Clinical predictors of pulmonary TB among South African adults with HIV

TB0038

Mendelsohn, S.C., Fiore-Gartland, A., Awany, D., Mulenga, H., Mbandi, S.K., Tameris, M., Walzl, G., Naidoo, K., Churchyard, G., Scriba, T.J. and Hatherill, M., 2022. Clinical predictors of pulmonary tuberculosis among South African adults with HIV. EClinicalMedicine, 45.

CD4 count and antiretroviral initiation are associated with Mtb sensitization and TB disease.

Lower CD4 cell counts are associated with reduced IGRA positivity due to the loss or dysfunction of Mtb-specific T-cell memory responses in HIV.

Clinical prediction models are inadequate for detecting incipient and subclinical TB among people with HIV.

Subclinical TB cases missed by symptom screening may perpetuate Mtb transmission.

There is a need for more sensitive TB screening tools to find “missing” TB cases in high-incidence settings.

Novel active case-finding approaches are needed that do not rely on the presence of symptoms.

Simple clinical prediction models could be used as triage tools in resource-limited settings.

Chest radiography and computer-aided detection offer promise for affordable mass screening and have reasonable performance as a rule-out test for symptomatic individuals with presumptive TB.

 

Diabetes and risk of tuberculosis relapse

Lee, P.H., Lin, H.C., Huang, A.S.E., Wei, S.H., Lai, M.S. and Lin, H.H., 2014. Diabetes and risk of tuberculosis relapse: nationwide nested case-control study. PloS one, 9(3), p.e92623.

Presence of diabetes mellitus (DM) during anti-TB treatment was linked to a higher risk of TB relapse.

The association between DM and TB relapse decreased in individuals older than 60 years.

DM was independently related to an increased risk of TB relapse in the national cohort of TB patients.

Strengthen follow-up strategies for DM-TB patients after anti-TB treatment to detect relapse early.

TB programs should focus on rigorous glucose control for DM-TB patients.

Williams, V., Onwuchekwa, C., Vos, A.G., Grobbee, D.E., Otwombe, K. and Klipstein-Grobusch, K., 2022. Tuberculosis treatment and resulting abnormal blood glucose: a scoping review of studies from 1981-2021. Global Health Action, 15(1), p.2114146.

Diabetes as a Risk Factor for Tuberculosis (TB):

• Numerous studies suggest that diabetes (DM) is a risk factor for TB.
• It remains unclear whether TB or its treatment increases the risk of developing diabetes.
• Impaired glucose tolerance (IGT) may occur during treatment with anti-TB drugs and might resolve after treatment.
• This IGT could result from:
  • Undiagnosed diabetes.
  • A stress response to infection, which increases levels of stress hormones (interleukin-1, interleukin-6, TNF-alpha).
  • Abnormal pancreatic function or TB-induced pancreatitis affecting endocrine function.

Blood Glucose Testing During TB Treatment:

• The Fasting Blood Glucose (FBG) test was the most common method for estimating blood sugar, followed by the Oral Glucose Tolerance Test (OGTT) and HbA1c.
• There was no standardized approach for blood sugar testing; most studies used a combination of methods.
• In studies using multiple tests:
  • HbA1c values were higher.
  • Patients with baseline values in the DM or IGT range were more likely to maintain hyperglycemia throughout treatment.
• HbA1c is useful for identifying long-term glucose abnormalities.
• To better identify DM comorbidity during TB treatment, blood glucose screening timing should be standardized across patients and country programs.
• Some studies only repeated glucose measurements for patients with initial readings in the DM or IGT range, excluding those with normal baseline values.
  • This approach could miss new cases of DM or hyperglycemia during follow-up.
  • It may have been a cost-saving measure or focused on tracking patients with abnormal readings.

Trends in Blood Glucose Levels During TB Treatment:

• Mean blood glucose levels decreased in patients with baseline values in the DM or IGT range who were not previously diagnosed with DM after starting TB treatment.
• The prevalence of elevated blood glucose also decreased during follow-up, consistent with earlier findings that stress hormones in response to the disease may cause initial high blood glucose levels.
• Some patients experienced persistent hyperglycemia after TB treatment, which may be due to:
  • Undiagnosed diabetes before TB infection.
  • Pre-existing IGT, which develops into DM due to additional insulin resistance from infection.

Cavitary Lung Lesions and Hyperglycemia:

• The development of cavitary lung lesions suggests a severe immune response during TB infection and may be associated with hyperglycemia.
• Glucose values typically improve over time with effective TB treatment.
• Good TB treatment outcomes are achievable in DM patients with adequate glucose control.

 

Indoor air pollution from solid fuel and tuberculosis

Lin, H.H., Suk, C.W., Lo, H.L., Huang, R.Y., Enarson, D.A. and Chiang, C.Y., 2014. Indoor air pollution from solid fuel and tuberculosis: a systematic review and meta-analysis. The International journal of tuberculosis and lung disease, 18(5), pp.613-621.

Low Evidence for TB Link: The association between the use of solid fuels in households and tuberculosis (TB) is supported by very low levels of evidence.

Health Risks from Toxic Pollutants: Burning solid fuels can be hazardous, particularly when stoves are inefficient and ventilation is poor, leading to health issues such as acute lower respiratory infections in children under five, chronic obstructive pulmonary disease, and lung cancer.

Factors Affecting Pollutant Levels: The concentration of pollutants from burning solid fuels varies based on the stove type, burning location, and ventilation at the site. These factors help in quantifying pollutant concentrations.

Need for More Research: High-quality studies are required to better understand the relationship between domestic use of solid fuels and TB and to assess the scope of the issue.

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Lai, T.C., Chiang, C.Y., Wu, C.F., Yang, S.L., Liu, D.P., Chan, C.C. and Lin, H.H., 2016. Ambient air pollution and risk of tuberculosis: a cohort study. Occupational and environmental medicine, 73(1), pp.56-61.

Respirable risk factors such as active and passive smoking, and indoor air pollution from biomass, potentially impair airway defense mechanisms, increasing TB risk.

High levels of ambient air pollution in developing countries correlate with continued high tuberculosis rates, necessitating further investigation into its impact on global TB control.

Fine particles and traffic-related pollutants like nitrogen dioxide, nitrogen oxides, and carbon monoxide are linked to a higher risk of active tuberculosis.

Laboratory and ecological studies suggest a positive association between ambient air pollution and TB incidence.

The true relationship between ambient air pollution and TB might be underestimated due to potential residual confounding by area-level socioeconomic factors.

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Lin, H.H., Murray, M., Cohen, T., Colijn, C. and Ezzati, M., 2008. Effects of smoking and solid-fuel use on COPD, lung cancer, and tuberculosis in China: a time-based, multiple risk factor, modelling study. The Lancet, 372(9648), pp.1473-1483.

Tobacco smoking and indoor air pollution from solid-fuel use are primary global risk factors for chronic obstructive pulmonary disease (COPD) and lung cancer.

These factors significantly contribute to mortality from these diseases in developing countries.

Smoking is an independent risk factor for tuberculosis, exacerbating the spread and severity of the disease.

Implementing moderate to complete reductions in smoking and solid-fuel use through tobacco taxation, advertising bans, and fuel pricing could decrease deaths from COPD and lung cancer.

Reduction in these risk factors would also significantly decrease tuberculosis incidence by minimizing the duration of infectiousness through effective treatment.

These diseases pose substantial economic burdens, particularly in developing countries, due to healthcare costs, reduced labor market participation, and hindered human capital accumulation.

The burden is disproportionately higher in low-income or marginalized communities.

Programs targeting low-income communities could offer cleaner fuels or stoves, nutritional supplements, and tuberculosis testing coupled with treatment adherence incentives.

Tobacco cessation initiatives could be integrated into tuberculosis treatment programs, possibly supported by financial incentives.

Revenue from tobacco taxes could subsidize Directly Observed Treatment, Short-course (DOTS), clean energy technologies, and nutrition programs for participating low-income households.

 

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India

Houben, R.M., Menzies, N.A., Sumner, T., Huynh, G.H., Arinaminpathy, N., Goldhaber-Fiebert, J.D., Lin, H.H., Wu, C.Y., Mandal, S., Pandey, S. and Suen, S.C., 2016. Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models. The Lancet Global Health, 4(11), pp.e806-e815.

Aggressive scaling of a single intervention is not enough to meet the post-2015 End TB Strategy targets globally.

In South Africa:

• A combination of targeted interventions could substantially reduce tuberculosis:
  • Continuous isoniazid preventive therapy for individuals on antiretroviral therapy.
  • Expanded facility-based screening for tuberculosis symptoms at health centers.
  • Enhanced tuberculosis care.
• Using these interventions, significant reductions in tuberculosis are feasible, and meeting the 2025 targets is possible.

For other high-burden countries like China and India, additional country-specific interventions are required:

• In China, addressing latent tuberculosis in the elderly.
• In India, combating undernutrition to help reach the global tuberculosis targets.

  

Cost-effectiveness and resource implications of aggressive action on TB

Menzies, N.A., Gomez, G.B., Bozzani, F., Chatterjee, S., Foster, N., Baena, I.G., Laurence, Y.V., Qiang, S., Siroka, A., Sweeney, S. and Verguet, S., 2016. Cost-effectiveness and resource implications of aggressive action on tuberculosis in China, India, and South Africa: a combined analysis of nine models. The Lancet global health, 4(11), pp.e816-e826.

Health Outcomes:

• Substantial health gains were observed in India, China, and South Africa following expanded access to tuberculosis care.

Cost-Effectiveness:

• Most intervention approaches were highly cost-effective compared to current practices and conventional cost-effectiveness thresholds.
• Efforts to improve access to care proved to be notably beneficial and cost-effective in each setting analyzed.

Policy Considerations:

• Significant differences in the effectiveness and efficiency of various approaches necessitate careful planning in service expansion.
• Implementing expanded services effectively would require substantial new funding.

Cost Implications:

• Incremental costs for tuberculosis services varied by scenario and country, sometimes more than doubling the existing funding needs.

Economic and Health Benefits:

• Expansion of tuberculosis services generally reduced patient-incurred costs.
• In India and China, most interventions resulted in net cost savings from a societal perspective.

 

Dye, C., Garnett, G.P., Sleeman, K. and Williams, B.G., 1998. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. The Lancet, 352(9144), pp.1886-1891.

The fall in tuberculosis incidence under DOTS is greater in younger populations than in older ones.

Non-curative treatment can prevent death without eliminating infectiousness. See also: https://tbreadingnotes.blogspot.com/2024/10/quantifying-global-number-of.html

In countries where tuberculosis incidence is stable and HIV-1 is absent:

• A control program reaching WHO targets (70% case detection, 85% cure) would reduce the incidence rate by 11% per year (range 8–12%).
• It would reduce the death rate by 12% per year (range 9–13%).

If tuberculosis has been in decline for several years, the same case detection and cure rates would have a smaller effect on incidence. See also: https://tbreadingnotes.blogspot.com/2024/10/type-2-diabetes-mellitus-and-recurrent.html

DOTS saves a greater proportion of deaths than cases, with a larger difference in the presence of HIV-1.

HIV-1 epidemics increase tuberculosis incidence but do not significantly reduce the preventable proportion of cases and deaths. See also: https://tbreadingnotes.blogspot.com/2024/08/immunologic-metabolic-and-genetic.html

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Sorokina, M., Ukubayev, T. and Koichubekov, B., 2023. Tuberculosis incidence and its socioeconomic determinants: developing a parsimonious model. Annali di Igiene, Medicina Preventiva e di Comunita, 35(4): 468-479.

· There is a strong relationship between economic indicators and health expenditure.

· In bivariate analysis, per-capita GDP, per-capita income, proportion of the poor, unemployment rate, CHE per capita, number of GPs, and number of TB hospital beds were significant predictors of TB incidence rate.

· Two key components, economic development and healthcare capacity, were identified.

· Both economic development and healthcare capacity have a significant negative effect on TB incidence.

· The findings are based on population-level data and indicate that stronger economies and better healthcare systems reduce TB incidence, though the results cannot be applied to individuals directly.

Tuberculosis in Healthcare Workers

Pan S-C, Chen Y-C, Wang J-Y, Sheng W-H, Lin H-H, Fang C-T, et al. (2015) Tuberculosis in Healthcare Workers: A Matched Cohort Study in Taiwan. PLoS ONE 10(12): e0145047.

Tuberculosis (TB) is considered a significant occupational hazard for healthcare workers (HCWs) in Taiwan.

The incidence of active TB among HCWs in the study hospital was higher than that of the general population in Taiwan when adjusted for age, sex, and diagnosis year.

The outcomes of TB in HCWs were notably better compared to non-HCW patients treated in the same setting.

Factors such as the healthy worker effect, more rapid diagnosis, and less delay in treatment contributed to lower TB mortality among HCWs.

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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). https://doi.org/10.1186/s12913-023-10015-7

TB and diabetes are usually treated in separate facilities, which is a significant challenge in low- and middle-income countries (LMICs).

Financial constraints, including loss of employment due to TB and the out-of-pocket costs for diabetes medications, pose major barriers to diabetes self-management.

Financial incentives, such as participation allowances, are important for encouraging diabetes self-care and improving glycaemic control outcomes.

Health education about diabetes management offered through TB programs is beneficial but needs further enhancement with supportive resources.

There is a need for culturally appropriate messaging and information about the use of phytotherapies in diabetes management.

Often, individuals seek diabetes management information from the internet and community due to inadequate resources available through TB-DOTS (Directly Observed Treatment, Short-course) programs.

TB programs should consider monitoring and managing diabetes, especially in patients with previously diagnosed or advanced disease, to reduce the risk of diabetes-related catastrophic health costs during TB treatment.

 

Enhanced DM management reduce the risk and improve the outcome of TB

Lo, H.Y., Yang, S.L., Lin, H.H., Bai, K.J., Lee, J.J., Lee, T.I. and Chiang, C.Y., 2016. Does enhanced diabetes management reduce the risk and improve the outcome of tuberculosis?. The International Journal of Tuberculosis and Lung Disease, 20(3), pp.376-382.

Diabetic TB patients face higher risks of treatment failure, death, and recurrent TB compared to non-diabetic TB patients.

Patients with diabetes mellitus (DM) enrolled in an enhanced case management program for DM had a lower likelihood of developing TB.

If they developed TB, patients in the enhanced DM management program experienced better outcomes than those not enrolled in the program.

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In low and moderate TB incidence countries, TB often concentrates in specific groups, notably those with diabetes. In Taiwan, diabetes mellitus (DM) is the leading risk factor for pulmonary TB. After adjusting for confounders, type 2 DM is an independent risk factor for TB nationwide, though the association is stronger for type 1 DM. Poor glycemic control can increase the hazard ratio for TB in adults under 65, with men and individuals aged 55–64 at greater risk. TB patients with heart failure, ischemic heart disease, stroke, hypertension, dyslipidemia, chronic kidney disease, and liver disease are more likely to have DM.

Interestingly, obesity does not increase TB risk despite its link to diabetes. TB incidence and mortality have decreased in Taiwan, yet DM remains the fifth leading cause of death. In newly diagnosed TB patients, those with DM experience higher mortality rates. Proper TB treatment has been shown to improve glycemic control, possibly due to TB-induced hyperglycemia through stress dysglycemia mechanisms. Both anti-TB and antidiabetic treatments may help mitigate hyperglycemia.

Chronic hyperglycemia impairs immunity to M. tuberculosis and affects lung perfusion, reducing immune response in diabetic patients. Those with poor glycemic control (fasting plasma glucose >130 mg/dL) have a higher TB hazard, while those with good control (FPG <130 mg/dL) do not significantly differ from non-diabetics. Diabetics with HbA1c >7% are more likely to be smear-positive for TB compared to those with HbA1c <7%.

Initial two-year metformin (MET) use reduces active TB risk, with a greater effect at higher dosages. MET also reduces DM-related mortality during TB treatment. Ezetimibe, a cholesterol-lowering drug, shows promise as adjunctive therapy for TB by lowering latent TB prevalence, intracellular lipid content, and M. tuberculosis growth in leukocytes among diabetic patients. While DM significantly raises the odds of multidrug-resistant TB (MDR-TB), the impact of glycemic control on MDR-TB outcomes remains unclear.

Source: Wang, M.C. and Cervantes, J., 2019. Glycemic control in tuberculosis: lessons learned from Taiwan. Asian Pacific Journal of Tropical Medicine, 12(10), pp.438-441. https://journals.lww.com/aptm/fulltext/2019/12100/glycemic_control_in_tuberculosis__lessons_learned.2.aspx

Association of obesity, diabetes, and risk of tuberculosis

Lin, H.H., Wu, C.Y., Wang, C.H., Fu, H., Lönnroth, 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.

Obesity and Tuberculosis Paradox: Despite the association between obesity (high BMI) and diabetes, and diabetes being a risk factor for tuberculosis (TB), epidemiological data shows that higher BMI actually correlates with a reduced risk of TB.

Study Cohort Characteristics: Higher BMI in the study cohorts was associated with male gender, older age, current use of tobacco and alcohol, lower educational attainment, higher prevalence of diabetes, and lower household income (in the NHIS cohort).

Mediation and Pathway Analyses: Higher BMI significantly increased the odds of diabetes; diabetes increased the odds of active TB; however, obesity directly correlated with a reduced TB risk: 71.9% reduced odds in the NHIS cohort and 67.3% in the NTC cohort.

Inverse Association Across BMI Levels: Across all BMI levels, there was an inverse association with TB risk, with obese individuals having a two-thirds reduction in TB risk compared to normal-weight individuals.

Dual Effects of High BMI: A harmful effect mediated through diabetes and a strongly protective direct effect not mediated through diabetes; the overall effect of high BMI on TB risk was dominated by the direct protective effect.

Effect of Combined Obesity and Diabetes: Obese/diabetic individuals had similar or even lower TB risk compared to nondiabetic normal-weight individuals.

Exclusion of Reverse Causation and Confounding: The study accounted for potential confounders and the BMI data was collected at baseline, ruling out reverse causation (TB causing weight loss); residual confounding by socioeconomic status remains a possible limitation, as lower socioeconomic status is linked to both higher BMI and greater TB risk.

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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.

- Numerous studies and systematic reviews confirm diabetes mellitus (DM) as a major risk factor for active TB disease and latent TB infection.

- Incident cases of active TB were identified from the National Tuberculosis Registry in Taiwan.

See also: https://tbreadingnotes.blogspot.com/2024/08/a-model-for-propagation-and-control-of.html

- TB is a notifiable disease in Taiwan; presumptive TB cases must undergo sputum smear examinations at least twice and sputum cultures.

- All confirmed TB cases are registered in the National Tuberculosis Registry and receive standardized and free treatment.

- In this study, patients with smear-positive or culture-positive results are defined as active TB cases.

-  Prediabetes is associated with a 27% reduced risk of active TB disease compared to normoglycaemia.

- The biological mechanism of this inverse association and its implications for global nutrition transition and TB control require further investigation.

See also: https://tbreadingnotes.blogspot.com/2024/08/prevalence-of-various-forms-of-active.html

- This is the first longitudinal study investigating the association between prediabetes and the risk of TB.

- The novel finding has critical implications for the dual epidemic of diabetes and tuberculosis.

- Given the protective association of obesity and prediabetes with tuberculosis, the global nutrition transition may represent a double-edged sword for global TB control.

- More research is needed to fully understand the biological mechanism and public health implications of the relationship between prediabetes and TB. 

Modelling the effect of discontinuing universal BCG vaccination in Taiwan

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.

Discontinuing the BCG vaccine could increase the tuberculosis (TB) burden, requiring careful consideration against the costs and adverse effects of the vaccination program.

In regions with high vaccine efficacy (VE), stopping BCG could negatively impact health more than it would reduce side effects, due to the increased TB burden.

Improving early TB detection and starting treatment promptly might be more effective than BCG vaccination in controlling TB.

The immunity provided by BCG may wane over time, making the elderly less protected or not protected at all, even if they were vaccinated at birth.

Even in scenarios where BCG offers strong protection for up to 40 years, older adults are least affected by the cessation of the BCG vaccination program.

Instead of completely stopping the BCG vaccination, implementing selective vaccination could be a more viable alternative.

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.

Diagnosing tuberculosis (TB) in children is challenging due to difficulties in collecting sputum samples and the paucibacillary nature of pulmonary TB in children.

Alternative specimen collection methods like induced sputum and gastric aspirate require specialized equipment and trained personnel, which are often unavailable at primary health centers (PHC) and sometimes even at district hospitals (DH).

As a result, many children with symptoms suggestive of TB do not receive appropriate diagnostic tests, even at the DH level.

Stool samples can be collected more easily in young children across various settings and can be used to identify Mycobacterium tuberculosis using Xpert MTB/RIF testing.

Nasopharyngeal aspirates (NPA) are easier to collect than gastric aspirate or induced sputum and, when combined with stool samples, offer similar sensitivity to Xpert MTB/RIF testing on gastric aspirates or induced sputum.

Decentralization of pediatric TB services to the DH level could be cost-effective in Cambodia and Côte d’Ivoire, but decentralization to the PHC level 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.

Implementing decentralization, particularly focused on PHCs, would require significant financial investment in the early phases.

The PHC-focused strategy is more costly and less effective than the DH-focused strategy due to the need for diagnostic equipment across more facilities and the higher TB diagnosis rates at the DH level.

Higher TB diagnosis rates at DHs may be due to care-givers bringing more severely ill children there first or because children are referred from PHCs with more advanced disease.

All children at DHs had chest X-rays (CXR) performed, while at PHCs, only children with persisting symptoms after 7 days were referred for CXR, contributing to higher TB detection in the DH-focused strategy.

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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.

• Faster Decline in Tuberculosis Burden: The use of a new diagnostic tool is expected to reduce the burden of pulmonary tuberculosis more rapidly compared to continued reliance on smear microscopy.
• Influence of Contextual Factors: The impact of the new diagnostic tool on tuberculosis epidemiology is significantly influenced by contextual factors that are unrelated to the tool's performance.
• Greatest Impact in Certain Settings: The epidemiological impact of the new tool is most significant in areas where access to tuberculosis care is good but where existing diagnostic strategies have low sensitivity, such as limited access to chest X-rays for smear-negative cases.
• Lesser Impact in Equipped Laboratories: The new diagnostic tool may have a lesser impact at the population level if implemented in reference laboratories that are poorly accessible but already have sensitive diagnostic tools like culture.
• Increased Patient Trust: A new diagnostic test could boost patients' confidence in the healthcare system and encourage physicians to consider tuberculosis diagnosis more readily, reducing delays for both patients and the health system.
• Reduced Diagnostic Default: A new test with a quick turnaround time would lessen the need for multiple visits to the healthcare system, thereby decreasing the likelihood of patients defaulting on diagnosis.