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Differences in the risk of mood disorders in patients with asthma-COPD overlap and in patients with COPD alone: a nationwide population-based retrospective cohort study in Korea

Respiratory Research201920:80

https://doi.org/10.1186/s12931-019-1039-5

  • Received: 9 July 2018
  • Accepted: 1 April 2019
  • Published:

Abstract

Background

Although feelings of anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), little is known about the estimates of their incidence in patients with asthma-COPD overlap (ACO), which has been described and acknowledged as a distinct clinical entity. We aimed to estimate the risk of depression and anxiety among patients with ACO and compare it with the risk among those with COPD alone in the general population.

Methods

We conducted a nationwide population-based retrospective cohort study using the Korean National Sample Cohort database between 1 January, 2002, and 31 December, 2013. Patients who were diagnosed with COPD (International Classification of Diseases, 10th revision [ICD-10] codes J42-J44) at least twice and prescribed COPD medications at least once between 2003 and 2011 were classified into two categories: patients who were diagnosed with asthma (ICD-10 codes J45-J46) more than twice and at least once prescribed asthma medications comprised the ACO group, and the remaining COPD patients comprised the COPD alone group. Patients who had been diagnosed with depression or anxiety within a year before the index date were excluded. We defined the outcome as time to first diagnosis with depression and anxiety. Matched Cox regression models were used to compare the risk of depression and anxiety among patients with ACO and patients with COPD alone after propensity score matching with a 1:1 ratio.

Results

After propensity score estimation and matching in a 1:1 ratio, the cohort used in the analysis included 15,644 patients. The risk of depression during the entire study period was higher for patients with ACO than for patients with COPD alone (adjusted hazard ratio, 1.10; 95% confidence interval, 1.03–1.18; P value = 0.0039), with an elevated risk in patients aged 40–64 years (1.21; 1.10–1.34; 0.0001) and in women (1.18; 1.07–1.29; 0.0005). The risk of anxiety was higher for patients with ACO than for patients with COPD alone (1.06; 1.01–1.12; 0.0272), with a higher risk in patients aged 40–64 years (1.08; 1.00–1.17; 0.0392); however, the risk was not significant when stratified by sex.

Conclusions

This population-based study revealed a higher incidence of depression and anxiety in patients with ACO than in patients with COPD alone.

Keywords

  • Asthma-COPD overlap
  • Depression
  • Anxiety
  • Mood disorder

Background

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is associated with aging and tobacco consumption; however, other exposures have also been causally related. Comorbidities contribute to the overall severity and economic burden of COPD [1]. Among such comorbidities, anxiety and depression contribute to a substantial burden of COPD-related morbidity, notably by impairing quality of life and reducing adherence to treatment [2]. In addition, recent studies have investigated the relationship between depression and anxiety with asthma, and they have shown that asthma is associated with depression and anxiety [35]. To date, most respiratory studies have included either patients with asthma alone (no COPD) or patients with COPD alone (no asthma) [6]. However, patients older than 40 years may present with mixed features of both COPD and asthma, which has been called Asthma-COPD overlap (ACO) [7]. Although previous studies have reported on the clinical features and poor outcomes of ACO [8, 9], there is still a debate over the defining features and disease severity of ACO [10]. Nevertheless, one of the relevance of the ACO is to identify patients with COPD who may have underlying eosinophilic inflammation that responds better to inhaled corticosteroids [9]. ACO can be useful for clinicians in terms of identifying patients with an expected poor outcome through overlapping clinical characteristics of asthma and COPD [10, 11]. Therefore, coexistence of asthma and COPD can serve as a criterion to assume ACO in a patient with COPD.

In 2017, the Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) committees released an updated document on the description of asthma-COPD overlap (ACO), which is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD [7]. Compared with patients with COPD alone, patients with ACO are often considered to have different clinical manifestations, with more respiratory symptoms (such as dyspnoea and wheezing), worse health-related quality of life, more frequent exacerbations, and more comorbidities [1214]. A previous cohort study showed a higher risk of depression in the ACO cohort compared to non-ACO cohort (adjusted HR 1.67, 95% CI 1.48–1.88) [15]. To avoid selection bias, the authors set a propensity score matched non-ACO cohort set as a comparison cohort using sex, age, and comorbidities; however, the difference in the use of ICS and oral steroid between the two cohorts remained significant. In addition, the socioeconomic status or health-care use have not been considered in the process of selecting non-ACO cohort. Therefore, selection bias still cannot be ruled out. In contrast, ACO and COPD share several common characteristics, including persistent airflow limitation and smoking, which comprise a critical diagnostic criterion and a source of these diseases, respectively [7]. Considering that asthma is a heterogeneous disease that includes patients with wide variations in the age of onset, disease severity, pulmonary function, body mass index, presence of atopy, and Th2 eosinophil inflammation [1618], the COPD alone cohort is likely to serve as a more appropriate comparison group to achieve clinically meaningful results.

In addition, treatment options and responses may differ depending on whether a patient has COPD alone or ACO [9, 19]; therefore, it is important to determine comorbidities associated specifically with ACO and COPD. Because mood disorder is a common comorbidity in chronic respiratory diseases, including asthma and COPD [20], it is important to identify mood disorders and provide additional treatment to reduce the disease burden. However, unlike the prevalence of other comorbidities, the incidence of depression and anxiety among patients with ACO compared to COPD alone is little known. Therefore, we conducted a population-based retrospective cohort study to estimate the risks of depression and anxiety among patients with ACO and compared them with the risks among those with COPD alone.

Methods

Data source

This study used the National Sample Cohort data from the National Health Insurance Service (NHIS–NSC) of Korea. The NHIS uses a systematic sampling approach to randomly select a representative population of approximately 1 million people between 2002 and 2013, which is 2.2% of the total population. The sample cohort was compared with the entire population with respect to the average total annual medical expenses, residence distribution, and the mean and standard deviation of health insurance premiums; the differences were negligible during the cohort years [21]. The data gives researchers access to demographic data – including sex, age recorded at 5–year intervals, income level, and date of death – as well as the health care data – including clinical diagnoses, medical procedures, expenditures, and drug prescriptions. Information on prescribed drugs included the generic drug name, prescription date, duration, and route of administration.

Study population

To investigate the risk of depression and anxiety in patients with ACO and patients with COPD alone, we constructed a COPD cohort using National Sample Cohort data for the period between January 2003 and December 2011. The COPD cohort included patients older than 40 years who had been diagnosed with COPD at least twice as a principal or secondary diagnosis coded according to the International Classification of Disease, tenth revision (ICD-10 codes J42, J43, and J44) and with at least 1 prescription for ≥1 of the following COPD medications: inhaled corticosteroids (ICSs), inhaled long-acting β2-agonists (LABAs), an ICS and a LABA combined in a single inhaler (ICS/LABA), inhaled short-acting β2-agonists (SABAs), inhaled long-acting muscarinic antagonists (LAMAs), short-acting muscarinic antagonists (SAMAs), a SAMA and a SABA combined in a single inhaler (SAMA/SABA), oral leukotriene antagonists, xanthine derivatives, mast cell stabilizers, and systemic corticosteroids (CSs). Within the COPD cohort, patients were divided into ACO and COPD alone groups, based on the following asthma criteria: (1) diagnosis with asthma at least twice, as a principal or secondary diagnosis (ICD-10 codes J45 and J46); (2) at least one prescription for ≥1 of the following asthma medications: ICSs, LABAs, ICS/LABA, SABAs, oral leukotriene antagonists, xanthine derivatives, mast cell stabilizers, and systemic CSs. Patients who met both criteria for COPD and asthma were defined as ACO.

Patients were excluded from the analysis of the incidence of depression and anxiety if they were diagnosed with depression or anxiety within 1 year of the index date. A study flow chart is presented in Fig. 1.
Fig. 1
Fig. 1

The selection of study subjects. COPD, chronic obstructive pulmonary disease; ICD-10, International Classification of Diseases; ACO, asthma-COPD overlap

Follow-up to depression and anxiety

We defined the outcome as time to first diagnosis with depression (ICD-10: F32 and F33) or anxiety (ICD-10: F40-F42) as the primary or secondary diagnosis after the index date. The index date was defined as the first date that both definitions of COPD and asthma were met. For example, if a patient with asthma met the definition of COPD later, the patient was considered eligible for inclusion in the ACO cohort from the day the patient met the definition of COPD. Patients with COPD alone were defined as those who met the definition of COPD but did not meet the definition of asthma, and the index date was defined as the first date when the patient met the definition of COPD. Follow-up was considered to have started on the index date and to have ended on the date of first diagnosis with depression or anxiety, the date the patient died, or 31 December, 2013 (Fig. 2).
Fig. 2
Fig. 2

Design of the retrospective cohort study

Potential confounders

Age, sex, comorbidities, and concurrent medications are all possible confounders of the association between ACO or COPD and depression or anxiety. We calculated the Charlson comorbidity index to estimate the severity of disease according to previous diagnoses within one year before the index date. We selected as confounders any comorbidities that may influence the risk of depression or anxiety, which included hypertension, diabetes, hyperlipidaemia, ischaemic heart disease, sleep disorders, alcohol-related illnesses, epilepsy, cancer, arthritis, Parkinson’s disease, dementia, obesity, cerebrovascular disease, and atherosclerosis [22]. Concurrent medications were identified based on the prescriptions within 6 months before the date of each outcome to adjust the effect of using the medications just before the occurrence of the outcomes; in analysing the incidence of depression, we used the prescription information within 6 months before the date of depression, and in the same way, we used the prescription information within 6 months before the date of anxiety in analysing the incidence of anxiety. Benzodiazepines, digitalis, and calcium antagonists – including diltiazem, nifedipine, and verapamil – were selected as confounders because they were the frequently reported medications that might increase the risk of depression or anxiety [23]. In addition, patients’ history of exacerbation and healthcare utilization were also included as potential confounders. Within the ACO and COPD cohort, patients were classified by the frequency of exacerbations they experienced within one year before the index date: frequent (≥2), infrequent (1), and not exacerbated (0). Indicators for exacerbation were identified based on ICD codes (primary diagnosis) related to COPD (or asthma in ACO) present in combination with one of the following: (1) hospitalization, (2) emergency department visit, or (3) outpatient visit with either an oral corticosteroid or antibiotic prescription within 5 days of the visit [24, 25]. To take into account for healthcare use other than for exacerbation, we included non-exacerbation related healthcare use in the preceding year of the index date as a potential confounder, which was further classified by the type of healthcare use: (1) hospitalizations, (2) emergency department visit, or (3) outpatient visit.

Statistical analysis

We estimated the propensity scores for being defined as having ACO regardless of the outcomes by using multiple logistic regression analysis with the following variables: age category, sex, Charlson comorbidity index, history of comorbidities, exacerbations, and healthcare use in previous year, insurance type and index year. We assessed the model discrimination using the C statistic. Matching was performed using a Greedy 5 → 1 digit matching macro with the estimated propensity score [26]. We used a standardized difference to compare baseline characteristics between patients with ACO and patients with COPD alone. We defined significant difference as an absolute value greater than 0.1 [27].

We calculated the incidence rate per 1000 person-years by dividing the number of diagnoses of depression or anxiety by the total number of person-years at risk and multiplying the results by 1000. We also calculated the associated 95% confidence interval (CI). For construction of the multivariable model, we included the use of concurrent medications prescribed within 6 months before the date of the outcome as the adjusting variable. We used the Cox regression models to estimate the adjusted hazard ratios (aHRs) and their 95% CIs for depression and anxiety after adjusting for the concurrent medications in the propensity-based matched cohort.

We also conducted a subgroup analysis for the incidence of depression and anxiety according to age group, sex, comorbidities, and concurrent medications. We did subgroup analysis with interaction terms to see whether the association between ACO and incident depression or anxiety differed significantly by comorbidities and concurrent medications. All tests were 2-sided, with a significance level of 0.05. All data transformations and statistical analyses were conducted using SAS version 9.4 for Windows (SAS Institute, Cary, NC, USA).

Results

From the NHIS-NSC database, 28,116 COPD patients aged over 40 were diagnosed with COPD more than twice between January 2003 and December 2011. Of these, we identified 15,648 patients with ACO and 12,468 patients with COPD alone. After excluding patients who were diagnosed with anxiety or depression within 1 year before the index date, 12,866 patients were included in the initial cohort of ACO and 10,699 patients were included in the initial cohort of COPD alone. After propensity score estimation and matching in a one to one ratio, the cohort used in the analysis of depression and anxiety in patients with ACO versus patients with COPD alone included 15,644 patients (Fig. 1). Table 1 shows that clinical characteristics (age, sex, Charlson comorbidity index, history of comorbidities, exacerbations and healthcare use in previous year, insurance type, and index year) were not significantly different between patients with ACO and patients with COPD alone.
Table 1

Comparison of clinical characteristics between patients with ACO versus patients with COPD alone

Category

No. of patients (%)

P value

Standardized differencea

ACO (n = 7822)

COPD alone (n = 7822)

Age group (years)

 40–64

3700(47.3)

3718(47.53)

0.7732

0.00461

  ≥ 65

4122(52.7)

4104(52.47)

Sex

 Male

4170(53.31)

4176(53.39)

0.9234

0.00154

 Female

3652(46.69)

3646(46.61)

Charlson comorbidity index

 0

1436(18.36)

1537(19.65)

0.3501

0.03368

 1

2645(33.81)

2603(33.28)

 2

1649(21.08)

1642(20.99)

 3

877(11.21)

855(10.93)

  ≥ 4

1215(15.53)

1185(15.15)

History of comorbidities in previous year

 Hypertension

2741(35.04)

2671(34.15)

0.2394

0.01881

 Diabetes

1558(19.92)

1519(19.42)

0.4328

0.01254

 Hyperlipidaemia

1319(16.86)

1313(16.79)

0.898

0.00205

 Ischaemic heart disease

633(8.09)

595(7.61)

0.2586

0.01806

 Sleep disorder

600(7.67)

559(7.15)

0.2107

0.02001

 Alcohol-related illness

238(3.04)

225(2.88)

0.5397

0.00981

 Epilepsy

67(0.86)

62(0.79)

0.6585

0.00707

 Cancer

895(11.44)

874(11.17)

0.596

0.00848

 Arthritis

1552(19.84)

1537(19.65)

0.7632

0.00482

 Parkinson’s disease

41(0.52)

42(0.54)

0.9124

0.00176

 Dementia

72(0.92)

86(1.1)

0.2629

0.0179

 Obesity

3(0.04)

7(0.09)

0.2058

0.02023

 Cerebrovascular disease

621(7.94)

606(7.75)

0.6555

0.00713

 Atherosclerosis

168(2.15)

160(2.05)

0.6553

0.00714

History of exacerbation in previous year

 0

62(0.79)

70(0.89)

0.4844

0.01118

 1

1636(20.92)

1688(21.58)

0.3095

0.01625

  ≥ 2

6124(78.29)

6064(77.52)

0.2476

0.01849

Healthcare utilization in previous year

 Hospitalization

1327(16.96)

1347(17.22)

0.671

0.00679

 ED visit

723(9.24)

701(8.96)

0.5409

0.00978

 Outpatient visit

7321(93.59)

7302(93.35)

0.5385

0.00983

Insurance type

 Health insurance

7529(96.25)

7504(95.93)

0.3022

0.0165

 Medical-aid beneficiary

293(3.75)

318(4.07)

Index year

 2003

1483(18.96)

1435(18.35)

0.3245

0.01575

 2004

1107(14.15)

1032(13.19)

0.0809

0.02791

 2005

910(11.63)

943(12.06)

0.4142

0.01306

 2006

847(10.83)

916(11.71)

0.0811

0.0279

 2007

765(9.78)

816(10.43)

0.1761

0.02163

 2008

770(9.84)

809(10.34)

0.3006

0.01655

 2009

768(9.82)

714(9.13)

0.1404

0.02358

 2010

565(7.22)

547(6.99)

0.5754

0.00896

 2011

607(7.76)

610(7.8)

0.9286

0.00143

ACO asthma-COPD overlap, COPD chronic obstructive pulmonary disease, ED emergency department

aA standardized mean difference of greater than 0.1 represents significant difference between the two cohorts

As shown in Table 2, the incidence rate of depression was 44.0 per 1000 person-years in patients with ACO and 38.2 per 1000 person-years in patients with COPD alone. The crude HR of depression among patients with ACO was 1.15 (95% CI, 1.08–1.23). After adjustment for the medications prescribed within 6 months before the date of the outcome, the adjusted HR was 1.10 (95% CI, 1.03–1.18; P value = 0.0039). An increased risk of depression was observed among patients aged 40–64 years with an adjusted HR of 1.21 (95% CI, 1.10–1.34; P value = 0.0001), whereas the difference in risk among patients ≥65 years was not significant between patients with ACO and patients with COPD alone. In women, the risk of depression was higher in patients with ACO (aHR, 1.18; 95% CI, 1.07–1.29; P value = 0.0005); however, in men, the difference in risk between ACO patients and patients with COPD alone was not significant (aHR, 1.03; 95% CI, 0.93–1.13; P = 0.5718).
Table 2

Risk of depression and anxiety in patients with ACO versus patients with COPD alone

Category

ACO (n = 7822)

COPD alone (n = 7822)

Crude HR (95% CI)

Adjusteda HR (95% CI)

P value for adjusted HR

Events

PY

Rate

Events

PY

Rate

Depression

 Overall

1908

43,380

44.0

1654

43,342

38.2

1.15(1.08–1.23)

1.10(1.03–1.18)

0.0039

  Age groups (years)

   40–64 (n = 7418)

886

22,402

39.5

727

22,817

31.9

1.24(1.13–1.37)

1.21(1.10–1.34)

0.0001

    ≥ 65 (n = 8226)

1022

20,978

48.7

927

20,525

45.2

1.08(0.99–1.18)

1.01(0.93–1.11)

0.7537

  Sex

   Male (n = 8346)

879

22,891

38.4

792

22,448

35.3

1.09(0.99–1.20)

1.03(0.93–1.13)

0.5718

   Female (n = 7298)

1029

20,490

50.2

862

20,894

41.3

1.22(1.11–1.33)

1.18(1.07–1.29)

0.0005

Anxiety

 Overall

3017

37,927

79.5

2780

38,155

72.9

1.09(1.04–1.15)

1.06(1.01–1.12)

0.0272

  Age groups (years)

   40–64 (n = 7418)

1416

19,663

72.0

1318

20,155

65.4

1.10(1.02–1.19)

1.08(1.00–1.17)

0.0392

    ≥ 65 (n = 8226)

1601

18,263

87.7

1462

18,000

81.2

1.08(1.00–1.16)

1.04(0.97–1.11)

0.3314

  Sex

   Male (n = 8346)

1394

20,536

67.9

1272

20,462

62.2

1.09(1.01–1.18)

1.06(0.98–1.14)

0.1349

   Female (n = 7298)

1623

17,391

93.3

1508

17,693

85.2

1.09(1.02–1.17)

1.06(0.99–1.14)

0.0891

Bold results represent statistically significant

ACO asthma-COPD overlap, COPD chronic obstructive pulmonary disease, PY person-year; Rate, incidence rate (per 1000 person-years); HR, hazard ratio

aAdjusted for medications - including calcium antagonists (diltiazem, nifedipine, verapamil), corticosteroids, digitalis, and benzodiazepines - prescribed within 6 months before the date of outcome

The incidence rate of anxiety was 79.5 per 1000 person-years in patients with ACO and 72.9 per 1000 person-years in patients with COPD alone. The crude HR of anxiety in patients with ACO was 1.09 (95% CI, 1.04–1.15). After adjustment for the medication prescribed within 6 months before the date of outcome, the adjusted HR was 1.06 (95% CI, 1.01–1.12; P value = 0.0272). In patients aged 40–64 years, the risk of anxiety in patients with ACO was significant when compared with that in patients with COPD alone (aHR, 1.08; 95% CI, 1.00–1.17; P value = 0.0392), and ACO patients ≥65 years also did not have a significantly higher risk of anxiety (aHR 1.04; 95% CI, 0.97–1.11; P value = 0.3314). The risk of anxiety was not significant in men (aHR, 1.06; 95% CI, 0.98–1.14; P value = 0.1349), nor in women (aHR, 1.06; 95% CI, 0.99–1.14; P value = 0.0891).

Table 3 shows the risk of depression in subgroups according to history of comorbidities in the previous year and use of concurrent medications within 6 months before the date of outcome. We found no difference in risk associated with the comorbidities and concurrent medications, except alcohol-related illness and use of corticosteroids. The hazard ratio was higher among patients with pre-existing alcohol-related illness than those without the illness (aHR, 2.12; 95% CI, 1.44–3.12 versus aHR, 1.08; 95% CI, 1.01–1.16; P value for interaction = 0.0008). Table 4 shows the risk of anxiety according to history of comorbidities in previous year and use of concurrent medications within 6 months before the date of outcome. Any comorbidities and concurrent medications did not increase the risk of anxiety.
Table 3

Subgroup analyses of risk of depression in patients with ACO versus patients with COPD alone

Category

ACO (n = 7822)

COPD alone (n = 7822)

Adjusteda HR (95% CI)

P value for interaction

Events

PY

Rate

Events

PY

Rate

History of comorbidities in previous year

 Hypertension

  Yes (n = 5412)

716

14,214

50.4

621

13,641

45.5

1.05(0.94–1.17)

0.2998

  No (n = 10,232)

1192

29,166

40.9

1033

29,701

34.8

1.13(1.04–1.23)

 

 Diabetes

  Yes (n = 3077)

456

7961

57.3

367

7642

48.0

1.10(0.96–1.27)

0.9458

  No (n = 12,567)

1452

35,419

41.0

1287

35,700

36.1

1.10(1.02–1.18)

 

 Hyperlipidemia

  Yes (n = 2632)

383

6425

59.6

337

6538

51.5

1.13(0.98–1.31)

0.6766

  No (n = 13,012)

1525

36,955

41.3

1317

36,805

35.8

1.10(1.02–1.18)

 

 Ischaemic heart disease

  Yes (n = 1228)

181

3189

56.8

142

2812

50.5

1.09(0.87–1.36)

0.8601

  No (n = 14,416)

1727

40,191

43.0

1512

40,530

37.3

1.10(1.03–1.18)

 

 Sleep disorder

  Yes (n = 1159)

228

2750

82.9

187

2546

73.4

1.10(0.91–1.34)

0.9332

  No (n = 14,485)

1680

40,630

41.3

1467

40,796

36.0

1.10(1.03–1.18)

 

 Alcohol-related illness

  Yes (n = 463)

81

1207

67.1

39

1317

29.6

2.12(1.44–3.12)

0.0008

  No (n = 15,181)

1827

42,173

43.3

1615

42,026

38.4

1.08(1.01–1.16)

 

 Epilepsy

  Yes (n = 129)

24

289

83.1

10

271

36.9

2.11(1.00–4.45)

0.0601

  No (n = 15,515)

1884

43,092

43.7

1644

43,071

38.2

1.10(1.03–1.17)

 

 Cancer

  Yes (n = 1769)

271

4426

61.2

184

4243

43.4

1.31(1.09–1.58)

0.0562

  No (n = 13,875)

1637

38,954

42.0

1470

39,099

37.6

1.07(1.00–1.15)

 

 Arthritis

  Yes (n = 3089)

442

8333

53.0

413

8150

50.7

0.99(0.87–1.13)

0.1019

  No (n = 12,555)

1466

35,048

41.8

1241

35,192

35.3

1.14(1.06–1.23)

 

 Parkinson’s disease

  Yes (n = 83)

10

144

69.3

9

141

63.7

0.59(0.22–1.60)

0.5441

  No (n = 15,561)

1898

43,236

43.9

1645

43,201

38.1

1.10(1.03–1.18)

 

 Dementia

  Yes (n = 158)

15

227

66.1

22

223

98.5

0.76(0.39–1.50)

0.1681

  No (n = 15,486)

1893

43,153

43.9

1632

43,119

37.8

1.11(1.04–1.18)

 

 Obesity

  Yes (n = 10)

0

19

0.0

3

35

86.6

1.99(NA)

0.8967

  No (n = 15,634)

1908

43,361

44.0

1651

43,308

38.1

1.10(1.03–1.18)

 

 Cerebrovascular disease

  Yes (n = 1227)

172

2867

60.0

157

2642

59.4

0.96(0.77–1.20)

0.1887

  No (n = 14,417)

1736

40,514

42.8

1497

40,700

36.8

1.12(1.04–1.20)

 

 Atherosclerosis

  Yes (n = 328)

47

751

62.6

33

722

45.7

1.23(0.79–1.94)

0.7111

  No (n = 15,316)

1861

42,630

43.7

1621

42,620

38.0

1.10(1.03–1.18)

 

Use of concurrent medications within 6 months before the date of outcomes

 Calcium antagonists

  Yes (n = 892)

149

2150

69.3

109

1796

60.7

1.09(0.85–1.40)

0.7505

  No (n = 14,752)

1759

41,230

42.7

1545

41,546

37.2

1.10(1.03–1.18)

 

 Corticosteroids

        

  Yes (n = 7658)

1192

22,314

53.4

848

18,580

45.6

1.15(1.05–1.26)

0.1887

  No (n = 7986)

716

21,066

34.0

806

24,762

32.6

1.05(0.95–1.16)

 

 Digitalis

        

  Yes (n = 509)

67

1186

56.5

51

1007

50.7

1.11(0.77–1.61)

0.9571

  No (n = 15,135)

1841

42,194

43.6

1603

42,335

37.9

1.10(1.03–1.18)

 

 Benzodiazepines

        

  Yes (n = 5425)

1098

13,671

80.3

943

12,750

74.0

1.08(0.99–1.18)

0.2176

  No (n = 10,219)

810

29,709

27.3

711

30,593

23.2

1.14(1.03–1.26)

 

Bold results represent statistically significant P value for interaction

ACO asthma-COPD overlap, COPD chronic obstructive pulmonary disease, PY person-year; Rate, incidence rate (per 1000 person-years); HR, hazard ratio

aAdjusted for medications - including calcium antagonists (diltiazem, nifedipine, verapamil), corticosteroids, digitalis, and benzodiazepines - prescribed within 6 months before the date of outcomes

Table 4

Subgroup analyses of risk of anxiety in patients with ACO versus patients with COPD alone

Category

ACO (n = 7822)

COPD alone (n = 7822)

Adjusteda HR (95% CI)

P value for interaction

Events

PY

Rate

Events

PY

Rate

History of comorbidities in previous year

 Hypertension

  Yes (n = 5412)

1115

12,372

90.1

993

11,984

82.9

1.06(0.97–1.15)

0.977

  No (n = 10,232)

1902

25,555

74.4

1787

26,171

68.3

1.06(0.99–1.13)

 

 Diabetes

  Yes (n = 3077)

654

6938

94.3

574

6758

84.9

1.07(0.96–1.20)

0.8967

  No (n = 12,567)

2363

30,989

76.3

2206

31,397

70.3

1.06(1.00–1.12)

 

 Hyperlipidemia

  Yes (n = 2632)

582

5597

104.0

514

5797

88.7

1.12(1.00–1.27)

0.2248

  No (n = 13,012)

2435

32,330

75.3

2266

32,359

70.0

1.05(0.99–1.11)

 

 Ischaemic heart disease

  Yes (n = 1228)

273

2819

96.8

202

2513

80.4

1.20(1.00–1.44)

0.155

  No (n = 14,416)

2744

35,108

78.2

2578

35,643

72.3

1.05(0.99–1.11)

 

 Sleep disorder

  Yes (n = 1159)

314

2363

132.9

277

2095

132.2

1.02(0.86–1.20)

0.5789

  No (n = 14,485)

2703

35,564

76.0

2503

36,060

69.4

1.06(1.01–1.12)

 

 Alcohol-related illness

  Yes (n = 463)

103

1156

89.1

82

1116

73.5

1.16(0.86–1.55)

0.6018

  No (n = 15,181)

2914

36,771

79.2

2698

37,039

72.8

1.06(1.00–1.12)

 

 Epilepsy

  Yes (n = 129)

23

286

80.5

19

236

80.6

1.12(0.60–2.11)

0.9961

  No (n = 15,515)

2994

37,641

79.5

2761

37,920

72.8

1.06(1.01–1.12)

 

 Cancer

  Yes (n = 1769)

351

3962

88.6

316

3710

85.2

0.98(0.84–1.15)

0.2878

  No (n = 13,875)

2666

33,964

78.5

2464

34,445

71.5

1.07(1.01–1.13)

 

 Arthritis

  Yes (n = 3089)

718

6980

102.9

690

6866

100.5

1.00(0.90–1.10)

0.1798

  No (n = 12,555)

2299

30,947

74.3

2090

31,290

66.8

1.08(1.02–1.15)

 

 Parkinson’s disease

  Yes (n = 83)

16

118

135.0

16

125

128.0

0.73(0.34–1.60)

0.5775

  No (n = 15,561)

3001

37,808

79.4

2764

38,030

72.7

1.06(1.01–1.12)

 

 Dementia

  Yes (n = 158)

20

196

102.2

24

226

106.4

1.19(0.64–2.22)

0.7515

  No (n = 15,486)

2997

37,731

79.4

2756

37,930

72.7

1.06(1.01–1.12)

 

 Obesity

  Yes (n = 10)

0

19

0.0

4

24

167.4

1.12(NA)

0.8607

  No (n = 15,634)

3017

37,907

79.6

2776

38,131

72.8

1.06(1.01–1.12)

 

 Cerebrovascular disease

  Yes (n = 1227)

257

2435

105.5

220

2382

92.3

1.11(0.92–1.33)

0.4783

  No (n = 14,417)

2760

35,491

77.8

2560

35,773

71.6

1.06(1.00–1.11)

 

 Atherosclerosis

  Yes (n = 328)

70

701

99.9

58

633

91.6

0.98(0.69–1.41)

0.5821

  No (n = 15,316)

2947

37,226

79.2

2722

37,522

72.5

1.06(1.01–1.12)

 

Use of concurrent medications within 6 months before the date of outcomes

 Calcium antagonists

  Yes (n = 859)

199

1837

108.3

152

1494

101.8

1.02(0.82–1.26)

0.3769

  No (n = 14,785)

2818

36,090

78.1

2628

36,662

71.7

1.06(1.01–1.12)

 

 Corticosteroids

  Yes (n = 7552)

1767

18,848

93.7

1405

15,795

89.0

1.05(0.98–1.13)

0.5356

  No (n = 8092)

1250

19,079

65.5

1375

22,360

61.5

1.08(1.00–1.17)

 

 Digitalis

  Yes (n = 511)

92

1054

87.3

76

939

80.9

1.12(0.82–1.53)

0.9439

  No (n = 15,133)

2925

36,873

79.3

2704

37,216

72.7

1.06(1.00–1.12)

 

 Benzodiazepines

  Yes (n = 5245)

1510

10,570

142.9

1400

10,238

136.7

1.05(0.97–1.12)

0.1742

  No (n = 10,399)

1507

27,357

55.1

1380

27,917

49.4

1.08(1.01–1.16)

 

ACO asthma-COPD overlap, COPD chronic obstructive pulmonary disease, PY person-year; Rate, incidence rate (per 1000 person-years); HR, hazard ratio

aAdjusted for medications - including calcium antagonists (diltiazem, nifedipine, verapamil), corticosteroids, digitalis, and benzodiazepines - prescribed within 6 months before the date of outcome

Table 5 shows the association between the use of concurrent medications prescribed within 6 months before the date of depression or anxiety and the incidence of depression or anxiety. Among the frequently reported four types of medication that might increase the risk of depression or anxiety, calcium channel blocker, corticosteroid, and benzodiazepines were significantly associated with a higher incidence of depression or anxiety. Digitalis did not show a significant association with the incidence of depression or anxiety.
Table 5

Associations between the use of concurrent medications and incidence of mood disorders

Types of concurrent medicationsa

Depression

Anxiety

Adjustedb HR (95% CI)

P value

Adjustedb HR (95% CI)

P value

ACO

1.10(1.03–1.18)

0.0039

1.06(1.01–1.12)

0.0272

Calcium channel blockers

1.30(1.15–1.48)

< 0.0001

1.14(1.02–1.27)

0.018

Corticosteroids

1.20(1.12–1.28)

< 0.0001

1.19(1.13–1.26)

< 0.0001

Digitalis

1.02(0.85–1.23)

0.8139

0.88(0.75–1.02)

0.098

Benzodiazepines

2.92(2.73–3.13)

< 0.0001

2.54(2.41–2.68)

< 0.0001

Bold results represent statistically significant

ACO asthma-COPD overlap, COPD chronic obstructive pulmonary disease, HR hazard ratio

aMedications were considered as concurrent if they were prescribed within 6 months before the date of depression or anxiety

bAdjusted for medications - including calcium antagonists (diltiazem, nifedipine, verapamil), corticosteroids, digitalis, and benzodiazepines - prescribed within 6 months before the date of outcome

Discussion

Principal findings

In this population-based cohort study, we evaluated the association between ACO and the risk of depression and anxiety. Compared to patients with COPD alone, patients with ACO had a 1.10-fold increased risk of depression and 1.06-fold increased risk of anxiety. The risk of depression was higher in patients aged 40–64 years old and in women, but was not affected by presence of comorbidities within 1 year from the index date nor the use of concurrent medications within 6 months before the date of outcome, except the presence of alcohol-related illness. The risk of anxiety was higher in patients aged 40–64 years old, but was not affected by presence of comorbidities nor the use of concurrent medications. Our finding suggests that there is significant risk of depression and anxiety in patients with ACO compared with patients with COPD alone, irrespective of presence of comorbidities and use of concurrent medications.

Comparison with other studies

Our findings are consistent with a previous cohort study in that women and patients ≥65 years of age were found to have a higher rate of depression than men and patients < 65 years of age [15]. The higher incidence of depression in our Korean study population compared to that of in the Taiwanese population can be explained by the higher prevalence of mental disorders in Korea than in Taiwan [28, 29]. In addition, our results are also similar to those from a previous study which showed the risk of depression was greater in patient with alcohol-related illness [15].

To date, our study is the first longitudinal study that has examined the incidence of anxiety disorders in patients with ACO. Our results with respect to the incidence of anxiety showed a higher rate of anxiety in women than in men, which is consistent with previously reported patterns of the prevalence of anxiety disorders in Korea [30]. In addition, a retrospective cohort study has reported that anxiety is more prevalent in patients with ACO than in those with COPD alone, with an odds ratio of 1.18 (95% CI, 1.10–1.27) [19]. Our results showed that the risk of anxiety is increased in patients with ACO compared with COPD alone. However, when we compared the risk of anxiety in ACO versus COPD patients in association with different treatments, the use of corticosteroid did not significantly increase the risk of anxiety. That is, the risk of anxiety in the patients with ACO, compared with patients with COPD alone, did not change with the use of corticosteroid.

Several studies have shown that patients with ACO have more severe respiratory symptoms, more frequent exacerbations and hospitalizations than those with COPD alone [7, 31]. In addition, COPD is treated mainly with bronchodilators, whereas ICS is recommended for the treatment of ACO patient with features of asthma [7]. Therefore, patients with ACO are not only exposed to frequent use of systemic corticosteroids due to exacerbations, but they are also more treated with regular ICS, compared to those with COPD alone. Corticosteroids exposure leading to mood disorder can be explained by the fact that chronic corticosteroid use has been associated with alterations in central and peripheral serotonin levels [32, 33]. Further studies are needed to understand the mechanism behind the higher risk of mood disorder in patients with ACO compared to those with COPD.

Association between alcohol-related illness and higher incidence of depression in patients with ACO can be explained by a research that showed acetaldehyde causing bronchoconstriction indirectly via histamine-mediated process in asthma patients [34]. Through the process of ethanol metabolism, mainly by aldehyde dehydrogenase (ALDH), ethanol is oxidized to acetaldehyde, which is further oxidized to acetate. However, many East Asian people were reported to be deficient in ALDH2, one of the ALDH isozymes [35]. When they ingest ethanol, their blood acetaldehyde and histamine levels increase significantly due to insufficient metabolic activity, and the increased histamine may result in bronchoconstriction [34, 36]. Therefore, alcohol-related illnesses in ACO patients may cause more frequent exacerbations and lead to increased risk of depression. However, why the risk of anxiety was not affected by the presence of alcohol-related illness remains unexplained, and further studies are needed.

Previous studies have shown that mood disorders cause frequent exacerbations in asthma and COPD patients [37, 38]; this can be caused by the low compliance with medication [39]. Anxiety and depression have also been associated with the activation of the hypothalamic-pituitary-adrenal axis [40], which could increase the systemic inflammatory responses and increase the risk of exacerbation. Acute exacerbation is a key indicator for assessing the degree of disease control and prognosis in patients with chronic respiratory diseases such as asthma, COPD, and ACO, because it increases mortality and lowers the quality of life [41, 42]. When an impact of the 10% increase in the relative risk of the depression is estimated in each population of 10,000 patients with ACO and with COPD alone, 1000 patients with ACO will be at risk of developing depression, compared to those with COPD alone. A previous study showed that the rate of acute exacerbation in COPD patients with mood disorders increased by 56% compared to those without mood disorders [38]. This suggests that additional 1000 ACO patients are at higher risk of developing acute exacerbations, leading to poor clinical prognosis. Therefore, our results demonstrate a need for clinicians to carefully examine for signs of mood disorders in addition to respiratory symptoms.

Strengths and limitations

Our study has several strengths. First, to our knowledge, this is the first population-based cohort study comparing the risk of depression and anxiety between patients with ACO versus patients with COPD alone. The risk reported in previous studies was based on the comparison of patients with and without ACO, and the results showed there is a significant difference in the risk of depression between the two patient groups [15]. However, our study revealed that the increased risk is also observed in patients with ACO when they are compared with patients with COPD alone; thus, providing a basis for the importance of monitoring and paying greater attention to the signs or symptoms of depression and anxiety in patients with ACO. Second, the use of a national sample cohort database was able to yield highly representative results and overcome the possible limitations (such as insufficient statistical power) arising from a small number of patients.

Certain potential limitations should be considered when interpreting our findings. The first limitation is the definition of ACO in our study, and because this is a very contentious area already, the ACO cohort in this study was based on a subset of the COPD cohort. There is no formal definition of ACO [7]; therefore, we defined ACO based on the clinical diagnoses and corresponding prescribed medications. Although the definition of ACO has varied widely, the prevalence of ACO in our study is similar to that in previous studies [8, 12], which is estimated to be 52 to 55% of patients with COPD in database studies and 1.6 to 4.5% in the general population. The prevalence of ACO in our study was 56% (15,648/28,116) in patients with COPD and 1.4% (15,648/1,113,656) in the general population. Secondly, the measurement of outcomes was based on claims data, which does not capture patients with depression or anxiety that are not recorded in claims data (e.g. mild cases). Although there is a potential for inaccuracies in coding and for incompleteness of records, previous studies have validated the ICD-10 code-based definitions for diabetes and acute myocardial infarction (AMI), which were compared with medical records reviews and demonstrated positive predictive values of 72.3 to 87.2% for diabetes and > 70% for AMI [43, 44]. Third, residual confounding may exist due to the observational nature of this study. Several variables that could have affected the outcomes were not fully captured in the database, including smoking status, family history of mental illness, disease duration or severity, education level, and income level.

Conclusions

The present study of a large population-based cohort study revealed that, compared with patients with COPD alone, patients with ACO have an increased risk of depression and anxiety.

Abbreviations

ACO: 

Asthma-COPD overlap

COPD: 

Chronic obstructive pulmonary disease

CSs: 

corticosteroids

GINA: 

Global Initiative for Asthma

GOLD: 

Global Initiative for Chronic Obstructive Lung Disease

ICD-10: 

International Classification of Diseases, 10th revision

ICSs: 

inhaled corticosteroids

LABAs: 

long-acting β2-agonists

LAMAs: 

long-acting muscarinic antagonists

NHIS: 

National Health Insurance Service

NSC: 

National Sample Cohort data

SABAs: 

short-acting β2-agonists

SAMAs: 

short-acting muscarinic antagonists

Declarations

Acknowledgments

Not applicable.

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), which was funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC15C1335).

Availability of data and materials

The data that support the findings of this study are available from the National Health Insurance Sharing Service (https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do) but restrictions apply to the availability of these data, which were used under permission for the current study only, and, therefore, they are not publicly available.

Authors’ contributions

All authors participated in the design and conduction of the study, interpretation of the results, and review and approval of the manuscript.

Ethics approval and consent to participate

This study was approved by the institutional review board of Sungkyunkwan University in South Korea (SKKU-IRB-2018-03-024). All personal identifying information for the included patients was anonymous; therefore, informed consent for this study was waived by the institutional review board.

Consent for publication

Not applicable.

Competing interests

This study used the National Health Insurance Service data (NHIS-2018-2-133). The authors declare no competing interest with the NHIS.

Publisher’s Note

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Authors’ Affiliations

(1)
School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, 16419, South Korea
(2)
Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

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