Comorbidity of somatic chronic diseases and decline in physical functioning:

Journal of Clinical Epidemiology 57 (2004) 55–65

Comorbidity of somatic chronic diseases and decline in physical functioning: the Longitudinal Aging Study Amsterdam Didi M.W. Kriegsmana,b,*, Dorly J.H. Deegb,c, Wim A.B. Stalmana,b a Department of General Practice, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands Institute for Research in Extramural Medicine, EMGO Institute, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands c Department of Psychiatry, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands Accepted 3 June 2003

b

Abstract Objective: To assess the association of decline in physical functioning with number of chronic diseases and with specific comorbidity in different index diseases. Methods: A longitudinal design was employed using data from 2,497 older adults participating in the Longitudinal Aging Study Amsterdam. Logistic regression analyses were used to determine influence of chronic diseases on change in physical functioning, operationalized using the Edwards-Nunnally index. Results: Decline in physical functioning was associated with number of chronic diseases (adjusted ORs from 1.58 for 1, to 4.05 for ⭓3 diseases). Comorbidity of chronic nonspecific lung disease and malignancies had the strongest exacerbating influence on decline. An exacerbating effect was also found for arthritis in subjects with diabetes or malignancies and for stroke in subjects with chronic nonspecific lung disease or malignancies. A weaker effect than expected was observed for diabetes in subjects with stroke, malignancies, cardiac disease, or peripheral atherosclerosis. Conclusion: Comorbidities involving chronic diseases that share etiologic factors or pathophysiologic mechanisms appear to have a weaker negative influence on decline in physical functioning than expected. Results indicate that combinations of diseases that both influence physical functioning, but through different mechanisms (locomotor symptoms vs. decreased endurance capacity) may be more detrimental than other combinations. 쑖 2004 Elsevier Inc. All rights reserved. Keywords: Comorbidity; Chronic disease; Longitudinal studies; Activities of daily living

1. Introduction The role of chronic diseases and comorbidity as determinants of mobility limitations is intuitively important, but not well understood. A higher number of chronic diseases is consistently associated with a higher prevalence of mobility limitations [1–3], and longitudinally with a higher incidence of mobility loss [4]. In elderly people, the specific chronic diseases that are most consistently associated with either a higher prevalence or higher incidence of mobility limitations include arthritis [2,5–9], cardiac diseases [2,4,6–9], cerebrovascular disorders [2,4–7,9], chronic obstructive pulmonary disease [6–9], diabetes mellitus [2,4,7–9], and, to a lesser extent, cancer [2,7–9] and atherosclerosis [2,9].

* Corresponding author. Tel.: ⫹31-20-44-48194/48199; fax: ⫹31-2044-48361. E-mail address: [email protected] (D.M.W. Kriegsman). 0895-4356/04/$ – see front matter 쑖 2004 Elsevier Inc. All rights reserved. doi: 10.1016/S0895-4356(03)00258-0

Generally, the presence of chronic diseases in population surveys is measured by self-reports pertaining to the presence or absence of a specific disease, and comorbidity is defined as the number of chronic diseases reported (see end of “Discussion” section). Using this definition, comorbidity consistently shows a strong association with all kinds of health outcomes, such as mobility limitations, perceived health, use of health care facilities, and mortality [10,11]. Previous research, however, has shown that specific combinations of chronic diseases may have a different influence on physical functioning than would be expected on the basis of the addition of the influences of the individual diseases [2]. Moreover, the influence of comorbidity in specific chronic diseases deserves further study. Little is known about whether this influence differs across specific chronic diseases [2]. Although there has been an enormous increase in publications addressing the impact of comorbidity [11] and the

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evidence supporting comorbidity as a risk factor for functional decline is considered to be strong [10,11], relatively few studies have employed a longitudinal design. In the recent review by Gijsen et al. [11], 18 cross-sectional and only six longitudinal studies addressing the influence of comorbidity on functional status or quality of life were identified. Most of these studies (50%) used a comorbidity index or count. Of the longitudinal studies, two studies were confined to cancer patients, two studies dealt with patients who experienced stroke, one focused on persons with knee osteoarthritis, and one with comorbidity of anxiety disorders. Thus, the differences in patient groups hamper comparison and generalization of the findings from these studies. In the present study, we investigate the impact of comorbidity in the general population, that is, the number of chronic diseases, as well as that of comorbidity of specific chronic diseases on 3-year change in physical functioning. The additional influence of comorbidity on change in physical functioning in specific chronic diseases is investigated for chronic diseases that often afflict the elderly, and that have been repeatedly shown to influence physical functioning and thereby the ability of older people to live independently in the community. Seven specific chronic diseases with a high prevalence in the elderly population were selected: chronic nonspecific lung disease (CNSLD: asthma, chronic bronchitis or pulmonary emphysema), cardiac disease (including myocardial infarction), peripheral atherosclerosis, stroke, diabetes mellitus, arthritis (rheumatoid arthritis or osteoarthritis), and malignancies. 2. Methods 2.1. Design The present study uses a longitudinal design. Data were collected in the context of the Longitudinal Aging Study Amsterdam (LASA) [12], a longitudinal study on predictors and consequences of changes in physical, cognitive, emotional, and social functioning among older persons. In this study, data from the first two measurement cycles, conducted in 1992/1993 (baseline: T1) and 1995/1996 (follow-up: T2), are used. 2.2. Subjects A sample of people aged 55 to 85 years, stratified according to age, gender, and expected attrition due to mortality after 5 years of follow-up in each age group, was drawn from the population registries of 11 municipalities in three culturally distinct geographic areas in the west, north-east, and south of The Netherlands. The cohort was recruited in 1991 for the NESTOR-LSN study “Living arrangements and social networks of older adults” (response rate 62.3%) [13]. After 11 months, the participants in NESTOR-LSN were approached for the first LASA cycle. Details of the procedures and results of the fieldwork are described elsewhere [14]. From the initial sample of 3,805 persons who participated

in NESTOR-LSN, a total of 3,107 participated in the main interview of LASA at baseline (81.7%). Of the persons who did not participate, 260 (6.8% of initial sample) proved to be ineligible (deceased or not able due to severe physical and/ or cognitive impairments). Of the other 438 nonparticipants, 394 (10.4% of initial sample) refused and 44 (1.2% of initial sample) could not be contacted. The corrected response percentage of the first LASA cycle, excluding those who were ineligible, therefore, was 87.6%. Older age was significantly associated with ineligibility due to severe physical or cognitive impairments (P ⬍ .0001) but not with refusal to participate [15]. Three years after the baseline interview, between September 1995 and September 1996, all respondents were approached for a follow-up interview (T2). Of the 3,107 subjects who participated at baseline, 418 (13.5%) had died, 17 (0.5%) could not be contacted, 90 (2.9%) refused to participate, and 85 (2.7%) had missing information on the outcome measure for this study. Thus, 2,497 subjects (80.4% of participants in the baseline interview) were available for the analyses. Multivariate analysis of determinants of attrition between baseline and follow-up due to mortality showed that death was predicted by being male [female vs. male: odds ratio (OR) 0.43, 95% confidence interval (CI) 0.32–0.56], older (for each year older: OR 1.08, 95%CI 1.06–1.10), institutionalized (OR 1.80, 95% CI 1.10–2.97), cognitively impaired (Mini-Mental State Examination [MMSE] score ⬍24: OR 1.94, 95%CI 1.39–2.70), limited in physical functioning (for each higher level of functioning: OR 0.94, 95%CI 0.91–0.97), and by the baseline presence of peripheral atherosclerosis (OR 1.78, 95%CI 1.25–2.53), diabetes mellitus (OR 2.83, 95%CI 2.00–3.99), and malignancies (OR 1.96, 95%CI 1.38–2.78). Attrition due to missing outcome information at T2 (because of refusal, ineligibility, or missing data) was predicted by being institutionalized (OR 2.57, 95%CI 1.19–5.56), being cognitively impaired (MMSE score ⬍24: OR 2.28, 95%CI 1.44–3.59) and by the baseline absence of cardiac disease (OR 0.59, 95%CI 0.36–0.95) and other chronic diseases (OR 0.71, 95%CI 0.51–0.99). The number of chronic diseases (out of seven) was predictive for attrition due to mortality (one disease: OR 1.31, 95%CI 0.97–1.78; two diseases: OR 1.77, 95%CI 1.25–2.50; more than three diseases: OR 2.82, 95%CI 1.88–4.22; all vs. no disease), but not for attrition because of missing information on the outcome. 2.3. Measurements 2.3.1. Physical functioning Physical functioning was measured by self-report. Questions were asked about the degree to which the respondent had difficulty performing six usual daily activities: going up and down the stairs, getting (un-)dressed, sitting down and rising from a chair, cutting own toenails, walking 400 meters, and using own or public transportation [16]. Respondents could indicate whether they were able to perform the

D.M.W. Kriegsman et al. / Journal of Clinical Epidemiology 57 (2004) 55–65

activity without difficulty, with some difficulty, with much difficulty, only with help, or not at all. These response categories were coded as 5, 4, 3, 2, and 1, respectively, and sum scores (range 6–30) were calculated, with lower scores indicating more limitations in physical functioning. The sum scores at T1 and T2 were used to measure change during the 3 years of follow-up. 2.3.2. Change in physical functioning To determine whether decline in physical functioning occurred between baseline (T1) and follow-up (T2), we used the Edwards-Nunnally index (EN-index) [17]. Contrary to difference scores that indicate the amount of change between two measurements, the EN-index determines the probability of substantial individual change and avoids the problem of regression to the mean. Based on the scale reliability of the six items at T1 (Cronbach’s α ⫽ 0.87) and the 90%CI of the mean sum score at T1 (27.7, SD 4.1), the EN-index computes whether a significant change between T1 and T2 has occurred. Because the study deals with individual change, the 90% CI is suitable as criterion value. Substantial change in physical functioning is computed for each subject using the formula (Cronbach’s α * (T1 ⫺ mean) ⫹ mean ⫹ 1.645 * SE), in which T1 is the individual’s physical functioning score at baseline, Cronbach’s α is the scale reliability for physical functioning at baseline, mean is the mean physical functioning score at baseline, SD is the standard deviation of the physical functioning score at baseline, SE is the standard error ⫽ SD * 冪(1⫺Cronbach’s α). No change has occurred when the individual’s physical functioning score at follow-up T2 ⭓ (Cronbach’s α * (T1 ⫺ mean) ⫹ mean ⫺ 1.645 * SE) and T2 ⭐ (Cronbach’s α * (T1 ⫺ mean) ⫹ mean ⫹ 1.645 * SE). Substantial decline in physical functioning is present when T2 ⬍ (Cronbach’s α * (T1 ⫺ mean) ⫹ mean ⫺ 1.645 * SE), and improvement has occurred when T2 ⬎ (Cronbach’s α * (T1 ⫺ mean) ⫹ mean ⫹ 1.645 * SE). Thus, according to the EN-index, a distinction was made between no change (mean difference between T1 and T2: ⫺0.1; SD 0.9), decline (mean difference: ⫺6.2; SD 4.2) and improvement (mean difference: 5.0; SD 1.8) in physical functioning. Using the EN-index implies that whether or not decline is significant is dependent on the individual’s baseline score. For example, respondents with a baseline score of 30 (maximum) need to decline at least 2.7 points to be classified as declined. For respondents with baseline scores of 25, 20, or 15, respectively, the corresponding minimum amount of decline is 2.1, 1.4, and 0.8 points. 2.3.3. Chronic diseases The presence of chronic diseases was assessed by asking the respondents explicitly whether they had or had had any of the following seven chronic diseases or disease events: chronic nonspecific lung disease (CNSLD: asthma, chronic bronchitis. or pulmonary emphysema), cardiac disease (including myocardial infarction), peripheral atherosclerosis,

57

stroke, diabetes mellitus, arthritis (rheumatoid arthritis or osteoarthritis), and malignancies. Answers were coded as “yes” or “no” for each of these diseases, which are considered the index diseases in the present study. The accuracy of self-reports of these diseases compared to general practitioner information was shown to be adequate [18]. At follow-up, chronic disease status was assessed using the same procedure. In view of the types of diseases, those chronic diseases that were reported at baseline were also defined present at follow-up. Incident chronic diseases were defined as present when, compared to baseline, a chronic disease was reported present at follow-up that was not reported at baseline. 2.3.4. Covariates Covariates that were considered as potential confounders included the presence of any other chronic disease than the seven index diseases, gender, age, educational level, urbanization level of the area of residence, partner status, institutionalization, and the presence of clinically relevant depressive symptomatology and cognitive impairment. The presence of other chronic diseases was assessed by asking the respondents whether they had any other chronic disorder in addition to those seven diseases that were explicitly asked. A maximum of two other chronic diseases was registered, and this was coded as 0 when no additional chronic disease was reported and as 1 when one or two additional chronic diseases were reported. The variable “other chronic diseases” includes, among others, neurologic diseases, osteoporosis, serious neck and back problems, serious liver and kidney diseases, endocrinologic diseases, varicose veins and venous insufficiency, hypertension, consequences of accidents or surgery, chronic locomotor problems not covered elsewhere, dizziness, and disorders of the eyes or ears. Although we have no information about the accuracy of self-reports of these other diseases, the analyses were adjusted for the presence of any other disease. This may be overadjustment and result in weaker associations between the specific diseases and change in physical functioning. Gender and age of the subjects were derived from the municipal registries. Educational level was determined by asking the respondents which was their highest level of education attained, and this was categorized in four levels: elementary school, lower vocational education, secondary school (general intermediate through general secondary education), and higher vocational or university education. Urbanization level was defined as the number of addresses within 1 square kilometer of the respondent’s home [19]. Categories range from “not urbanized” (⬍500 addresses/km2) through “very highly urbanized” (⬎2,500 addresses/km2). For partner status, a distinction was made between subjects who were living together with a partner (either married or not), vs. those who were not living together with a partner (either never married, widowed, divorced, or married but living separately). Institutionalized respondents were those living in a residential or nursing home.

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The presence of depressive symptoms was assessed by means of the Dutch version [20] of the Center for Epidemiologic Studies Depression Scale (CES-D) [21], which proved to have satisfactory psychometric properties (Cronbach’s α ⫽ 0.87) [20]. A clinically relevant level of depressive symptomatology was considered present when the total score, which ranges from 0 to 60, was ⭓16, which is the generally accepted cutoff score. The presence of impairment in cognitive functioning was determined by using the MMSE [22]. A total score, range 0–30, was computed by summing the individual item scores (taking the highest of the “serial 7” item and the “reversed spelling” item). A score ⭐23 was considered to indicate the presence of a clinically relevant impairment in cognitive function, whereas a score ⭓24 was considered normal [23,24]. 2.4. Analyses Bivariate associations between independent variables and decline in physical functioning were examined using χ2tests and t-tests, as appropriate. To determine the influence of the number of baseline chronic diseases (out of seven) and incident diseases on decline in physical functioning, logistic regression analysis was used, adjusted for gender, age, educational level, level of urbanization, institutionalization, baseline physical functioning, CES-D and MMSE-scores, and the presence of other diseases at baseline. Logistic regression analyses were also used to determine the influence of comorbid chronic diseases on decline in physical functioning for subjects with a specific chronic disease at baseline. For each of the seven specific index chronic disease groups, a regression model was built, adjusted for the covariates that had a significant influence on decline in the previous logistic regression model. The ORs and 95% CIs, indicating the influence of specific chronic diseases in subjects with the index disease were all compared with the influence of the specific disease in the total study sample. To confirm whether the influence of specific combinations of two chronic disease also was significantly different in the total study sample, interactions between specific diseases were tested using the stepwise backward method.

3. Results Characteristics of the total study sample (n ⫽ 2,497), as well as differences in characteristics between subjects with no change and decline in physical functioning, are presented in Table 1. The majority of subjects showed no change in physical functioning during the 3 years of follow-up (73.6% no change, 21.4% decline, 5.0% improvement). Because the number of subjects who improved was small (n ⫽ 126), their results are not presented separately and multivariate logistic regression analyses were not conducted. Decline in

physical functioning is associated with being female, older age, lower educational level, not living with a partner, being institutionalized, clinically relevant depressive symptomatology and cognitive impairment, having chronic diseases (both the seven index diseases separately and the number of chronic diseases), incidence of chronic disease during follow-up, and with a lower baseline level of physical functioning. Table 2 provides descriptive information on the baseline prevalence of (specific) comorbidity among subjects with different index diseases in the total study sample. Differences were tested using the program Confidence Interval Analysis [25]. Comorbidity is common in all index diseases. The prevalence of comorbidity is lowest in subjects with arthritis (44.8%) and cardiac disease (58.7%), and highest in those with peripheral atherosclerosis (77.8%) and stroke (73.0%). Compared to the prevalence in the total study sample, CNSLD is significantly more common in subjects with peripheral atherosclerosis or arthritis. Cardiac disease is more common among those with CNSLD, peripheral atherosclerosis, or stroke. Peripheral atherosclerosis is significantly more common in subjects with any of the other index diseases except in those with malignancies. Stroke is reported more often by subjects with cardiac disease, peripheral atherosclerosis, or diabetes mellitus. Diabetes mellitus is more often reported by subjects with peripheral atherosclerosis, stroke, or malignancies. Arthritis is more common among those with CNSLD, peripheral atherosclerosis, diabetes mellitus, or malignancies. Finally, malignancies are more often reported by subjects with diabetes mellitus or arthritis. Adjusted for covariates, decline in physical functioning was strongly associated with the number of chronic diseases, with ORs ranging from 1.58 for one of the seven diseases to 4.05 for ⭓3 diseases (see Table 3). In case of incident disease(s) between baseline and follow-up, the likelihood of decline in physical functioning was increased as well, with an OR of 1.70. Of the covariates, independent associations with decline were observed for gender (females having a higher risk than males), age (higher risk when older), baseline physical functioning (lower risk when better), CES-D score (higher risk when ⭓16), MMSE score (higher risk when ⬍24), and the presence of any other chronic disease at baseline (higher risk). In the total study sample, adjusted for all covariates, decline in physical functioning was significantly associated with baseline presence of CNSLD (OR 1.62, 95%CI 1.16– 2.25), stroke (OR 3.36, 95%CI 2.10–5.37), diabetes mellitus (OR 2.00, 95%CI 1.29–3.09), and arthritis (OR 1.62, 95%CI 1.26–2.08), but not with cardiac disease, peripheral atherosclerosis, and malignancies. Furthermore, decline was associated with incident stroke (OR 2.83, 95%CI 1.68–4.74), diabetes mellitus (OR 2.92, 95%CI 1.56–5.47), and malignancies (OR 1.78, 95%CI 1.04–3.05), but not with incident CNSLD, cardiac disease, peripheral atherosclerosis, and arthritis.

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Table 1 Characteristics of the total study sample and associations between independent variables and decline in physical functioning

Gender: Male Female Age (mean ⫾ SD) Educational level: Elementary school Lower vocational education Secondary school Higher vocational/university Level of urbanization Not (⬍500) Little (500–1,000) Somewhat (1,000–1,500) Highly (1,500–2,500) Very highly (⬎2,500) Living with partner at T1 No Yes Institutionalized at T1 No Yes CES-D score at T1 ⬍16 ⭓16 MMSE score at T1 ⭓24 ⬍24 Chronic diseases at T1 CNSLD No Yes Cardiac disease No Yes Peripheral atherosclerosis No Yes Stroke No Yes Diabetes mellitus No Yes Arthritis No Yes Malignancies No Yes Other disease(s) No Yes Number of chronic diseases [excluding other disease(s)] No chronic disease 1 chronic disease 2 chronic diseases ⭓3 chronic diseases Number of chronic diseases [excluding other disease(s)] (mean ⫾ SD) Incident chronic disease(s) between T1 and T2 No Yes Physical functioning T1 (mean ⫾ SD) T2 (mean ⫾ SD) Change between T1 and T2 (mean ⫾ SD)

Total study sample (N ⫽ 2497)

No change (N ⫽ 1837)

Decline (N ⫽ 534)

N

N

N

%

2,497 1,170 1,327 69.2 2,494 1,037 505 656 296 2,497 591 454 543 369 540 2,491 865 1,626 2,497 2,445 52 2,474 2,150 324 2,485 2,296 189 2,490 2,232 258 2,490 2,035 455 2,490 2,332 158 2,490 2,379 111 2,490 2,353 137 2,490 1,685 805 2,489 2,295 194 2,490 1,419 1,071 2,489 1,085 885 373 146

%

%

P-value ⬍.001

46.9 53.1 ⫾8.6

915 922 67.5

49.8 50.2 ⫾8.2

207 327 73.8

38.8 61.2 ⫾8.1

41.6 20.2 26.3 11.9

693 380 519 243

37.8 20.7 28.3 13.2

272 101 113 47

51.0 18.9 21.2 8.8

23.7 18.2 21.7 14.8 21.6

438 350 411 247 391

23.8 19.1 22.4 13.4 21.3

128 87 98 103 118

24.0 16.3 18.4 19.3 22.1

34.7 65.3

550 1283

30.0 70.0

252 280

47.4 52.6

97.9 2.1

1812 25

98.6 1.4

511 23

95.7 4.3

86.9 13.1

1640 185

89.9 10.1

414 113

78.6 21.4

92.4 7.6

1741 90

95.1 4.9

447 82

84.5 15.5

89.6 10.4

1681 151

91.8 8.2

446 87

83.7 16.3

81.7 18.3

1551 281

84.7 15.3

404 129

75.8 24.2

93.7 6.3

1744 88

95.2 4.8

475 58

89.1 10.9

95.5 4.5

1787 45

97.5 2.5

475 58

89.1 10.9

94.5 5.5

1761 71

96.1 3.9

477 56

89.5 10.5

67.7 32.3

1328 504

72.5 27.5

300 233

56.3 43.7

92.2 7.8

1698 133

92.7 7.3

484 49

90.8 9.2

57.0 43.0

1106 726

60.4 39.6

249 284

46.7 53.3

43.6 35.6 15.0 5.9

911 640 223 57

49.8 35.0 12.2 3.1

150 198 113 72

28.1 37.1 21.2 13.5

⬍.001 ⬍.001

.006

⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001

.14 ⬍.001 ⬍.001

0.85 2,482 1,795 687

⫾0.95

27.7 26.6 ⫺1.1

⫾4.1 ⫾5.3 ⫾3.6

72.3 27.7

0.70 1,382 446 28.7 28.6 ⫺0.1

⫾0.84 75.6 24.4 ⫾3.2 ⫾3.0 ⫾0.9

1.26 325 204 25.9 19.7 ⫺6.2

⫾1.13

⬍.001 ⬍.001

61.4 38.6 ⫾5.1 ⫾5.9 ⫾4.2

⬍.001 ⬍.001 ⬍.001

60

D.M.W. Kriegsman et al. / Journal of Clinical Epidemiology 57 (2004) 55–65

Table 2 Prevalences of (specific) comorbidity in subjects with different index diseases at baseline (n ⫽ 2497) Presence of comorbidity

n CNSLD n ⫽ 258, 10.4% (95%Cl 9.1–11.5) ⫺only (excl. “other”)* ⫺specific comorbidity

79 179

% Within index disease (95%Cl)

n

⫹cardiac disease

61

⫹peripheral atherosclerosis ⫹stroke

29 19

⫹diabetes mellitus

22 111

⫹malignancies

30

⫺⫹other Cardiac disease n ⫽ 455, 18.3% (95%Cl 16.7–19.7) ⫺only (excl. “other”) ⫺specific comorbidity

132

188 267

⫹CNSLD

61

⫹peripheral atherosclerosis ⫹stroke

63 43

⫹diabetes mellitus

35 158

⫹malignancies

46

⫺⫹other Peripheral atherosclerosis n ⫽ 158, 6.3% (95% Cl 5.4–7.4) ⫺only (excl. “other”) ⫺specific comorbidity

206

35 123

% Within index disease (95%Cl)

23.6 (18.5–28.8) 11.2 (7.4–15.1) 7.4 (4.5–11.3) 8.5 (5.5–12.6) 43.0 (37.0–49.1) 11.6 (7.7–15.5) 51.2 (45.1–57.3)

41.3 58.7 (54.2–63.2)

⫹arthritis

Presence of comorbidity

Specific comorbidity

30.6 69.4 (63.8–75.0)

⫹arthritis

Table 2 Continued

13.4 (10.3–16.5) 13.8 (10.7–17.0) 9.5 (6.9–12.5) 7.7 (5.4–10.5) 34.7 (30.4–39.1) 10.1 (7.3–12.9) 45.3 (40.7–49.8)

22.2 77.8 (71.4–84.3)

⫹CNSLD

29

⫹cardiac disease

63

⫹stroke

18

⫹diabetes mellitus

22

⫹arthritis

71

18.4 (12.3–24.4) 39.9 (32.2–47.5) 11.4 (6.4–16.3) 13.9 (8.5–19.3) 44.9 (37.2–52.7) (Continued)

n

% Within index disease (95%Cl)

Specific comorbidity

n

⫹malignancies

20

⫺⫹other

81

Stroke n ⫽ 111, 4.5% (95% Cl 3.4–5.3) ⫺only (excl. “other”) ⫺specific comorbidity

30 81

19

⫹cardiac disease

43

⫹peripheral atherosclerosis ⫹diabetes mellitus

18

⫹arthritis

35

⫹malignancies

12

⫺⫹other

52

14

47 90

22

⫹cardiac disease

35

⫹peripheral atherosclerosis ⫹stroke

22 14

⫹arthritis

59

⫹malignancies

19

⫺⫹other

64

444 361

17.1 (10.1–24.1) 38.7 (29.7–47.8) 16.2 (9.4–23.1) 12.6 (6.4–18.8) 31.5 (22.9–40.2) 10.8 (5.0–16.6) 46.8 (37.6–56.1)

34.3 65.7 (57.7–73.6)

⫹CNSLD

Arthritis n ⫽ 805, 32.3% (95% Cl 30.4–34.1) ⫺only (excl. “other”) ⫺specific comorbidity

12.7 (7.5–17.8) 51.3 (43.5–59.1)

27.0 73.0 (64.7–81.2)

⫹CNSLD

Diabetes mellitus n ⫽ 137, 5.5% (95% Cl 4.6–6.5) ⫺only (excl. “other”) ⫺specific comorbidity

% Within index disease (95%Cl)

16.1 (9.9–22.2) 25.5 (18.2–32.9) 16.1 (9.9–22.2) 10.2 (5.2–15.3) 43.1 (34.8–51.4) 13.9 (8.1–19.7) 46.7 (38.4–55.1)

55.2 44.8 (41.4–48.3)

⫹CNSLD

111

⫹cardiac disease

158

⫹peripheral atherosclerosis ⫹stroke

71 35

13.8 (11.4–16.2) 19.6 (16.9–22.4) 8.8 (7.0–11.0) 4.3 (3.1–6.0) (Continued)

D.M.W. Kriegsman et al. / Journal of Clinical Epidemiology 57 (2004) 55–65 Table 2 Continued Presence of comorbidity

n

% Within index disease (95%Cl)

Specific comorbidity

n

⫹diabetes mellitus

59

⫹malignancies

82

⫺⫹other Malignancies n ⫽ 194, 7.8% (95% Cl 6.7–8.9) ⫺only (excl. “other”) ⫺specific comorbidity

393

62 132

% Within index disease (95%Cl) 7.3 (5.6–9.4) 10.2 (8.1–12.3) 48.8 (45.2–52.3)

32.0 68.0 (61.5–74.6)

⫹CNSLD

30

⫹cardiac disease

46

⫹peripheral atherosclerosis ⫹stroke

20 12

⫹diabetes mellitus

19

⫹arthritis

82

⫺⫹other

93

15.5 (10.4–20.6) 23.7 (17.7–29.7) 10.3 (6.0–14.6) 6.2 (3.2–10.6) 9.8 (6.0–14.9) 42.3 (35.3–49.2) 47.9 (40.9–55.0)

* Only (excl. “other”): none of the other index diseases.

Table 4 presents the results of the multivariate logistic regression analyses concerning the influence of specific combinations of chronic diseases on decline in physical functioning. For each of the seven specific chronic diseases a regression model was constructed, including subjects who reported to have the index disease at baseline, and adjusted for gender, age, baseline physical functioning, CES-D, and MMSE scores. Because educational level, level of urbanization, living with a partner, and being institutionalized did not have a significant influence on decline (see Table 3), the analyses were not adjusted for these variables. In subjects with CNSLD a decline in physical functioning was significantly associated with the additional presence of stroke (OR 7.01), arthritis (OR 2.03), or malignancies (OR 3.12) at baseline. For subjects with cardiac disease, decline in physical functioning was associated with additional CNSLD (OR 2.19), stroke (OR 4.51), arthritis (OR 2.49), and the incidence between baseline and follow-up of any of the seven specific chronic diseases (OR 2.13). In subjects with peripheral atherosclerosis or stroke, comorbid chronic diseases were not significantly associated with decline in physical functioning. Subjects with diabetes mellitus at baseline ran a higher risk on decline in physical functioning during follow-up when additional arthritis was present at baseline (OR 3.15) or when the incident chronic disease occurred

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Table 3 Results of logistic regression analysis of decline and improvement (both vs. no change) in physical functioning on the number of chronic diseases at baseline Decline

Gender (male vs. female) Age (per year older) Educational level: Elementary school (reference) Lower vocational education Secondary school Higher vocational/university Level of urbanization: Not (⬍500; reference) Little (500–1,000) Somewhat (1,000–1,500) Highly (1,500–2,500) Very highly (⬎2,500) Living with partner at T1 (yes vs. no) Institutionalized at T1 (yes vs. no) Baseline physical functioning (higher score ⫽ better) CES-D score at T1⭓16 MMSE score at T1⬍24 Other disease(s) at baseline (yes vs. no) Number of seven chronic disease(s) at baseline: No disease (reference) 1 disease 2 diseases ⭓3 diseases Incident disease(s) (yes vs. no)

OR

95%Cl

1.38 1.07

1.08–1.76 1.05–1.09

1.00 1.08 0.93 0.82

0.80–1.45 0.70–1.24 0.55–1.21

1.00 0.83 0.71 1.22 0.80 0.92 0.63 0.95

0.59–1.17 0.51–1.00 0.86–1.73 0.57–1.11 0.72–1.18 0.30–1.33 0.92–0.97

1.46 2.12 1.26

1.07–1.99 1.45–3.08 1.00–1.57

1.00 1.58 1.96 4.05 1.70

1.22–2.05 1.42–2.70 2.58–6.34 1.34–2.15

(OR 2.20). In subjects with arthritis at baseline, only incident of chronic disease during follow-up (OR 2.17) was associated with decline in physical functioning. Subjects who reported malignancies at baseline had a significantly higher risk for functional decline when they also had CNSLD (OR 9.87), stroke (OR 13.09), arthritis (OR 4.79), or when incident chronic disease occurred during follow-up (OR 3.35). Compared to the influence of CNSLD in the total study sample, the influence of CNSLD as a comorbid disease in different index diseases was not significantly different, except for subjects with malignancies, in whom the influence of comorbid CNSLD on decline in physical functioning was considerably larger. For cardiac disease the differences in influence across the index diseases were small and the influence of cardiac disease as a comorbid disease was not significant in the total study sample, nor in any of the index diseases. Peripheral atherosclerosis also had no significant influence. The influence of stroke as a comorbid disease was comparable to its influence in the total study sample for subjects with cardiac disease, peripheral atherosclerosis, and arthritis. For subjects with CNSLD or malignancies the influence of comorbidity of stroke on decline in physical functioning appeared to be stronger, whereas for subjects with diabetes it appeared to be somewhat less strong, compared to the total study sample. The influence of comorbidity of

2.03–84.62 0.24–5.01 1.72–13.33 — 1.32–8.49 13.09 1.10 4.79 — 3.35 0.99–5.30 0.97–3.59 — 0.56–1.80 1.44–3.26 2.30 1.87 — 1.01 2.17 0.30–5.75 — 1.67–8.50 0.12–1.89 1.16–7.34 1.32 — 3.15 0.48 2.20 — 0.42 1.81 2.19 2.45 0.90–11.35 0.33–3.30 0.74–4.21 0.40–4.77 0.90–4.99 3.20 1.04 1.76 1.38 2.11 2.03–10.03 0.33–2.20 1.44–4.32 0.55–2.67 1.25–3.63 1.96–25.08 0.67–7.32 1.05–3.94 1.23–7.89 0.88–3.32 7.01 2.22 2.03 3.12 1.71

4.51 0.85 2.49 1.21 2.13

— 0.84–3.66 0.55–3.55 — 1.75 1.40

2.19 — 1.65

1.11–4.30 — 0.83–3.25

1.48 1.65 —

2.46 2.07 1.83

— 0.08–2.10 0.60–5.44 0.40–11.83 0.81–7.45

3.11–31.36 0.64–4.54 0.42–8.39 9.87 1.70 1.88 0.99–2.58 0.97–2.36 0.68–2.34 1.60 1.52 1.26 0.76–10.06 0.35–2.83 0.32–4.44 2.76 1.00 1.20

95%Cl

0.58–3.78 0.73–3.73 —

0.64–9.47 0.78–5.47 0.46–7.36

2.18

OR 95%Cl

0.76–1.56 1.09

OR 95%Cl

0.56–3.44 1.39

OR 95%Cl

0.29–2.15

OR

0.79

95%Cl

0.76–3.97 1.74

OR 95%Cl

0.44–1.25 0.74

OR 95%Cl

0.42–1.49 0.79

OR 95%Cl OR

Other disease(s) 1.26 1.01–1.58 at baseline Prevalent specific disease(s) at baseline CNSLD 1.61 1.16–2.22 Cardiac disease 1.22 0.93–1.62 Peripheral 1.23 0.81–1.86 atherosclerosis Stroke 3.23 2.09–5.28 Diabetes mellitus 1.93 1.25–2.96 Arthritis 1.64 1.29–2.07 Malignancies 0.88 0.59–1.30 Incident chronic 1.79 1.41–2.26 disease(s)

Arthritis N ⫽ 726 Diabetes mellitus N ⫽ 123 Stroke N ⫽ 103 Peripheral atherosclerosis N ⫽ 143 Cardiac disease N ⫽ 402 CNSLD N ⫽ 236 Total study sample N ⫽ 2333

Table 4 Results of logistic regression analyses in the total study sample and in subjects with a specific chronic disease at baseline: influence of comorbid chronic diseases at baseline and incident disease(s) on decline in physical functioning (adjusted for gender, age, baseline physical functioning, CES-D and MMSE scores)

0.90–5.29

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Malignancies N ⫽ 178

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diabetes mellitus on decline in physical functioning was not significant in any of the index diseases, although it predicted decline in the total study sample. Compared to the influence of diabetes mellitus in the total study sample, comorbidity of diabetes appeared to have a somewhat weaker influence in subjects with cardiac disease, atherosclerosis, stroke, or malignancies. The influence of arthritis as a comorbid disease was clearly stronger for subjects with diabetes or malignancies, and somewhat stronger for those with cardiac disease. Compared to the influence of malignancies on decline in physical functioning in the total study sample, comorbidity of malignancies had a significantly stronger influence in subjects with CNSLD. The influence of incident chronic disease(s) during the 3 years of follow-up on decline in physical functioning was comparable for subjects with baseline presence of CNSLD, cardiac disease, peripheral atherosclerosis, stroke, diabetes mellitus, and arthritis, although not significant for CNSLD, atherosclerosis, and stroke. For subjects with malignancies at baseline, additional incident disease(s) appeared to have a somewhat stronger influence than in the total study sample. In the total study sample two combinations of chronic diseases had a significantly different influence than expected (P ⬍ .05 for the product term): the influence of the combined presence of CNSLD and malignancies was stronger (OR 4.64, 95%CI 1.65–13.01), and the influence of the combined presence of stroke and diabetes mellitus was weaker (OR 0.19, 95%CI 0.05–0.76). 4. Discussion It appears useful to first compare our results regarding the frequency of occurrence of specific combinations of chronic diseases with those from previous studies. Most of the disease combinations that occur in a higher frequency than expected involve so-called causal comorbidities [26] (coexistence based on a proven common pathophysiologic cause): cardiac disease, peripheral atherosclerosis, stroke, and diabetes mellitus. This is in line with reports from other studies [2,27,28]. In addition, we found some combinations of chronic diseases that are not causally related to be more frequent than expected: noncausal comorbidities (concurrent or cluster comorbidity) [26]. Some of these combinations have been reported previously: CNSLD and arthritis [29], diabetes mellitus and malignancies [30], and arthritis and malignancies [30]. Other combinations that we found, however, were not reported to occur more frequently in the literature: CNSLD and peripheral atherosclerosis or cardiac disease [29], diabetes mellitus, and arthritis [27]; whereas some other combinations that we did not find were reported: CNSLD and malignancies [29], cardiac disease, and diabetes mellitus [27]. Possible mechanisms explaining the presence of specific combinations of chronic diseases in a frequency beyond chance include: (1) common etiologic factors (e.g., smoking increases the risk for both CNSLD and cardiovascular diseases, as well as several types of malignancies) [29,31]; (2)

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common pathophysiologic pathways (e.g., atherosclerosis, is involved in the occurrence of cardiac disease, peripheral atherosclerosis, and stroke); (3) regular medical care for a chronic disease may increase the likelihood of detection of other diseases (e.g., diabetes mellitus and malignancies) [32,33]; (4) consequences of a chronic disease may increase the risk of another disease to manifest itself (e.g., lack of physical activity in severe CNSLD may result in more symptoms of arthritis) [29]. In causal comorbidities, all of these mechanisms may be involved, whereas in noncausal comorbidities only the latter two mechanisms can explain higher frequencies of occurrence. We found a strong association between a higher number of chronic diseases (out of seven) and a higher risk for decline in physical functioning during 3 years of follow-up. This result is in line with those of other studies [4]. The occurrence of one or more new chronic diseases (out of seven) during follow-up was associated with an additional increase in the risk for decline, which has also been reported previously [4,34]. In our total study sample decline in physical functioning during follow-up was significantly predicted by baseline presence of CNSLD, stroke, diabetes mellitus, and arthritis, and by incidence of stroke, diabetes mellitus, and malignancies. Most previous studies have addressed cross-sectional associations between the presence of specific chronic diseases and limitations in physical functioning. Results of these studies are largely comparable with our results as far as the influence of prevalent chronic diseases on decline is concerned, although the longitudinal associations in our study appear to be less strong for some diseases [2,6,35–37]. The few longitudinal studies, however, also report somewhat less strong associations compared to cross-sectional studies [4,5]. Not all our results are consistent with these other longitudinal studies. The most remarkable difference is that we found a considerably stronger influence of diabetes. Contrary to our results, Guralnik et al. [4] did not find incident diabetes to be associated with decline in physical functioning. For stroke and malignancies comparable results were reported, but the influence of incident cardiac disease was not observed [4]. The study of Guralnik et al. [4], however, only included older people without any limitations in physical functioning at baseline, whereas our study also included those with limitations in physical functioning and thus also determined the influence of chronic diseases on further decline. The study of Kiely et al. [34], which focussed on rate of decline, included people with limitations and reported results more comparable with ours. Regarding differences between the influence of prevalent and incident diseases, Markides et al. [36] reported malignancies to be associated with mobility limitations particularly for those with a recent (⬍3 years) diagnosis, whereas no such difference was observed for stroke and cardiac disease. This is in line with our results. With regard to the impact of specific comorbidity for older people with different index diseases, comparison of

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our results with those reported in the literature is considerably hampered by the lack of previous studies on this subject. In our study, only one combination of specific chronic diseases showed an additional negative influence on the risk for decline in physical functioning, which was confirmed in the total study sample: CNSLD and malignancies. Two combinations appeared to have a somewhat stronger influence in the disease-specific analyses which, however, was not confirmed in the total study sample: CNSLD and stroke, and stroke and malignancies. The combined presence of CNSLD and malignancies was cross-sectionally shown to be associated with an additional risk for physical limitations in the Women’s Health and Aging Study, but no additional risk was found for the combinations of CNSLD and stroke and of stroke and malignancies [35]. For older people with diabetes mellitus or malignancies as the index disease, comorbidity of arthritis was associated with a significantly higher risk for decline in physical functioning compared to the influence of arthritis in the total study sample. This has not been reported before, but both of these combinations point to a stronger influence of comorbid diseases characterized by locomotor symptoms in index diseases with other characteristics. The same is true for the additional negative influence of comorbid stroke in subjects with malignancies, which has been reported before in one cross-sectional study [2]. For other combinations of chronic diseases that have been reported to be crosssectionally associated with an increased risk for physical limitations [2,35] we did not find an additional impact longitudinally. Verbrugge et al. [2] reported exacerbating effects of stroke with diabetes and atherosclerosis, diabetes with cardiac disease, atherosclerosis with arthritis or malignancies, cardiac disease with malignancies, and arthritis with cardiac disease. The study of Fried et al. [35], which was confined to women, also reported exacerbating effects of cardiac disease and malignancies. In our study, a so-called “damping” effect (a weaker effect than expected) [2] of comorbidity was found for some combinations of chronic diseases, all of which involved diabetes mellitus. A damping effect that was confirmed in the total study sample was found for diabetes and stroke. In addition, compared to the total study sample, diabetes mellitus appeared to have a somewhat weaker effect on decline in older people with cardiac disease, peripheral atherosclerosis, or malignancies as index disease. In contrast, Verbrugge et al. [2] reported an exacerbating effect of diabetes and stroke cross-sectionally. For diabetes and cardiac disease, previous cross-sectional studies were inconsistent, with one reporting an exacerbating effect [2] and the other no effect [35]. The observed damping effects were unexpected, particularly because in the total study sample the influence of both baseline presence and incidence during followup of diabetes mellitus was larger than that of any of the other chronic diseases except stroke. The most probable explanation is selective drop-out due to mortality: older people with diabetes mellitus at baseline were almost three times

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more likely to have died during follow-up than those without diabetes. As a result, the influence of diabetes mellitus as a comorbid disease may not be representative of individual risk for decline in physical functioning. Those people with diabetes in addition to another chronic disease who completed follow-up may have been less frail or less susceptible to the negative influence of comorbid diabetes than those who died. To some extent, our results are thus comparable with studies on mortality in people with diabetes [38], that showed a decrease in excess mortality for people with diabetes with advancing age, and with studies reporting no influence of comorbidity in diabetes on glycemic control [39]. Another possible explanation is that in older people with diabetes, who are regularly seen by the general practitioner, comorbid chronic diseases are detected in earlier stages. This possibility has been confirmed for malignancies [32], and is likely for cardiovascular diseases for which diabetes patients are regularly screened. The occurrence of any incident chronic disease during the 3 years of follow-up was associated with an additional increase in the risk for decline in physical functioning for older people who reported baseline presence of cardiac disease, diabetes mellitus, arthritis, or malignancies. Unfortunately, our numbers were too small to enable examination of the influence of specific incident diseases. Some limitations of our study should be mentioned before drawing further conclusions. Our data on chronic diseases and physical limitations were based on subjects’ self-reports, which might be considered a limitation. Previously, however, we have shown that self-reports of the seven index diseases were sufficiently accurate compared with general practitioner information [18], the latter being a reliable source as far as the presence of chronic diseases is concerned [40]. For physical limitations it was established that the constituting items represented a general underlying dimension that was equally valid for each of the specific chronic diseases [9]. Another limitation is that we have focussed our study on the influence of a limited number of specific chronic diseases and that disease severity was not taken into account. Our main focus, however, was to assess differences between the influence of comorbidity across various index diseases. For future studies, it seems worthwhile to include diseasespecific measures of severity and symptom load. Finally, for the assessment of limitations in physical functioning we have used a total score on a set of different items, and change was defined as decline vs. no change according to the Edwards-Nunnally index. Previously, it has been shown that the influence of specific chronic diseases and of combinations of diseases may be different for various aspects of physical functioning [6,35–37]. We decided beforehand to use logistic regression analyses of dichotomized outcomes (decline vs. no change) instead of linear regression analyses of absolute or residualized change in physical functioning. Although this results in some loss of information, we were primarily interested in substantial and clinically relevant decline, rather than in subtle changes of physical function

scores. Moreover, ORs are easier to interpret from a clinician’s point of view. Summarizing, we have found some results supporting a difference between causal and noncausal comorbidity. This applies in particular to the damping effects for comorbidity of diabetes mellitus in older people with cardiovascular disease. However, no damping was observed for other combinations of cardiovascular diseases, and other explanations may be more likely. Our results indicate that combinations of chronic diseases that both influence physical functioning, but through different mechanisms (locomotor symptoms and decreased endurance capacity) are perhaps more detrimental than other types of combinations. Examples of such combinations include CNSLD and stroke, and arthritis and cardiac disease. The study of comorbidity remains a challenging exercise. This study has contributed some insights on effects of specific comorbidities in the general population, and at the same time has uncovered a wealth of important issues that remain to be addressed. These should preferably be investigated in longitudinal studies. Our paper covers both “comorbidity” (the existence or occurrence of any distinct additional entity during the clinical course of a patient who has the index disease under study) and “multimorbidity” (the cooccurrence of multiple chronic or acute diseases and medical conditions within one person) [41]. Although these are different concepts, we use the word “comorbidity” to cover both for the following reasons: (a) in our article, the distinction between “comorbidity” and “multimorbidity” cannot always be clearly made (e.g., in the analyses presented in Table 4); (b) “comorbidity” is a more widely used and accepted term than “multimorbidity” (“comorbidity” is a Medical Subject Heading in most bibliographic databases, such as PubMed, whereas “multimorbidity” is not).

Acknowledgments This contribution is based on data from the Longitudinal Aging Study Amsterdam (LASA), which is funded mainly by a long-term grant from The Netherlands Ministry of Health, Welfare and Sports.

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