ORIGINAL ARTICLE Year : 2022  |  Volume : 11  |  Issue : 4  |  Page : 400-406

Pulmonary tuberculosis and diabetes mellitus: Clinical profile and outcomes

John Titus George1, Angel T Miraclin1, Sowmya Sathyendra1, Joy Sarojini Michael2, Jasmin Prasad3, Grace Rebekah4
1 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Community Health, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission09-Sep-2022Date of Decision12-Oct-2022Date of Acceptance17-Nov-2022Date of Web Publication10-Dec-2022

Correspondence Address:
John Titus George
Department of Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijmy.ijmy_154_22

Background: India is endemic for Tuberculosis (TB), contributing to the world's highest number of active cases. Diabetes (DM), with its increasing burden in India, could contribute to adverse outcomes among patients with TB. Methods: Consecutive patients with sputum smear positive pulmonary tuberculosis were included in the study. We defined cases as those patients with diabetes at recruitment. Controls were non diabetics (NDM). Sputum samples for AFB smears, AFB culture and Xpert PCR along with blood samples for glycosylated Haemoglobin and glucose levels were collected at recruitment and at 6 months from patients with sputum positive pulmonary TB. Blood glucose levels and sputum smears were repeated at 2 months and monthly till they tested negative. The primary outcome studied was mortality at 6 month follow-up. The secondary outcomes included the time to conversion of sputum smears and cure rates between cases and controls. Results: We recruited 124 patients of which 68 were cases. Mortality after therapy was 15% in cases and 7% in controls, however, the difference was not statistically significant. Equal proportions in each group (Diabetics: 9% vs. NDM 9%) had persistent smear positivity at 2 months. There was no association between delayed sputum conversion and uncontrolled diabetes. Only about 57% of cases and 50% of controls were documented to have completed treatment or been cured. A significant reduction in HbA1c after 6 months of Antituberculous therapy was noted among the cases. [Mean difference – 1.76, P-value – 0.001, 95% CI of difference – (1.01 – 2.52)]. Conclusions: Diabetes did not have adverse outcomes in the form of increased mortality or delayed sputum conversion rates. The high proportion of loss to follow-up seems to be a trend of concern, which should be addressed emergently.

Keywords: Diabetes mellitus, glycaemic control, outcomes, pulmonary tuberculosis

How to cite this article:
George JT, Miraclin AT, Sathyendra S, Michael JS, Prasad J, Rebekah G. Pulmonary tuberculosis and diabetes mellitus: Clinical profile and outcomes. Int J Mycobacteriol 2022;11:400-6
How to cite this URL:
George JT, Miraclin AT, Sathyendra S, Michael JS, Prasad J, Rebekah G. Pulmonary tuberculosis and diabetes mellitus: Clinical profile and outcomes. Int J Mycobacteriol [serial online] 2022 [cited 2022 Dec 12];11:400-6. Available from: https://www.ijmyco.org/text.asp?2022/11/4/400/363157   Introduction 

India has a significant burden of diabetes mellitus (DM) with an age-adjusted prevalence of 9.6%. These numbers are only bound to increase with lifestyle changes leading to an increasing prevalence of DM in the country.[1],[2] DM has been shown to impair the innate and adaptive immune responses necessary to counter chronic infections like tuberculosis (TB).[3],[4],[5] Nearly 44% of the 10 million new cases of TB detected globally in 2018 were from South East Asia.[6],[7] Around 40% of the Indian population is estimated to be infected with Mycobacterium tuberculosis bacilli and the vast majority have latent rather than active TB. Around nine lakh people were diagnosed to have sputum-positive TB in India in 2014. One-fourth of the global incident TB cases occur in India annually.[8],[9],[10] Diabetics have a threefold risk of developing active TB.[11] It has been suggested that in India, DM contributes to 20% of those with sputum-positive pulmonary TB (SPPTB).[12] DM can lead to poor treatment outcomes in patients with TB; however, the evidence for the same is contradictory.[13],[14],[15],[16],[17],[18] Hence, we conducted a prospective observational study to assess and compare the treatment outcomes and sputum conversion rates among patients with SPPTB with and without DM. We also planned to study the effects of glycemic control on treatment outcomes.

  Methods 

This single-center prospective observational cohort study was conducted in a tertiary care center in South India. All patients with SPPTB were consecutively recruited from the outpatient department and inpatient wards of the Departments of General Medicine and Community Health from March to December 2017 and were followed up for 6 months. We planed to assess mortality, treatment outcomes, and sputum conversion rates among patients with SPPTB with and without DM. We also planned to study the effects of glycemic control on treatment outcomes. This study was approved by the Institutional Review Board, number-10518, date–February 1, 2017.

All adults more than 18 years of age newly diagnosed to have bacteriologically confirmed pulmonary TB were recruited after written informed consent was obtained. Patients with human immunodeficiency virus infection, resistance to any of the first-line antituberculous agents, or pregnancy were excluded.

At recruitment, sputum acid-fast bacilli (AFB) smears, AFB culture, Xpert TB polymerase chain reaction (PCR), and chest X-ray reports were documented. Blood was drawn to estimate glycosylated hemoglobin A1c (HbA1C) and glucose levels for all patients. We defined cases as those patients with DM (if they were previously diagnosed or if they fulfilled the American Diabetic Association Classification for the Diagnosis of DM). Nondiabetic (NDM) patients were considered controls. Patients were assessed at 2 months, wherein sputum AFB smears and blood glucose levels were documented. Those with sputum AFB smear positivity were followed up monthly till sputum smears were negative. At 6 months, sputum AFB smear, AFB culture, Xpert TB PCR, HbA1C, and blood glucose levels were repeated.

The outcomes which were looked at were delayed sputum conversion as defined as a positive sputum AFB smear at 2 months and treatment outcomes. All the case definitions for TB were as per the World Health Organization (WHO) definitions and reporting framework for TB.[19] The outcomes in patients with DM were compared with those without DM.

The treatment success rate among the nondiabetic TB patients was assumed to be 90% (based on Revised National Tuberculosis Control Program reports). Assuming a 75% treatment success rate among diabetics with TB, with a power of 90% and confidence level of 95%, a sample size of 109 patients in each group was calculated. Hence, a total of 220 patients were planned to be recruited.[20]

Data entry was done using EpiData software version 3.1. Descriptive and inferential statistical analyses were done using SPSS version 23 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.). Bivariate and multivariate analysis of data and appropriate tests of significance were employed. P ≤ 0.05 was considered statistically significant to refute the null hypothesis.

  Results 

We recruited 130 patients with newly diagnosed TB. Six patients were excluded as they were found to have drug resistance at 2 months [Figure 1]. Of the 124 newly diagnosed SPPTB patients, [Figure 1] 68 patients (54.8%) had DM and 56 (45.2%) were NDM. The baseline demographic details [Table 1] were comparable among the diabetics and NDM. There was a male predominance in both the DM and NDM groups. The patients in the DM group were on an average, 13.4 years older than those in the NDM group. The number of patients from rural and urban areas was comparable in both the groups. Most of the patients were from the upper and lower middle classes in both the groups. The most common symptoms among the patients were cough, expectoration, loss of appetite, loss of weight, and fever. Extrapulmonary TB was recorded in 19% of the NDMs and 9% of the DM. The DM patients had a higher number of patients with a history of smoking. The mean weight and body mass index (BMI) were significantly lesser in the NDM group. There was no difference in the bacillary load in the sputum in both the groups. The NDM group had a significantly lower albumin level as compared to the DM group. The mean duration of diabetes among the diabetics was 5.6 years and only <10% of these patients were newly diagnosed to have DM. Around 25% of the patients required insulin. Uncontrolled DM was noted in 75% of the DM patients. At least one complication of DM was seen in 38% of the diabetics. 15% mortality was noted in the DM group compared to 7% mortality in the NDM group which was not statistically significant. Similar proportions in each group (diabetics: 9% vs. NDM 9%) had persistent smear positivity at 2 months. No significant association between DM and sputum smear conversion was noted. Furthermore, uncontrolled DM did not have a significant effect on delayed sputum conversion.

In the DM group, 57% and 50% in the NDM group were either cured or had completed treatment successfully [Table 2]. There was no significant difference in treatment completion or cure in between the groups (P = 0.47, respiratory rate –1.14, 95% confidence interval [CI]–[0.83–1.6]). Nine diabetic patients and six nondiabetic patients had completed treatment but were unable to produce sputum at 6 months. Hence, in accordance with the WHO case definitions, their outcomes were taken as “treatment completed.”

The outcomes in patients who were not followed up at 6 months but were sputum negative at any point in time before the 5 month were taken as “treatment completed” as per the WHO case definitions. The treatment outcomes of 28% and 43% of the patients in the DM and NDM group, respectively, were classified as “not evaluated,” according to the WHO classification.

There was a significant reduction in mean HbA1c from 9.5% at recruitment to 7.8 at 6 months, in the DM group while receiving ATT (P = 0.001, mean difference – 1.76 95% CI of difference – [1.01–2.52]). The median HbA1c at enrolment and 6 months in the DM group was 9.4%, and 7.3% respectively.. However, only 27 patients with DM could be evaluated at 6 months. The mean HbA1c at enrolment and at 6 months was 5.4% (median Hba1c at both enrolment and 6 months was 5.4%) in the NDM group. Only 41 (60%) diabetics and 30 (53%) nondiabetics had followed up at 2 months and only 27 (40%) and 23 (40%) patients had reviewed at 6 months, respectively. This highlights the loss to follow-up and is a significant finding as noncompliance and irregular treatment/follow-up contributes significantly to the interplay between TB and DM and can lead to poor outcomes.

  Discussion 

In our study, among 68 diabetics and 56 NDM with newly diagnosed SPPTB, we did not observe a significant difference in mortality rates between the diabetics (15%) and NDM groups (7%). There was also no significant difference in the proportion of patients with delayed sputum conversion between the diabetics and the NDM groups. The treatment outcomes studied were also comparable in the DM and NDM groups. Similar to our study, a few studies also reported no negative effects of DM on TB treatment success, sputum conversion and mortality.[21],[22],[23] However, a few other studies showed contrasting reports as elaborated below. Baker et al., in a systematic review of literature, estimated a pooled relative risk of 1.69 (95% CI, 1.36–2.12) for treatment failure and death among patients with both TB and DM, when compared to those with TB without DM.[24] Another study from Taiwan, also noted an elevated risk of unfavorable outcomes and 1 year mortality among TB patients with DM when compared to those without DM.[25] A study from India also showed a longer duration for sputum conversion TB patients with DM when compared to those without DM. Higher treatment failures were also noted in this study.[26]

A significantly lower average weight and BMI was noted in the NDM group when compared with the DM group in our study. We could hypothesize that the degree of immunosuppression caused by DM was as severe as the immunosuppression due to undernutrition in the NDM group, which could have led to an increased risk of developing active TB. Factors contributing to this level of immunosuppression in diabetics need to be studied.

The pathogenic mechanisms involved in the role of DM in TB is unclear, but a few studies have highlighted the dysfunctional innate and adaptive immune responses in patients with DM and TB.[3],[5],[27],[28] Reduced production of interferon gamma and interleukin (IL)-12 has also been documented in diabetic patients with TB. The immunomodulatory effects of insulin, whereby it reduces the Th1 immunity and downregulates the production of proinflammatory cytokines has also been implicated as a potential mechanism.[3] Altered phagocytic function of alveolar macrophages in patients with TB and DM has also been demonstrated in a few studies.[29]

Worsening of glycemic control necessitating the use of insulin and drug interactions between antitubercular therapy (ATT) and oral antidiabetic agents have been demonstrated in patients with DM and TB.[30],[31] A state of insulin resistance and reduced production of insulin secondary to the production of inflammatory cytokines like IL-6 and tumor necrosis factor alpha has been noted in patients with TB and DM. The association between poor glycemic control and increased sputum AFB load, cavitary lesions, and increased risk of DM has been reported in a few studies, which was not demonstrated in our study[21],[32],[33] The significant reduction in mean HbA1c before and after treatment of TB in diabetics, in our study, highlights the impact of TB treatment on glycemic control (mean difference – 1.76, 95% CI of difference – [1.01–2.52] P = −0.001]. Similar findings were demonstrated in two studies from India.[23],[34] In diabetics with TB, The effects of antituberculous therapy on glycaemic control have not been studied appropriately, to the best of our knowledge and is an avenue worth exploring.

Although our study did not show worse outcomes in patients with DM and TB, the point that needs to be highlighted is the low rate of follow-up in patients with TB. This agrees with unpublished retrospective data from our center, which also showed a significant loss to follow-up among patients with TB. This probably leads patients to stop therapy and can worsen the existing disease itself and also contribute to the burden of multidrug drug resistant TB.

The need of the hour is a vigorous program by which all patients with TB need to be meticulously followed up. In this era of digital communication and networking, a new method of directly observed treatment short course, wherein patients can be followed up, reminded about appointments over phone calls, messages, or by creating appropriate patient apps may be considered.

  Conclusions 

In this study, we demonstrated that there was no difference in the mortality rates, rates of delayed sputum conversion, and rates of cure or treatment completion among diabetic and nondiabetic patients with SPPTB. We also could not demonstrate any association between poor glycemic control and delayed sputum conversion or mortality.

Limitations of the study

There was a significant loss to follow-up in this study, which led to outcome data being unavailable in some patients. Furthermore, we were unable to achieve the target sample size. We also did not compare other outcomes such as dissemination of TB, recurrence, relapse, duration of treatment and stay, requirement of prolonged therapy, hospitalization, and change in ATT regimens, which could also contribute to different outcomes.

Ethical statement

This study was approved by the Institutional Review Board number-10518, Date – February 1, 2017. Informed consent was obtained from all patients prior to recruitment.

Acknowledgments

The authors would like to thank Dr. Alice Joan Mathuram, Dr. Vignesh C.V, Dr. O. C. Abraham, Dr. Ramya. I, and Dr. Asha Elizabeth Mathew for their valuable comments and input.

Financial support and sponsorship

This study was supported by Fluid Research Grant of Christian Medical College, Vellore, Tamil Nadu, India. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1]
 
 
  [Table 1], [Table 2]