Diabetes and Tuberculosis

Abstract

The increase in type 2 diabetes mellitus (DM) patients in countries where tuberculosis (TB) is also endemic has led to the reemerging importance of DM as a risk factor for TB. DM causes a 3-fold increase in TB risk and a 2-fold increase in adverse TB treatment outcomes. Given the sheer numbers of DM patients worldwide, there are now more TB patients with TB-DM comorbidity than TB-HIV coinfection. There is an urgent need to implement strategies for TB prevention and control among the millions of DM patients exposed to Mycobacterium tuberculosis. This chapter summarizes the current epidemiological, clinical, and immunological knowledge on TB and DM and their clinical and public health implications. These include the underlying mechanisms for TB risk in DM patients and their clinical and sociodemographic characteristics that distinguish them from TB patients without DM. TB-DM comorbidity is posing a new challenge for integrating the short-term care for TB with the long-term care for DM, particularly in low- and middle-income countries.

Figure 1

Convergence of countries with highest burden of TB and DM worldwide. Among the ten countries with the highest number of diabetes patients worldwide, six are also among the 22 high-burden countries that contribute 80% of the TB cases worldwide (40).

Figure 2

Increase in the prevalence of TB-DM among TB cases over eight year period. Longitudinal analysis of the prevalence of TB-DM among newly-diagnosed TB patients reported to the state of Tamaulipas in northeastern Mexico, reveals an increase of 2.8% between 2006 and 2014 that is not attributed to an increase in blood glucose testing for DM diagnosis at TB clinics. Adapted from reference (20), with permission.

Figure 3

Impact of diabetes on the natural history of TB: association with dysfunctional immunity and clinical characteristics. Exposure of Mtb-naïve individuals to a pulmonary TB patient generally results in no infection (70%) or LTBI (30%) or primary TB. 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 will increase by 3-fold, although the contribution of DM to LTBI, primary TB or re-activation TB has not been quantified. Once TB develops, possible treatment outcomes include cure, treatment failure or death. DM increases these outcomes. Among presumably cured individuals TB relapses can occur. A previous history of TB does not confer immunity against all strains and re-exposure to another Mtb strain can lead to re-infection. DM can also increase re-infection risks. Bold arrows and “DM” indicate stages of TB where 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 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 Mtb antigens is likely to influence the development, clinical presentation and outcomes of TB but the mechanisms involved are poorly understood (87). PTB, pulmonary TB; EPTB, extrapulmonary TB; LTBI, latent TB infection.

Figure 4

Lower phagocytosis of Mtb by monocytes from patients with DM. Monocytes from TB-naive individuals +/− DM were cultured in RPMI plus 20% fresh or heat-inactivated autologous serum. Mtb were added and after 2 h the non-bound bacteria were washed. Then the associated (bound or phagocytosed) Mtb were stained with auramine (orange) and monocyte nuclei with DAPI (blue)(left panel). The percent of monocytes with at least one associated Mtb was quantified using fluorescence microscopy. Adherence of Mtb to monocytes is medicated by antibodies to mycobacteria spp (Ab) and serum complement (C′) in fresh serum and the corresponding Fc receptors and complement receptors on monocytes. Upon serum heat inactivation, Mtb binding is only mediated by antibodies (64).

Figure 5

Higher IFN-γ secretion in response to PPD in TB patients with high HbA1c (versus normal HbA1c) despite their DM status. Whole blood from TB patients +/− DM was incubated with purified protein derivative (PPD) from Mtb and after 18-24h the secretion of IFN-γ was quantified by ELISA in the culture supernatants. Results are shown in scatter plots where each circle represents one TB patient: black dots= DM and white dots= no 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 level. IFN-γ values are provided in natural log (Ln) scale (35).