Effect of Poor Glycemic Control in Newly Diagnosed Patients with Smear-Positive Pulmonary Tuberculosis and Type-2 Diabetes Mellitus

Introduction

According to the World Health Organization’s Global Tuberculosis Report 2014, TB continues to be the most important infectious disease in terms of incidence and mortality. Current estimates suggest that 9 million new cases and 1.5 million deaths have occurred in 2013.¹ India, with approximately 2-3 million new cases of TB, is the world’s largest TB epidemic country.^1,2 The incidence rate of TB in India is in the range of 160 to 180 per 100,000 population, which is a disproportionately high burden compared to other developing countries¹ Several risk factors have played, and will continue to play, a role in escalating this public health problem in India. One of the most important of these risk factors, the effect of which on TB was underestimated for several years in our country, is diabetes mellitus (DM) especially poorly controlled DM.

There is an accelerating pandemic of type-2 DM worldwide. Currently, 230 million people live with DM worldwide and it is anticipated that about 366 million could be affected by 2030. By that time, 80% of those will be living in low- and middle-income countries where active TB is widespread.^2-4 Eight of the ten countries with the highest incidence of diabetes are also classified as high burden countries for TB by the World Health Organization (WHO).⁵ The consequences of these converging epidemics led WHO to declare both DM and TB as global epidemics. The synergistic relationship between TB and DM has been creating a growing concern around the world. Recently, WHO and the International Union Against TB and Lung Disease (The Union) have acknowledged the need for international guidelines on the joint management and control of TB and DM. They have published a provisional collaborative framework for the care and control of both diseases.⁶ The recent estimates suggest that there were 20-30 million people in India with DM in 2000 and projected to reach as high as 80 million by 2030. India is advancing towards becoming the diabetic capital of the world, as every fifth diabetic in the world is an Indian. This surge in DM prevalence in India is severely affecting TB control program and the impact is similar to TB-HIV co-infection.^7,8

The prevention and treatment of both TB and DM present major public health challenges in all settings across the globe, particularly when DM is poorly controlled. Given the rising incidence trends of both diseases, it is generally important to understand the association in detail within this setting so that any relevant information can be utilized to aid local TB and DM prevention and control. Evidence from clinical practice and the literature suggests that approximately half of the most common chronic disorders like DM are undetected, that half of those detected are not treated, and that half of those treated are not controlled: the ‘rule of halves’ is still applicable in Indian population.⁹ In our country, a significant number of DM patients remain undiagnosed and also uncontrolled or poorly controlled after diagnosis. Several studies done in the past proved that DM is associated with increased incidence of TB, but studies linking poor glycemic control and the severity of TB are scarce. Therefore, the present study was planned to understand the impact of PGC pre-treatment on the severity of TB and TB treatment outcome in newly diagnosed pulmonary TB (PTB) patients with type-2 DM.

Patients and Methods

In this prospective study, 630 newly diagnosed smear-positive pulmonary TB (PTB) patients with DM were enrolled during January 2012 to December 2014. The patients were registered for treatment in the Departments of Pulmonary Medicine, Internal Medicine, Diabetes and Endocrine Department and DOTS centre (TB unit) at a tertiary care hospital. The diagnosis of smear-positive PTB was done according to the RNTCP (revised national tuberculosis control program in India, 2013) criteria and Type-2 DM according to guidelines from WHO. The exclusion criteria were pregnancy, HIV infection, connective tissue disorders, chronic renal failure, chronic liver disease, malignancies on long-term steroid or cytotoxic drug therapy, chronic alcoholics, and previously treated for TB.

Results

From the 7,400 TB suspects screened 1,935 new PTB cases were identified. In total, 774(40%) patients had concomitant type-2 DM (old or new). About 99 patients were excluded from the study, as they did not meet the inclusion criteria. During the follow-up, 45 patients out of the 675 were lost and the remaining 630 patients were analyzed. As shown in figure 1, 423 patients had HBA1c (poor glycemic control, PGC) level≥7% and 207 patients had HBA1c (optimal glycemic control, OGC) level<7%. There were 288 (68.09%) males in the PGC group and 135 (65.22%) in the OGC group. The demographic parameters of all the patients are listed in table 1.

Discussion

To the best of our knowledge, this is the first kind of study in India to directly compare manifestations of PTB in optimally controlled DM and poorly controlled DM and demonstrated that clinical manifestations of PTB in diabetic patients are related to pre-treatment HbA1C. The percentage of diabetic patients with symptoms and positive-smear was higher in patients with HbA1C>7%. Our study also demonstrated that the influence of DM on the outcome of TB treatment was proportionately related to pretreatment of HbA1C. These observations complement and extend the recently published study by Chiang et al.¹⁴ They established that the proportions of patients with any symptom, cough, hemoptysis, tiredness, and weight loss were entirely the highest in diabetic patients with PGC and these patients were significantly more likely to be smear-positive and remain smear-positive after 2 months of treatment. Our interpretations were in line with another study by Leung et al.¹⁵ They demonstrated that among patients with the results of sputum culture at 2 months of treatment, diabetic patients were significantly more likely to be culture-positive as compared with non-diabetic patients (adj. OR 1.63, 95% CI 1.14-2.34) and the association was significantly influenced by the level of HbA1c.

Current observations of more extensive lung disease, lung cavitations, and high positive sputum smears among PGC patients were in agreement with many of those reported in previous studies.^15,16 Noteworthy evidence from the current study was that the poor PGC was negatively associated with cure or treatment completion, even after controlling the baseline socio-demographic variables, comorbidities, extent of lung disease, lung cavitations, and bacteriology. Park et al.¹⁷ also established that uncontrolled diabetics have more cavities, high positive smear rates, and poor culture conversion after two months of therapy. Another interesting analysis by Webb and colleagues is worth mentioning, which showed a higher mean HbA1c among TB-DM in comparison to DM without TB. They also hypothesized that in patients with PGC (hazard ratio 1.39, 95% CI 1.18-1.63), per unit increase in HbA1c and contact with a TB source case (P=0.0011) was associated with prevalent TB disease.¹⁸

The present study confirms and complements the findings of Chiang et al.,¹⁹ stating that the proportions of patients with DM with any cavity, cavitatory lesions over upper lung field, cavitatory lesions over lower lung field, large cavity (>3 cm), and multiple cavities were all highest among patients with PGC. The atypical radiological findings of lower lung field lesions and multilobar involvement with far advanced tuberculosis, as noted in our PGC patients, have been significantly affected by HbA1c levels similar to findings in a study by Park et al.¹⁷ These atypical radiological manifestations will lead to a significant delay in TB diagnosis, which is a matter of serious concern. Clinicians should have a high degree of suspicion and should screen all such patients for DM and HbA1C.

The observations in our study, in spite of using standard four-drug short course regimens for drug-susceptible TB, were under a fully functioning treatment program setting that also allowed individualized regimen modification and treatment prolongation. Relapse rates were also as high as 16.5% in PGC when compared to 2.3% in OGC patients.

India TB-Diabetes Study Group (the corresponding author of the present article is also a member of the group) screened TB patients for DM. They found that the prevalence of DM in patients with TB in tertiary care hospitals was around 16% and as high as 20% in South India. They strongly recommended screening all TB patients for DM at all levels of health care facilities.^19,20 In our study, the proportion of patients with newly diagnosed DM was as high as 22.85%.

The effects of DM and PGC on clinical parameters (lung cavitations, positive sputum smear) and slower smear conversion after initiation of treatment emphasize a serious need for prevention of community-level transmission. In the current study, even for patients with initial drug-sensitive TB, the treatment completion rates fell substantially below the WHO target of 85% among poorly controlled DM patients. The high proportion of these patients also raises concern over the emergence of drug resistance and secondary spread within the community. In our study, we noted that 47 of 423 patients (11.11%) with poor control had MBR-TB confirmed either by culture or by the Xpert MTB/RIF technique.²¹ The emerging results from our study, as well as many studies discussed above, have demonstrated that a large number of DM patients with TB, despite successful treatment, still ran a substantially higher risk of developing active TB again compared with the overall TB risk in the general population. The unfavorable outcome in these TB patients with prolonged poorly controlled DM poses the risk of extended period of contagiousness and may transmit mycobacteria to their contacts for a longer period, both before the diagnosis and after the initiation of treatment.

DM is expected to delay the Millennium Development Goals of WHO. The Global Plan to Stop TB 2006-2015, established by the Stop TB Partnership, set the target for the elimination of TB by 2050 with a 50% reduction in prevalence by 2015. WHO global TB report 2013 highlighted that while significant progress is being made in many aspects of tuberculosis control, it is too slow and altogether off-target with only a 2% decrease in prevalence per year.^22,23 Such discouraging report highlights the urgent need for addressing important risk factors like DM, especially poorly controlled DM at all levels of health care services.²⁴ It is essential to note that interventions to decrease the prevalence of DM and optimal control of DM in patients with TB (or in the general population) may have an important impact on the incidence of TB and treatment outcome as well. In the absence of global guidelines on the collective management and control of TB and DM, national programs of all countries need to establish a coordinated response to these two diseases at both the organisational and clinical levels. It is also necessary to add DM prevention and control strategies to TB control programs and vice versa and to evaluate their effectiveness.

A major strength of our study is the prospective design, which avoided the problems of control selection in case-control studies and obscured temporality in cross-sectional studies. Availability of thorough DM and HbA1C details of all patients made it possible to demonstrate a clear relationship between PGC and PTB treatment outcome. The study is limited by the fact that it is a single-centre study, the results of which cannot be generalized. However, this provides a window of opportunity for clinicians and researchers to carry out further studies with the involvement of different geographical areas across India. In addition, studies can be performed to assess the impact of early screening for DM and HbA1C on TB treatment outcome in such high-risk patients. Our study was not powered to assess the relationship between poorly controlled DM and MDR-TB. It is essential to clarify, in a program setting by randomized controlled trials, many unanswered issues in this field (e.g. to what extent the unsatisfactory outcome of TB in DM patients can be prevented by optimal glycemic control?). Furthermore, glycemic status of patients after diagnosis and during the treatment was an important factor as this may affect the outcome of the study since post treatment HbA1c levels were not assessed. Our study was not powered to establish the association between PGC and MDR-TB. Further studies are needed to clarify the association between PGC and an increased risk of drug-resistant TB. In addition, extra-pulmonary and smear-negative pulmonary TB cases were not included in the study. Perhaps this has added to selection bias prevention.

Conclusion

Pre-treatment poor glycemic control is associated with a significant increased risk of advanced and more severe TB disease in the form of lung cavitations, positive sputum smear, and slower smear conversion after initiation of treatment. Poor glycemic control has a profound negative effect on treatment completion, cure, and relapse rates in patients with pulmonary tuberculosis with diabetes.

Conflict of Interest: None declared.