the 5EU and 62.0 years (SD =12.2) in the US. Nearly all patients (99.7% and 99.8% in the 5EU and US, respectively) reported at least some frequency (ie, not "none") of at least one of the five symptoms assessed ([Figures 2](#f2-copd-12-529){ref-type="fig"} and [3](#f3-copd-12-529){ref-type="fig"}). Further, 83.5% and 85.6%, respectively, of patients reported experiencing at least one symptom "often".

Dyspnea was the most common symptom (62.8% and 70.0% reported experiencing it "always" or "often"). Coughing, wheezing, and mucous production were also common and generally similar in their frequency (\~32%--47% reporting experiencing these symptoms "always" or "often"). Infections were the most infrequently reported symptom (only 20.3% and 12.9% reported experiencing them "always" or "often"). However, there were significant differences across modified GOLD 2014 groups with respect to symptom frequency in the 5EU. For all symptoms, patients in Group D reported the highest frequency (all *P*\<0.05). In the case of coughing and wheezing, patients in Group B reported the second highest frequency. The differences across modified GOLD 2014 groups for the US mirrored the results found in 5EU (results not shown).

Differences between patients who experienced at least one symptom were always compared with all other patients with respect to demographics, health history, and disease history ([Table 3](#t3-copd-12-529){ref-type="table"}). Patients in the 5EU with more frequent symptoms were significantly more likely to be in the UK, older, and a former smoker and significantly less likely to have a university education, be employed, and have private insurance (all *P*\<0.05). Patients with more frequent symptoms also exercised fewer days per month (*P*\<0.05). Patients with frequent symptoms in the US were significantly less likely to have a university education and were more likely to be a former smoker (both *P*\<0.05).

With respect to disease history, patients in the 5EU with more frequent symptoms were significantly more likely to have experienced a worsening of symptoms, an unexpected hospitalization, and attributed the causes of their COPD episodes to exercise and occupational hazards (all *P*\<0.05; [Table 3](#t3-copd-12-529){ref-type="table"}). Patients in the US with more frequent symptoms had been diagnosed longer and were more likely to have experienced a worsening of symptoms, worsening of symptoms that lasted days or more, and a longer length of exacerbations (all *P*\<0.05).

Controlling for demographics and health history variables, the combined frequency of symptoms was significantly associated with reduced health status in both the 5EU and the US ([Table 4](#t4-copd-12-529){ref-type="table"}). For every 1-unit increase (eg, "never" to "rarely"; "sometimes" to "often") in any of the five assessed symptoms, an associated decrease of 0.67 (5EU) and 0.87 (US) points on MCS was observed. The effects on PCS were larger (0.79 and 0.78, respectively, decreases).

Increased symptom frequency was also associated with increased rates of work-related impairment and health care resource use ([Table 5](#t5-copd-12-529){ref-type="table"}). For every 1-unit increase, a 6% and 9% increase in overall work impairment was observed in the 5EU and US, respectively (both *P*\<0.05). Additionally, for every 1-unit increase in symptom frequency, a 9% and 11%, respectively, increase was observed in the number of ER visits in the past 6 months, as well as a 6% and 5% increase observed in the number of hospitalizations (all *P*\<0.05).

The abovementioned results suggest that symptoms are frequently experienced among patients with COPD using the SOC; however, this could be a function of poor adherence. Although these patients are prescribed the appropriate SOC, they may not take the medication regularly. Indeed, as shown in [Table 6](#t6-copd-12-529){ref-type="table"}, adherence was modest with over a fifth of patients categorized as having "low adherence". For patients in 5EU, adherence was fairly consistent across the different GOLD groups, with the proportion of highly adherent patients ranging from 29.2% for Group A to 34.7% for Group D. For patients in the US, adherence was best among those in Group C (49.26% had high adherence) and worst among those in Group A (39.48% had high adherence) (both *P*\<0.05). Non-adherence was also significantly associated with more frequent symptoms and poorer health outcomes. Patients in the 5EU with low adherence reported significantly more frequent symptoms and worse MCS and health utility scores compared with both patients with moderate and high levels of adherence (all *P*\<0.05; [Table 7](#t7-copd-12-529){ref-type="table"}). Patients with low adherence also reported more presenteeism (ie, health-related impairment experienced while at work), overall work impairment, activity impairment, and hospitalizations in the past 6 months relative to patients with high adherence (all *P*\<0.05). Patients in the US with low adherence reported significantly more frequent symptoms, worse MCS, PCS, and health utility scores compared with patients with high levels of adherence (both *P*\<0.05; [Table 7](#t7-copd-12-529){ref-type="table"}). Similarly, differences between patients with high and low adherence were also observed with respect to absenteeism, overall work impairment, activity impairment, health care provider visits, ER visits, and hospitalizations (all *P*\<0.05). Differences between patients with medium and low adherence were only observed with respect to overall work impairment and health care provider visits.

Discussion
==========

Although prior research has uncovered a significant relationship between COPD symptoms and health outcomes,[@b10-copd-12-529]--[@b12-copd-12-529] such studies have focused on the broad COPD population. This study focused on those who were being treated with the appropriate SOC based on their modified GOLD 2014 group. The results suggest that even with proper SOC treatment, patients are still reporting a number of symptoms, with dyspnea being the most common. This finding was consistent with prior literature, which has repeatedly demonstrated the high frequency of dyspnea among patients with COPD.[@b11-copd-12-529]--[@b13-copd-12-529] Nearly all patients reported at least some frequency of symptoms, and \>80% reported experiencing at least one symptom "often".

Consistent with the work done in COPD more broadly,[@b11-copd-12-529]--[@b13-copd-12-529] our study found that an increasing frequency of symptoms was associated with a significant decrement in mental and physical health status and health utilities in both the US and 5EU. Indeed, increasing the frequency of just one symptom from "rarely" to "always" would equate to a clinically meaningful change in all health status measures (ie, 3 points in MCS and PCS and 0.03 points in health utilities). Increasing frequency of symptoms was also significantly associated with increases in work impairment, daily activity limitations, and health care resource use. In general, increasing the frequency of just one symptom from "rarely" to "always" would equate to a 30% increase in impairment and health care resource use. These findings were similar across regions and highlight the tremendous impact the symptom experience can have on economic outcomes.

Although these findings suggest a substantial symptom burden among patients being appropriately treated, it is important to consider the role of adherence. Not all patients prescribed the SOC were using their medication appropriately, which was associated with the presence and frequency of their symptoms. Approximately 70% of patients reported at least some level of non-adherence, and \~20% of patients reported engaging in several non-adherent behaviors. Non-adherence was associated with significantly greater frequency of symptoms. These non-adherence rates are consistent with review papers that have cited that more than half of patients with COPD are not using their medications as prescribed.[@b27-copd-12-529] We found significant, albeit modest, associations between poor adherence and health outcomes. So, although adherence likely plays an important role for improving the symptom experience among patients treated with the SOC, it does not represent the only factor. Improved management of these patients may help to improve their health status, ability to improve work productivity, and reduce societal costs.

Limitations
===========

There are several limitations of the study that should be noted. All data are patient reported and not clinically verified by patient medical records and thus could be associated with increased measurement error. Patients with definite COPD or of certain GOLD groups may be misclassified because of inaccurate patient reporting of diagnoses or treatment variables. For example, no FEV~1~ information was available, so our modified GOLD classification relied upon dyspnea and unexpected hospitalizations. Additionally, some self-reported measures may be less accurate than others. For example, the frequency of experiencing infection as a COPD symptom was asked. Physician-reported infection is likely more accurate than patient-reported infection. Patients may under or over report infection, which would then add noise to the model. Thus, the effect of symptoms (including infection) on health outcomes may be underestimated. It is also important to note that the data used for this study are a few years old (as old as 2011 in some cases for European respondents), and certain treatment approaches, such as dual bronchodilation or free triple combinations, may not have been common. The patient symptom experience may change as new treatment alternatives and combinations are incorporated into clinical practice. The data are also cross-sectional, which prevents drawing causal inferences between the various independent variables and health outcomes. Finally, although the NHWS is broadly representative of the 5EU and US population with respect to key demographic characteristics, there are other ways in which the NHWS sample overall (and specifically the COPD subsample receiving the appropriate SOC) may differ from the respective population. For example, the average age of the current sample was slightly lower than what has been observed in prior research of COPD patients (eg, 16% of the COPD population in the US is aged 65 years and older based on governmental data,[@b28-copd-12-529] yet 12% of our NHWS sample was aged 65 years and older). It is possible that elderly respondents in poorer health are underrepresented in the NHWS data. COPD patients with more severe disease symptoms and thus poorer health may also have less motivation to participate in an online survey and therefore may be underrepresented in NHWS. The low response rate of the surveys should also be considered; though given the online methodology, this low rate is likely due primarily to failure to contact respondents via email rather than respondent self-selection. Finally, \>30% of patients with COPD in both the US and 5EU cohort had asthma, representing the broader COPD population and not the COPD population without the asthma--COPD overlap syndrome (ACOS). This threat to external validity may limit the extent to which the study results can be generalized.

Conclusion
==========

Patients with COPD who are using the appropriate SOC based on their modified GOLD 2014 group still experience a number of symptoms, which has a significant effect on both humanistic and economic outcomes. Adherence among these patients is modest and contributes to poor outcomes, though does not entirely explain the symptom experience in this group. Unmet medical needs still exist among patients with COPD using the SOC in the US and 5EU.

This study was funded by AstraZeneca. MD's current affiliation at the time of the submission is: Ipsos, New York, NY, USA. Part of the abstract of this paper was presented at the American Thoracic Society (ATS) 2016 International Conference in San Francisco, California, May 13--18, 2016, as an oral presentation with interim findings (<http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A6156>).

**Disclosure**

BD, NK, GB, and UH are full-time employees of AstraZeneca. During the conduct of the study, MD was a full-time employee of Kantar Health, the organization that received funding from AstraZeneca. The authors report no other conflicts of interest in this work.

![Assignment of modified GOLD groups.\
**Abbreviations:** GOLD, Global Initiative for Chronic Obstructive Lung Disease; NHWS, National Health and Wellness Survey; mMRC, modified Medical Research Council Dyspnea scale.](copd-12-529Fig1){#f1-copd-12-529}

![Frequency of symptoms among COPD patients using the SOC in the 5EU.\
**Abbreviation:** SOC, standard of care.](copd-12-529Fig2){#f2-copd-12-529}

![Frequency of symptoms among COPD patients using the SOC in the US.\
**Abbreviation:** SOC, standard of care.](copd-12-529Fig3){#f3-copd-12-529}

###### 

SOC medications used for each modified GOLD 2014 group

  Modified GOLD 2014 group   SOC medications
  -------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  A                          Short-acting anticholinergic pro re nata (prn) or Short-acting beta~2~-agonist prn or Long-acting anticholinergic or Long-acting beta~2~-agonist or Short-acting beta~2~-agonist and Short-acting anticholinergic or theophylline
  B                          Long-acting anticholinergic or Long-acting beta~2~-agonist or Long-acting anticholinergic and Long-acting beta~2~-agonist or Short-acting beta~2~-agonist and/or Short-acting anticholinergic or theophylline
  C                          Inhaled corticosteroid + Long-acting beta~2~-agonist or Long-acting anticholinergic or Long-acting anticholinergic and Long-acting beta~2~-agonist or Long-acting anticholinergic and Phosphodiesterase-4 inhibitor or Long-acting beta~2~-agonist and Phosphodiesterase-4 inhibitor or Short-acting beta~2~-agonist and/or Short-acting anticholinergic or theophylline
  D                          Inhaled corticosteroid + Long-acting beta~2~-agonist and/or Long-acting anticholinergic or Inhaled corticosteroid + Long-acting beta~2~-agonist and Long-acting anticholinergic or Inhaled corticosteroid + Long-acting beta~2~-agonist and Phosphodiesterase-4 inhibitor or Long-acting anticholinergic and Long-acting beta~2~-agonist or Long-acting anticholinergic and Phosphodiesterase-4 inhibitor or carbocysteine or Short-acting beta~2~-agonist and/or Short-acting anticholinergic or theophylline

**Abbreviations:** SOC, standard of care; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

###### 

Demographic and health history differences between patients who reported experiencing at least one symptom "always" and patients who did not

  Variable                                   5EU (France, Germany, Italy, Spain, UK)   US                                                                           
  ------------------------------------------ ----------------------------------------- ------------ ------------ --------- -------------- ------------ ------------ -------
  Country                                                                                                        0.008                                              --
   France (%)                                311 (15.5)                                183 (15.2)   128 (15.9)             --             --           --           
   Germany (%)                               773 (38.5)                                441 (36.7)   332 (41.2)             --             --           --           
   UK (%)                                    493 (24.6)                                329 (27.4)   164 (20.4)             --             --           --           
   Italy (%)                                 230 (11.5)                                137 (11.4)   93 (11.6)              --             --           --           
   Spain (%)                                 199 (9.9)                                 111 (9.2)    88 (10.9)              --             --           --           
  Female (%)                                 917 (45.7)                                542 (45.1)   375 (46.6)   0.521     686 (41.2)     417 (40.6)   269 (42.2)   0.519
  Age (years) (mean ± SD)                    57.6±13.2                                 58.2±12.8    56.8±13.8    0.024     62.0±12.2      62.0±11.9    61.9±12.7    0.867
  Married/living with partner (%)            1,227 (61.2)                              731 (60.9)   496 (61.6)   0.736     950 (57.0)     569 (55.4)   381 (59.7)   0.08
  University educated (%)                    1,233 (61.5)                              710 (59.1)   523 (65.0)   0.008     393 (23.6)     224 (21.8)   169 (26.5)   0.028
  Annual household income (5EU)                                                                                  0.077                                              --
   Below country median (%)                  1,115 (55.6)                              691 (57.5)   424 (52.7)             --             --           --           
   Above country median (%)                  708 (35.3)                                401 (33.4)   307 (38.1)             --             --           --           
   Decline to answer (%)                     183 (9.1)                                 109 (9.1)    74 (9.2)               --             --           --           
  Annual household income (US)                                                                                   --                                                 0.098
   \<\$25K (%)                               --                                        --           --                     534 (32.1)     350 (34.0)   184 (28.8)   
   \$25K to \<\$50K (%)                      --                                        --           --                     544 (32.7)     336 (32.7)   208 (32.6)   
   \$50K to \<\$75K (%)                      --                                        --           --                     256 (15.4)     143 (13.9)   113 (17.7)   
   \$75K or more (%)                         --                                        --           --                     254 (15.2)     150 (14.6)   104 (16.3)   
   Decline to answer (%)                     --                                        --           --                     78 (4.7)       49 (4.8)     29 (4.5)     
  Employed (%)                               666 (33.2)                                377 (31.4)   289 (35.9)   0.036     347 (20.8)     206 (20.0)   141 (22.1)   0.314
  Private insurance (5EU) (%)                377 (18.8)                                203 (16.9)   174 (21.6)   0.008     --             --           --           --
  Insurance (US) (%)                         --                                        --           --           --        1,546 (92.8)   951 (92.5)   595 (93.3)   0.565
  Alcohol use (%)                            1,456 (72.6)                              865 (72.0)   591 (73.4)   0.493     898 (53.9)     548 (53.3)   350 (54.9)   0.537
  Smoking behavior                                                                                               \<0.001                                            0.019
   Never smoked (%)                          346 (17.2)                                188 (15.7)   158 (19.6)             190 (11.4)     101 (9.8)    89 (13.9)    
   Former smoker (%)                         879 (43.8)                                567 (47.2)   312 (38.8)             896 (53.8)     573 (55.7)   323 (50.6)   
   Current smoker (%)                        781 (38.9)                                446 (37.1)   335 (41.6)             580 (34.8)     354 (34.4)   226 (35.4)   
  Days exercised in past month (mean ± SD)   4.8±8.0                                   4.5±7.7      5.3±8.2      0.044     4.7±7.9        4.5±7.8      5.1±8.1      0.104
  CCI (mean ± SD)                            1.8±1.8                                   1.8±1.7      1.8±2.0      0.63      2.2±1.8        2.3±1.7      2.2±1.8      0.54
  BMI category                                                                                                   0.437                                              0.297
   Underweight (%)                           55 (2.7)                                  31 (2.6)     24 (3.0)               46 (2.8)       31 (3.0)     15 (2.4)     
   Normal weight (%)                         705 (35.1)                                420 (35.0)   285 (35.4)             379 (22.7)     228 (22.2)   151 (23.7)   
   Overweight (%)                            647 (32.3)                                392 (32.6)   255 (31.7)             494 (29.7)     299 (29.1)   195 (30.6)   
   Obese (%)                                 573 (28.6)                                338 (28.1)   235 (29.2)             733 (44.0)     458 (44.6)   275 (43.1)   
   Decline to provide weight (%)             26 (1.3)                                  20 (1.7)     6 (0.7)                14 (0.8)       12 (1.2)     2 (0.3)      
  Self-reported depression (%)               543 (27.1)                                330 (27.5)   213 (26.5)   0.615     555 (33.3)     352 (34.2)   203 (31.8)   0.308
  Asthma (%)                                 740 (36.9)                                449 (37.4)   291 (36.1)   0.574     525 (31.5)     319 (31.0)   206 (32.3)   0.591
  Allergic rhinitis (%)                      521 (26.0)                                319 (26.6)   202 (25.1)   0.462     776 (46.6)     468 (45.5)   308 (48.3)   0.274
  Cardiovascular disease (%)                 433 (21.6)                                274 (22.8)   159 (19.8)   0.102     459 (27.6)     286 (27.8)   173 (27.1)   0.754

**Note:** Symptoms considered in the classification of respondents were dyspnea, fits of coughing, infection, mucous production, and wheezing.

**Abbreviations:** SD, standard deviation; CCI, Charlson comorbidity index; BMI, body mass index.

###### 

Disease characteristics between patients who reported experiencing at least one symptom "always" and patients who did not

  Variable                                                       5EU (France, Germany, Italy, Spain, UK)   US                                                                                  
  -------------------------------------------------------------- ----------------------------------------- --------------- ------------- --------- --------------- ------------- ------------- ---------
  Years diagnosed (mean ± SD)                                    12.6±12.4                                 12.8±12.3       12.3±12.6     0.423     11.2±10.8       11.7±11.2     10.3±10.0     0.008
  Has experienced worsening of symptoms (%)                      471 (23.5%)                               293 (24.4%)     178 (22.1%)   0.009     978 (58.7%)     626 (60.9%)   352 (55.2%)   0.021
  Has experienced worsening of symptoms lasting days/weeks (%)   280 (14.0%)                               163 (13.6%)     117 (14.5%)   0.86      445 (26.7%)     312 (30.4%)   133 (20.8%)   \<0.001
  Experiences need for antibiotics (%)                           562 (28.0%)                               322 (26.8%)     240 (29.8%)   0.743     779 (46.8%)     486 (47.3%)   293 (45.9%)   0.591
  Experiences need for oral steroids (%)                         395 (19.7%)                               237 (19.7%)     158 (19.6%)   0.259     899 (54.0%)     558 (54.3%)   341 (53.4%)   0.741
  Had an unexpected hospitalization (%)                          179 (8.9%)                                116 (9.7%)      63 (7.8%)     0.037     370 (22.2%)     243 (23.6%)   127 (19.9%)   0.075
  Length of exacerbations                                                                                                                0.892                                                 \<0.001
   No exacerbations (%)                                          1,726 (86.0%)                             1,038 (86.4%)   688 (85.5%)             1,221 (73.3%)   716 (69.6%)   505 (79.2%)   
   1 week or less (%)                                            60 (3.0%)                                 34 (2.8%)       26 (3.2%)               77 (4.6%)       48 (4.7%)     29 (4.5%)     
   1--2 weeks (%)                                                57 (2.8%)                                 34 (2.8%)       23 (2.9%)               80 (4.8%)       59 (5.7%)     21 (3.3%)     
   2 weeks to 1 month (%)                                        87 (4.3%)                                 50 (4.2%)       37 (4.6%)               140 (8.4%)      97 (9.4%)     43 (6.7%)     
   1--2 months (%)                                               41 (2.0%)                                 22 (1.8%)       19 (2.4%)               73 (4.4%)       51 (5.0%)     22 (3.4%)     
   2 months or more (%)                                          35 (1.7%)                                 23 (1.9%)       12 (1.5%)               75 (4.5%)       57 (5.5%)     18 (2.8%)     
  Main cause of COPD episodes                                                                                                                                                                  
   Allergies (%)                                                 473 (23.6%)                               273 (22.7%)     200 (24.8%)   0.274     437 (26.2%)     258 (25.1%)   179 (28.1%)   0.182
   Exercise (%)                                                  694 (34.6%)                               455 (37.9%)     239 (29.7%)   \<0.001   488 (29.3%)     311 (30.3%)   177 (27.7%)   0.274
   Illness (%)                                                   889 (44.3%)                               540 (45.0%)     349 (43.4%)   0.477     559 (33.6%)     343 (33.4%)   216 (33.9%)   0.837
   Occupational hazards (%)                                      288 (14.4%)                               194 (16.2%)     94 (11.7%)    0.005     299 (18.0%)     190 (18.5%)   109 (17.1%)   0.47
   Pollutants (%)                                                441 (22.0%)                               277 (23.1%)     164 (20.4%)   0.154     514 (30.9%)     323 (31.4%)   191 (29.9%)   0.524
   Smoking (%)                                                   922 (46.0%)                               540 (45.0%)     382 (47.5%)   0.273     928 (55.7%)     585 (56.9%)   343 (53.8%)   0.209
   Stress/anxiety (%)                                            485 (24.2%)                               302 (25.1%)     183 (22.7%)   0.216     407 (24.4%)     260 (25.3%)   147 (23.0%)   0.299
   Weather (%)                                                   805 (40.1%)                               499 (41.5%)     306 (38.0%)   0.113     648 (38.9%)     403 (39.2%)   245 (38.4%)   0.744

**Note:** Symptoms considered in the classification of respondents were dyspnea, fits of coughing, infection, mucous production, and wheezing.

**Abbreviation:** SD, standard deviation.

###### 

Adjusted effect of the COPD symptom score on health status

  Dependent variables    5EU (France, Germany, Italy, Spain, UK)   US                                               
  ---------------------- ----------------------------------------- -------------- ---------- ------- -------------- ----------
  MCS                    −0.67                                     −0.81, −0.53   \<0.0001   −0.87   −1.03, −0.71   \<0.0001
  PCS                    −0.79                                     −0.9, −0.68    \<0.0001   −0.78   −0.89, −0.67   \<0.0001
  Health utility score   −0.01                                     −0.01, −0.01   \<0.0001   −0.01   −0.01, −0.01   \<0.0001

**Notes:** *b* = regression parameter estimate. All 5EU models controlled for country, age, sex, education, household income, employment, insurance, smoking habits, exercise behavior, cardiovascular disease, and modified GOLD 2014 group. All US models controlled for age, sex, marital status, education, income group, smoking habits, exercise, and modified GOLD 2014 group.

**Abbreviations:** CI, confidence interval; MCS, mental component summary; PCS, physical component summary; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

###### 

Adjusted effect of the COPD symptom score on work productivity loss and health care resource use

  Dependent variables                                5EU (France, Germany, Italy, Spain, UK)   US                                                         
  -------------------------------------------------- ----------------------------------------- ------------ ------ ---------- ------ ------------- ------ ----------
  Absenteeism%                                       0.09                                      0.04, 0.14   1.09   0.0006     0.08   −0.04, 0.21   1.09   0.1887
  Presenteeism%                                      0.06                                      0.04, 0.08   1.06   \<0.0001   0.10   0.06, 0.14    1.11   \<0.0001
  Overall work impairment%                           0.06                                      0.04, 0.07   1.06   \<0.0001   0.09   0.05, 0.13    1.09   \<0.0001
  Activity impairment%                               0.05                                      0.04, 0.05   1.05   \<0.0001   0.05   0.04, 0.06    1.05   \<0.0001
  Health care provider visits in the past 6 months   0.04                                      0.03, 0.06   1.04   \<0.0001   0.02   0.01, 0.04    1.02   0.0026
  ER visits in the past 6 months                     0.08                                      0.05, 0.12   1.09   \<0.0001   0.10   0.07, 0.13    1.11   \<0.0001
  Hospitalizations in the past 6 months              0.06                                      0.02, 0.1    1.06   0.0050     0.05   0.01, 0.08    1.05   0.0130

**Notes:** *b* = regression parameter estimate. Rate ratio indicates the increase in the outcome associated with a 1-unit increase in frequency of a single symptom (eg, in the 5EU, a respondent who has fits of coughing "sometimes" has 1.05 times \[5% higher\] the level of overall work impairment compared with a 5EU respondent who "never" has fits of coughing). All 5EU models controlled for country, age, sex, education, household income, employment, insurance, smoking habits, exercise behavior, cardiovascular disease, and modified GOLD 2014 group. All US models controlled for age, sex, marital status, education, income group, smoking habits, exercise, and modified GOLD 2014 group.

**Abbreviations:** CI, confidence interval; ER, emergency room; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

###### 

Adherence rates in the 5EU and USusing the MMAS-8

  MMAS-8 group           5EU (France, Germany, Italy, Spain, UK)   US
  ---------------------- ----------------------------------------- -------------
  MMAS-8 group                                                     
  High adherence (%)     337 (31.3%)                               672 (40.3%)
  Medium adherence (%)   421 (39.2%)                               627 (37.6%)
  Low adherence (%)      317 (29.5%)                               367 (22.0%)

**Abbreviation:** MMAS-8, 8-item Morisky Medication Adherence Scale.

###### 

Adjusted effect of the COPD medication adherence on symptom frequency, health status, work productivity loss, and health care resource use among patients

  Dependent variables                                               MMAS-8 group     5EU (France, Germany, Italy, Spain, UK)   US                                                      
  ----------------------------------------------------------------- ---------------- ----------------------------------------- -------------- ---------- -------------- -------------- --------
  Total symptom score (ie, summed frequency of all five symptoms)   High adherence   16.68                                     16.08, 17.27   0.0162     15.75          15.44, 16.05   0.0041
  Medium adherence                                                  16.84            16.28, 17.40                              0.0468         16.09      15.79, 16.40   0.2354         
  Low adherence                                                     17.33            16.74, 17.93                                             16.33      15.95, 16.71                  
  SF-36v2: MCS                                                      High adherence   43.81                                     41.95, 45.68   \<0.0001   46.05          45.06, 47.05   0.0002
  Medium adherence                                                  41.38            39.61, 43.14                              0.0669         44.23      43.24, 45.22   0.3021         
  Low adherence                                                     39.96            38.09, 41.82                                             43.56      42.33, 44.80                  
  SF-36v2: PCS                                                      High adherence   38.24                                     36.73, 39.75   0.8790     35.14          34.34, 35.93   0.0482
  Medium adherence                                                  37.57            36.14, 39.00                              0.2187         35.03      34.23, 35.82   0.0711         
  Low adherence                                                     38.34            36.83, 39.86                                             34.09      33.1, 35.08                   
  SF6D: health state utility score                                  High adherence   0.60                                      0.59, 0.62     \<0.0001   0.62           0.61, 0.62     0.0001
  Medium adherence                                                  0.58             0.57, 0.60                                0.0763         0.60       0.59, 0.61     0.2104         
  Low adherence                                                     0.57             0.55, 0.59                                               0.59       0.58, 0.60                    
  Absenteeism%                                                      High adherence   5.56                                      2.10, 14.72    0.0844     2.10           0.76, 5.80     0.0211
  Medium adherence                                                  11.83            4.83, 28.98                               0.8330         2.66       0.96, 7.40     0.0578         
  Low adherence                                                     12.80            5.82, 28.17                                              7.55       2.36, 24.15                   
  Presenteeism%                                                     High adherence   27.48                                     19.83, 38.08   0.0042     23.77          17.63, 32.03   0.4283
  Medium adherence                                                  31.96            23.76, 43.00                              0.0350         23.12      17.45, 30.62   0.3067         
  Low adherence                                                     41.81            31.11, 56.20                                             27.41      19.86, 37.83                  
  Overall work impairment%                                          High adherence   32.40                                     23.34, 44.98   0.0057     26.89          20.19, 35.81   0.0336
  Medium adherence                                                  40.51            30.08, 54.55                              0.1365         28.09      21.49, 36.73   0.0484         
  Low adherence                                                     48.73            36.53, 65.02                                             38.22      28.29, 51.63                  
  Activity impairment%                                              High adherence   48.59                                     42.97, 54.95   0.0008     51.63          48.81, 54.61   0.0052
  Medium adherence                                                  53.16            47.31, 59.73                              0.0486         53.43      50.55, 56.48   0.0556         
  Low adherence                                                     58.85            51.98, 66.62                                             57.31      53.46, 61.44                  
  Health care provider visits in the past 6 months                  High adherence   9.15                                      7.78, 10.77    0.7233     8.70           7.88, 9.61     0.018
  Medium adherence                                                  9.09             7.80, 10.59                               0.6144         8.74       7.93, 9.63     0.0177         
  Low adherence                                                     9.40             7.99, 11.06                                              10.18      9.02, 11.48                   
  ER visits in the past 6 months                                    High adherence   0.54                                      0.34, 0.85     0.1215     0.51           0.41, 0.64     0.0289
  Medium adherence                                                  0.78             0.52, 1.19                                0.8975         0.68       0.55, 0.85     0.7799         
  Low adherence                                                     0.76             0.50, 1.18                                               0.71       0.54, 0.93                    
  Hospitalizations in the past 6 months                             High adherence   0.32                                      0.20, 0.52     0.0089     0.32           0.24, 0.41     0.0021
  Medium adherence                                                  0.49             0.32, 0.76                                0.3420         0.46       0.36, 0.58     0.3358         
  Low adherence                                                     0.59             0.38, 0.92                                               0.53       0.40, 0.72                    

**Notes:** In the 5EU, all models controlled for country, age, sex, marital status, education, employment, insurance, alcohol use, smoking habits, CCI, BMI group, depression, asthma, allergic rhinitis, cardiovascular disease, COPD severity, exacerbation length, COPD causes, and modified GOLD 2014 group. In the US, all models controlled for age, sex, marital status, education, income, employment, insurance, alcohol use, smoking habits, CCI, exercise, depression, asthma, COPD severity, exacerbation length, COPD causes, and modified GOLD 2014 group.

**Abbreviations:** MMAS-8, 8-item Morisky Medication Adherence Scale; CI, confidence interval; SF-36v2, Short Form-36 version 2; MCS, mental component summary; PCS, physical component summary; SF6D, Short Form-6 Dimension; ER, emergency room; CCI, Charlson comorbidity index; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
