Association between diabetes mellitus and multi-drug-resistant tuberculosis: evidence from a systematic review and meta-analysis

The global tuberculosis (TB) burden continues to be a major public health challenge despite efforts to reduce its impact. Globally in 2016, there were an estimated 10.4 million incident cases of TB, equivalent to 140 cases per 100, 000 population [1]. Of these incident cases of TB in 2016, an estimated 1.9 million were attributed to undernourishment, 1.0 million to HIV, 0.8 million to smoking, and 0.8 million to diabetes [1]. In the era of the sustainable development goals, post-2015, the “End TB Strategy” targets to reduce TB incidence by 80% by year 2030 [2]. However, the global epidemiological and demographic transitions pose significant challenge to TB control programs by changing the relative importance of different risk factors for TB [3, 4].

The global diabetes mellitus (DM) epidemic poses a significant bottleneck to the TB control program [3, 4]. The International Diabetes Federation (IDF) estimated that, globally in 2013, 382 million adults have diabetes of whom 80% live in low-and middle-income countries. Further increase in the global burden of diabetes is predicted, reaching 592 million by 2035 [5]. People with diabetes, compared to non-diabetic controls, were two- to three-fold more likely to develop TB [6, 7]. In 2013, an estimated 15% of adult cases of TB worldwide were attributed to diabetes, which corresponds to 1 million cases of diabetes-associated TB per year [3]. Impaired immunity in diabetic patients is thought to contribute to the evolution of latent TB infection to active cases. Moreover, people with TB who have DM have a poorer response to treatment than do those without DM, and are therefore at a higher risk of TB treatment failure, death, and relapse after cure [3, 8]. Treatment failure in turn adds another significant challenge to the global TB control program, a drug-resistant TB [1, 9].

Multi-drug-resistant tuberculosis (MDR-TB), resistance to at least isoniazid and rifampicin, results from either primary infection with resistant bacteria or may develop in the course of a patient’s treatment [9]. In 2016, there were an estimated 600,000 incident cases of MDR-TB. In the same year, an estimated 4.1% of new cases and 19% of previously treated TB cases had MDR-TB [1]. The emergence of multi-drug resistance across the world poses a global threat as the treatment is difficult, expensive, and a major healthcare cost burden to developing countries [10]. Most cases of MDR-TB arise from a mixture of physician error, inadequate and incomplete treatment, and patient non-compliance during treatment of susceptible TB [11, 12]. Research reports also indicate that patients with MDR-TB and a co-morbidity of DM have a poor treatment response compared with non-diabetic MDR-TB controls [13].

The additional risk of DM for the development of MDR-TB, however, remains controversial [14‐16]. Many previous studies have found a 2.1 to 8.8 times increased risk of MDR-TB among TB patients co-morbid with diabetes [17‐21]. In addition, observational studies from Israel, Georgia, and Mexico showed that TB patients with DM had a higher risk of developing MDR-TB [22‐24]. In contrast, several others reported that there is no increased risk of MDR-TB among TB patients who have DM [25‐28]. Similarly, none but one of the previously conducted systematic reviews and meta-analysis [29] reported DM as an independent risk factor for MDR-TB. However, the pooled estimate in that study was based on limited number of studies which mostly implemented a cross-sectional or case-control study design. By conducting a comprehensive search until July 2018, we identified more studies and included six new cohort studies [30‐35]. Therefore, with the present systematic review and meta-analysis, we aimed to assess the pooled effect estimate of DM on the development of MDR-TB with the careful inclusion of data from appropriately conducted observational studies.

In this study, we pooled estimates on the association between DM and MDR-TB from 24 observational studies and identified a significant and positive association with a low between-study heterogeneity. In a pooled estimate of studies which adjusted for at least one confounding factor, stronger association was observed by study design, type of TB, method of TB diagnosis, type of DM, method of DM diagnosis, and country income level.

The pooled effect estimate, in subgroup analyses of 13 studies which adjusted for at least one confounding factor, on the association between DM and MDR-TB (OR = 2.43, 95% CI 1.90 to 3.12, I² = 19.1%, P value = 0.250) was consistent in the direction of association, but stronger than what was reported in a previous systematic review and meta-analysis (OR = 1.71, 95% CI 1.32 to 2.22, I² = 46.8%, P value = 0.020) [29]. This difference could be due to the fact that Liu et al. [29] mixed three studies which reported unadjusted OR [21, 49, 54], while we included three new cohort studies that reported adjusted OR [30, 33, 35]. Compared to a similar prior meta-analysis [29], we included 10 additional studies [14, 25, 28, 30‐35, 51] and supplemented this with strong analytical rigor. Thus, our meta-analysis fortifies the evidence base for the association between DM and MDR-TB. Our results are also in agreement with a review that showed TB and DM co-morbidity were more likely to be evident among people with anti-TB drug resistance [55], signifying a clear association between the two diseases. In another review, Baker et al. [8] did not find an increased risk of MDR-TB among people with DM. However, it is worth mentioning that this study aimed to review literature on the impact of DM on TB outcomes, and this particular sub-analysis included only four studies. Although not having MDR-TB as an outcome, another review noted significant associations in the pooled risk of association between DM and active TB without regarding the type of study design implemented [56].

Signifying a stability of association, we found a significant and positive association between DM and MDR-TB in subgroup analyses of studies which adjusted for at least one confounding factor. The association persisted irrespective of the country where the primary studies were conducted which covered diverse population groups, how DM or TB diagnosis was made, and study design of the primary studies. However, pooled estimate of a weaker strength was found in studies which did not adjust for at least one confounding factor (OR = 1.45, 95% CI 1.05 to 2.02). We included studies which reported unadjusted effect estimate to reduce inflation of the pooled effect estimate from the adjusted only analysis, increase the number of available studies for analysis, and widen the representativeness of our findings [57]. Although unadjusted findings lack adjustment by statistical methods, they attempted to adjust at the design level albeit still suffering from an unobserved confounding effect. Therefore, we suggest our findings should be interpreted with caution.

In subgroup analyses of studies which adjusted for at least one confounding factor on the association between DM and MDR-TB, there was an increased risk in lower middle-income countries (OR = 2.95, 95% CI 1.69 to 5.16) compared to that found in upper middle-income countries (OR = 2.32, 95% CI 1.65 to 3.28) and high-income countries (OR = 2.13, 95% CI 1.29 to 3.52). This might be due to more studies in high-income- or upper middle-income country settings diagnosed DM by blood test (FBS or HbA1c) or confirmed TB diagnosis based on culture which may have reduced bias due to misclassification [19, 23, 30, 48, 50, 52]. Consistent with our finding that there was an increased risk of MDR-TB among TB-DM co-morbid patients in lower middle-income countries, a meta-analysis by Al-Rifai et al. [56] reported that there was a higher risk of TB-DM association in lower middle-income countries compared to high-and upper middle-income countries.

A strong association was found in subgroup analyses by TB type in studies which reported adjusted estimate, where DM increased the risk of MDR-TB among new TB patients (OR = 2.36, 95% CI 1.59 to 3.51) and in those with undefined TB type (OR = 2.72, 95% CI 1.88 to 3.94). However, due to inadequate number of studies which adjusted for at least one confounding factor and included only previously treated TB patients, we did not present a pooled estimate on the risk of MDR-TB among previously treated TB-DM co-morbid patients. Therefore, we are not able to confirm whether DM is indeed not a risk factor for MDR-TB among previously treated TB patients. The meta-analysis by Liu et al. [29] also reported similar findings on the risk of any MDR-TB (OR = 1.94, 95% CI 1.42 to 2.65) and primary MDR-TB (OR = 1.69, 95% CI 1.09 to 2.62) among TB patients co-morbid with DM. Due to the addition of three cohort studies [30, 33, 35], which were not included in the Liu et al.’s meta-analysis [29], we reported a stronger pooled effect estimate for the increase in the risk of MDR-TB among new- and any-TB patients co-morbid with DM. Similarly, irrespective of the study design used in the primary studies which adjusted for at least one confounding factor, we consistently found a significant and positive association between DM and MDR-TB in cross-sectional (OR = 1.72 95% CI 1.23 to 2.41), case-control (OR = 2.89, 95% 2.02 to 4.12), and cohort studies (OR = 3.36, 95% CI 1.82, 6.20). Similar findings were reported by Liu et al. for case-control studies but not for cross-sectional studies [29]. Because only one cohort study was included [53] by Liu et al. [29], we cannot compare the pooled estimate from cohort studies in our meta-analysis to theirs. Though it is difficult to establish causality based on evidence from observational studies, we believe that these pooled estimates from studies which controlled for potential confounding factors further solidify the existence of a strong association between DM and MDR-TB among patients co-morbid with TB.

In this study, we have shown the most substantial evidence to date on the association between DM and MDR-TB by including a comprehensive list of studies carried out in various settings around the world. Methodologically, we conducted a cumulative meta-analysis to see the trend of evidence and performed a single study influence analysis and subgroup analysis. However, we would also like to acknowledge potential limitations of this study. Firstly, we have not included studies published in non-English languages. Given majority of MDR-TB cases and co-morbidities are from Russia, China, and India [1], exclusion of studies from these countries might bias our finding. Secondly, the inclusion of studies which did not consistently define the type of TB and did not control for potential confounding factors increased the observed heterogeneity among studies. However, in an attempt to deal with this, we have performed and reported sensitivity analysis. Finally, potential misclassification regarding a non-uniform diagnosis of DM and TB among participants included in the different studies might have contributed to varying risk estimates. This is particularly observed in the stratified analysis based on diagnosis of DM and TB, where higher estimates were observed for those diagnosed based on information obtained from medical records and self-reports, (diagnosis of DM: FBS from medical record, OR = 2.68, 95% CI 1.45 to 4.96; HbA1c, OR = 2.42, 95% CI 1.49 to 3.93; self-report, OR = 2.33,, 95% CI 1.65 to 3.29) and (diagnosis of TB: culture confirmed, OR = 1.97, 95% CI 1.51 o 2.57; AFB only from medical record, OR = 3.73, 95% CI 2.33 to 5.97).

In conclusion, our results demonstrate that a more robust TB treatment and follow-up might be necessary for patients with DM. In light of the global DM epidemic [5], this study emphasizes the message that there is a strong need for a bi-directional screening and co-management approach in the attempt to halt the TB-DM co-morbidity [58]. Even though countries representing diverse income levels were not included in our study, we stress the need to maximize efforts to prevent DM and TB co-morbidity and reduce the burden of MDR-TB in countries with varying economical standings. The integrated and collaborative effort between TB and DM control programs will ultimately count on achieving the global “End TB Strategy” [2]. Efforts to control DM can have a substantial beneficial effect on TB outcomes, particularly in the case of MDR-TB. Policymakers can focus on new targets pertaining to an enhanced care plan for DM patients with TB, particularly among the slightest evidence of problems with adherence or prolonged and complicated infections. Furthermore, focus on the early identification and treatment of individuals with the co-morbidity can result in an enhanced treatment outcome. We recommend future prospective cohort studies to focus on bacteriologically confirmed TB cases that objectively diagnose DM, with clearly defined types of both TB and DM coupled with robust controls for potential confounding.