Chapter 35 : Diabetes and Tuberculosis

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The global increase in type 2 diabetes mellitus (DM) is a recognized reemerging risk and challenge to tuberculosis (TB) control ( ). Individuals with DM have three times the risk of developing TB, and there are now more individuals with TB-DM comorbidity than TB-HIV coinfection ( ). The association between DM and TB was first described centuries ago by Avincenna, a Persian philosopher, and the comorbidity was a frequent topic in the medical literature in the first half of the 20th century ( ). But this literature dwindled as the association became less evident with the introduction of insulin for DM patients and antibiotics for TB. In the 1980s, publications on joint TB-DM began to reemerge in parallel with the DM “pandemic”: the global prevalence of DM among adults has increased by 20% in less than 30 years ( ), and the number of individuals with DM is predicted to reach 642 million worldwide by 2040, with most (80%) of the patients living in low- and middle-income countries where TB is also endemic ( ). Consequently, the World Health Organization has identified DM as a neglected, important, and reemerging risk factor for TB ( ). In this chapter, “DM” refers mostly to type 2 DM since it is the most prevalent form, but type 1 DM in children has also been associated with TB ( ). This chapter describes the epidemiology of TB-DM, the impact of DM on the clinical presentation and outcomes of TB, the underlying biology that favors the co-occurrence of the two diseases, and the public health implications for TB control and DM management.

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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Figure 1

Convergence of countries with highest burden of TB and DM worldwide. Among the 10 countries with the highest number of DM patients worldwide, 6 are also among the 22 high-burden countries that contribute 80% of the TB cases worldwide ( ).

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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Figure 2

Increase in the prevalence of TB-DM among TB cases over an 8-year period. Longitudinal analysis of the prevalence of TB-DM among newly diagnosed TB patients reported to the state of Tamaulipas in northeastern Mexico revealed an increase of 2.8% between 2006 and 2014 that is not attributable to an increase in blood glucose testing for DM diagnosis at TB clinics. Adapted from reference with permission. LCI and UCI, lower and upper confidence inter„vals, respectively.

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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Figure 3

Impact of DM on the natural history of TB: association with dysfunctional immunity and clinical characteristics. Exposure of -naïve individuals to a pulmonary TB patient generally results in no infection (70%) or LTBI or primary TB (30%). Among those infected, the lifetime risk of reactivation TB is 10%. If the host has DM (most likely chronic and poorly controlled DM), the TB risk will increase 3-fold, although the contribution of DM to LTBI, primary TB, or reactivation TB has not been quantified. Once TB develops, possible treatment outcomes include cure, treatment failure, or death. DM increases the last two outcomes. TB relapses can occur among presumably cured individuals. A history of TB does not confer immunity against all strains, and exposure to another strain can lead to reinfection. DM can also increase reinfection risks. Bold arrows and “DM” indicate stages of TB in which DM appears to have an impact. As the natural history of TB evolves in the DM host, so does the immune response with characteristics that contrast with those in the non-DM host. The TB-DM host is more likely to present with clinical characteristics associated with enhanced TB transmission, but the impact of disease spread in the community has not been systematically studied (bottom text box; “DM?”). The dysfunctional immune response of the DM host to antigens is likely to influence the development, clinical presentation, and outcomes of TB, but the mechanisms involved are poorly understood ( ). PTB, pulmonary TB; EPTB, extrapulmonary TB; LTBI, latent TB infection; Mtb, .

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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Figure 4

Lower phagocytosis of by monocytes from patients with DM. Monocytes from TB-naive individuals with and without DM were cultured in RPMI medium’plus 20% fresh or heat-inactivated autologous serum. was added, and after 2 h, the nonbound bacteria were washed. Then the associated (bound or phagocytosed) organisms were stained with auramine (orange), and monocyte nuclei were stained with 4[prime],6-diamidino-2-phenylindole (DAPI) (blue) (left image). The percent of monocytes with at least one associated organism was quantified using’fluorescence microscopy. Adherence of to monocytes is mediated by antibodies to mycobacteria (Ab) and serum complement (C′) in fresh serum and the corresponding Fc receptors and complement receptors on monocytes. Upon serum heat inactivation, binding is mediated only by antibodies ( ).

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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Figure 5

Higher IFN-γ secretion in response to purified protein derivative in TB patients with high HbA1c (versus normal HbA1c) despite their DM status. Whole blood from TB patients with and without DM was incubated with purified protein derivative from , and after 18 to 24 h, the secretion of IFN-γ in the culture supernatants was quan„tified by enzyme-linked immunosorbent assay. Results are shown in a scatter plot in which each circle represents one TB’patient. Black circles, DM patients; white circles, patients without DM. The horizontal line indicates the median IFN-γ level. The vertical line at the HbA1c level of 6.2% of total hemoglobin’indicates the upper limits of normal (left) and elevated’(right) HbA1c levels. IFN-γ values are provided in natural log (Ln) scale ( ).

Citation: Restrepo B. 2017. Diabetes and Tuberculosis, p 595-606. In Schlossberg D (ed), Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TNMI7-0023-2016
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