American Journal of Epidemiology Vol. 167, No.

12
ª The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. DOI: 10.1093/aje/kwn075
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Original Contribution

Diabetic Control and Risk of Tuberculosis: A Cohort Study

Chi C. Leung1, Tai H. Lam2, Wai M. Chan3, Wing W. Yew4, Kin S. Ho3, Gabriel M. Leung2, Wing S.
Law1, Cheuk M. Tam1, Chi K. Chan1, and Kwok C. Chang1

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1
Tuberculosis and Chest Service, Department of Health, Hong Kong, People’s Republic of China.
2
Department of Community Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China.
3
Elderly Health Service, Department of Health, Hong Kong, People’s Republic of China.
4
Tuberculosis and Chest Unit, Grantham Hospital, Hong Kong, People’s Republic of China.

Received for publication September 6, 2007; accepted for publication March 6, 2008.

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 tuber-
culosis 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.

aged; diabetes mellitus; tuberculosis

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, met-
abolic 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 per-
sons aged 65 years or more are eligible for voluntary enroll-
ment. A nominal annual membership fee of about US
$13.75 is charged, with a waiver mechanism for those re-
ceiving 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 cli-
ent, 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

Correspondence to Dr. Chi Chiu Leung, Wanchai Chest Clinic, 99 Kennedy Road, Wanchai, Hong Kong, People’s Republic of China (e-mail:
cc_leung@dh.gov.hk).

1486 Am J Epidemiol 2008;167:1486–1494


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 suspi-
cious of active tuberculosis or radiologic abnormalities were
referred to the 18 chest clinics under a centralized Tubercu-
losis and Chest Service. Under such an appropriate service
infrastructure, a study was performed to examine prospec-
tively 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, ed-
ucational level, marital status, housing situation, working
status, public means-tested financial assistance status, coex-
isting medical conditions, recent weight loss, hospital ad-
mission 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 en-
rollment 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 noti-
fication of tuberculosis, death, or December 31, 2005,
whichever occurred first. Information on the date of tuber-
culosis notification, bacteriologic status, form of tuberculo-
sis, and previous tuberculosis history was retrieved from the
notification registry. The diagnosis of and clinical informa-
tion 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 de-
fined as active tuberculosis with pulmonary involvement, irre-
spective of whether there was extrapulmonary involvement.
Similarly, extrapulmonary tuberculosis was defined as active
Am J Epidemiol 2008;167:1486–1494
Diabetic Control and Tuberculosis 1487
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. Univar-
iate analysis was followed by Cox regression analysis of the
effect of diabetes mellitus on the respective development of
active tuberculosis, culture-confirmed tuberculosis, pulmo-
nary tuberculosis, and extrapulmonary involvement. The
effect of diabetic control at baseline as reflected by the
hemoglobin A1c level was similarly assessed. The propor-
tional 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 ex-
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clusion 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 re-
cruited 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 presenta-
tion 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.
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 tubercu-
losis, 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 tubercu-
losis 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 re-
treatment (with past tuberculosis history) cases (17.2 per-
cent). There was no significant difference in the proportion
of retreatment tuberculosis cases between diabetic and non-
diabetic subjects (13.8 percent vs. 18.0 percent: p ¼ 0.335).
Pulmonary involvement was found in 426 cases (89.3 per-
cent), 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, pulmo-
nary, and extrapulmonary (all or alone) tuberculosis are
summarized in table 2. Of the 394 patients who underwent
1488 Leung et al.

TABLE 1. Background characteristics of the cohort, Hong Kong, People’s Republic of

China, 2000–2005

No diabetes With diabetes

All cohort
Variable mellitus mellitus p value*
(n ¼ 42,116)
(n ¼ 35,672) (n ¼ 6,444)

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

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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, %y 42.8 39.2 62.5 <0.001
Cardiovascular disease, %z 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.

y Previously diagnosed by physician or newly diagnosed on enrollment.
z 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.

Am J Epidemiol 2008;167:1486–1494
 Diabetic Control and Tuberculosis 1489

TABLE 2. Incidence of tuberculosis among diabetic and nondiabetic subjects, Hong Kong, People’s Republic of China, 2000–2005

No diabetes mellitus With diabetes mellitus

All cohort (n ¼ 42,116)
(n ¼ 35,672) (n ¼ 6,444)
95%
Rate/ Rate/ Rate/ Relative
Tuberculosis 95% 95% 95% confidence p value
No. of 100,00 No. of 100,00 No. of 100,00 risk*
confidence confidence confidence interval
cases person- cases person- cases person-
interval interval interval
years years years

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 8 25 11, 50 1.05 0.49, 2.31 0.907

* Relative risk of tuberculosis for diabetic versus nondiabetic group.

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voluntary testing for human immunodeficiency virus, only found to have diabetes on enrollment. Within the diabetic
one (0.25 percent) was infected. subjects, baseline hemoglobin A1c levels were available for
A total of 6,444 subjects (15.3 percent) of the entire co- 4,690 (72.8 percent) subjects with known diabetes mellitus
hort either had known history of diabetes mellitus or were at enrollment, with a mean hemoglobin A1c of 7.62 (1.37

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

Active tuberculosis Culture-confirmed tuberculosis

Rate/ Rate/
Diabetes mellitus No. 95% Unadjusted 95% 95% Unadjusted 95%
No. of 100,000 No. of 100,000
confidence relative confidence confidence relative confidence
cases person- cases person-
interval risk* interval interval risk* interval
years years

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 8 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 A1cy 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 4 78 21, 200 0.56 0.15, 1.45 3 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 A1cy 1,186 6 102 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 7 239 96, 492 0.67 0.27, 1.40 5 171 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 A1cy 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.

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

Am J Epidemiol 2008;167:1486–1494
1490 Leung et al.

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

Types/forms of tuberculosis
Active Culture confirmed Pulmonary Extrapulmonary*
Diabetic status
95% 95% 95% 95%
Hazard Hazard Hazard Hazard
confidence confidence confidence confidence
ratioy ratioy ratioy ratioy
interval interval interval interval

Before exclusionz
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

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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 ¼ 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 ¼ 0.001 p < 0.001 p ¼ 0.980

* Any extrapulmonary involvement.

y Sex- and age-adjusted hazard ratio.
z 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.

percent). Diabetic subjects who developed active tuberculo-
sis 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 per-
cent) 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 di-
abetic 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 sub-
jects 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 con-
founding 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 hemoglo-
bin A1c <7 percent and
7 percent. The potential interac-
tion between diabetes mellitus and body mass index was
considered, but the interaction term of ‘‘diabetes mellitus
categories 3 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 pro-
portional 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.
DISCUSSION
In this study, diabetes mellitus was associated with a mod-
est increase in risk of active, culture-confirmed, and pulmo-
nary tuberculosis, but not extrapulmonary tuberculosis
(tables 2 and 5). The increased risk was observed predom-
inantly 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 tuberculo-
sis is well reported (1–4), but prospective cohort data are

Am J Epidemiol 2008;167:1486–1494
 Diabetic Control and Tuberculosis 1491

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

Types/forms of tuberculosis
Active Culture confirmed Pulmonary Extrapulmonary*
Diabetic status
95% 95% 95% 95%
Hazard Hazard Hazard Hazard
confidence confidence confidence confidence
ratioy ratioy ratioy ratioy
interval interval interval 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 ¼ 0.995

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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 ¼ 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 ¼ 0.001 p ¼ 004 p < 0.001 p ¼ 0.967

* Any extrapulmonary involvement.

y 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.

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 exam-
ined diabetic control as reflected by hemoglobin A1c (1–4).
Indeed, notwithstanding the various acute and chronic in-
fections frequently observed among diabetic subjects, rela-
tively 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 sub-
jects 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 His-
panics (3). Diabetic control was shown to be the predomi-
nant 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 con-
founding 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 differ-
ences 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 extra-
pulmonary 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,

Am J Epidemiol 2008;167:1486–1494
1492 Leung et al.
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.
pulmonary tuberculosis patients were found to have a higher
prevalence of diabetes mellitus than those with extrapulmo-
nary tuberculosis (20). Differential effects of diabetes mel-
litus on pulmonary and extrapulmonary tuberculosis would
help to explain such an observation.
Extrapulmonary involvement is a hallmark of most im-
munocompromising conditions. Use of the tumor necrosis
factor inhibitors infliximab and etanercept has been associ-
ated with a very high tuberculosis risk (21, 22), but a high
proportion of extrapulmonary involvement was observed
(21–23). Among individuals infected with human immuno-
deficiency virus, extrapulmonary tuberculosis involvement
is also a feature of advanced immunodeficiency (24). Be-
sides diabetic control, a relatively specific effect on pulmo-
nary 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 im-
plicated 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 tuber-
culosis 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 mea-
sures (30). As we examined the differences between sub-
groups in this cohort, there should be good internal validity.
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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 tubercu-
losis 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 per-
cent 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 set-
tings. 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 di-
abetes 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 di-
abetes 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 di-
abetes mellitus (3). Further studies will therefore be
Am J Epidemiol 2008;167:1486–1494

required to assess the effect of diabetic control in younger
subjects. The past history of tuberculosis was not specifi-
cally included for all enrolled subjects, but only 17.2 percent
of observed tuberculosis cases had a past tuberculosis his-
tory. 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 tuber-
culosis 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 mel-
litus 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 signifi-
cantly. 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 dia-
betes 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 di-
abetic control and suggestive symptoms.
ACKNOWLEDGMENTS
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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