The predictors of pulmonary tuberculosis in Xpert MBT/Rif positive and resistant assay patients with diabetes mellitus Текст научной статьи по специальности «Клиническая медицина»

RESEARCH STUDIES

DOI: 10.5281/zenodo.1299008 UDC: 616.24-002.5:616.379-008.64

The predictors of pulmonary tuberculosis in Xpert MBT/Rif positive and resistant assay patients with diabetes mellitus

*Lesnic Evelina1, MD, PhD, Associate Professor; Malic Alina1, MD; Kulcitkaia Stela1, MD, PhD Associate Professor; Niguleanu Radu2, MD, PhD, Associate Professor; Jucov Artiom3, MD, PhD, Associate Professor; Gutu-Grecu Mariana4, MD; Cula Eugenia4, MD; Tolmaciov Mihai4, MD

department of Pneumophtisiology, 2Department of Morphopathology, 3Department of Family Medicine Nicolae Testemitsanu State University of Medicine and Pharmacy 4Chiril Draganiuc Institute of Phtisiopneumology, Chisinau, the Republic of Moldova

^Corresponding author: evelina.lesnic@usmf.md. Received March 12, 2018; accepted June 22, 2018

Abstract

Background: One of the most important among risk factors for active tuberculosis development represents diabetes mellitus. The aim of the study was the assessment of the predictive factors for pulmonary tuberculosis in Xpert MBT/Rif resistant assay patients with diabetes mellitus. Material and methods: A retrospective, selective, descriptive and case-control study was performed. Were enrolled 119 pulmonary drug resistant tuberculosis patients, diagnosed and hospitalized in the Municipal Clinical Hospital of Phthysiopneumology of Chisinau city in the period of 01.01.201301.01.2015. The patients were distributed in 2 groups: the 1st group - 34 MDR-TB patients with diabetes mellitus and the 2nd - 85 MDR-TB patients. Investigations were performed according to the National Clinical Protocol - 123.

Results: The biological characteristics of the pulmonary MDR-TB patients with diabetes mellitus were old age with associated diseases, which contributed to a lower treatment outcome. For MDR-TB groups were common social-economic vulnerability, late detection as symptomatic cases and a high treatment success rate.

Conclusions: Patients with MDR-TB and diabetes mellitus need an individualized approach for an early TB detection and prompt initiation of the adequate treatment regimen according of the susceptibility testing results. Key words: tuberculosis, Xpert MBT/Rif, diabetes mellitus.

Introduction

Tuberculosis is one of the most important challenges for the health care system and was declared a global emergency in 1993 [45, 46, 47]. In 2017 were registered 9 million new cases globally. The Republic of Moldova ranked among 30 countries with the biggest burden of multidrug-resistant tuberculosis (MDR-TB), an estimated disease incidence of 101/100.000 [7]. Health indicators that evaluate the achievement of the sustainable development goals associated with tuberculosis are: HIV prevalence, diabetes prevalence, alcohol use disorders and tobacco smoking prevalence and health expenditure per capita. Diabetes mellitus is an important public health problem, one of four priority non-communicable diseases targeted by the development goals. Diabetes mellitus leads to complications and premature death. In the Republic of Moldova every 10th citizen suffers from disturbances of glucose metabolism and the indices are continuously rising. National capacity to prevent and control tuberculosis is reflected by the early case detection, especially of MDR-TB cases. The incidence of MDR-TB among new and relapsed cases was 19/100.000

and 64.6/100.000 among retreated cases. Patients with both types of diabetes mellitus represent one of the risk groups for tuberculosis and should be annually screened by the chest X-ray. The association of the diabetes mellitus and pulmonary tuberculosis usually occurs in patients where diabetes was the previous diagnosed disease [15]. If both, tuberculosis and diabetes mellitus are detected simultaneously, diabetes worsens the tuberculosis outcome. One half of patients with diabetes mellitus develop tuberculosis in the first three years after the exposure to the infection [5]. Factors associated with the increased risk for tuberculosis are: disturbances of the innate resistance, dysfunction of alveolar macrophages, low cellular immunity response to the specific and non-specific infections, and reduced capacity of the organism to produce antibodies, low levels of interferon gamma, microangyopathy (inclusive pulmonary) and micronutrient deficiency [35].

The first clinical signs of tuberculosis in patients with diabetes mellitus have a low specificity: increased weakness, decreased appetite, loss of the weight, and worsening of the diabetes symptoms [18]. The development of the chronic

forms of tuberculosis - fibro-cavernous type, occurs when the organism's defenses are depleted [29]. The evolution of tuberculosis in diabetes mellitus is unfavorable due to disturbances of glucose metabolism [35]. Late detection and late onset of the therapy, dietary errors and inadequate treatment represent the causes of the worsening of tuberculosis process under the specific treatment. In diabetic patients, blood sugar levels increase, diuresis and glucosuria increase, acidosis may appear, patients have the feeling of dry mouth, thirst, frequent urination and important weight loss [14, 15].

Antidiabetic therapy in tuberculosis patients should be individualized and depends on the patient's state, the tuberculosis extensibility and the severity of diabetes [27,40]. Each patient with diabetes mellitus must be hospitalized. First of all, it is necessary to compensate the metabolic disorders with a physiological diet and optimal doses of anti-diabetic drugs. Anti-tuberculosis therapy should be administrated with caution due to high rate of adverse reactions [39].To prevent possible side effects patients must be strictly monitored.

Although, most of the diabetic patients are misdiag-nosed regarding tuberculosis, several factors are involved: low specificity of the clinical signs and atypical radiological aspects. The relevant localization of the pulmonary tuberculosis is upper and posterior segments of the lungs: I, II, VI and X, while in diabetic patients tuberculosis is identified in segments III, IV and V. In patients with carbohydrate metabolism disorders predominate the inferior lobe involvement and may be revealed multiple cavities [18].

According to the WHO recommendation microbiological methods remain the golden standard for pulmonary tuberculosis diagnosis. Conventional microscopy for identification of acid-fast-bacilli is the first step in TB detection algorithm. The low sensibility of the conventional microscopy diminishes the detection efficiency of TB patients. The long duration of the culture methods delays TB diagnoses. WHO recommends using Xpert MTB/Rif assay in adults, children and persons living with HIV or other risk factors. Xpert MTB/Rif assay represents in vitro diagnostic medical device owned by Cepheid Company. Xpert MTB/Rif assay used with Cepheid Xpert MBT/Rif system is a semi-nested, quantitative, real-time polymerase chain reaction testing for the DNA detection of all Mycobacterium tuberculosis (MBT) complex species and rifampicin resistance mutations of the rpoB gene [23]. Several standard results must be known for appropriate interpretation of Xpert MBT/Rif system: 1. MTB detected & RIF resistance means that MTB target is present and mutation of rpoBgene is detected; 2. MTB detected & RIF susceptible means that MTB target is present and no mutation of rpoB gene has been detected; 3. MTB not detected - MTB target is not detected within the sample. Despite of clearly defined interpretations the test results must be always correlated with laboratory and clinical data of the investigated patient. Data established that sputum examination through Xpert MBT/Rif assay shows sensitivity among culture positive specimens in an average 97.3% and

among smear positive patients - 99.5%. The specificity rate comparing with non-tuberculosis patients was 97.9% [31]. However negative result does not exclude active tuberculosis.

The aim of the study was the assessment of the predictive factors of pulmonary tuberculosis in Xpert MBT/Rif resistant assay patients with diabetes mellitus.

Material and methods

It was performed a retrospective, selective, descriptive and case-control study targeting peculiarities of pulmonary MDR-TB patients, diagnosed and hospitalized in the Municipal Clinical Hospital of Phthysiopneumology of Chisinau city in the period of 01.01.2014-01.01.2016, distributed in two groups. Including criteria in the 1st group: age >18 years old; patients with pulmonary tuberculosis, established as a new case and diagnosed with diabetes mellitus before tuberculosis; positive and resistant Xpert MBT/Rif assay; including criteria in the 2nd group: age > 18 years old; patients with pulmonary tuberculosis established as a new case without associated diabetes mellitus; positive and resistant Xpert MBT/Rif assay. The total number of 119 cases was distributed in 2 groups: the 1st group (the 1st Group) included 34 patients and the second group (the 2nd Group) included 85 patients. Collection of primary material involved the extraction of data from medical record forms. The individual schedule included information about: anamnesis, clinical examination, results of radiological investigations (chest radiography, high resolution computer tomography), results of microbiological investigations (smear microscopy by Ziehl-Neelson coloration and culture on classic solid medium Lowenstein-Jensen or liquid medium). Investigations were performed according to the National Clinical Protocol - 123 Tuberculosis in adults. Statistical analysis methods used in the study were: comparative, synthesis and discriminant analysis. Mathematic and statistical assessment was carried out by checking the quantitative and qualitative features. Accumulated material was tabled in simple and complex groups. Statistical study was performed using Microsoft Excel XP soft. The predictibility value of each involved factor was calculated using two by two tables. Relative risk and confidence interval was calculated according to the established formula [7]. The interval of 1.2 to 1.6 was assessed as a low predictive factor, 1.6 to 2.4 - as a mild predictive factor, and more than 2.5 - as a high predictive factor.

Results

Assessing general, social and economical peculiarities it was established the statistical predominance of male vs female in both groups: 21 (61.8%) vs 13 (38.2%) in the 1st group and 61 (71.1%) vs 24 (28.3%) in the 2nd group. Comparing the groups it was established a moderate predomination of male in the 2nd group comparing with the 1st group, so male/female ratio=1.6/1 in the 1st group and 2.5/1 in the 2nd group. Assessing the patients according to the age groups it was established the statistical predominance of the young

patients (18-34 years) in the 2nd group 40 (47.1%) comparing with the 1st group 4 (11.8%) and older than 55 years in the 1st group 19 (55.8%) vs 15 (17.6%) in the 2nd group. Summing patients in two subgroups: under 44 and older than 44 years, it was identified a statistical difference between the predominance of patients less than 44 years in the 2nd group 52 (61.7%) vs 6 (17.6%) in the 1st group and older than 44 years in the 1st group 28 (82.3%) vs 25 (29.4%) patients in the 2nd group. Considering that old age represents the specific feature for the group with diabetes and MDR-TB it was assessed as a high risk factor for tuberculosis (OR=11,2 95% CI: 5.8-60). The data are presented in the table 1.

Table 1

Distribution in sex and age groups

Groups Indices MDR-TB&DM MDR-TB p

n = 34 (P%) n =85(P%)

Sex Men 21 (61.8%) 61 (71.1%) >0.05

Women 13 (38.2%) 24 (28.3%) >0.05

18-44 years 18-24 0 12 (14.1%) <0.05

25-34 4 (11.8%) 28 (33.1%) <0.05

35-44 2 (5.8%) 12 (14.1%) >0.05

>44 years 45-54 9 (26.5%) 10 (11.8%) >0.05

55-64 12 (35.2%) 12 (14.1%) <0.05

>65 years 7 (20.6%) 3 (3.5%) <0.05

Among patients of both groups a similar distribution from rural and urban areas was established, however homeless were detected only in the 2nd group - 6 (7.1%) patients. Distribution of patients by economic groups was relevant. Due to the old age of the patients with TB-MDR and DM, employed persons statistically predominated in the 1st group 14 (41.2%) vs 21 (24.%) in the 2nd group. Socially vulnerable patients were more frequently registered in the TB-MDR group: 52 (61.7%) unemployed patients vs 8 (23%) in the 1st group. Low living conditions also predominated in the 2nd group 68 (80.1%) vs 21 (61.7%) in the 1st group due to high rate of unemployed patients. Retired patients predominated in the MDR-TB+DM group: 8 (23.5%) vs 8 (9.4%) in the 1st group; the same situation was determined for the persons with disabilities: 4 (11.8%) vs 7 (8.3%) patients, respectively (tab. 2).

Table 2

Main demographic, social and economical characteristics

The social risk groups with epidemiological role were evaluated. Migrants constituted a similar part in both groups, ex-detained were identified only in the MDR-TB group (13 (15.3%) cases). Exposure to tuberculosis infection (TB contact) statistically predominated in the 1st group - 11 (52.9%) vs 25 (29.4%) in the 2nd group and was identified as a low risk factor (OR=1.1 CI 95% 0.5-2.7). All patients in the 1st group and half of the 2nd group had associated diseases. So, the co-morbitities were established as a high risk factor (OR=45; CI 95% 42-48) for developing tuberculosis. In 15 (44.1%) patients of the 1st group diabetes mellitus was diagnosed at the same time as tuberculosis. Regarding the harmful habits, active tobacco smoking and alcohol drinking statistically prevailed in the 2nd group. Tobacco smokers were 63 (74.1%) in the 1st group vs 13 (39.2%) in the 2nd group and alcohol abusers were 38 (44.7%) in the 1st group vs 7 (20.6%) cases in the 2nd group (tab. 3).

Table 3

Distribution in risk groups

High risk groups Indices MDR-TB&DM MDR-TB p

n = 34 (P%) n = 85 (P%)

High risk groups Migrants 6 (17.6%) 16 (18.8%) >0.05

Ex-detained 0 13 (15.3%) <0.05

TB contact 11(52.9%) 25 (29.4%) <0.01

HIV infection 1 (2.9%) 2(2.6%) >0.05

Associated diseases 34 (100%) 36 (42.4%) <0.05

Psychiatric disorders 1 (2.9%) 8(9.4%) >0,05

Associated harmful habits Tobacco smoking 13 (39.2%) 63 (74.1%) <0.001

Alcohol abusers 7 (20.6%) 38 (44.7%) <0.05

By studing the civil status it was identified a statistical higher rate of married patients in the 1st group: 16 (47.1%) vs 15 (17.6%) patients in the 2nd group and of the divorced and widowed persons: 10 (29.4%) vs 22 (7.1%), respectively. Single persons predominated in the 2nd group due to young age of most of the patients. When assessing the educational level it was established that one half of both groups graduated general school. The incomplete general educational level was more frequently identified in the patients from the 2nd group: 24 (28.2%) vs 6 (17.6%) in the 1st group. Higher education level was established in a limited number of cases in both groups. No statistical differences were established between the groups of tuberculosis patients (tab. 4).

Table 4

Main social characteristics

Groups Indices MDR-TB&DM MDR-TB p

n = 34 (P%) n = 85 (P%)

Demo- Urban 17(50.1%) 41 (48.2%) >0.05

graphic Rural 14(41.2%) 38 (44.7) >0.05

Homeless 0 6 (7.1%) >0.05

Economic Employed 14 (41.2%) 21 (24.7%) >0.05

Unemployed 8 (23.5%) 52 (61.7%) <0.01

Retired 8 (23.5%) 8 (9.4%) >0.05

Students 0 5 (5.9%) >0.05

Disease disability 4 (11.8%) 7 (8.3%) >0.05

Life condi- Low living condi- 21 (61.7%) 68 (80.1%) <0.05

tions tions

Status Indices MDR-TB&DM MDR-TB P

n = 34 (P%) n = 85 (P%)

Marital Single 8 (23.5%) 48 (56.5%) <0.01

Married 16 (47.1%) 15 (17.6%) <0.001

Divorced/widowed 10 (29.4%) 22 (7.1%) <0.05

Education Primary/illiteracy 2 (5.7%) 8 (9.4%) >0.05

Incomplete secondary 6 (17.6%) 24 (28.2%) >0.05

General 16 (47.1%) 34 (40.1%) >0.05

Professional 6 (16.6%) 17 (20%) >0.05

Superior 4 (11.7%) 2 (2.4%) >0.05

Studying case-management it was identified that most of the patients from the 1st group comparing with the 2nd group were detected by high risk group screening, as recommended by the national protocol: 22 (64.1%) vs 13 (15.3%), respectively. As to symptomatic cases the patients were detected more often in the 2nd group: 60 (70.6%) vs 12 (35.3%) in the 1st group. By direct addressing were detected 12 (14.2%) patients in the 2nd group. Microscopic smear positive results were established in more than two thirds of patients of both groups: 22 (64.1%) in the 1st group and 61 (71.6%) in the 2nd group. Positive culture results were 24 (70.6%) patients in the 1st group and 76 (89.4%) in the 1st group. Positive results of Xpert MTB/Rif assay were more frequently identified in patients from the 2nd group: 76 (89.4%) vs 26 (76.5%) in the 1st group (tab. 5).

Table 5

Case-finding detection, microbiological characteristics and treatment outcomes

Characteristics Indices MDR-TB&DM MDR-TB p

n = 34 (P%) n = 85 (P%)

Case- Detected as 12 (35.3%) 60 (70.6%) <0.001

finding symptomatic case

Detected by ac- 22 (64.1%) 13 (15.3%) <0.001

tive screening

Direct addres- 0 12 (14.2%) <0.05

sing to the specialized hospital

Micro- Microscopy 22 (64.1%) 61 (71.6%) >0.05

biological Culture 24 (70.6%) 64 (75.3%) >0.05

positive results Xpert MTB/Rif 26 (76.5%) 76 (89.4%) >0.05

When identifying the radiological characteristics of pulmonary tuberculosis patients it was established lung pa-renchymal destruction in both groups: 25 (73.6%) in the 1st group and 61 (71.7%) cases in the 2nd group. Disseminated opacities were established at a similar rate in patients of both groups: 21 (61.7%) in the 1st group and 58 (68.2%) in the 2nd group. Both lungs were affected more frequently in patients of the 1st group: 24 (70.6%) vs 49 (57.6%) in the 2nd group, but the statistical threshold was not achieved. More than three affected segments had 65 (76.5%) patients in the 2nd group and 22 (64.7%) in the 1st group. Radiologic evolution under the specific treatment with second line antituberculosis drugs assessed as partial resorption was deter-

mined in a similar proportion in both groups: 28 (82.3%) in the 1st group and 76 (89.4%) in the 2nd group. Lung infiltrates progression was established in higher proportion in the 1st group: 7 (20.6%) vs 6 (7.1%) in the 2nd group, which contributed to the high rate of died patients. Although infiltrative TB form was diagnosed in the majority of patients, the severest forms such as disseminated TB and fibro-cav-ernous TB were diagnosed more frequently in the 1st group: 6 (17.6%) vs 9 (10.6%) in the 2nd group. Data are exposed in the table 6.

Table 6

Case-management characteristics and imagistic features

Characteristics Indices MDR-TB&DM MDR-TB p

n = 34 (P%) n = 85 (P%)

Imagistic Destruction 25 (73.6%) 61 (71.7%) >0.05

Dissemination 21 (61.7%) 58 (68.2%) >0.05

Both lungs 24 (70.6%) 49 (57.6%) >0.05

Extensive TB 22 (64.7%) 65 (76.5%) >0.05

Partial resorption 28 (82.3%) 67 (78.8%) >0.05

Progression 7 (20.6%) 6 (7.1%) >0.05

Clinical radiological forms Infiltrative 28 (82.3%) 76 (89.4%) >0.05

Disseminated 4 (11.7%) 8 (9.4%) >0.05

Fibro-caver-nous 2 (5.9%) 1 (1.2%) >0.05

Treatment outcome was assessed using the standardized indices. The success rate was lower than recommended by WHO (85%) in both groups. The lowest success rate was registered in the 1st group: 20 (58.8%) vs the 2nd group 66 (77.6%). Poor outcomes predominated in the 1st group: 14 (41.2%) vs the 2nd group 11 (12.9%). The highest rate of died patients was identified in the 1st group: 6 (17.5%) comparing with the 2nd group 3 (3.5%) (tab. 7).

Table 7

Treatment outcome types

Outcome MDR-TB&DM MDR-TB p

n = 34 (P%) n = 85 (P%)

Successfully treated 20 (58.8%) 66 (77.6%) <0.05

Died 6 (17.5%) 3 (3.5%) >0.05

Lost to follow-up 5 (14.7%) 8 (9.4%) >0.05

Failure 3 (8.8%) 5 (5.8%) >0.05

Considering all above exposed data it was established that the most relevant general and biological characteristics of the pulmonary MDR-TB patients associated with diabetes mellitus were old age and comorbid state. They were more frequently divorced or widowed and were detected by active screening according to the national recommendations (tab. 8).

The most relevant social-economic characteristics of the pulmonary MDR-TB patients were economical disadvan-taged state, low living conditions, single civil state and life history of imprisonment. They were more frequently detec-

Table 8

Odds Ratio assessing factors associated with diabetes mellitus and MDR-TB in patients with Xpert MBT/Rif resistant results

Factors Odds Ratio

Old age (more than 55) 11.2 (95% CI: 5.8-60), p<0.001

Comorbid state 45 (95% CI: 42-48), p<0.001

Detected by active screening 11.2 (95% CI:11.7-11.4),p<0.05

Divorced or widowed 1. (95% CI: 1.16-1.3), p<0.05

ted as to symptomatic cases and were directly addressedto the specialised hospital. Despite the low social-economic state and late detection associated with the passive way of detection they had a high treatment success, demonstrating the strong impact on the disease outcome of the diabetes mellitus (tab. 9).

Table 9

Odds Ratio assessing factors associated with MDR-TB in patients with Xpert MBT/Rif resistant results

Factors Relative Risk

History of imprisonment 5.6 (95% CI: 5.3-5.9), p<0.05

Economicaly disadvantaged state (unemployment) 5.12 (95% CI: 2.9-13.6), p<0.001

Low living conditions 2.5 (95% CI: 1.5-3.8), p<0.001

Single-civil state 3.9 (95% CI: 3.7-4.1), p<0.01

Detected as symptomatic case 4.2 (95% CI: 4.1-4.3), p<0.001

Detected by addressing to the specialized hospital 5.3 (95% CI: 4.9-5.7), p<0.05

Successfully treated 1.3 (95% CI: 1.25-1.37), p<0.05

Discussion

Association of tuberculosis and diabetes represents an epidemiological challenge and important problem for the health system in the Republic of Moldova. It was established that the tuberculosis prevalence rate among patients with diabetes is 1.8-9.5 times higher than in the general population [48].

In the Republic of Moldova 12.3% of the population have diabetes or reduced tolerance to glucose and 409 patients died due to diabetic complications in 2015 [7]. Since the tuberculosis incidence in the Republic of Moldova slowly decreased, the rate of MDR-TB increased. MDR-TB represents another serious threat to the global disease control. In clinical study was established a strong association between the risk factors and MDR-TB. There are several risk factors which increase the risk for MDR-TB in patients with diabetes: previous treatment, young age, HIV associated infection, smoking, alcohol and other substances abuse [14]. Some clinical studies denoted a high rate (10-23%) of MDR-TB among patients with diabetes [15, 20, 40, 42]. Other cited factors were: HIV co-infection, age older than 45, overweight, and male sex [13, 20].

If tuberculosis is detected earlier a more favorable outcome can be achieved. A severe course of tuberculosis with

a tendency to the rapid progression and lung parenchyma destruction occurs mainly in patients with untreated diabetes mellitus or in late detected tuberculosis [6].

Our study demonstrated a strong influence of diabetes on tuberculosis outcome. Obtained results were similar to other studies, which determined a high rate of failure and death among patients with tuberculosis and diabetes [5, 10, 24, 29, 38]. Poor treatment outcomes could be explained by the co-morbidities such as diabetes, HIV infection, and social determinants of health (unemployment, educational level, income distribution, social vulnerability, health services accessibility) [10]. Nowadays, in the Republic of Moldova the global prevalence of tuberculosis among patients with diabetes is high and reflects the general epidemiologi-cal situation.

Conclusions

The treatment success rate among patients with drug resistant tuberculosis and diabetes was low due to following contributing factors: old age and comorbid state.

More frequently patients with drug resistant tuberculosis and diabetes were detected by active screening and had a civil unfavorable state (divorced and widowed), associated with old age.

References

1. Alisjahbana B, Sahiratmadja E, Nelwan E J, et al. The effect of type 2 diabetes mellitus on the presentation and treatment response of pulmonary tuberculosis. Clinical Infectious Diseases. 2007;45(4):428-35.

2. Alisjahbana B, van Crevel R, Sahiratmadja E, den Heijer M, Maya A. Diabetes mellitus is strongly associated with tuberculosis in Indonesia. Int J Tuberc Lung Dis. 2006;10(6):696-700.

3. Baghaei P, Marjani M, Javanmard P, et al. Diabetes mellitus and tuberculosis facts and controversies. J Diabetes Metab Disord. 2013;12(1):58. doi: 10.1186/2251-6581-12-58

4. Baker MA, Harries AD, Jeon CY, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Medicine. 2011;9:81. doi: 10.1186/1741-7015-9-81.

5. Bacchetti P, Gripshover B, Grunfeld C, Heymsfield S, et al. Study of fat redistribution and metabolic change in HIV infection (FRAM). J Acquir Immune Defic Syndr. 2005;40:119-20.

6. Beyrer C. HIV epidemiology update and transmission factors: risks and risk contexts. 16th International AIDS Conference epidemiology plenary. Clin Infect Dis. 2007;44(7):981-7.

7. Centrul National de Management in Sanatate [National Center for Health Management]. Indicatori preliminari privind sânâtatea po-pulatiei si activitatea institutiilor medico-sanitare pe anii 2016-2017 [Preliminary indices on the health of the population and activity of the medical sanitary institutions for 2016-2017]. Chisinau: The Center; 2018, 218 p. Romanian.

8. Chang J-T, Dou H-Y, Yen C-L, et al. Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multidrug-resistance. J Formos Med Assoc. 2011;110(6):372-81. doi: 10.1016/ s0929-6646(11)60055-7.

9. Chao W-C, Yen C-L, Wu Y-H, et al. Increased resisting may suppress reactive oxygen species production and inflame some activation in type 2 diabetic patients with pulmonary tuberculosis infection. Microbes Infect. 2015;17(3):195-204. doi: 10.1016/j.micinf.2014.11.009.

10. Pizzol D, Di Gennaro F, Chhaganlal K, et al. Prevalence of diabetes mellitus in newly diagnosed pulmonary tuberculosis in Beira, Mozambique. Afr Health Sci. 2017 Sep;17(3):773-9.

11. Diedrich R, O'Hern J, Wilkinson J. HIV-1 and the M. tuberculosis granuloma: a systematic review and meta-analysis. Tuberculosis. 2016;98:62-76. doi: 10.1016/j.tube.2016.02.010.

12. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009;9(12):737-46. doi: 10.1016/S1473-3099(09)70282-8.

13. Faurholt-Jepsen D, Range N, PrayGod G. The role of anthropometric and other predictors for diabetes among urban Tanzanians with tuberculosis. Int J Tuberc Lung Dis. 2012;16(12):1680-5. doi: 10.5588/ ijtld.12.0360.

14. Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax. 2006 Feb;61(2):158-63.

15. Garcia F, Solis J, Calderon J, Luque E, Zacarias E. Prevalence of diabetes mellitus and related risk factors in an urban population. Revista de la Sociedad Peruana de Medicina Interna. 2007;20:90-4.

16. Gupta KB, Gupta R, Atreja A, Verma M, Vishvkarma S. Tuberculosis and nutrition. Lung India. 2009;26(1):9-16. doi: 10.4103/09702113.45198.

17. Idris I, Donnelly R. Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug. Diabetes Obes Metab. 2007;9(2): 153-65. doi: 10.1111/j.1463-1326.2007.00705.x.

18. Jabbar A, Hussain SF, Khan AA. Clinical characteristics of pulmonary tuberculosis in adult Pakistani patients with co-existing diabetes mellitus. East Mediterr Health J. 2006;12(5):522-7.

19. Jee SH, Golub JE, Jo J, Park IS, Ohrr H, Samet JM. Smoking and risk of tuberculosis incidence, mortality, and recurrence in South Korean men and women. Am J Epidemiol. 2009;170(12):1478-85. doi: 10.1093/ aje/kwp308.

20. Kibirige D, Ssekitoleko R, Mutebi E. Overt diabetes mellitus among newly diagnosed Ugandan tuberculosis patients: a cross sectional study. BMC Infect Dis. 2013;13:122. doi: 10.1186/1471-2334-13-122.

21. Kumari P, Meena LS. Factors affecting susceptibility to M. tuberculosis: a close view of immunological defence mechanism. Appl Biochem Biotechnol. 2014;174(8):2663-73. doi: 10.1007/s12010-014-1217-3.

22. Lachmandas E, van den Heuvel CN, Damen MS, Cleophas MC, et al. Diabetes mellitus and increased tuberculosis susceptibility: the role of short-chain fatty acids. J Diabetes Res. 2016;2016:15. doi: 10.1155/2016/6014631.6014631

23. Lagman M, Ly J, Saing T, et al. Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One. 2015;10(3). doi: 10.1371/journal.pone.0118436.e0118436

24. Leung CC, et al. Lower risk of tuberculosis in obesity. Arch Intern Med. 2007;167(12):1297-304. doi: 10.1001/archinte.167.12.1297.

25. Lonnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Soc Sci Med. 2009;68(12): 2240-6.

26. Lopez N, Gonzalez-Curiel I, Castaneda-Delgado J, et al. Vitamin D supplementation promotes macrophages' anti-mycobacterial activity in type 2 diabetes mellitus patients with low vitamin D receptor expression. Microbes Infect. 2014;16(9):755-61. doi: 10.1016/j. micinf.2014.06.010.

27. Madsbad S. Treatment of type 2 diabetes with incretin-based therapies. Lancet. 2009;373(9662):438-9. doi: 10.1016/S0140-6736(08)61247-7.

28. Magee MJ, Kempker RR, Kipiani M, et al. Diabetes mellitus is associated with cavities, smear grade, and multidrug-resistant tuberculosis in Georgia. Int J Tuberc Lung Dis. 2015;19(6):685-92. doi: 10.5588/ ijtld.14.0811.

29. Mi F, et al. Diabetes mellitus and tuberculosis: pattern of tuberculosis, two-month smear conversion and treatment outcomes in Guangzhou, China. Trop Med Int Health. 2013;18(11):1379-85. doi: 10.1111/ tmi.12198.

30. Muller LM, Gorter KJ, Hak E, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005;41(3):281-8. doi: 10.1086/431587.

31. Narasimhan P, Wood J, Macintyre CR, Mathai D. Risk factors for tuberculosis. Pulm Med. 2013;2013:11. doi: 10.1155/2013/828939.828939

32. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis. 2006;43(7):848-54. doi: 10.1086/507543.

33. O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. The immune response in tuberculosis. Annu Rev Immunol. 2013;31:475-527.

34. Ottenhoff TH, Verreck FA, Hoeve MA, van de Vosse E. Control of human host immunity to mycobacteria. Tuberculosis. 2005;85(1-2):53-64. doi: 10.1016/j.tube.2004.09.011.

35. Baghaei P, Marjani M, Javanmard P, Tabarsi P, Masjedi MR. Diabetes mellitus and tuberculosis facts and controversies. J Diabetes Metab Disord. 2013;12(1):58.

36. Pathak R, Mishra K, Moonan K, et al. Can intensified tuberculosis case finding efforts at nutrition rehabilitation centers lead to pediatric case detection in Bihar, India? J Tuberc Res. 2016;4(1):46-54. doi: 10.4236/ jtr.2016.41006.

37. Liu Q, Li W, Xue M, Chen Y, et al. Diabetes mellitus and the risk of multidrug-resistant tuberculosis: a meta-analysis. Sci Rep. 2017;7:1090.

38. Rasanathan K, Sivasankara Kurup A, Jaramillo E, Lönnroth K. The social determinants of health: key to global tuberculosis control. Int J Tuberc Lung Dis. 2011 Jun;15 Suppl 2:30-36.

39. Restrepo BI, Schlesinger LS. Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus. Tuberculosis. 2013;93 Suppl:S10-4. doi: 10.1016/S1472-9792(13)70004-0.

40. Singh R, Gothi D, Joshi J. Multidrug resistant tuberculosis: role of previous treatment with second line therapy on treatment outcome. Lung India. 2007;24:54-7. doi: 10.4103/0970-2113.44204.

41. Singla R, Khan N, Al-Sharif N, Ai-Sayegh MO, Shaikh MA, Osman MM. Influence of diabetes on manifestations and treatment outcome of pulmonary TB patients. Int J Tuberc Lung Dis. 2006;10(1):74-9.

42. Tanrikulu AC, Hosoglu S, Ozekinci T, Abakay A, Gurkan F. Risk factors for drug resistant tuberculosis in southeast Turkey. Trop Doct. 2008;38(2):91-3. doi: 10.1258/td.2007.070131.

43. Trinh QM, Nguyen HL, Nguyen VN, Nguyen TV, et al. Tuberculosis and HIV co-infection-focus on the Asia-Pacific region. Int J Infect Dis. 2015;32:170-8. doi: 10.1016/j.ijid.2014.11.023.

44. Webb EA, Hesseling AC, Schaaf HS, et al. High prevalence of Mycobac-terium tuberculosis infection and disease in children and adolescents with type 1 diabetes mellitus. Int J Tuberc Lung Dis. 2009;13(7):868-74.

45. World Health Organization. Fact sheet on tuberculosis [Internet]. Geneva: WHO; 2016 [cited 2017 Oct 16]. Available from: http://www. who.int/tb/publications/factsheets/en/

46. World Health Organization. Global tuberculosis report 2016 [Internet]. Geneva: WHO; 2016 [cited 2017 Oct 16]. Available from: http://apps. who.int/medicinedocs/documents/s23098en/s23098en.pdf

47. World Health Organization. Treatment guidelines for drug-resistant tuberculosis, 2016 update [Internet]. Geneva: WHO; 2016 [cited 2017 Oct 16]. Available from: http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/

48. Zheng C, Hu M, Gao F. Diabetes and pulmonary tuberculosis: a global overview with special focus on the situation in Asian countries with high TB-DM burden. Glob Health Action. 2017;10(1):1-11. doi: 10.1080/16549716.2016.1264702.

49. Zozulinska D, Majchrzak A, Sobieska M, Wiktorowicz K, Wierusz-Wysocka B. Serum interleukin-8 level is increased in diabetic patients. Diabetologia. 1999;42(1):117-8. doi: 10.1007/s001250051124.