TUGAS MATA KULIAH WAJIB UMUM

EPIDEMIOLOGI DASAR

(Confounding, Bias, Variability)

Disusun oleh

Kelompok Program Studi Sp-1 Patologi Klinik dan AAAM

Yuaniati Valentina 13092119001

Ananda Dewa 130921190002

Laila Kurnia Pramono 13092119003

Felicia Nathania Kosasih 130921190004

Desy Arissandy 130921190005

Lastri Supriatin 130921190006

Sefti Atletika Asiani 131620190001

Najmah Nur Islami 131620190002

Aceng Hamudin 131620190003

Nadilla Natasha 131620190004

Afifa Khairinnisa 131620190005

Dosen Pengampu Mata Kuliah

Dr. Yulia Sofiatin, dr. , Sp.PD

PROGRAM STUDI MAGISTER ILMU KEDOKTERAN DASAR

FAKULTAS KEDOKTERAN

UNIVERSITAS PADJADJARAN

2019
INT J TUBERC LUNG DIS 10(6):696–700

© 2006 The Union

Diabetes mellitus is strongly associated with tuberculosis

in Indonesia

B. Alisjahbana,* R. van Crevel,† E. Sahiratmadja,‡ M. den Heijer,§ A. Maya,* E. Istriana,¶

H. Danusantoso,¶ T. H. M. Ottenhoff,# R. H. H. Nelwan,** J. W. M. van der Meer†
* Department of Internal Medicine, Medical Faculty, Padjadjaran University, Bandung, Indonesia; † Department of
Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; ‡ Eijkman Institute
of Molecular Biology, Jakarta, Indonesia; § Department of Endocrinology, Epidemiology and Biostatistics, Radboud
University Nijmegen Medical Center, Nijmegen, The Netherlands; ¶ Indonesian Tuberculosis Control Association, Jakarta
Branch, Jakarta, Indonesia; # Department of Immunohematology and Bloodbank, Leiden University Medical Center,
Leiden, The Netherlands; ** Infectious Disease Working Group, Medical Faculty, University of Indonesia, Jakarta,
Indonesia

SUMMAR Y

SETTING: Diabetes mellitus is a known risk factor for

tuberculosis (TB), but no studies have been reported
from South-East Asia, which has a high burden of TB
and a rapidly growing prevalence of diabetes.
To examine if and to what extent diabetes
O B JE C T I VE :
is associated with an increased risk of TB in an urban
setting in Indonesia.
Case-control study comparing the prevalence
DE SI GN :
of diabetes mellitus (fasting blood glucose level >126
mg/dl) among newly diagnosed pulmonary TB patients
and matched neighbourhood controls.
RESULTS:Patients and control subjects had a similar age
(median 30 years) and sex distribution (52% male), but
malnutrition was more common among TB patients
(median body mass index 17.7 vs. 21.5 kg/m 2). HIV in-
fection was uncommon (1.5% of patients). Diabetes mel-
litus was present in 60 of 454 TB patients (13.2%) and
18 of 556 (3.2%) control subjects (OR 4.7; 95%CI 2.7–
8.1). Adjustment for possible confounding factors did
not reduce the risk estimates. Following anti-
tuberculosis treatment, hyperglycaemia reverted in a
minority (3.7%) of TB patients.
CONCLUSION: Diabetes mellitus is strongly associated with
TB in young and non-obese subjects in an urban setting
in Indonesia. This may have implications for TB control
and patient care in this region.
KEY W OR DS : tuberculosis; pulmonary; diabetes melli- tus
type 2; relative odds; case-control study; Indonesia

THE PREVALENCE of diabetes mellitus is increas-

ing worldwide, especially in Asia,1 where tuberculo-
sis (TB) is highly endemic. 2 Most textbooks state
that diabetes is a risk factor for TB, but little is
known about the nature and strength of this rela-
tionship. Original studies on this subject were
mostly conducted more than 40 years ago, and
primarily in the United States and Europe.3–5 To
our knowledge, only one published Asian report
shows that diabetic patients have an increased risk
of developing pulmo- nary tuberculosis (PTB).6 If
diabetes is a risk factor for TB in this part of the
world, this will have impor- tant consequences for
TB control and patient care, as diabetes co-
morbidity is related to a higher TB case fatality s
rate.7 We therefore examined to what extent
diabetes is associated with an increased risk of TB
in Indonesia.
METHODS
At Perkumpulan Pemberantasan Tuberculosis
Indo- nesia, an out-patient TB clinic in central
Jakarta, and Hasan Sadikin General Hospital,
Bandung, consecu- tive new PTB patients aged over
15 years of age were included in the study.
Diagnosis was based on clinical presentation and
chest X-ray examination, confirmed by microscopic
detection of acid-fast bacilli. Treatment consisted of
a standard regimen, 2HRZE/4H3R3,* ac- cording to
the Indonesian National TB Programme. Social
workers visited the patient’s community and
*H = isoniazid; R = rifampicin; Z = pyrazinamide; E = etham-
butol. Numbers before the letters indicate the duration in months of
the phase of treatment; numbers in subscript indicate the num- ber
of times the drug is taken each week.

Correspondence to: Reinout van Crevel, Department of Internal Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The
Netherlands. Tel: (+31) 243618819. Fax: (+31) 243541734. e-mail: r.vancrevel@ aig.umcn.nl
Article submitted 11 November 2005. Final version accepted 15 January 2006
randomly selected a control subject of the same sex
and age (±10%) living within the same rukun te-
tangga, the smallest residential unit in Indonesia,
which consists of 15–30 households. First-degree
relatives of patients were excluded. Control
subjects with signs and symptoms suggesting active
TB or a history of prior anti-tuberculosis treatment
were also excluded. Written informed consent was
obtained from all sub- jects, and the study was
approved by the ethics com- mittee of the Faculty
of Medicine, University of Indo- nesia, Jakarta.
No anti-diabetic agents were taken within 48 h
be- fore blood sampling for measurement of fasting
blood glucose (FBG) concentrations. Diabetes
mellitus was diagnosed if FBG was >126 mg/dl,
and FBG concen- trations were considered
impaired for >110 and <126 mg/dl, in accordance
with World Health Organiza- tion (WHO) criteria.8
In all patients, FBG concentra- tions were
measured before and after one month of anti-
tuberculosis treatment and thereafter in a subset of
89 patients. For those patients with discordant
clas- sification before and during anti-tuberculosis
treat- ment, the classification of diabetes was
applied to the first FBG measurement only. Semi-
quantitative mea- surement of glycosuria was done
using urine dipsticks (Combur test, Roche, Jakarta,
Indonesia). Urine glu- cose concentrations >30
mg/dl were considered ab- normal. Plasma
creatinine was measured to identify additional
renal co-morbidity if considered abnormal (normal
value <90 mmol/l for females and <110 mmol/l
for males). Human immunodeficiency virus (HIV)
testing was conducted using the dipstick test
(Determine, Abbott Diagnostics, Hoofddorp, The
Netherlands).
Crude and adjusted odds ratios (ORs) were
calcu- lated as estimates of the relative risks with
corre- sponding 95% confidence intervals (CI) and
a logistic regression model. Adjusted ORs reflect
the risk of TB for people with diabetes mellitus
compared to normal individuals after adjustment
for variables including:
sex, age, body mass index (BMI, calculated as
kg/m2), presence of TB contact in the family or
household, in- come and number of individuals per
household.
RESULTS
Between March 2001 and March 2005, 481 new
PTB patients were recruited, of whom 454 were
included for further analysis. Twenty-seven were
excluded be- cause of a past history of TB (n = 6)
and incomplete data (n = 21). Patients had a
median age of 30.0 years (range 15–75), and 238
(52.4%) were male (Table 1). All were newly
diagnosed with PTB confirmed by sputum
microscopy. Mycobacterium tuberculosis cul- ture
results were available in 373 patients, and were
positive in 328 (87.9%). Patients presented after a
median of 3 months (range 1 week to over 1 year)
with cough (98.9%), haemoptysis (42.5%),
shortness of breath (66.1%), fever (77.3%) and
weight loss (84.1%). Cases had a median BMI of 17.7
kg/m2 (range 11.2–31.4). Antibodies against HIV
were present in 6 of 402 TB patients examined
(1.5%) and none of the 40 controls tested. Mild
elevation of plasma creatinine was found in one of
234 cases examined.
Six hundred and twenty-two subjects were re-
cruited as matched controls. Sixty-six were
excluded for further analysis because of suspected
TB (n = 22), history of TB treatment (n = 7) or
incomplete data (n = 37). The remaining 556
controls had a similar sex distribution, age (median
30.0 years; range 15–
76) and socio-economic background as the patients
(Table 1). Control subjects had a higher body weight
than patients, while history of TB contact was less
common (Table 1).
Diabetes mellitus was more common in patients
with TB than in control subjects (Figure). Sixty TB
patients (13.2%) had diabetes compared with 18
(3.2%) controls (OR 4.7, 95%CI 2.7–8.1) (Table 2).
Impaired FBG was present in 15 TB patients (3.3%)
and five controls (0.9%, OR 4.2, 95%CI 1.5–11.7).

Table 1 Characteristics of TB patients control subjects

and
TB patients Control subjects
(n = 454) (n = 556)
n (%) n (%) P value
Male sex 238 (52.4) 292 (52.5) 0.513
Age classification, years
“19 35 (7.7) 51 (9.2) 0.506
20–29 187 (41.2) 215 (38.7)
30–39 99 (21.8) 138 (24.8)
“40 133 (29.3) 152 (27.3)
Income (US $/capita/day) (n = 438) (n = 535)
<1 137 (31.3) 165 (30.8) 0.823
1–2 173 (39.5) 204 (38.1)
>2 128 (29.2) 166 (31.0)
Overcrowding (>2 individuals per bedroom) 256 (56.4) 325 (58.4) 0.361
History of TB contact 239 (52.6) 166 (29.9) <0.001
Body mass index, kg/m2, median (range) 17.7 (11.2–31.4) 21.5 (13.4–40.1) <0.001
 Figure Fasting blood glucose concentrations according to body mass index among TB patients

(A) and control subjects (B).

* Reference category, odds ratio = 1.

Glycosuria was present in 43 of 415 TB cases FBG = fasting blood glucose; OR = odds ratio; CI = confidence interval.
(10.4%) and 16 of 413 controls (3.6%),
corresponding to an
OR of 3.1 (95%CI 1.7–5.6) (Table 2).
The median age of TB patients with diabetes,
im- paired FBG and no diabetes was 45.0, 45.0 and
27.1 years, respectively (P < 0.001). The median
BMI was 21.2, 16.9 and 17.8 kg/m2, respectively
(Figure, A). Di- abetes was newly diagnosed in 36/60
patients (60.0%) and 12/18 controls (66.7%) with
diabetes. Among 24 patients with a history of
diabetes, only 19 (79.2%) were being treated, all with
oral hypoglycaemic agents. Repeated measurement
during TB treatment showed normalisation of FBG
in 2/53 (3.7%) patients who initially had FBG >126
mg/dl, and conversion to di- abetes in 6/295
(2.0%) patients with normal FBG before TB
treatment.
Possible confounding of the relationship
between diabetes and TB was examined using
logistic regres- sion. Sex, income and overcrowding
did not alter the OR significantly. History of TB
contact was signifi- cantly more common among
cases than controls (Table 1); however, adjustment
to this variable did not reduce the risk estimates.
TB patients had a lower BMI than controls, but
adjustment for BMI increased the risk estimates,
showing that the association be- tween TB and
diabetes is not explained by differences in BMI.

Table 2 Tuberculosis risk in diabetes, impaired

FBG and glucosuria

Cases Controls

n (%) n (%) OR (95%CI)

Total tested, n 454 556

Normal FBG (<110 mg 379 (83) 533 (96) 1.0*
%)
Impaired FBG
(“110, <126 mg%) 15 (3) 5 (1) 4.2 (1.5–11.7)
Diabetes (“126 mg%) 60 (13) 18 (3) 4.7 (2.7–8.1)
Total tested, n 415 413
No glucosuria 372 (90) 398 (96) 1.0*
Glucosuria 43 (10) 15 (4) 3.1 (1.7–5.6)
DISCUSSION
We have found a strong association of TB and
diabe- tes in two urban clinics in Indonesia. We
believe this is the first study to examine this
association in Indone- sia, where more than 10%
of the world’s TB patients live,2 and one of the first
in South-East Asia. Almost 15% of relatively
young, lean TB patients in our clinic presented
with diabetes. This rate was much lower in control
subjects with a similar age and socio- economic
background. Adjustment for possible con-
founding factors did not reduce the strength of
the association.
Diagnosis of diabetes by a single measurement
of FBG in PTB patients can be confounded by
disease activity. Previous studies have shown that
blood glu- cose levels may normalise during
treatment of TB,9,10 but in our study this occurred
in only a small minority of patients.
It seems unlikely that the strong association
be- tween TB and diabetes can be attributed to
other fac- tors, as socio-economic factors, living
conditions and presence of co-morbidity were
similar. Adjustment for the higher frequency of TB
contacts among the cases did not lower the risk
estimates. This difference may have been due to
recall bias. Both cases and controls had probably
been exposed to TB as they came from the same
(mostly overcrowded) urban en- vironment, with
an estimated TB incidence of 128 per 100 000
population.2 We also investigated whether a
difference in BMI can explain the association be-
tween TB and diabetes. TB patients had a much
lower BMI at presentation than control subjects,
as they lose, on average, 10–15% of their body
weight dur- ing their illness. Diabetes cases had a
significantly higher BMI in both patients and
controls and, as a result, adjustment for BMI
actually increased the risk estimates.
As this was a case-control study, we can only
hypoth-
esise about the cause-effect relationship between
TB and diabetes. On the one hand, TB may have
triggered the development of diabetes, e.g., by
inflammation- associated insulin resistance. Effective
anti-tuberculosis
treatment only normalised hyperglycaemia in a
small proportion of the diabetes patients, which
pleads against this hypothesis. A second possibility
is that di- abetes was already present in these
subjects, acting as a risk factor for the development
of TB. Forty per cent of TB patients presenting with
hyperglycaemia had a history of diabetes. As the
study subjects were very poor, with limited access
to regular health care, the proportion with
undiagnosed diabetes may in fact have been higher.
Immunological studies support the hypothesis that
diabetes is a risk factor for TB. Pro- duction of
interferon-gamma, which is crucial for host
defence against TB, has been found to be low in
diabetic mice infected with M. tuberculosis,11 and it
has been shown that alveolar macrophages in TB
patients with diabetes show less activation. 12 Co-
hort studies performed in Europe and the United
States in the 1930s also support this hypothesis:
diabetics showed a three- to four-fold increased
risk of devel- oping TB.4
A recent case-control study of TB patients in
Mex-
ico reported a higher risk estimate than ours: the
prevalence of diabetes was 29.6%, which was 6.8-
fold higher than the background prevalence of
diabe- tes in the study area.3 Previous studies from
Korea, Europe and the US in which diabetes
patients were prospectively followed, reported risk
estimates simi- lar to ours.3–6,14,15
Compared to Western standards, patients with
di- abetes in our study had a remarkable
phenotype, as they were relatively young and
certainly not obese. It should be noted that
diabetics in Asia are generally younger and leaner
than diabetics in Europe.16 The prevalence of
diabetes in our control group was sim- ilar to
previous data from a survey among the general
population in Indonesia, and from other countries
in Asia.1
If diabetes, as our study suggests, is such a
strong risk factor for TB, this may have significant
clinical and epidemiological implications. In 2025,
75% of diabetics will live in developing countries
where more than 90% of TB cases reside. 1,2 An
increasing preva- lence of diabetes in these
countries may thus threaten the success of TB
control. Because diabetes was un- noticed and
untreated in the majority of TB patients in our
setting, it seems wise to screen TB patients for
diabetes. Based on our study, we would recommend
screening all TB patients above 35 years of age at
least once, and looking for symptoms of diabetes in
younger patients. Screening and earlier manage-
ment of diabetes may reduce the risk of developing
active TB. Future studies are needed to confirm this
hypothesis.
Acknowledgements
This study is an indirect result of the project ‘Immunogenetic basis of
susceptibility to and disease manifestations of mycobacterial
infections’, conducted within the ‘Scientific Programme Indonesia
Netherlands’ (SPIN) and supported by the Royal Academy of Arts and
Sciences (KNAW), the Netherlands. We thank Prof Sangkot Marzuki,
director of the Eijkman Institute of Molecular Biology, Jakarta, for his
kind support in this collaborative project and Cees Tack for critically
reviewing the manuscript.
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CONTEXTE : Le diabète sucré est un facteur de risque
connu pour la tuberculose (TB), mais aucune étude n’a
été rapportée à ce sujet en Asie du Sud-Est, qui connaît
un fardeau élevé de TB et une prévalence rapidement
croissante du diabète.
OBJECTIF : Examiner si et dans quelle mesure le diabète
est associé à un risque accru de TB dans un contexte
urbain en Indonésie.
SCHÉMA : Etude cas-contrôle comparant la prévalence du
diabète sucré (taux de glucose sanguin à jeun >126
mg/dl) parmi les patients dont la TB pulmonaire a été
nouvellement diagnostiquée et parmi des contrôles de
voisinage appariés.
RÉSULTATS : L’âge médian des patients et des sujets-
contrôle était similaire (30 ans), de même que la distri-
La diabetes representa un fac-
MARCO DE R E FE R E N C I A :
tor de riesgo reconocido de tuberculosis (TB), pero no se
ha publicado ningún estudio en pacientes del sureste
asiático, una región con alta carga de morbilidad por
TB y una prevalecía rápidamente creciente de diabetes.
OBJETIVO : Evaluar si existe y cuantificar la posible cor-
relación entre la diabetes y un riesgo aumentado de TB,
en un medio urbano en Indonesia.
Fue este un estudio de casos y testigos que
MÉT ODO S :
comparó la prevalecía de diabetes (glucemia en
ayunas
>126 mg/dl) en pacientes con diagnóstico reciente de
TB pulmonar y en un grupo testigo constituido por una
muestra emparejada de personas del vecindario.
RESULTADOS : La edad en el grupo estudiado y el grupo
testigo fue semejante (mediana 30 años), al igual que la
distribución por sexo (52% de hombres), pero la desnu-
RÉSUMÉ
bution par sexe (52% de sexe masculin), mais la malnu-
trition est plus fréquente chez les patients TB (index
masse corporelle médian 17,7 versus 21,5 kg/m 2). L’in-
fection VIH est rare (1,5% des patients). Le diabète
sucré est présent chez 60 des 454 patients tuberculeux
(13,2%) et chez 18 des 556 sujets-contrôle (3,2%) (OR
4,7 ; IC 95% 2,7–8,1). L’ajustement pour des facteurs
confondants possibles n’a pas réduit le risque estimé. A
la suite du traitement de la TB, l’hyperglycémie a
régressé chez une minorité (3,7%) des patients
tuberculeux.
CONCLUSION : Il existe une association étroite entre le
diabète sucré et la TB chez des sujets jeunes non obèses
dans un contexte urbain en Indonésie. Ceci peut avoir
dans cette région des implications pour la lutte anti-
tuberculeuse et les soins aux patients.
RESUMEN
trición fue más frecuente en el grupo de pacientes con
TB (mediana del índice de masa corporal 17,7 kg/m 2
comparada con 21,5 kg/m2). La observación de infec-
ción por el VIH (1,5% de los pacientes) fue poco fre-
cuente. Se encontró diabetes en 60 de 454 pacientes con
TB (13,2%) y en 18 de 556 testigos (3,2% ; OR 4,7 ; IC
95% : 2,7–8,1). El ajuste con respecto a los posibles fac-
tores de confusión no redujo la estimación del riesgo.
Después del tratamiento antituberculoso, la hipergluce-
mia regresó en una minoría de los pacientes con TB
(3,7%).
CONCLUSIÓN : Se observó una alta correlación entre la
diabetes y la TB en los individuos jóvenes no obesos en
un entorno urbano en Indonesia. Esta observación po-
dría tener implicaciones en la lucha contra la TB y el
tratamiento de los pacientes en esta región.
Diabetes Mellitus is strongly associated with tuberculosis in Indonesia

VARIABEL

Variabel bebas: Tuberculosis pada pasien dewasa muda dan tidak obesitas

Variabel terikat: Diabetes Mellitus

ERROR

o Random error
 Kesalahan pengambilan data pasien TB
Kesalahan dapat terjadi saat pengambilan data-data pasien TB secara
consecutive dari pasien poliklinik klinik TB di Jakarta pusat dan RSHS Bandung.
 Kesalahan pada saat menegakkan diagnosis TB berdasarkan pemeriksaan dahak
dan foto thorax pada pasien yang diambil sebagai sample penelitian.
o Systematic error
 Selection bias
 Consecutive sampling pada penelitian dilakukan di RSHS dan klinik TB di
Jakarta; belum bisa mewakili Indonesia.
 Jumlah sampel kurang
 Pasien TB yang tidak berobat ke poliklinik atau rumah sakit tidak
termasuk ke dalam penelitian.
 Measurement bias
 Dalam penelitian pengukuran laboratorium digunakan dalam mengukur
kadar glukosa darah puasa dan juga glukosa pada urine (dengan urine
dipstick). Quality control yang kurang baik pada peralatan di
laboratorium dan penggunaan dipstick yang expired dapat menghasilkan
measurement bias.
 Confounding:
 Umur
 Jenis kelamin
 Gaya hidup (merokok, aktivitas fisik, pola makan)
 Kepadatan Penduduk
 Riwayat Kontak TB
 BMI
 Penyakit co-morbid lain

Uji statistik: Regresi logistik