TBC 001: Research Needs and Patient Care Recommendations

• TB and Cardiovascular Risk: A diagnosis of TB is linked to a higher risk of cardiovascular diseases (CVD), such as acute myocardial infarction and stroke. This relationship is influenced by factors like older age, male gender, and pre-existing chronic non-communicable diseases (NCDs).
• TB Treatment Duration and NCD Risk: The overall duration of TB treatment doesn't typically predict NCD occurrence; however, patients treated for 7–12 months exhibit higher NCD incidences than those treated for six months or less.
• Physiological Mechanisms: TB can increase blood glucose levels and induce hyperglycemia or diabetes mellitus (DM) through mechanisms involving stress, pro-inflammatory cytokines, and metabolic disturbances. Chronic TB infection is also a recognized risk factor for developing NCDs.
• Impact of TB on Lipid Metabolism and Lung Health: Active TB affects lipid levels, typically reducing cholesterol which may influence susceptibility to TB and immune response. Post-TB lung damage often results in conditions like chronic bronchitis and fibrosis, increasing chronic lung disease burden.
• Research Needs and Patient Care Recommendations: Given TB's association with increased CVD risk, TB programs should include cardiovascular health assessments. More research is required to understand TB's impact on metabolism and its complex relationship with DM. Proper research designs are essential to distinguish TB's direct and indirect effects on cardiovascular health.
• Effective Glycemic Control and TB Management: Effective glycemic control is emphasized as crucial for improving TB treatment outcomes and reducing transmission risks, particularly in diabetic patients.
• Diagnostic Delays and Screening Improvements: Many TB cases are not identified promptly, leading to delays in treatment. Improved diagnostic models incorporating additional information beyond WHO recommendations could enhance screening accuracy, especially in high TB burden, low-resource settings. A low-cost, applicable TB risk score is needed to replace or supplement the current WHO symptom screen.
• Challenges and Future of TB Control: The incidence and mortality reductions for tuberculosis are expected to be slow, and current targets for 2025 are unlikely to be met with passive surveillance alone. Active and enhanced surveillance could accelerate declines, but benefits are uncertain without new vaccines or prophylactic treatments for latent infections.
• Multidrug-Resistant Tuberculosis (MDR TB): MDR TB often results from person-to-person transmission. Reducing MDR TB could be achieved by improving treatment of drug-susceptible TB and enhancing MDR TB diagnosis and treatment. Improved prediction models for MDR TB using factors like age, history of TB treatment, and HIV status could lead to earlier diagnosis and better management.
• Chronic Kidney Disease (CKD) and TB Risk: The increasing global burden of CKD highlights its correlation with TB. Advanced CKD stages bring higher comorbidity rates and increased TB risk, particularly from stage 3 onwards. TB prevention should target CKD patients at stage 3 or higher, following WHO guidelines for active LTBI screening.
• Diabetes and TB Risk: Diabetes increases the risk of active TB and is linked to higher rates of treatment failure, relapse, and mortality. Poor glycemic control further elevates TB risk. Effective management of diabetes, including early detection and bi-directional screening for DM and TB, could significantly reduce TB cases and improve overall public health outcomes.
• TB and Diabetes Mellitus (DM) Relationship: Diabetes increases the risk of developing active tuberculosis (TB), contributes to worse clinical outcomes including higher rates of treatment failure, relapse, and death, and has a similar impact on active TB cases as HIV/AIDS. This is particularly significant as the prevalence of DM is rising fastest in low- and middle-income countries with high TB burdens.
• Epidemiology and Control of TB: Progress in reducing TB incidence and mortality is slow, with many regions unlikely to meet current targets by 2025 using passive surveillance alone. Enhanced surveillance strategies, possibly including new vaccines or prophylactic treatments for latent infections, might be necessary to achieve future reductions in TB incidence and mortality.
• Challenges in TB and DM Co-management: The coexistence of TB and DM poses significant challenges, exacerbated by limited resources for research and treatment programs. There is a critical need for large-scale clinical trials to find better treatment and management methods for patients with both conditions.
• TB Control Among the Elderly: As countries approach TB elimination goals, focusing control measures on the elderly is crucial due to their higher risk of developing active TB, largely due to immune senescence. This demographic often experiences TB that rarely spreads to younger populations due to age-specific social interactions.
• BCG Vaccination and TB Control: While the immunity provided by the BCG vaccine may wane over time, particularly affecting the elderly, the discontinuation of BCG could increase TB burden, especially in regions with high vaccine efficacy. Selective vaccination strategies might be more appropriate than complete cessation.
• Obesity and Tuberculosis Paradox: Despite the link between obesity (high BMI), diabetes, and increased TB risk, epidemiological data show that higher BMI is associated with a reduced risk of TB. This protective effect is dominant over the harmful effects mediated through diabetes, illustrating complex interactions between obesity, diabetes, and TB risk.
• Local Epidemiology and TB Control: Effective TB control requires an adaptive approach tailored to local epidemiology. In low- and moderate-incidence countries, the TB burden is increasingly concentrated among the elderly, except in the migrant population, and in specific high-risk and vulnerable groups in moderate-to-low burden settings.
• Social Determinants and TB Risk: There is growing interest in the role of social determinants and risk factors in TB epidemiology. Understanding these factors is crucial for designing effective prevention and control strategies that address both direct and indirect effects of conditions like DM on TB incidence.
• Challenges in TB and Diabetes Co-Management: TB and diabetes are typically treated in separate facilities, presenting a significant challenge in low- and middle-income countries (LMICs). This separation complicates comprehensive care for patients suffering from both conditions.
• Financial Barriers and Incentives: Financial constraints are a major barrier to effective diabetes management, especially due to the loss of employment during TB treatment and the costs associated with diabetes medications. Financial incentives, such as participation allowances, can play a crucial role in encouraging self-care and improving glycemic control outcomes.
• Health Education and Support: Providing health education about diabetes management through TB programs has shown benefits but requires further enhancement with additional supportive resources. There is also a need for culturally appropriate messaging, including information on the use of phytotherapies.
• Internet and Community Resources: Due to the lack of adequate resources in TB-DOTS programs, many individuals turn to the internet and community for diabetes management information, indicating a gap in the current healthcare provision.
• Integrated Monitoring and Management: TB programs should integrate diabetes monitoring and management, particularly for patients with previously diagnosed or advanced diabetes, to mitigate the risk of catastrophic health costs associated with diabetes during TB treatment.
• Latent Tuberculosis Infection (LTBI) Management: LTBI treatment, aimed at preventing the progression to active TB, is particularly recommended in low TB-burden countries for high-risk groups such as people living with HIV, contacts of TB cases, patients on certain medical treatments, and those with specific health conditions like silicosis.
• Diabetes and LTBI Risk: Studies provide mixed results on the risk of LTBI in diabetics, with a cohort study indicating a non-significant increased risk, while cross-sectional studies suggest a modest pooled odds ratio, indicating a limited benefit from targeting diabetics for LTBI screening exclusively.
• Socioeconomic Status and TB Exposure: Lower socioeconomic status, common among diabetics, may increase TB exposure due to network dynamics, emphasizing the need for targeted preventive measures in these populations.

References:

1.????????????? Salindri, A.D., Wang, J.Y., Lin, H.H. and Magee, M.J., 2019. Post-tuberculosis incidence of diabetes, myocardial infarction, and stroke: retrospective cohort analysis of patients formerly treated for tuberculosis in Taiwan, 2002–2013. International Journal of Infectious Diseases, 84, pp.127-130.

2.????????????? Basham CA, Smith SJ, Romanowski K, Johnston JC (2020). Cardiovascular morbidity and mortality among persons diagnosed with tuberculosis: A systematic review and meta-analysis. PLoS ONE, 15(7), e0235821.

3.????????????? Magee, M.J., Salindri, A.D., Gujral, U.P., Auld, S.C., Bao, J., Haw, J.S., Lin, H.H. and Kornfeld, H., 2018. Convergence of non-communicable diseases and tuberculosis: a two-way street?. The International Journal of Tuberculosis and Lung Disease, 22(11), pp.1258-1268.

4.????????????? Ko, T.H., Chang, Y.C., Chang, C.H., Liao, K.C.W., Magee, M.J. and Lin, H.H., 2023. Prediabetes and risk of active tuberculosis: a cohort study from Northern Taiwan. International Journal of Epidemiology, 52(3), pp.932-941.

5.????????????? Lee P-H, Fu H, Lai T-C, Chiang C-Y, Chan C-C, Lin H-H (2016) Glycemic Control and the Risk of Tuberculosis: A Cohort Study. PLoS Med 13(8): e1002072.

6.????????????? Chiang CY, Bai KJ, Lin HH, Chien ST, Lee JJ, Enarson DA, et al. (2015) The Influence of Diabetes, Glycemic Control, and Diabetes-Related Comorbidities on Pulmonary Tuberculosis. PLoS ONE 10(3): e0121698.

7.????????????? Van Wyk, S.S., Lin, H.H. and Claassens, M.M., 2017. A systematic review of prediction models for prevalent pulmonary tuberculosis in adults. The International Journal of Tuberculosis and Lung Disease, 21(4), pp.405-411.

8.????????????? Shu, CC., Wei, YF., Yeh, YC. et al. The impact on incident tuberculosis by kidney function impairment status: analysis of severity relationship. Respir Res 21, 51 (2020).

9.????????????? Lin, H.H., Wang, L., Zhang, H., Ruan, Y., Chin, D.P. and Dye, C., 2015. Tuberculosis control in China: use of modelling to develop targets and policies. Bulletin of the World Health Organization, 93, pp.790-798.

10.?????????? Lin HH, Shin SS, Contreras C, Asencios L, Paciorek CJ, Cohen T. Use of spatial information to predict multidrug resistance in tuberculosis patients, Peru. Emerg Infect Dis. 2012 May;18(5):811-3.

11.?????????? Bao, J., Hafner, R., Lin, Y., Lin, H.H. and Magee, M.J., 2018. Curbing the tuberculosis and diabetes co-epidemic: strategies for the integration of clinical care and research. The International Journal of Tuberculosis and Lung Disease, 22(10), pp.1111-1112.

12.?????????? Fu, H., Lin, HH., Hallett, T.B. et al. Explaining age disparities in tuberculosis burden in Taiwan: a modelling study. BMC Infect Dis 20, 191 (2020).

13.?????????? Fu, H., Lin, H.H., Hallett, T.B. and Arinaminpathy, N., 2018. Modelling the effect of discontinuing universal Bacillus Calmette-Guérin vaccination in an intermediate tuberculosis burden setting. Vaccine, 36(39), pp.5902-5909.

14.?????????? Lin, H.H., Wu, C.Y., Wang, C.H., Fu, H., L?nnroth, K., Chang, Y.C. and Huang, Y.T., 2018. Association of obesity, diabetes, and risk of tuberculosis: two population-based cohorts. Clinical Infectious Diseases, 66(5), pp.699-705.

15.?????????? Lee, P.H., Fu, H., Lee, M.R., Magee, M. and Lin, H.H., 2018. Tuberculosis and diabetes in low and moderate tuberculosis incidence countries. The International Journal of Tuberculosis and Lung Disease, 22(1), pp.7-16.

16.?????????? Lee, M.R., Huang, Y.P., Kuo, Y.T., Luo, C.H., Shih, Y.J., Shu, C.C., Wang, J.Y., Ko, J.C., Yu, C.J. and Lin, H.H., 2017. Diabetes mellitus and latent tuberculosis infection: a systemic review and metaanalysis. Clinical Infectious Diseases, 64(6), pp.719-727.

17.?????????? Oliveira Hashiguchi, L., Cox, S.E., Edwards, T. et al. How can tuberculosis services better support patients with a diabetes co-morbidity? A mixed methods study in the Philippines. BMC Health Serv Res 23, 1027 (2023).