Diabetes and tuberculosis : how strong is the association and what is the public health impact?

Abstract

Introduction : Recent research has generated discussion upon the historically noted association between tuberculosis (TB) and diabetes mellitus (DM). However, evidence on the direction of the association, its magnitude, specificity and impact remains sparse. The primary aim of this thesis was to identify whether rates of TB (all sub-types, pulmonary (PTB) and extra pulmonary (EPTB)) are raised amongst those with DM (all sub-types, type 1 (T1DM) and type 2 (T2DM)), or the converse. Further to this, to estimate the magnitude and direction of any such associations. A secondary aim of the thesis was to investigate whether key TB outcomes differ amongst those with co-morbid DM and TB comparative to those with TB disease alone. Methods : The Oxford Record Linkage Study (ORLS) is a database containing records of all hospital admissions and all deaths (regardless of where they occurred), in defined populations within the former Oxford National Health Service Region. ORLS1 covers the years 1963 to 1998 and ORLS2 covers the years 1999 to 2008, the two databases are not linkable. The Health Improvement Network (THIN) is a database containing electronic medical records collected at General Practice clinics throughout the United Kingdom (UK). Retrospective cohort analyses were carried out using data from ORLS1, ORLS2 and THIN. All patients in the datasets were classified as exposed to (having had) or unexposed to (not having had) TB (all sub-types, PTB or EPTB) and exposed or unexposed to DM (all sub-types, T1DM or T2DM). In the ORLS1 and ORLS2 datasets, standardised rate ratios (RR) and corresponding 95% confidence intervals (95% CI) were calculated and compared for DM (all sub- types, T1DM and T2DM) in individuals who have had and have not had TB (all sub- types, PTB or EPTB). Similarly, RR and 95% CI were calculated and compared for TB (all sub-types, PTB or EPTB) in patients with and without DM (all sub-types, T1DM and T2DM). Within THIN datasets, the incidence rate ratio (IRR) and 95% CI of DM (all sub-types, T1DM and T2DM) were calculated using negative binomial regression, with TB (all sub-types, PTB or EPTB) as an explanatory variable. Similarly, the IRR and 95% CI for TB (all sub-types, PTB or EPTB) were calculated using negative binomial regression, with DM (all sub-types, T1DM or T2DM) as an explanatory variable. Systematic searching was performed to identify studies comparing TB outcomes amongst those with and without DM. Data from these studies were utilised to inform meta-analyses that assessed all cause mortality, bacterial clearance rate and TB relapse or recurrence rate amongst individuals with DM and co-morbid TB comparative to those with TB alone. Results Significant increases in TB rates (all sub-types) and pulmonary tuberculosis (PTB) rates were identified amongst individuals with DM comparative to those without DM within the Oxford Record Linkage Study datasets. The RR of TB (all sub-types) was increased amongst individuals with DM (all sub- types) compared to those without in ORLS1 (RR 1.77 (95% CI 1.45-2.15), P-value <0.001) and ORLS2 (RR 2.56 (95% CI 1.78-3.69), P-value <0.001). The RR of PTB was also increased amongst individuals with DM (all sub-types) compared to those without in ORLS1 (RR 1.72 (95% CI 1.22-2.37), P-value <0.001) and ORLS2 (RR 3.33 (95% CI 1.51-6.62), P-value 0.001). There was a statistically significant elevation of risk for TB amongst those with T2DM compared to those without in ORLS1 (RR 1.58 (95%CI1.15-2.14), P-value 0.003) and ORLS2 (RR 3.33 (95% CI 1.51-6.62), P-value 0.001). There was no significant association between the rates of TB amongst those with T1DM compared to those without in ORLS1. The ORLS 2 dataset was too small to complete this analysis. No significant association was found between the rate of EPTB amongst those with DM comparative to those without in either ORLS1 or ORLS2. There was also no significant association between having had TB (all sub-types, PTB or EPTB) and subsequent risk of DM (all sub-types, T1DM or T2DM) in either ORLS1 or ORLS2. In THIN dataset the risk of TB (all sub-types) was found to be increased amongst individuals with DM (all sub-types), T1DM and T2DM when compared to those without. Thus, the IRR of TB (all sub-types) were significantly increased amongst individuals with DM (all sub-types) (IRR 1.50 (95%CI 1.27-1.76) P-value <0.001), T1DM (IRR 1.46 (95%CI 1.10-1.92) P-value 0.008) and T2DM (IRR 1.54 (95%CI 1.30-1.82) P-value < 0.001) compared to those without DM. The rate of PTB amongst individuals with DM (all sub-types), T1DM, or T2DM compared to those without were not significantly raised within THIN. The rate of EPTB was raised amongst those with T1DM (IRR 2.09 (95%CI 1.19-3.66), P-value 0.010) but was not raised amongst those with DM (all sub-types) (IRR 1.43 (95% CI 0.99-2.07), P-value 0.055) or those with T2DM (IRR 1.39 (95%CI 0.93-2.06), P-value 0.11) when compared to those without DM. In THIN dataset the rates of DM (all sub-types), T1DM and T2DM were found to be raised amongst individuals who have had TB (all sub-types), PTB and EPTB when compared to those who have not. The rate of DM (all sub-types) was increased amongst those who have had TB (all sub-types) (IRR 5.65 (95% CI 5.19-6.16) P-value <0.001), PTB (IRR 5.74 (95% CI 5.08-6.50) P-value <0.001) and EPTB (IRR 4.66 (95% CI 3.94-5.51) P-value <0.001) when compared to those who have not had TB. The rate of T1DM was increased amongst those who have had TB (all sub-types) (IRR 5.49 (95% CI 5.02-6.02) P-value <0.001), EPTB (IRR 0.84 (95% CI 0.35-2.03) P-value <0.001) but not amongst those who have had PTB (IRR 1.09 (95% CI 0.62-1.93) P-value 0.77) when compared to those who have not had TB. The rate of T2DM was increased amongst those who have had TB (all sub-types) (IRR 2.21 (95% CI 1.68-2.91) P-value <0.001), PTB (IRR 5.38 (95% CI 4.73-6.12) P-value <0.001) and EPTB (IRR 4.36 (95% CI 3.65-5.22) P-value <0.001) when compared to those who have not had TB. However, within THIN dataset these estimates of association were being promoted by a significant age by TB interaction effect. Utilising systematic review techniques, twenty five studies were identified which reported upon TB outcomes amongst those with compared to without DM. Meta- analyses showed individuals with co-morbid TB and DM had no significant difference in bacterial clearance rate after 2-3 months of treatment (1,675 participants, 6 trials, Relative Risk (RR) 1.38 (95% CI 0.97-1.97)), no significant difference in risk of TB recurrence & relapse (1,225 participants, 4 trials RR 1.20 (95% CI 0.93-1.54)), but a statistically significant increased risk of all cause mortality (12,128 participants, 18 trials, RR 1.97 (95% CI 1.53-2.55)) comparative to those with TB in isolation. Discussion TB risk is increased in those with compared to those without DM within a UK setting. However, it remains unclear if risk of PTB and EPTB are raised amongst those with DM comparative to those without. It also remains unclear as to whether risk of DM is increased amongst those who have had TB comparative to those who have never had TB. Individuals with co-morbid disease are at a greater risk of mortality during active TB disease than those with TB alone, however risk of TB relapse and recurrence are the same. Consideration of the association between DM and TB may become more important for improving TB control and TB treatment as DM prevalence rises in the UK and globally. In areas where TB is endemic TB screening amongst those with DM and TB prophylaxis may be needed to reduce or stabilise numbers developing active disease. Also, the increasing numbers suffering from co-morbid TB and DM will need heightened clinical attention in order to improve TB mortality outcomes.