Addressing the Dual Burden of Type 2 DM and Pulmonary Tuberculosis

Patients with Type 2 Diabetes Mellitus (T2DM) and Pulmonary Tuberculosis (PTB) are at a higher risk of poor glycemic control, frequent infections, and unhealthy lifestyle behaviors such as smoking, alcohol use, and physical inactivity. Risk factors for having both conditions include lymphopenia, smoking, history of TB exposure, and poor glycemic control, while being overweight or obese appears to lower the risk of concurrent PTB in T2DM patients.

Diabetes is a recognized risk factor for tuberculosis (TB), and its role is emphasized in the global post-2015 TB strategy. However, collaboration between TB and diabetes programs is inadequate in most countries. Thirteen countries, including Afghanistan, China, India, and Indonesia, account for 60% of new TB cases worldwide. Stabilizing diabetes prevalence in these countries could reduce TB incidence by over 20% and mortality by nearly 43% by 2035, potentially preventing over 1 million TB deaths. However, the impact depends on factors like relapse rates and the effect of rising BMI, which can counteract diabetes' negative effects on TB.

The need for integration between communicable and non-communicable disease sectors is clear. Proposed strategies include bidirectional screening for diabetes and TB and adapting treatment frameworks like DOTS for non-communicable diseases in resource-limited areas.

On the diagnostic front, laboratories are better prepared to test resistance to established drugs like fluoroquinolones and linezolid than to newer drugs like bedaquiline, essential for multidrug-resistant TB (MDR-TB). Phenotypic drug susceptibility tests (pDSTs), requiring biosafety level 3 labs, are time-consuming but effective, though faster molecular tests like Xpert MTB/RIF and line probe assays (LPAs) are becoming more common. Whole-genome sequencing (WGS) is also being explored for its comprehensive resistance profiling, though it remains expensive and labor-intensive.

New methods like the Thin-Layer Agar method and QuantaMatrix Multiplexed Assay Platform show promise for drug resistance detection in low-resource settings. Advanced sequencing technologies such as the MinION platform offer cost-effective solutions, and emerging tools like MALDI-TOF are competing with WGS in the diagnostic space.

The rising prevalence of diabetes, particularly in middle- and low-income countries, poses a major challenge to TB control efforts. This trend is compounded by smoking, which remains a significant risk factor for TB, especially in countries like Pakistan. With over 80% of global TB cases concentrated in 30 countries, focused interventions are essential. England, with its low TB incidence, still faces disparities, particularly among foreign-born individuals and those with social risk factors like homelessness or substance abuse.

Preventing diabetes could significantly impact TB incidence and mortality, and coordinated public health strategies that address both diseases are urgently needed to achieve long-term control.

Sources:

1. Shi H, Yuan Y, Li X, Li YF, Fan L, Yang XM. Analysis of the influencing factors and clinical related characteristics of pulmonary tuberculosis in patients with type 2 diabetes mellitus. World J Diabetes 2024; 15(2): 196-208.
2. Pan, S.C., Ku, C.C., Kao, D., Ezzati, M., Fang, C.T. and Lin, H.H., 2015. Effect of diabetes on tuberculosis control in 13 countries with high tuberculosis: a modelling study. The lancet Diabetes & endocrinology, 3(5), pp.323-330. https://tbreadingnotes.blogspot.com/2024/07/effect-of-diabetes-on-tuberculosis.html
3. Sanchini, A., Lanni, A., Giannoni, F. and Mustazzolu, A., 2024. Exploring Diagnostic Methods for Drug-Resistant Tuberculosis: A Comprehensive Overview. Tuberculosis, p.102522. https://tbreadingnotes.blogspot.com/2024/09/exploring-diagnostic-methods-for-drug.html
4. Khalid N, Ahmad F, Qureshi FM. Association amid the comorbidity of Diabetes Mellitus in patients of Active Tuberculosis in Pakistan: A matched case control study. Pak J Med Sci. 2021;37(3):816-820.
5. Meghji, J., Kon, O.M. and Ainley, A., 2023. Clinical tuberculosis. Medicine, 51(11), pp.768-773. https://tbreadingnotes.blogspot.com/2024/08/clinical-tuberculosis.html

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Addressing TB Transmission and Complications in High-Risk Populations

• The proportion of individuals with dysglycemia (DM or pre-DM) did not differ significantly between those with favorable and unfavorable outcomes.
• Dysglycemia was more frequent in TB patients who experienced treatment failure or death.
• Individuals with favorable outcomes had lower HbA1c levels compared to those with treatment modification, treatment failure, or death.
• Among patients with unfavorable outcomes, those with treatment modification had lower HbA1c levels than those with treatment failure or death.
• Weight loss was more common in individuals with DM than those with pre-DM or normoglycemia.
• A higher proportion of TB patients with dysglycemia had a positive smear at baseline compared to those with normoglycemia.
• DM was independently associated with unfavorable TB treatment outcomes, but not pre-DM or dysglycemia overall.
• HbA1c values were independently linked to unfavorable TB outcomes.
• DMTB (Diabetes Mellitus with Tuberculosis) patients required significantly longer treatment for cure, completion, and sputum conversion.
• Compromised immune function due to diabetes leads to more severe infections, higher mycobacterial loads, higher treatment failure rates, and delayed mycobacterial clearance in DMTB patients.
• DMTB patients had a higher percentage of MDR-TB (Multi-Drug Resistant Tuberculosis) and were more likely to develop MDR-TB than TB-only patients.
• Pulmonary TB patients with type 2 diabetes may require a more intensive anti-TB regimen and careful follow-up for MDR-TB.
• The adapted tool to measure tuberculosis-related stigma in Indonesian workplaces is valid, reliable, and ready for broader external validation but may need refinement for rural areas and different cultural contexts.
• Mycobacterium tuberculosis, discovered by Robert Koch in 1882, spreads through air droplets released by infected individuals.
• Diagnostic methods like microscopy, culture, chest radiology, and the BCG vaccine have been available for over a century, and effective TB drugs since the 1950s.
• In 1995, WHO launched the DOTS strategy to diagnose and treat TB effectively.
• TB transmission is higher in high-incidence settings and among high-risk groups, but passive case finding is insufficient to reduce transmission; active case finding is essential.
• In high-incidence settings, most TB cases result from recent infections, while in low-incidence settings, TB arises from reactivation of old infections.
• Breaking the TB transmission chain requires measures like cough triage, respiratory isolation, improved ventilation, personal respiratory protection, and timely treatment.
• Ongoing TB transmission persists due to untreated, undiagnosed, or underreported infectious TB cases, exacerbated by limited access to TB services and misdiagnoses.
• Population-wide active case finding, supported by sensitive screening methods and political and community engagement, is crucial to control TB in high-incidence areas.

Sources:

1. Chang, J.T., Dou, H.Y., Yen, C.L., Wu, Y.H., Huang, R.M., Lin, H.J., Su, I.J. and Shieh, C.C., 2011. 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. Journal of the Formosan Medical Association, 110(6), pp.372-381.
2. Arriaga, M.B., Araújo-Pereira, M., Barreto-Duarte, B., Nogueira, B., Freire, M.V.C., Queiroz, A.T., Rodrigues, M.M., Rocha, M.S., Souza, A.B., Spener-Gomes, R. and Carvalho, A.C.C., 2022. The effect of diabetes and prediabetes on antituberculosis treatment outcomes: a multicenter prospective cohort study. The Journal of Infectious Diseases, 225(4), pp.617-626.
3. Soemarko, D.S., Halim, F.A., Kekalih, A., Yunus, F., Werdhani, R.A., Sugiharto, A., Mansyur, M., Wingfield, T. and Fuady, A., 2023. Developing a tool to measure tuberculosis-related stigma in workplaces in Indonesia: An internal validation study. SSM-Population Health, 21, p.101337.
4. Nguyen, T.A., Teo, A.K.J., Zhao, Y., Quelapio, M., Hill, J., Morishita, F., Marais, B.J. and Marks, G.B., 2024. Population-wide active case finding as a strategy to end TB. The Lancet regional health. Western Pacific, 46, p.101047.
5. Iskandar, D., Suwantika, A.A., Pradipta, I.S., Postma, M.J. and van Boven, J.F., 2023. Clinical and economic burden of drug-susceptible tuberculosis in Indonesia: national trends 2017–19. The Lancet Global Health, 11(1), pp.e117-e125.

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Decentralizing TB Services and Addressing TB-Diabetes Interactions

• Diagnosing tuberculosis (TB) in children is difficult due to challenges in collecting sputum samples and the paucibacillary nature of pediatric pulmonary TB.
• Alternative specimen collection methods like induced sputum and gastric aspirate require specialized equipment and trained personnel, often unavailable at primary health centers (PHCs) and sometimes even at district hospitals (DHs).
• Many children with TB symptoms do not receive appropriate diagnostic tests, even at the DH level.
• Stool samples are easier to collect in children and can be used to detect Mycobacterium tuberculosis through Xpert MTB/RIF testing.
• Nasopharyngeal aspirates (NPA) are easier to collect than gastric aspirates or induced sputum and, when combined with stool samples, offer similar sensitivity to Xpert MTB/RIF testing on gastric aspirates or induced sputum.
• Decentralizing pediatric TB services to DHs could be cost-effective in countries like Cambodia and Côte d’Ivoire, but decentralizing to PHCs is unlikely to be cost-effective in any country.
• Targeted decentralization to areas with high TB prevalence would likely be cost-effective in all countries.
• Decentralizing TB services to PHCs would require significant financial investment in the early stages, making the strategy more costly and less effective than the DH-focused approach due to the need for diagnostic equipment at more facilities and higher TB diagnosis rates at DHs.
• Higher TB diagnosis rates at DHs may be due to more severely ill children being brought to DHs or referred from PHCs with more advanced disease, and all children at DHs undergo chest X-rays (CXR), while only children with persistent symptoms after 7 days are referred for CXR at PHCs.
• The merging of diabetes and TB epidemics is most notable in South-East Asia, the Western Pacific, and the Middle East, where diabetes is highly prevalent, and while global TB rates are declining, diabetes prevalence is increasing due to obesity and ageing populations.
• In TB patients, diabetes increases the risk of mortality, treatment failure, and TB relapse, as high glucose conditions impair the immune response.
• Active TB induces insulin resistance, causing impaired glucose tolerance (IGT) in non-diabetic individuals, and 'stress-induced hyperglycaemia' resolves with TB treatment but signals a higher long-term risk of developing type 2 diabetes (T2D).
• Poorly controlled diabetes increases the risk of microvascular complications, including diabetic kidney disease (DKD), and in CKD patients, compromised immunity raises hospitalization and mortality risks as eGFR declines.
• In New Zealand, diabetic nephropathy is the leading cause of CKD, with diabetic kidney disease accounting for about half of all dialysis patients, but assessing the correlation between renal failure and diabetes is challenging due to unreliable HbA1c markers in CKD patients.
• TB-DM patients show higher HbA1c levels (10.47%) and elevated vitamin B12 levels compared to DM patients (8.17%), with the TB-DM group having more anemia, cardiovascular disease, and poor glycemic control.
• Nutritional deficiencies such as low serum albumin and vitamin D deficiency are more common in the TB-DM group, though these are not statistically significant.
• Recurrence of active TB can result from relapse or reinfection, and retreatment patients, who often use TB medications irregularly, have lower cure rates and experience more side effects.
• TB retreatment is associated with the presence of diabetes, higher HbA1c levels, and multiple previous TB episodes, with diabetic patients being at higher risk of retreatment.
• Social network analysis (SNA), enhanced by ethnographic data, offers valuable insights into TB transmission dynamics, as social contact intensity may increase TB exposure, an overlooked factor in conventional models, contributing to persistent latent TB infections despite interventions.

Sources:

1. d'Elbée, M., Harker, M., Mafirakureva, N., Nanfuka, M., Nguyet, M.H.T.N., Taguebue, J.V., Moh, R., Khosa, C., Mustapha, A., Mwanga-Amumpere, J. and Borand, L., 2024. Cost-effectiveness and budget impact of decentralising childhood tuberculosis diagnosis in six high tuberculosis incidence countries: a mathematical modelling study. EClinicalMedicine, 70, p.102528.
2. Kaur, R., Egli, T., Paynter, J., Murphy, R., Perumal, L., Lee, A., Harrison, A., Christmas, T., Lewis, C. and Nisbet, M., 2023. Tuberculosis and diabetes: increased hospitalisations and mortality associated with renal impairment. Internal Medicine Journal, 53(9), pp.1588-1594.
3. Patel, D.G., Baral, T., Kurian, S.J., Malakapogu, P., Saravu, K. and Miraj, S.S., 2024. Nutritional status in patients with tuberculosis and diabetes mellitus: A comparative observational study. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 35, p.100428.
4. Habib, M.A., Afrin, K., Efa, S.S., Hossain, M.D., Islam, M.R., Rahman, M.M., Islam, N., Afroz, F., Rahim, M.A. and Hossain, M.D., 2024. Effects of diabetes mellitus on retreatment of Tuberculosis: A multi-centered case-control study from Bangladesh. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 36, p.100450.
5. Pando, C., Hazel, A., Tsang, L.Y., Razafindrina, K., Andriamiadanarivo, A., Rabetombosoa, R.M., Ambinintsoa, I., Sadananda, G., Small, P.M., Knoblauch, A.M. and Rakotosamimanana, N., 2023. A social network analysis model approach to understand tuberculosis transmission in remote rural Madagascar. BMC Public Health, 23(1), p.1511.

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The Role of Smoking, Diabetes, and New Diagnostic Tools

Smoking and Tuberculosis (TB) Risk

• Current smoking is linked to a twofold increase in active TB risk compared to never-smokers, with risk increasing based on the number of cigarettes, years of smoking, and pack-years.
• Smoking accounts for 17% of TB cases in the studied population, emphasizing its role in TB incidence.
• Current smokers have a higher TB risk than former smokers, indicating reduced hazard among those who quit.
• The smoking-related TB risk is higher in individuals under 65, potentially due to early depletion of susceptible populations among older smokers.
• Smoking weakens key pulmonary defense mechanisms, making individuals more susceptible to TB upon exposure.

Diagnostic and Treatment Challenges in Drug-Resistant TB (DR-TB)

• Low Case Identification and Diagnosis: Only about a third of estimated DR-TB cases were identified and reported, with just a tenth of true cases diagnosed.
• Inadequate Diagnostic Support: Approximately half of the treatment regimens were backed by phenotypic drug susceptibility testing (pDST).
• High Unsuccessful Treatment Outcomes: Nearly half of patients initiating treatment had unsuccessful outcomes.
• Significant Delays in Treatment: Notable delays between diagnosis and treatment, especially for those living further away, employed individuals, and those with private sector engagement.
• Impact of Undetected DR-TB: Undetected DR-TB contributes to ongoing transmission, complicating global efforts to eliminate TB. Increased testing and treatment may strain health systems.
• Potential of Active Case Finding: Active case finding is cost-effective when integrated into a national TB program, aiding in the detection of DR-TB, especially new cases.
• Challenges in Urban Settings: In urban areas of Indonesia, delays and losses in DR-TB case finding, pDST testing, and treatment outcomes are prevalent. Improving diagnostic access and patient care linkages could reduce transmission.

New Diagnostic Tools for TB

• Accelerated Decline in TB Burden: A new diagnostic tool is expected to reduce pulmonary TB burden more rapidly than reliance on smear microscopy.
• Influence of Contextual Factors: The tool's impact on TB epidemiology is significantly affected by non-performance-related contextual factors.
• Greatest Impact in Certain Settings: The tool has the most impact in areas with good access to care but low-sensitivity diagnostic strategies.
• Lesser Impact in Equipped Laboratories: The tool's population-level impact may be reduced in reference labs with existing sensitive diagnostic tools, like cultures.
• Increased Patient Trust: A new diagnostic test can enhance patient trust in the healthcare system, potentially reducing delays in TB diagnosis.
• Reduced Diagnostic Default: Quick turnaround times may decrease the need for multiple healthcare visits, lowering patient default rates.

Drug-Resistant TB (DR-TB) Classification

• Mono-resistant TB: Resistance to one first-line anti-TB drug only.
• Isoniazid-resistant TB: Resistance to Isoniazid, but susceptibility to Rifampicin.
• Poly-resistant TB: Resistance to more than one first-line anti-TB drug, excluding both Isoniazid and Rifampicin.
• Rifampicin-resistant TB (RR): Resistance to Rifampicin, with or without resistance to other anti-TB drugs.
• Multidrug-resistant TB (MDR-TB): Resistance to at least both Isoniazid and Rifampicin.
• Pre-extensively drug-resistant TB: Resistance to Rifampicin, Isoniazid, and either Fluoroquinolones or one injectable drug.
• Extensively drug-resistant TB (XDR-TB): Resistance to any fluoroquinolone and at least one second-line injectable drug, in addition to MDR.

Key Anti-TB Drugs

• Rifampicin: Inhibits RNA synthesis by binding to RNA polymerase; side effects include hepatotoxicity, immunological reactions, and renal failure.
• Isoniazid: Inhibits mycolic acid synthesis in mycobacterial cell walls; side effects include neuropathy and hematological disorders.
• Ethambutol: Inhibits mycobacterial cell wall synthesis; causes bacterial aggregation and morphological changes.
• Pyrazinamide: Inhibits fatty acid synthesis in MTB, activated under acidic conditions.

MDR-TB Detection Methods

• Phenotypic Testing: Culture-based method with high sensitivity; results in 2-3 months.
• Genotypic Testing: Molecular tests identify resistance mutations; faster than phenotypic testing.
• GeneXpert: A NAAT test detecting TB and Rifampicin resistance within 2 hours.

TB and Diabetes Mellitus (DM) Relationship

• Pathophysiological Mechanisms: DM patients show diminished cellular immunity, impaired macrophage function, and reduced interferon gamma levels, increasing TB risk.
• Bidirectional Relationship: TB and DM often coexist, presenting a dual health challenge, especially in low and middle-income countries.
• Increased TB Risk in DM Patients: DM patients have a higher prevalence of active TB, which exacerbates the overall TB burden.

Sources:

1. Lin, H.H., Ezzati, M., Chang, H.Y. and Murray, M., 2009. Association between tobacco smoking and active tuberculosis in Taiwan: prospective cohort study. American journal of respiratory and critical care medicine, 180(5), pp.475-480.
2. Lestari, B.W., Nijman, G., Larasmanah, A., Soeroto, A.Y., Santoso, P., Alisjahbana, B., Chaidir, L., Andriyoko, B., Van Crevel, R. and Hill, P.C., 2024. Management of drug-resistant tuberculosis in Indonesia: a four-year cascade of care analysis. The Lancet Regional Health-Southeast Asia, 22:100294.
3. Lin, H.H., Dowdy, D., Dye, C., Murray, M. and Cohen, T., 2012. The impact of new tuberculosis diagnostics on transmission: why context matters. Bulletin of the World Health Organization, 90, pp.739-747.
4. Wulandari, D.A., Hartati, Y.W., Ibrahim, A.U. and Pitaloka, D.A.E., 2024. Multidrug-resistant tuberculosis. Clinica Chimica Acta, 559, p.119701.
5. Tariq, M., Zafar, S., Waheed, A., Afzal, N., Razzaq, R. and Batool, F., 2023. Prevalence of Various Forms of Active Tuberculosis in Patients with Diabetes. THE THERAPIST (Journal of Therapies & Rehabilitation Sciences), pp.33-37.

See also: TB Management

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