Associated Risk Factors for Latent Tuberculosis Infection in Subjects with Diabetes

Archives of Medical Research - (2015) 1 2 3 ORIGINAL ARTICLE 4 5 6 7 8 9 Gerardo Mart
ınez-Aguilar,a Carmen J. Serrano,a Julio Enrique Casta~ neda-Delgado,a,b 10 Q2 b b b 11 Q1 No
e Mac
ıas-Segura, Nicol
as Hern
andez-Delgadillo, Leonor Enciso-Moreno, Yolanda Garc
ıa de Lira,b 12 Ema Valenzuela-M
endez,b Benjam
ın G
andara-Jasso,b Joel Correa-Chac
on,b 13 a,b c Yadira Basti
an-Hern
andez, Martha Rodr
ıguez-Mor
an, Fernando Guerrero-Romero,c and 14 15 Jos
e Antonio Enciso-Morenoa 16 a Medical Research Unit of Zacatecas, IMSS, Zacatecas, Mexico 17 b Catedras CONACYT, National Council of Science and Technology (CONACyT- M
exico), Mexico City, Mexico 18 c Biomedical Research Unit, Mexican Institute of Social Security (IMSS), Durango, Mexico 19 20 Received for publication November 11, 2014; accepted March 30, 2015 (ARCMED-D-14-00656). 21 22 23 24 Background and Aims. Type 2 diabetes mellitus (DM2) confers a higher risk for active 25 tuberculosis (TB). However, information on associated risk factors for latent tuberculosis 26 infection (LTBI) inpatients with DM2 is limited. We conducted a cross-sectional study to 27 elucidate the prevalence of LTBI and its associated factors on Mexican adults with DM2 28 receiving medical care at the Mexican Social Security Institute (IMSS). 29 Methods. Six hundred patients with DM2 without a prior history of TB from outpatient 30 31 diabetes clinics were enrolled in the study. The tuberculin-skin-test (TST) was performed. 32 The presence of LTBI was defined by a TST value of $5 mm. A standardized interview 33 and physical examination were conducted to obtain clinical, demographic, and LTBI risk 34 factor information; all subjects were laboratory tested to determine the presence of exclu35 sion criteria. Microscopic examination of sputum samples and chest x-rays was per36 formed to identify potential active TB. Subjects with any finding suggesting active TB 37 or malignancy were excluded. A logistic regression model was used to identify variables 38 associated with LTBI. 39 40 Results. LTBI prevalence among patients with DM2 was 51.3%. Risk factors for LTBI 41 were living with a relative with TB, having been in prison, having hemoglobin values 42 O14 g/dL, and glycosylated hemoglobin (HbA1c) values of O7%. Blood pressure, eco43 nomic income, or anthropometric measurements were not associated risk factors. 44 Conclusions. Over one half of patients with DM harbor LTBI. Exposure to certain envi45 ronmental conditions and poorly controlled DM2 (HbA1c O7.0%) were risk factors for 46 47 having LTBI in persons with DM2. Ó 2015 IMSS. Published by Elsevier Inc. 48 Key Words: Latent tuberculosis, Diabetes mellitus type 2, Risk factors. 49 50 51 52 53 Introduction tuberculosis infection (LTBI) and 8.6 million individuals 54 developed tuberculosis (TB) in 2012 (2). In the same year, According to the World Health Organization (WHO), 347 55 The Ministry of Health in M
exico reported a TB prevalence 56 million persons worldwide are currently suffering from diaof 16.8 cases/100,000 inhabitants, without official data 57 betes mellitus (DM), mainly type 2 diabetes mellitus regarding LTBI prevalence. In Mexico, the bacillus Calm58 (DM2) (1), one third of the world’s population has latent 59 ette-Gu
erin (BCG) vaccine is applied at birth with a 60 coverage of O95% (3). The association between DM and Address reprint requests to: Jos
e Antonio Enciso-Moreno, Interior de la 61 TB has been suggested for some time (4,5); however, coAlameda # 45, Col. Centro, 98000 Zacatecas, Zacatecas, M
exico; Phone: 62 morbidities of these diseases were not reported until (þ52) (492) 9226019; FAX: ---; E-mail: [email protected]

Associated Risk Factors for Latent Tuberculosis Infection in Subjects with Diabetes

0188-4409/$ - see front matter. Copyright Ó 2015 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2015.03.009 ARCMED2005_proof ■ 9-4-2015 18-53-59

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80 years ago and are now firmly established (6,7). The association between these diseases is of greater importance for populations with low socioeconomic status and high prevalence rates of both conditions (6) but, as the result of globalization and high migration rates, detecting patients with DM and who are at risk for active TB is a global public health challenge (8). As in other countries, in Mexico there is an increase in the frequency of TB among patients with DM2, and a higher frequency of DM2 among individuals with TB, regardless of whether human immunodeficiency virus (HIV) infections have been reported (6,9e11). Given the worldwide distribution of these pathologies, the comorbidity of DM2-TB is expected to occur more frequently in regions with low income and/or poor healthcare services (6). Other risk factors for the comorbidity of active TB in patients with DM include low body weight (12), poor glycemic control (13e16) and nutritional deficiencies (17,18). It is well known that DM affects the immune system, impairing chemotaxis, phago- and monocyte activity, and also increasing T-cell activity. All these alterations are present during acute hyperglycemia (14,19). In addition, in patients with DM2, a decrease in circulating levels of Interferon gamma (IFg), interleukin 2 (IL-2), tumor necrosis factor a (TNF-a), and IL-17F (all of these implicated in the immune control of TB) have been reported (20). Although the association between DM2 and active TB is well established (9,11,21), the factors involved in the association between DM2 and LTBI are scarcely known and there are discrepancies (22e24) or no association at all (25e27). Over one quarter of patients with DM2 harbor LTBI (11,22e24). Given that reactivation of LTBI is influenced by the immune system, subjects with DM and LTBI may carry a greater risk for TB reactivation. The tuberculin skin test (TST) is the most used diagnostic test for LTBI, and it measures the cellular immune response against Mycobacterium tuberculosis (Mtb) antigens. Considering that patients with DM2 present deficiencies with regard to the immunity (28,29), it is possible that the current cut-off value for TST considered to detect LTBI in patients with DM2 is higher than it should be; therefore, it exhibits lower sensitivity with respect to persons without DM2. To gain insight into the association of LTBI and DM2, we conducted a cross-sectional study aimed at determining the risk factors associated with LTBI in Mexican adults with DM2 and the prevalence (using a TST $5-mm cutoff point) of LTBI in patients affiliated with the Mexican Social Security Institute (IMSS) in Durango and Zacatecas, states located in northern Mexico.

Materials and Methods Study Design and Characteristics With the approval of the Institutional Research Scientific and Ethics Committee (IMSS, 33-0119) and, after obtaining signed informed consent from the participants, we

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conducted a cross-sectional study. Subjects with a medical history of DM receiving hypoglycemic drugs and/or insulin treatment at IMSS primary healthcare services of Durango City, Durango, Guadalupe and Zacatecas, Zacatecas (cities located in the central region of Northern Mexico) were randomly selected and recruited between October 2006 and June 2007. We collected information on the entire population with a diagnoses of DM recorded at the primary Medical Care Units previously mentioned. A total of 11,587 (6,450 from Zacatecas, and 5,137 from Durango) electronic files were reviewed; a nominal list of eligible subjects was obtained, and a random selection of patients with DM was performed according to a computergenerated random numbers list. Clinical and laboratory tests were carried out to exclude patients with active TB. Patients who refused to participate were replaced, utilizing the same nominal list and random procedure. Health workers in the field visited the homes of the selected subjects, and adult men and non-pregnant women were invited to participate in the study. A standardized interview and physical examination were conducted to obtain clinical, demographic, and LTBI risk factor information; all subjects were laboratory tested in order to determine the presence of exclusion criteria. Use of immunosuppressant’s or previous LTBI treatment was considered a reason for exclusion. Also, microscopic examination of sputum samples and chest x-rays was performed to identify potential active TB infection only in subjects with signs or symptoms suggestive of active TB. Chest x-ray and sputum samples were reviewed by two experts in the field. Subjects with any finding suggesting of active TB or malignancy were excluded from the study. TST Application and Interpretation TST, i.e., Mantoux test, was performed on the volar side of the forearm employing a 5-UT dose of purified protein derivative PPD-S (Tubersol, Aventis Pasteur). TST were administered and measured by trained health promoters, and any induration was measured (in mm) after 72 h using the ballpoint pen technique method (30). Indurations of $5 mm were considered positive. Subjects with a positive TST but with no evidence of active TB were considered as having LTBI. Definitions and Risk Factor Assessment Individuals were allocated into two groups: TST-positive or TST-negative. Risk factors analyzed by questionnaire included the following: unemployment or annual income !$500 U.S. dollars (USD); living with a relative with TB; living in overcrowded conditions; a history of being in prison; a history of working in healthcare institutions and/or mines; cigarette smoking; use of illegal drugs, and alcohol consumption. Previous contact with a patient with TB, age, a clinical history of DM, and kidney failure were

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Latent Tuberculosis and Diabetes

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recorded. Anthropometric measurements included height (in m), weight (in kg), and waist (in cm) measured with the subjects wearing light clothing and without shoes. Waist circumference was taken as maximal circumference at the umbilicus level; Body mass index (BMI) was calculated dividing weight by height squared. Trained personnel performed all measurements. A venous whole blood sample was collected under fasting conditions on the same day that the individuals were enrolled and before TST application. Serum glucose and lipid profile were determined by glucose-oxidase and enzymatic methods, respectively. Intra- and inter-assay variations were 2.1 and 1.5% for the glucose-oxidase method and 2 and 3.0% for enzymatic method. Measurements were performed in an Express 500 Clinical Chemistry Autoanalyzer (Ciba Corning, Diagnostic Corp., Overling, OH). Mean blood glycosylated hemoglobin (HbA1c) level was determined by the Stanbio Glycohemoglobin test (Stanbio Laboratory), which had a 1.7% variation coefficient and an inter-assay correlation coefficient of 0.982. Sample Size Calculation and Statistical Analysis Sample size was estimated to achieve 80% power at the 5% significance level. As prevalence of LTBI in diabetic population is unknown, 50% was assumed for the case of a finite population. A total of 600 subjects were included: 308 positive for TST and 292 negative to the test. Normality was tested by a Kolmogorov-Smirnov normality test. Once this was confirmed, we proceeded with the analysis. Differences between groups were assessed by unpaired Student t test for numerical variables and c2 test for nominal variables. Analysis of variance (ANOVA) with Bonferroni post hoc test was employed when comparing three groups (according to TST cut-off values). Risk factors with significant differences on bivariate analysis were included as independent variables, and TST was a dependent variable in an age and gender adjusted logistic regression model. A 95% confidence interval (95% CI) was considered and a p value of !0.05 defined the level of statistical significance. Data were analyzed using the SPSS v.10.0 statistical software package (SPSS, Inc., Chicago, IL).

Results General Description of Clinical Characteristics of Participants A total of 605 subjects with DM, 412 (68.1%) females and 193 (31.9%) males, were enrolled in the study. Active TB was identified in five (0.82%) subjects; therefore, analysis was performed in 600 subjects, including 410 (68.3%) females and 190 (31.7%) males. Clinical and laboratory characteristics of the study population are depicted in Table 1.

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Table 1. Clinical and laboratory characteristics of patients with diabetes mellitus (n 5 600) Age (years)

54.0 ± 8.3 a

Annual income, USD Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL) Leukocytes (per mm3) Fasting glucose (mg/dL)a HbA1c (%) Total cholesterol (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL)a TST (mm) Serum creatinine (mg/dL)

$2,658 (range $1,635e$4,089) 30.0  5.3 96.8  11.7 145.4  26.6 85.5  12.1 14.6  1.9 7,211.2  1,897.7 167.5 (range 126.2e235.7) 7.8  1.7 198.1  50.6 47.0  15.0 213 (range 146‒302) 8.3  9.6 1.1  0.7

USD, U.S. dollars; TST, tuberculin skin test (Mantoux); HDL-C, highdensity lipoprotein cholesterol. Values are mean  standard deviation (SD) unless otherwise stated. a Median (25, 75 percentile).

Risk factors for TB were distributed as follows: 19 (3.2%) subjects were unemployed or had an annual income of !$500.00 USD annually; 34 (5.7%) and 75 (12.5%) of study participants were living with a relative with TB and in overcrowded conditions, respectively, 17 (2.8%) had a history of being in prison, 39 (6.5%) and 24 (4.0%) had a history of working in healthcare institutions and/or mines, respectively, 155 (25.8%) had a history of cigarette smoking, 19 (3.2%) had illegal drug use and 88 (14.7%), alcohol consumption. Differences in Clinical Characteristics and Risk Factors Regarding TST Positivity A total of 308 (51.3%) patients with DM had positive TST; of these, 71 (23.0%) had an area of induration of O5‒9 and 237 (77.0%) had a TST of $10. On the other hand, 292 (48.7%) subjects with DM had a TST of !5 mm. Table 2 presents the characteristics of subjects with DM stratified according to TST reactivity. Systolic and diastolic blood pressure and hemoglobin were higher in subjects with negative TST. Other significant differences in anthropometric and clinical characteristics between the groups were not found. Differences Among the Proportions of Several Variables in TST-Positive and -Negative Subjects with DM Table 3 illustrates the risk factor distribution among the groups under study, and the proportion of subjects within the TSTþ and TST‒ groups was analyzed. A history of being in prison, living with a relative with TB, HbA1c O7%, and Hb O14 g/dL were significantly higher in subjects with a positive TST. Variables with biological plausibility

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Table 2. Clinical and laboratory characteristics of patients with type 2 diabetes mellitus (DM2) according to (TST) reactivity (TST-positive, $5 mm)

Females, n (%) Age (years) Annual income, USDa Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL) Leukocytes (per mm3) Fasting glucose (mg/dL)a HbA1c (%) Total cholesterol (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL)a TST (mm) Serum creatinine (mg/dL)

TSTD

TSTe

308

292

p

205 (66.6) 53.4  8.2 $2,862 (range $1,738e$4,908) 30.4  5.2 97.3  11.3 142.2  24.2 84.3  11.2 15.0  1.8 7,130.4  1,847.1 164 (range 126.2e237.5) 7.5 (range 6.5e8.5) 198.6  51.8 46.7  15.7 203 (range 139‒296) 15.9  7.9 1.0  0.4

205 (70.2) 54.6  8.3 $2,453 (range $1,635e$4,090) 29.7  5.3 96.2  12.1 148.9  28.6 86.7  12.8 14.2  2.0 7,296.4  1,949.2 169 (range 126.5e234.5) 7.6 (range 6.8e8.7) 197.6  49.3 47.5  14.3 224.5 (range 151e306.7) 1.1  0.9

0.38 0.09 0.07 0.12 0.24 0.00 0.02 0.0001 0.28 0.81b 0.21 0.79 0.51 0.13b 0.39

TST, tuberculin skin test $5 mm; HDL-C, high-density-lipoprotein cholesterol. Values are mean  standard deviation (SD) unless otherwise noted. a Median (25th 75th percentile). b Estimated using Mann-Whitney U test.

showing statistical significant differences between the TST groups were utilized as independent variables. Thus, the age- and gender-adjusted logistic regression model included HbA1c O7%, Hb O14, a history of being in prison, and living with a relative with TB as independent variables, and TST as a dependent variable. Living with a relative with TB, having been in prison, hemoglobin O14 g/dL, and HbA1c O7% demonstrated to be risk factors for LTBI (Table 4). In addition, these risk factors were also compared considering three groups according to the TST value as follows: Group 1, !5 mm; Group 2, Table 3. Prevalence of tuberculosis risk factors in adults with diabetes mellitus (DM) (n 5 600)

Unemploymentb Living with a relative with TB Living in overcrowded conditions History of being in prison History of working in healthcare institutions History of working in mines Cigarette smoking Use of illegal drugs Alcohol consumption HbA1c O7.0% Hemoglobin O14 g/dL

TSTDa

TSTe

308

292

p

2.6 9.1 13.0 4.5 8.1

6.2 2.1 12.0 1.0 4.8

0.051 0.003 0.800 0.010 0.130

4.2 27.6 2.3 16.6 64.8 73.7

3.8 24.0 4.1 12.7 51.0 62.3

0.940 0.350 0.290 0.210 0.001 0.003

TST, tuberculin skin test. Values are (%). a Tuberculin skin test $5 mm. b Annual income !$500.00 U.S. dollars (USD).

$5‒9 mm, and Group 3, $10 mm. A significant difference was found in hemoglobin O14 g/dL ( p 5 0.000). Bonferroni post hoc test showed statistical significance between Groups 1 and 2 ( p 5 0.014) and between Groups 1 and 3 ( p 5 0.000), but not between groups 2 and 3 ( p 5 1.0). With respect to a history of being in prison ( p ! 0.03), a significant p value of 0.02 was found between Groups 1 and 3, likewise between Groups 2 and 3, but not between Groups 1 and 2. For the variable living with a relative with TB ( p 5 0.003), the post hoc analyses demonstrated a significant difference between Groups 1 and 3 ( p ! 0.000); but not between Groups 1 and 2 or between Groups 2 and 3. No statistical difference was found in HbA1c O7% ( p 5 0 0.13). Discussion A defective innate immune response to Mtb in DM2 (19) suggests that persons with DM2 could have a higher risk of LTBI during environmental exposure to Mtb. However, Table 4. Age- and gender-adjusted odds ratios and 95% confidence intervals for risk factors among adults with diabetes mellitus (n 5 600) 95% CI

Hemoglobin (O14 g/dL) History of being in prison Living with a relative with tuberculosis (TB) HbA1c (O7%)

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OR

Lower

Upper

p

1.21 4.05 1.26

1.09 1.10 1.11

1.33 14.47 1.97

!0.00 0.03 0.01

2.52

1.10

8.25

0.04

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Latent Tuberculosis and Diabetes

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despite the well-known link between DM and active TB, the effect of DM on the frequency of latent TB has been less explored. The few available reports on general population document a higher prevalence of LTBI among patients with DM with rates within the range of 28.2 and 42.4% (22e24). However, the relative risk (RR) of LTBI among patients with DM (vs. no DM) has not been systematically measured in contemporary epidemiological studies. Similarly, systematic studies to define a TST cut-off point in DM have not been performed. This is an issue of major importance given that immune status (19) and the response to vaccination and other antigens suggest the presence of anergy in persons with DM (31). Therefore, it may be possible that in this population, response to TST is also impaired. Different cut-off values for TST have been suggested for different countries and risk groups (28,32e35). In the present study we used TST $5 mm as the cut-off value to determine TST positivity and LTBI prevalence among patients with DM2. We found an LTBI prevalence of 51.3%, which is higher than that found in previous reports on Spain (42.2%) (24), Puerto Rico (42.4%) (23), and Singapore (28.2%) (22). LTBI prevalence found in subjects with DM is nearly as high as that documented in the same geographical region in household contacts (a group with confirmed exposure to a TB case and therefore with the highest risk of acquiring LTBI) of 53.6% (28). Acquisition of TB infection is primarily dependent on exogenous factors; however, reactivation of the disease is mainly under the influence of immune competence (36). An increase in the prevalence of LTBI infection leads to an increase in the incidence of active TB, with a rise in cases caused by reactivation (37); therefore, among subjects with a possible high risk for reactivation, such as those with DM, early identification of LTBI is required to reduce the risk of the active disease. In the present study, two factors related with exposure were associated with LTBI: living with a relative with TB and a history of being in prison. These findings are in agreement with previous reports showing that residents of prisons, as well as household contacts of TB cases, have an increased risk of active disease (32,36,38,39). On the other hand, we did not identify an association between LTBI and host-dependent risk factors such as age and BMI, a finding also in agreement with previous reports (26). Regarding clinical parameters, two factors were associated with LTBI in subjects with DM2: glycosylated hemoglobin (HbA1c) of O7% and Hb O14 g/dL. Since the early 1900s, it has been reported that the development of TB appears to follow the onset of DM in 85% of cases (7), suggesting that the risk of TB may be linked with DM2 onset-related hyperglycemia. High HbA1c is an indicator of poor glycemic control and has been associated with enhanced risk for complications and a reduction in life expectancy of persons with DM. Several articles report that

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suboptimal control of DM predisposes these patients to TB (14,16). Evidence supports the idea that poor control in DM, more than DM itself, is what increases the risk for pulmonary TB. Results of a longitudinal cohort study (5-year follow-up) that included 35,672 subjects with DM, aged 65 years or older, found that chronic hyperglycemia with HbA1c values of $7%, had a 3.63 (95% CI; 1.79e7.33) risk of developing pulmonary TB when compared with a group with better glycemic control (16). In our study we found a higher proportion of subjects with HbA1c values of O7% in the TST-positive than in the TSTnegative group and their association with LTBI was significant. Therefore, on the whole, our results suggest that poorly controlled DM represent a risk factor not only for TB reactivation, as was reported previously, but also for LTBI and its consequences. The role of high HbA1c on the innate and adaptive immune system has been explored in several studies. For instance, it has been revealed that there is a significant reduction in CD4þ and Th17 memory responses to Streptococcus pneumonia in patients with DM2 (29); this impaired memory response might explain the deficiency in antibody production that has been observed in persons with DM (40). In addition, the innate immunity against TB mediated by soluble molecules such as antimicrobial peptides (41) and neutrophils (42) is diminished in subjects with DM. The mechanisms linking an impaired immune system and high HbA1c have been associated with the receptor for advanced glycation end products (RAGE). Among its functions, RAGE participates in the control of T-cell activation and differentiation (43), perhaps through soluble RAGE (sRAGE), which regulates its activation. sRAGE is elevated in patients with DM2 (44) and could explain the apparent antagonism. This event has also been described as associated with neutrophil dysfunction (45). Further research is needed to determine whether this is the case for latently infected individuals with TB and comorbidities such as DM. With respect to the finding of hemoglobin O14 g/dL as a risk factor for LTBI in subjects with DM2, it was reported that chronic pulmonary disease can raise hemoglobin (46), but the role of elevated hemoglobin in active TB, LTBI, or progression to active TB has not been described. However, it is known that the iron status of the human host affects the pathogenicity of numerous infections including TB (47,48). Molecules regulating iron homeostasis might be affecting hemoglobin production (through increasing iron uptake). Hepcidin, an antimicrobial-like peptide hormone, controls the absorption of dietary iron and the distribution of iron among cell types in the body, and its synthesis is regulated by both iron and innate immunity. Hepcidin forms a key molecular bridge between iron trafficking and response to infection (47). Recently, it was described that in cells of the innate immune system harboring Mtb, mycobacterial lipoglycans were strong inducers of hepcidin messenger RNA (mRNA) (49). Therefore, it might be possible that in a host infected

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by Mtb, hepcidin could affect iron metabolism and, consequently, hemoglobin production. However, further research is required to clarify whether there is a link between hemoglobin and hepcidin in subjects with DM and LTBI. In this study, the presence of comorbidities such as HIV infection was not determined; consequently, this comprises a limitation of our design. Similarly, given the crosssectional design of the study, it is difficult to draw inferences of causality with certainty. However, our findings address the importance of performing studies in other populations to support or discard these inferences. To our knowledge, this is the first report on the prevalence of LTBI and its associated risk factors among Mexican subjects with DM2. This study showed a high prevalence of LTBI infection among subjects with DM2 residing in central and northwestern Mexico. The main risk factors associated with LTBI are related with higher exposure to Mtb, but also poor control of DM (HbA1c O7.0%) is associated with LTBI. Acknowledgments This work was supported by grants of FOMIX CONACYTeGobierno del Estado de Zacatecas 2005-02-14834, Instituto Cient
ıfico Pfizer (23/583), Fondos Sectoriales Salud CONACYT 14444, and FOFOI-IMSS (11/095).

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Latent Tuberculosis and Diabetes 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697

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