Latent TB Infection among Diabetic patients Soe Thiha, Ne Myo Aung, Zaw Myint, Tin Tin Mar, Mar Mar Kyi, Myo Lwin Nyein and Mon Mon Aung

Funding Departmental Research Conducted with the grant from Department of Medical Research Myanmar

Background Treatment of latent tuberculosis – measure to reduce TB burden High risk population should be targeted Diabetes Mellitus is associated with impaired immune function So, latent TB can easily be converted to active TB Burden of latent TB among diabetes?? Nathella PK and Babu S, Immunology, 2017

Method Aim – to determine the proportion of latent TB infection in diabetic patients and their characteristics Study Area – Medical ward of Insein General Hospital

Inclusion Criteria Exclusion Criteria – all patients who provided consent. Having previous Mantoux testing Having active TB infection or previous known TB infection Receiving immunoglobulin or corticosteroid or immunosuppressant Having chemotherapy for cancer Having HIV infection Pregnancy

The participants were asked with preformed questionnaire for their risk of tuberculosis and state of diabetic control and treatment The clinical characteristics (socio-demographic characteristics, medical history, diabetic control) of these patients were determined All the participants were done blood test to measure HbA1C level. If HbA1C ≥ 6.5% or there was history of diabetes, the participants were collected as diabetes group If HbA1C < 6.5% and there was no history of treating diabetes, these participants were collected as control group.

Tuberculin was injected intradermally at the fore-arm of all participants and read the result (induration) after 48 - 72 hours If the reaction (induration) was more than or equal to 10 mm, it was defined as latent TB The possible TB risk factors were statistically analysed for any association for latent TB

All hospitalized patients who meet inclusion criteria Exclude by exclusion criteria History taking and Physical Examination HbA1C level DM group Control group Tuberculin skin test Tuberculin skin test LTBI present LTBI present LTBI not present LTBI not present Compare clinical and socio-demographic profiles

Results 134 cases of diabetic cases and 194 cases of non-diabetic cases (as control) were tested for tuberculin test after screening for active TB

In diabetes group New diagnosed diabetes comprised for 43% (58/134) The mean duration of disease in previously diagnosed diabetes mellitus was 7 years Among the diabetes, cases with controlled diabetes (HbA1c less than 7) accounted for 12% (16/134)

Fifty four percent (73/134) of diabetic cases were found to have latent TB infection.

Diabetes mellitus increased the risk of latent TB infection by an odd ratio of 2.6 (95% CI 1.6 to 4.1) Diabetes mellitus (n=134) No diabetes (n= 194) LTBI (positive tuberculin) 73 61 No LTBI 133 54% vs 31% p value < 0.00001

In Diabetic Cases LTBI N = 73 No LTBI N = 62 p value Household member Mean (number) 6.5 (SD 2) 4.7 (SD 1.5) 0.011 TB Contact (percent) 68 15 < 0.00001 Family member with high risk of TB (percent) 60 8 Active Smoking (percent) 64 34 0.00005

In Diabetic Cases LTBI N = 73 No LTBI N = 62 p value Recently Diagnosed DM (percent) 51 65 0.08 DM Duration (mean) (in years) 3.5 (SD 5.3) 4.6 (SD 5.7) 0.7 HbA1c (mean) 9.4 (SD 1.6) 8.8 (SD 1.6) 0.5 Presence of BCG Scar (percent) 78 85 0.2

In Diabetic Cases LTBI N = 73 No LTBI N = 62 p value Low BMI (< 18.5) (percent) 4 5 0.8 High BMI (> 30) 57 43 0.08 Waist circumference (cm) (mean) 88.5 (SD 17.2) 81.4 (SD 16.3) 0.3

Discussion Diabetes mellitus predisposes to tuberculosis Early clearance (immediate removal of Mycobacterium tuberculosis soon after infection) was impaired in diabetic due to hypo-reactive alveolar macrophages, which causes persistent infection So, diabetes are more likely to get latent TB infection. Nathella PK and Babu S, Immunology, 2017

T-helper cell response and subsequent cytokines responses are impaired in diabetics resulting in more conversion of latent TB to active TB infection So, diabetes is high risk not only for getting latent tuberculosis but also for conversion of latent to active tuberculosis Nathella PK and Babu S, Immunology, 2017

These cases were increased risk of developing active TB In a study in Indonesia, the prevalence of latent TB in diabetics was 38.9% These cases were increased risk of developing active TB In this study the incidence of latent TB in diabetes was 54% Therefore it was significantly higher incidence of latent TB in the study area than in Bandung, Indonesia Koseomadinata RC, McAllister AM, Soetejoe NNM, et., al, Transaction Royal Society of Tropical Medicine and Hygiene, 2017

The risk is the same for acquisition of TB In a meta-analysis involving 13 studies, it was found that diabetes mellitus was significantly associated with risk of latent TB The risk is amplified if the patient resided or came from the community with high burden of TB There was an increased risk of latent TB infection among smokers and those with contact history of tuberculosis The risk is the same for acquisition of TB Lee MR, Huang YP, Kuo YT, et. al. Clinical Infectious Diseases, 2017

It also supported the concept that diabetic patients had impaired early clearance of tuberculosis It is also found that diabetes mellitus increased the risk of latent TB infection by an odd ratio of 2.6 (95% CI 1.6 to 4.1) than non-diabetes (control group) in this study So, diabetes patients are more susceptible to get latent tuberculosis.

The duration of diabetes did not have significant effect on the increased risk of latent TB Glycemic control did not have significant effect on latent TB However it should be interpreted cautiously because the proportion of controlled diabetes was as low as 12%.

Conclusion This study points out that diabetic patients should be tested for latent TB infection particularly in those with contact history of TB and diabetic smokers

Recommendation As diabetes is high risk for getting latent tuberculosis, all diabetes patients should be screened and treated for latent tuberculosis In particularly, diabetes smokers, diabetes with TB contact, diabetes living with high risk person for getting TB Are very high risk for latent tuberculosis These diabetes should be screened and treated for latent tuberculosis

Acknowledgement Special thank to Department of Medical Research Myanmar National Tuberculosis Programme

References 1. Nathella PK and Babu S (2017) Influence of diabetes mellitus on immunity to human tuberculosis, Immunology, 152; 13-24 2. Koseomadinata RC, McAllister AM, Soetejoe NNM, et. al. (2017) Latent TB infection and pulmonary TB disease among patients with diabetes mellitus in Bandung, Indonesia, Transaction Royal Society of Tropical Medicine and Hygiene; 111(2): 81-89 3. Lee MR, Huang YP, Kuo YT, et. al. (2017) Diabetes mellitus and latent TB infection: A systematic review and Meta-analysis; 64(6): 719-27

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