Abstract

Diabetes mellitus is associated with tuberculosis. A cohort of 42,116 clients aged 65 years or more, enrolled at 18 Elderly Health Service centers in Hong Kong in 2000, were followed up prospectively through the territory-wide tuberculosis registry for development of tuberculosis from 3 months after enrollment to December 31, 2005, by use of their identity card numbers as unique identifier. The effects of diabetes mellitus and diabetic control on tuberculosis risk were assessed with adjustment for sociodemographic and other background variables. Diabetes mellitus was associated with a modest increase in the risk of active, culture-confirmed, and pulmonary (with or without extrapulmonary involvement) but not extrapulmonary (with or without pulmonary involvement) tuberculosis, with adjusted hazard ratios of 1.77 (95% confidence interval: 1.41, 2.24), 1.91 (95% confidence interval: 1.45, 2.52), 1.89 (95% confidence interval: 1.48, 2.42), and 1.00 (95% confidence interval: 0.54, 1.86), respectively. Diabetic subjects with hemoglobin A1c <7% at enrollment were not at increased risk. Among diabetic subjects, higher risks of active, culture-confirmed, and pulmonary but not extrapulmonary tuberculosis were observed with baseline hemoglobin A1c ≥7% (vs. <7%), with adjusted hazard ratios of 3.11 (95% confidence interval: 1.63, 5.92), 3.08 (95% confidence interval: 1.44, 6.57), 3.63 (95% confidence interval: 1.79, 7.33), and 0.77 (95% confidence interval: 0.18, 3.35), respectively.

Diabetes mellitus has been well reported to be associated with increased risk of tuberculosis (1–4). However, few studies examined specifically the effect of diabetes control. The presence of a myriad of associated social factors, metabolic derangements, and comorbidities also poses major difficulties in dissecting the effect of diabetes mellitus from other potential confounders.

In Hong Kong, active tuberculosis disease is statutorily notifiable to the Department of Health, and the notification database has been computerized, with the identity card number as the unique identifier. The annual tuberculosis notification rate is about 90/100,000 population, and it is substantially higher in males and those older than 65 years (5). The Elderly Health Service provides a territory-wide and community-based health maintenance program to the elderly through 18 centers (6). All ambulatory elderly persons aged 65 years or more are eligible for voluntary enrollment. A nominal annual membership fee of about US $13.75 is charged, with a waiver mechanism for those receiving public financial assistance. The availability of such a community health program with minimum barrier access provides an opportunity to study a representative sample of the community-living elderly in Hong Kong. A standardized health questionnaire was administered to each enrolled client, followed by medical examination, chest radiographic examination, and regular screening for hypertension and diabetes mellitus. Hypertension was diagnosed when blood pressure was 140/90 mmHg or more after two repeated measurements (7). Diabetes mellitus was diagnosed, mainly by a fasting plasma glucose level of 7.0 mmol/liter or higher, together with confirmatory symptoms and/or blood/plasma glucose determinations (8). Patients with symptoms suspicious of active tuberculosis or radiologic abnormalities were referred to the 18 chest clinics under a centralized Tuberculosis and Chest Service. Under such an appropriate service infrastructure, a study was performed to examine prospectively the effect of diabetes mellitus and diabetic control on the risk of development of active tuberculosis.

MATERIALS AND METHODS

A cohort of clients who enrolled at the 18 Elderly Health Service centers from January 1, 2000, to December 31, 2000, was retrospectively assembled as previously reported (9). The date of enrollment, name, sex, age, identity card number, smoking status, alcohol use, language spoken, educational level, marital status, housing situation, working status, public means-tested financial assistance status, coexisting medical conditions, recent weight loss, hospital admission during the past 12 months, Activities of Daily Living score, body mass index, and hemoglobin A1c level were retrieved from the baseline health assessment database of the Elderly Health Service. The baseline database was cross-matched prospectively with the death registry and the tuberculosis notification registry by use of the identity card number as the unique identifier, supplemented by name and age, from 3 months (arbitrarily taken as 91 days) after enrollment to December 31, 2005. Diabetes mellitus and hypertension were defined as the corresponding physician-diagnosed conditions with or without treatment, and the updated diagnoses according to World Health Organization criteria (7, 8) after the screening at enrollment were used in the analysis. The hemoglobin A1c level, which reflected a time-weighted mean glycemic control over the previous 3–4 months, was checked at enrollment for those with a known history of diabetes mellitus, and a hemoglobin A1c level of less than 7 percent was taken as reflecting satisfactory glycemic control at baseline (10). The duration of follow-up in days was defined as the period from the start of matching (91 days after enrollment) to the date of notification of tuberculosis, death, or December 31, 2005, whichever occurred first. Information on the date of tuberculosis notification, bacteriologic status, form of tuberculosis, and previous tuberculosis history was retrieved from the notification registry. The diagnosis of and clinical information on all identified tuberculosis cases were verified by reviewing medical records retrieved from chest clinics and other relevant sources, as well as the public health records of the Tuberculosis and Chest Service. An active case of tuberculosis was defined as disease proven by isolation of Mycobacterium tuberculosis or, in the absence of bacteriologic confirmation, disease diagnosed on clinical, radiologic, and/or histologic grounds together with an appropriate response to antituberculosis treatment. Pulmonary tuberculosis was defined as active tuberculosis with pulmonary involvement, irrespective of whether there was extrapulmonary involvement. Similarly, extrapulmonary tuberculosis was defined as active tuberculosis with extrapulmonary involvement, irrespective of whether there was pulmonary involvement.

Disease incidence was calculated by assuming a Poisson distribution in the rate of occurrence of the events. Univariate analysis was followed by Cox regression analysis of the effect of diabetes mellitus on the respective development of active tuberculosis, culture-confirmed tuberculosis, pulmonary tuberculosis, and extrapulmonary involvement. The effect of diabetic control at baseline as reflected by the hemoglobin A1c level was similarly assessed. The proportional hazards assumption was examined by use of graphical methods (i.e., log minus log plots) and the time-dependent covariate method. As a countercheck for the robustness of the multivariate model, the analysis was repeated after exclusion of subjects with malignancies, body mass index <18.5, recent weight loss of 5 percent or more in 6 months, and hospital admission within 12 months of baseline. Two-tailed p < 0.05 was taken as statistically significant.

The study was approved by the Ethics Committee of the Department of Health of Hong Kong, People's Republic of China.

RESULTS

A total of 42,659 clients aged 65 years or more were recruited into the health maintenance program of the Elderly Health Service in 2000. Twenty-three duplicate entries, 304 subjects with a missing/invalid identity number, 127 with missing/incomplete information on sex, age, weight, and/or height, and 89 with known active tuberculosis on presentation or within 3 months of enrollment were excluded, leaving 42,116 subjects for analysis. The background characteristics of the cohort are shown in table 1. The data were over 99.9 percent complete for the variables listed.

TABLE 1.

Background characteristics of the cohort, Hong Kong, People's Republic of China, 2000–2005

Variable All cohort (n = 42,116) No diabetes mellitus (n = 35,672) With diabetes mellitus (n = 6,444) p value* 
Male sex, % 34.7 34.7 34.5 0.741 
Age, years (mean) 72.6 72.6 72.5 0.404 
Cantonese speaking, % 98.3 98.4 98.3 0.548 
Marital, %     
    Never married 3.8 4.0 3.0 <0.001 
    Married 60.6 60.6 60.7  
    Widowed/divorced/other 35.6 35.4 36.3  
Education, %     
    Postsecondary 3.6 3.6 3.7 0.008 
    Secondary 13.7 13.6 13.7  
    Primary 37.5 37.6 36.7  
    No formal 16.7 16.9 15.6  
    Illiterate 28.6 28.3 30.2  
Housing, %     
    Public 39.5 39.5 39.8 0.954 
    Privately rented 4.8 4.8 4.8  
    Privately owned 49.1 49.2 48.9  
    Other 6.6 6.6 6.5  
Working full-/part-time, % 4.5 4.6 3.9 0.014 
On public means-tested assistance, % 18.0 17.9 18.9 0.057 
Alcohol, %     
    Never 71.2 70.5 74.7 <0.001 
    Former drinker 10.1 9.7 11.9  
    Social 14.9 15.7 10.8  
    Regular 3.8 4.1 2.6  
Smoking, %     
    Never 70.8 70.6 72.3 <0.001 
    Former smoker 20.2 20.2 20.1  
    Current 9.0 9.3 7.6  
Body mass index, %     
    ≥30 6.3 5.9 8.3 <0.001 
    25–<30 34.6 33.6 39.8  
    23–<25 22.9 22.6 24.6  
    18.5–<23 31.4 32.5 25.5  
    <18.5 4.8 5.4 1.8  
Hypertension, %† 42.8 39.2 62.5 <0.001 
Cardiovascular disease, %‡ 14.4 13.4 19.9 <0.001 
COPD§/asthma, %¶ 5.7 5.9 5.1 0.012 
Malignant disease, % 0.7 0.7 0.6 0.308 
Recent weight loss, %# 2.7 2.5 3.9 <0.001 
Admission within 1 year, % 13.9 13.3 17.0 <0.001 
Activities of Daily Living, score (mean) 7.03 7.03 7.05 0.006 
Variable All cohort (n = 42,116) No diabetes mellitus (n = 35,672) With diabetes mellitus (n = 6,444) p value* 
Male sex, % 34.7 34.7 34.5 0.741 
Age, years (mean) 72.6 72.6 72.5 0.404 
Cantonese speaking, % 98.3 98.4 98.3 0.548 
Marital, %     
    Never married 3.8 4.0 3.0 <0.001 
    Married 60.6 60.6 60.7  
    Widowed/divorced/other 35.6 35.4 36.3  
Education, %     
    Postsecondary 3.6 3.6 3.7 0.008 
    Secondary 13.7 13.6 13.7  
    Primary 37.5 37.6 36.7  
    No formal 16.7 16.9 15.6  
    Illiterate 28.6 28.3 30.2  
Housing, %     
    Public 39.5 39.5 39.8 0.954 
    Privately rented 4.8 4.8 4.8  
    Privately owned 49.1 49.2 48.9  
    Other 6.6 6.6 6.5  
Working full-/part-time, % 4.5 4.6 3.9 0.014 
On public means-tested assistance, % 18.0 17.9 18.9 0.057 
Alcohol, %     
    Never 71.2 70.5 74.7 <0.001 
    Former drinker 10.1 9.7 11.9  
    Social 14.9 15.7 10.8  
    Regular 3.8 4.1 2.6  
Smoking, %     
    Never 70.8 70.6 72.3 <0.001 
    Former smoker 20.2 20.2 20.1  
    Current 9.0 9.3 7.6  
Body mass index, %     
    ≥30 6.3 5.9 8.3 <0.001 
    25–<30 34.6 33.6 39.8  
    23–<25 22.9 22.6 24.6  
    18.5–<23 31.4 32.5 25.5  
    <18.5 4.8 5.4 1.8  
Hypertension, %† 42.8 39.2 62.5 <0.001 
Cardiovascular disease, %‡ 14.4 13.4 19.9 <0.001 
COPD§/asthma, %¶ 5.7 5.9 5.1 0.012 
Malignant disease, % 0.7 0.7 0.6 0.308 
Recent weight loss, %# 2.7 2.5 3.9 <0.001 
Admission within 1 year, % 13.9 13.3 17.0 <0.001 
Activities of Daily Living, score (mean) 7.03 7.03 7.05 0.006 
*

Probability for the null hypothesis of no difference in the factor.

Previously diagnosed by physician or newly diagnosed on enrollment.

Previously diagnosed by physician, with or without drug treatment.

§

COPD, chronic obstructive pulmonary disease.

COPD and/or asthma as diagnosed by physician.

#

Recent weight loss of ≥5% within 6 months.

A total of 3,893 (9.2 percent) deaths were identified from the death registry. The mean duration of follow-up from the day of enrollment to death, development of active tuberculosis, or December 31, 2005 (whichever came first), was 1,827 (standard deviation: 325) days. A total of 510 new tuberculosis notifications were identified from the tuberculosis notification registry during the period of follow-up. Eight cases were duplicate entries due to early relapse. Twenty-five cases (six cases of bronchogenic carcinoma, 13 cases of non-tuberculous mycobacterial infection, six cases of old lung scars) were found to have an incorrect diagnosis after review of the records, leaving for analysis 477 cases of active tuberculosis, 326 (68.3 percent) of which were culture confirmed. The mean time interval of follow-up before notification was 881 (standard deviation: 583) days. There were 395 new cases (82.8 percent) and 82 retreatment (with past tuberculosis history) cases (17.2 percent). There was no significant difference in the proportion of retreatment tuberculosis cases between diabetic and nondiabetic subjects (13.8 percent vs. 18.0 percent: p = 0.335). Pulmonary involvement was found in 426 cases (89.3 percent), and extrapulmonary involvement was found in 87 cases (18.2 percent), including 36 cases (7.5 percent) with both. The incidences of active, culture-confirmed, pulmonary, and extrapulmonary (all or alone) tuberculosis are summarized in table 2. Of the 394 patients who underwent voluntary testing for human immunodeficiency virus, only one (0.25 percent) was infected.

TABLE 2.

Incidence of tuberculosis among diabetic and nondiabetic subjects, Hong Kong, People's Republic of China, 2000–2005

Tuberculosis All cohort (n = 42,116) No diabetes mellitus (n = 35,672) With diabetes mellitus (n = 6,444) Relative risk* 95% confidence interval p value 
No. of cases Rate/100,00 person-years 95% confidence interval No. of cases Rate/100,00 person-years 95% confidence interval No. of cases Rate/100,00 person-years 95% confidence interval 
Active 477 226 207, 248 383 214 193, 237 94 295 239, 362 1.38 1.09, 1.74 0.005 
Culture confirmed 326 155 138, 172 258 144 127, 163 68 214 166, 271 1.48 1.12, 1.95 0.004 
Pulmonary 426 202 183, 222 340 190 170, 211 86 270 216, 334 1.42 1.12, 1.80 0.003 
All extrapulmonary 87 41 33, 51 75 42 33, 53 12 38 9, 66 0.90 0.49, 1.65 0.733 
Extrapulmonary only 51 24 18, 32 43 24 17, 32 25 11, 50 1.05 0.49, 2.31 0.907 
Tuberculosis All cohort (n = 42,116) No diabetes mellitus (n = 35,672) With diabetes mellitus (n = 6,444) Relative risk* 95% confidence interval p value 
No. of cases Rate/100,00 person-years 95% confidence interval No. of cases Rate/100,00 person-years 95% confidence interval No. of cases Rate/100,00 person-years 95% confidence interval 
Active 477 226 207, 248 383 214 193, 237 94 295 239, 362 1.38 1.09, 1.74 0.005 
Culture confirmed 326 155 138, 172 258 144 127, 163 68 214 166, 271 1.48 1.12, 1.95 0.004 
Pulmonary 426 202 183, 222 340 190 170, 211 86 270 216, 334 1.42 1.12, 1.80 0.003 
All extrapulmonary 87 41 33, 51 75 42 33, 53 12 38 9, 66 0.90 0.49, 1.65 0.733 
Extrapulmonary only 51 24 18, 32 43 24 17, 32 25 11, 50 1.05 0.49, 2.31 0.907 
*

Relative risk of tuberculosis for diabetic versus nondiabetic group.

A total of 6,444 subjects (15.3 percent) of the entire cohort either had known history of diabetes mellitus or were found to have diabetes on enrollment. Within the diabetic subjects, baseline hemoglobin A1c levels were available for 4,690 (72.8 percent) subjects with known diabetes mellitus at enrollment, with a mean hemoglobin A1c of 7.62 (1.37 percent). Diabetic subjects who developed active tuberculosis subsequently had a higher mean hemoglobin A1c level than those who did not (8.30 percent vs. 7.61 percent: p < 0.001). Out of the 4,690 diabetic subjects, 1,620 (34.5 percent) had a hemoglobin A1c level below 7 percent, and 3,070 (65.5 percent) had a hemoglobin A1c level at or above 7 percent. Table 3 shows the incidence of active tuberculosis and culture-confirmed tuberculosis by different baseline diabetic control status. Subjects with hemoglobin A1c ≥7 percent had about a twofold risk of active or culture-confirmed tuberculosis (both p < 0.01) relative to elderly subjects without diabetes. Similar hazard ratios were found after adjustment for sex and age and after exclusion of subjects with some of the risk factors potentially associated with subclinical tuberculosis disease at baseline (table 4). The adjusted hazard ratios increased to 2.5-fold (2.80-fold for pulmonary tuberculosis) after adjustment for all confounding or potentially confounding sociodemographic and clinical variables (table 5). These adjusted hazard ratios were further increased to 3-fold when diabetic subjects with hemoglobin A1c <7 percent were used as the reference group instead (table 5). Diabetic subjects diagnosed only at enrollment and without known baseline hemoglobin A1c had an intermediate risk between those with hemoglobin A1c <7 percent and ≥7 percent. The potential interaction between diabetes mellitus and body mass index was considered, but the interaction term of “diabetes mellitus categories × body mass index categories” was removed from the final model because it failed to reach statistical significance. There was no evidence of violation of the proportional hazards on examination of the log minus log plots and testing by the time-dependent covariate method. Figure 1 depicts the hazard function curves of active tuberculosis for different diabetic control status categories in the overall Cox model.

FIGURE 1.

Cumulative hazards for active tuberculosis with respect to baseline diabetes mellitus (DM) status and hemoglobin A1c (HbA1c) level after adjustment for potentially confounding variables by Cox regression analysis, Hong Kong, People's Republic of China, 2000–2005.

FIGURE 1.

Cumulative hazards for active tuberculosis with respect to baseline diabetes mellitus (DM) status and hemoglobin A1c (HbA1c) level after adjustment for potentially confounding variables by Cox regression analysis, Hong Kong, People's Republic of China, 2000–2005.

TABLE 3.

Annual incidence of active tuberculosis and culture-confirmed tuberculosis among diabetic patients by baseline diabetic (and control) status as reflected by hemoglobin A1c level, Hong Kong, People's Republic of China, 2000–2005

Diabetes mellitus No. Active tuberculosis Culture-confirmed tuberculosis 
No. of cases Rate/100,000 person-years 95% confidence interval Unadjusted relative risk* 95% confidence interval No. of cases Rate/100,000 person-years 95% confidence interval Unadjusted relative risk* 95% confidence interval 
All cohort 42,116 477 226 207, 248   326 155 138, 172   
    No diabetes mellitus 35,672 383 214 193, 237 1.00 Referent 258 144 127, 163 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 1,620 11 136 68, 244 0.64 0.35, 1.16 99 43, 196 0.69 0.34, 1.39 
    Diabetes mellitus, hemoglobin A1c ≥7% 3,070 64 422 325, 539 1.97 1.51, 2.57 45 297 216, 397 2.06 1.50, 2.82 
    Diabetes mellitus, no hemoglobin A1c† 1,754 19 222 133, 346 1.03 0.65, 1.64 15 175 98, 288 1.21 0.72, 2.04 
   p < 0.001    p < 0.001   
Females 27,498 199 143 124, 164   125 90 75, 107   
    No diabetes mellitus 23,279 165 140 119, 163 1.00 Referent 102 86 71, 105 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 1,019 78 21, 200 0.56 0.15, 1.45 58 12, 171 0.68 0.14, 2.03 
    Diabetes mellitus, hemoglobin A1c ≥7% 2,014 24 237 152, 352 1.69 1.05, 2.61 45 158 90, 256 1.83 1.01, 3.11 
    Diabetes mellitus, no hemoglobin A1c† 1,186 102 38, 223 0.73 0.26, 2.61 15 175 98, 288 0.79 0.21, 2.08 
   p < 0.001    p < 0.001   
Males 14,618 278 388 344, 437   201 281 243, 322   
    No diabetes mellitus 12,393 218 358 312, 409 1.00 Referent 156 256 218, 300 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 601 239 96, 492 0.67 0.27, 1.40 171 55, 398 0.67 0.21, 1.59 
    Diabetes mellitus, hemoglobin A1c ≥7% 1,056 40 793 567, 1,080 2.22 1.54, 3.12 29 575 385, 826 2.24 1.46, 3.35 
    Diabetes mellitus, no hemoglobin A1c† 568 13 480 256, 821 1.34 0.70, 2.34 11 406 203, 727 1.59 0.78, 2.92 
   p < 0.001    p < 0.001   
Diabetes mellitus No. Active tuberculosis Culture-confirmed tuberculosis 
No. of cases Rate/100,000 person-years 95% confidence interval Unadjusted relative risk* 95% confidence interval No. of cases Rate/100,000 person-years 95% confidence interval Unadjusted relative risk* 95% confidence interval 
All cohort 42,116 477 226 207, 248   326 155 138, 172   
    No diabetes mellitus 35,672 383 214 193, 237 1.00 Referent 258 144 127, 163 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 1,620 11 136 68, 244 0.64 0.35, 1.16 99 43, 196 0.69 0.34, 1.39 
    Diabetes mellitus, hemoglobin A1c ≥7% 3,070 64 422 325, 539 1.97 1.51, 2.57 45 297 216, 397 2.06 1.50, 2.82 
    Diabetes mellitus, no hemoglobin A1c† 1,754 19 222 133, 346 1.03 0.65, 1.64 15 175 98, 288 1.21 0.72, 2.04 
   p < 0.001    p < 0.001   
Females 27,498 199 143 124, 164   125 90 75, 107   
    No diabetes mellitus 23,279 165 140 119, 163 1.00 Referent 102 86 71, 105 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 1,019 78 21, 200 0.56 0.15, 1.45 58 12, 171 0.68 0.14, 2.03 
    Diabetes mellitus, hemoglobin A1c ≥7% 2,014 24 237 152, 352 1.69 1.05, 2.61 45 158 90, 256 1.83 1.01, 3.11 
    Diabetes mellitus, no hemoglobin A1c† 1,186 102 38, 223 0.73 0.26, 2.61 15 175 98, 288 0.79 0.21, 2.08 
   p < 0.001    p < 0.001   
Males 14,618 278 388 344, 437   201 281 243, 322   
    No diabetes mellitus 12,393 218 358 312, 409 1.00 Referent 156 256 218, 300 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 601 239 96, 492 0.67 0.27, 1.40 171 55, 398 0.67 0.21, 1.59 
    Diabetes mellitus, hemoglobin A1c ≥7% 1,056 40 793 567, 1,080 2.22 1.54, 3.12 29 575 385, 826 2.24 1.46, 3.35 
    Diabetes mellitus, no hemoglobin A1c† 568 13 480 256, 821 1.34 0.70, 2.34 11 406 203, 727 1.59 0.78, 2.92 
   p < 0.001    p < 0.001   
*

Relative to the group without diabetes mellitus.

Hemoglobin A1c not checked at baseline, mainly because of diagnosis only at enrollment.

TABLE 4.

Sex- and age-adjusted hazard ratios of active, culture-confirmed, pulmonary, and extrapulmonary tuberculosis by baseline diabetic (and control) status in Cox regression analysis before and after exclusion of those subjects with risk factors possibly related to subclinical tuberculosis at baseline, Hong Kong, People's Republic of China, 2000–2005

Diabetic status Types/forms of tuberculosis 
Active Culture confirmed Pulmonary Extrapulmonary* 
Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval 
Before exclusion‡         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.63 0.34, 1.14 0.68 0.33, 1.37 0.58 0.30, 1.12 0.87 0.28, 2.77 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.03 1.56, 2.65 2.13 1.55, 2.93 2.16 1.64, 2.84 0.80 0.32, 1.97 
    Diabetes mellitus, no hemoglobin A1c 1.06 0.67, 1.69 1.25 0.74, 2.10 1.07 0.66, 1.75 1.13 0.41, 3.08 
 p < 0.001 p < 0.001 p < 0.001 p = 0.950 
After exclusion of other risk factors§         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.68 0.33, 1.36 0.62 0.26, 1.52 0.59 0.26, 1.32 1.22 0.38, 3.90 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.08 1.51, 2.85 2.07 1.40, 3.04 2.21 1.58, 3.08 1.08 0.43, 2.71 
    Diabetes mellitus, no hemoglobin A1c 1.23 0.73, 2.08 1.47 0.82, 2.64 1.34 0.78, 2.30 1.16 0.36, 3.72 
 p < 0.001 p = 0.001 p < 0.001 p = 0.980 
Diabetic status Types/forms of tuberculosis 
Active Culture confirmed Pulmonary Extrapulmonary* 
Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval 
Before exclusion‡         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.63 0.34, 1.14 0.68 0.33, 1.37 0.58 0.30, 1.12 0.87 0.28, 2.77 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.03 1.56, 2.65 2.13 1.55, 2.93 2.16 1.64, 2.84 0.80 0.32, 1.97 
    Diabetes mellitus, no hemoglobin A1c 1.06 0.67, 1.69 1.25 0.74, 2.10 1.07 0.66, 1.75 1.13 0.41, 3.08 
 p < 0.001 p < 0.001 p < 0.001 p = 0.950 
After exclusion of other risk factors§         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.68 0.33, 1.36 0.62 0.26, 1.52 0.59 0.26, 1.32 1.22 0.38, 3.90 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.08 1.51, 2.85 2.07 1.40, 3.04 2.21 1.58, 3.08 1.08 0.43, 2.71 
    Diabetes mellitus, no hemoglobin A1c 1.23 0.73, 2.08 1.47 0.82, 2.64 1.34 0.78, 2.30 1.16 0.36, 3.72 
 p < 0.001 p = 0.001 p < 0.001 p = 0.980 
*

Any extrapulmonary involvement.

Sex- and age-adjusted hazard ratio.

Adjusted for sex and age group without exclusion of any subjects.

§

Subjects with malignancies, body mass index of <18.5, recent weight loss of ≥5% in 6 months, and hospital admission within 12 months at baseline.

TABLE 5.

Effects of baseline diabetes (and control) status on active tuberculosis, culture-confirmed tuberculosis, pulmonary tuberculosis, and any extrapulmonary involvement after controlling for other confounding variables in Cox proportional hazard analysis, Hong Kong, People's Republic of China, 2000–2005

Diabetic status Types/forms of tuberculosis 
Active Culture confirmed Pulmonary Extrapulmonary* 
Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval 
Diabetes mellitus or not         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus 1.77 1.41, 2.24 1.91 1.45, 2.52 1.89 1.48, 2.42 1.00 0.54, 1.86 
 p < 0.001 p < 0.001 p < 0.001 p = 0.995 
All categories         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.81 0.44, 1.48 0.86 0.42, 1.75 0.77 0.40, 1.50 0.99 0.31, 3.17 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.56 1.95, 3.35 2.69 1.94, 3.72 2.80 2.11, 3.70 0.88 0.35, 2.20 
    Diabetes mellitus, no hemoglobin A1c 1.32 0.83, 2.10 1.54 0.91, 2.60 1.37 0.84, 2.23 1.24 0.45, 3.41 
 p < 0.001 p < 0.001 p < 0.001 p = 0.967 
With known hemoglobin A1c         
    Diabetes mellitus, hemoglobin A1c <7% 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c ≥7% 3.11 1.63, 5.92 3.08 1.44, 6.57 3.63 1.79, 7.33 0.77 0.18, 3.35 
 p = 0.001 p = 004 p < 0.001 p = 0.967 
Diabetic status Types/forms of tuberculosis 
Active Culture confirmed Pulmonary Extrapulmonary* 
Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval Hazard ratio† 95% confidence interval 
Diabetes mellitus or not         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus 1.77 1.41, 2.24 1.91 1.45, 2.52 1.89 1.48, 2.42 1.00 0.54, 1.86 
 p < 0.001 p < 0.001 p < 0.001 p = 0.995 
All categories         
    No diabetes mellitus 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c <7% 0.81 0.44, 1.48 0.86 0.42, 1.75 0.77 0.40, 1.50 0.99 0.31, 3.17 
    Diabetes mellitus, hemoglobin A1c ≥7% 2.56 1.95, 3.35 2.69 1.94, 3.72 2.80 2.11, 3.70 0.88 0.35, 2.20 
    Diabetes mellitus, no hemoglobin A1c 1.32 0.83, 2.10 1.54 0.91, 2.60 1.37 0.84, 2.23 1.24 0.45, 3.41 
 p < 0.001 p < 0.001 p < 0.001 p = 0.967 
With known hemoglobin A1c         
    Diabetes mellitus, hemoglobin A1c <7% 1.00 Referent 1.00 Referent 1.00 Referent 1.00 Referent 
    Diabetes mellitus, hemoglobin A1c ≥7% 3.11 1.63, 5.92 3.08 1.44, 6.57 3.63 1.79, 7.33 0.77 0.18, 3.35 
 p = 0.001 p = 004 p < 0.001 p = 0.967 
*

Any extrapulmonary involvement.

Hazard ratio adjusted for sex, age, smoking, alcohol use, language, marital status, education, housing, working status, public means-tested financial assistance status, body mass index, cardiovascular disease, hypertension, chronic obstructive pulmonary disease/asthma, malignancy, recent weight loss of ≥5% within 6 months, hospital admission within 12 months, and Activities of Daily Living scores, with categories as listed in table 1.

DISCUSSION

In this study, diabetes mellitus was associated with a modest increase in risk of active, culture-confirmed, and pulmonary tuberculosis, but not extrapulmonary tuberculosis (tables 2 and 5). The increased risk was observed predominantly among diabetic subjects with baseline hemoglobin A1c ≥7 percent, while those with baseline hemoglobin A1c <7 percent were not at increased risk (tables 3, 4, and 5).

The association between diabetes mellitus and tuberculosis is well reported (1–4), but prospective cohort data are notably scarce, possibly because of the practical difficulty of following up a large number of patients over a prolonged period, and none of the available studies specifically examined diabetic control as reflected by hemoglobin A1c (1–4). Indeed, notwithstanding the various acute and chronic infections frequently observed among diabetic subjects, relatively little is known about the underlying mechanism(s) or the exact role of diabetic control on infection risks (11). In vitro immune studies and skin testing among diabetic subjects have shown possible impairment of adaptive immune responses among diabetic subjects (12–15), but there have been conflicting results with regard to the role of diabetic control (11, 14–16). The current study provided the first unequivocal demonstration, in vivo, of the primary impact of diabetic control on the development of tuberculosis.

The excess risk in this study is considerably lower than that reported in another Asian population (1) or the Hispanics (3). Diabetic control was shown to be the predominant determinant of increased tuberculosis risk in this study. Of some interest is the underlying reason why subjects with well-controlled diabetes mellitus were not at increased risk of pulmonary tuberculosis even after control of other confounding variables, including body mass index. Indeed, their risk was consistently on the low side, and this could have led to a lower relative risk for diabetic subjects as a whole. Major ethnic differences were reported in another study, with relative risks varying from 2.95 among Hispanics, 1.31 among non-Hispanic Whites, and 0.93 among non-Hispanic Blacks (17). The underlying mechanism(s) for such major ethnic differences remains obscure, and differences in prevalence of latent infection and/or annual disease incidence are not expected to affect internal comparisons within population subgroups. Our results suggest that better diabetic control would reduce tuberculosis risk, which might therefore confound the ethnic differences as observed.

The increased risk of diabetes mellitus was relatively specific for pulmonary tuberculosis but not extrapulmonary tuberculosis. Although a type II error was possible with the limited number of extrapulmonary tuberculosis cases, the adjusted hazard ratios of diabetes mellitus for any extrapulmonary involvement were rather close to or below one, irrespective of the diabetic control. Most of the previous studies focused mainly on pulmonary disease (1–4), and diabetes mellitus has been associated with more frequent lower lung field lesions and increased cavity formation (18, 19). In a case-control study in the United States, pulmonary tuberculosis patients were found to have a higher prevalence of diabetes mellitus than those with extrapulmonary tuberculosis (20). Differential effects of diabetes mellitus on pulmonary and extrapulmonary tuberculosis would help to explain such an observation.

Extrapulmonary involvement is a hallmark of most immunocompromising conditions. Use of the tumor necrosis factor inhibitors infliximab and etanercept has been associated with a very high tuberculosis risk (21, 22), but a high proportion of extrapulmonary involvement was observed (21–23). Among individuals infected with human immunodeficiency virus, extrapulmonary tuberculosis involvement is also a feature of advanced immunodeficiency (24). Besides diabetic control, a relatively specific effect on pulmonary tuberculosis has also been reported for smoking (25) and body mass index (9, 26). Although the effect of smoking on pulmonary tuberculosis is readily accounted for by its site-specific action (27, 28) and the more frequent lower lung field involvement in diabetics could also be compatible with a perfusion-related factor, a close interplay between the energy metabolism and immune system could well be implicated in the relatively specific pulmonary effect of both diabetic control and body mass index. Further exploration of the exact mechanism(s) mediating the link between diabetic control and host defense might therefore be warranted.

Incomplete case ascertainment is always a major concern in prospective cohort analyses. The cohort was followed up through a territory-wide notification registry and a death registry, which captured, respectively, tuberculosis cases and deaths all over Hong Kong. The presence of a good health-care infrastructure, the statutory requirement for all adult citizens to carry an identity card, the statutory tuberculosis notification system, and the widespread use of the identity card number as a unique identifier were important factors that facilitated the current study. Undernotification remains a concern with regard to all notifiable diseases (29). However, the cohort was already under the care of a service in the Department of Health and had ready access to the chest clinics in the same department for free tuberculosis treatment. In a local audit of tuberculosis notifications, the undernotification rate was only 3 percent in the chest clinics even before the introduction of specific improvement measures (30). As we examined the differences between subgroups in this cohort, there should be good internal validity.

No information was available about the tuberculin status or the newer interferon assays because such screening was not regularly performed. The sensitivity of the tuberculin skin test has been shown to be affected by advanced age (31), while insufficient information is available for the new interferon release assays (32). Although active tuberculosis disease was the outcome actually measured in this study, it would still be difficult to separate the effect of diabetes mellitus on infection risk, disease development, or both in the absence of baseline infection data. However, exposure is a prerequisite for infection. If diabetes mellitus was indeed associated with an increase in risk of tuberculosis infection, such an association might be expected to be mediated through increased exposure, possibly as a consequence of various confounding sociodemographic and nosocomial factors. In this regard, it is noteworthy from tables 4 and 5 that the association between diabetes mellitus and tuberculosis disease persisted even after control of these potential confounders or hospital admissions. A study of molecular clustering in Hong Kong also suggested that up to 80 percent of the tuberculosis cases in Hong Kong occurred as a result of endogenous reactivation of remote infection rather than recent transmission (33). With the significant past burden of tuberculosis (5), a high proportion of latent tuberculosis infection is expected among this elderly cohort. A previous study has reported a tuberculin reactivity rate (10 mm) of 68.6 percent, in the absence of recent contact history, among inmates of old-age homes after two-stage tuberculin skin testing (34). Furthermore, the effect of diabetes mellitus was seen predominantly on pulmonary tuberculosis and not extrapulmonary involvement. Such an observation might be in favor of an effect on disease manifestation, rather than solely as a result of increased exposure.

This is a study on a cohort of elderly in community settings. Type II diabetes mellitus is increasingly prevalent in both developed and developing areas (35–38). In Hong Kong, 97 percent of diabetes mellitus cases are type II diabetes mellitus (39). Although no specific attempt was made to distinguish type I and type II diabetes mellitus in this study, practically all diabetes mellitus cases included in the cohort were expected to be suffering from type II diabetes mellitus, judging from the their advanced age (36). Higher relative tuberculosis risks have been reported among younger diabetic subjects (1, 16) or those with type I diabetes mellitus (3). Further studies will therefore be required to assess the effect of diabetic control in younger subjects. The past history of tuberculosis was not specifically included for all enrolled subjects, but only 17.2 percent of observed tuberculosis cases had a past tuberculosis history. There could well be concern that tuberculosis could affect the diabetic control before it was clinically manifest. However, only tuberculosis cases occurring 3 months after recruitment were included in the analysis, and exclusion of subjects with factors potentially associated with subclinical tuberculosis disease did not alter the effect. The prospective design of the study and the relatively uniform rate of tuberculosis in each subgroup during the 5 years of follow-up (figure 1) are not in support of reverse causality. With the urine and blood screening at enrollment, most diabetes mellitus patients should have been picked up. Some elderly subjects could develop diabetes mellitus afterwards, but the number of incident diabetes mellitus cases should be relatively small and unlikely to affect our findings significantly. The hemoglobin A1c level was used to reflect longer term diabetic control, rather than single blood sugar levels. Only the baseline level of hemoglobin A1c for those with known diabetes mellitus at enrollment was available, as clinical follow-up of established conditions was regularly carried out in other institutions. However, this would also avoid the potential issue of reverse direction of causality for interim hemoglobin A1c measurements.

With rapidly increasing prevalence of diabetes mellitus in many parts of the world, intensified efforts on basic, clinical, and epidemiologic research are called for to contain the adverse health effects of this new epidemic. The impact of diabetic control on tuberculosis risk also highlights the need for good diabetic control among patients with known diabetes mellitus. Monitoring of hemoglobin A1c should be carried out regularly among diabetic patients, especially in a high tuberculosis prevalence country, where interaction between the old scourge and the new enemy could further aggravate human suffering. A heightened clinical awareness of tuberculosis is also indicated among those with poor diabetic control and suggestive symptoms.

The authors wish to thank the staffs of the Elderly Health Service and the Tuberculosis and Chest Service for their assistance in collection of the raw data.

Conflict of interest: none declared.

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