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The Effect of Type 2 Diabetes Mellitus on the Presentation and Treatment Response of Pulmonary Tuberculosis

  1. Bachti Alisjahbana1,
  2. Edhyana Sahiratmadja3,
  3. Erni J. Nelwan4,
  4. Anugrah Maya Purwa1,
  5. Yana Ahmad1,
  6. Tom H. M. Ottenhoff5,
  7. Ronald H. H. Nelwan4,
  8. Ida Parwati2,
  9. Jos W. M. van der Meer6, and
  10. Reinout van Crevel6
  1. 1Internal Medicine Department, Medical Faculty, Padjadjaran University, Bandung, Indonesia
  2. 2Clinical Pathology Department, Medical Faculty, Padjadjaran University, Bandung, Indonesia
  3. 3Eijkman Institute of Molecular Biology, University of Indonesia, Jakarta, Indonesia
  4. 4Infectious Disease Working Group, Medical Faculty, University of Indonesia, Jakarta, Indonesia
  5. 5Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden
  6. 6Department of Internal Medicine, Radboud University Nijmegen Medical Center, The Netherlands
  1. Reprints or correspondence: Dr. Reinout van Crevel, Dept. of Internal Medicine, Radboud University Medical Center Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands (r.vancrevel{at}aig.umcn.nl).
 
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Abstract

Background.Diabetes mellitus (DM) is a known risk factor for tuberculosis (TB), and with the increasing prevalence of type 2 DM in less developed regions, many patients with TB will have concomitant DM. Presently, little is known about the effect of DM on the clinical presentation and treatment outcome of TB.

Methods.In an urban setting in Indonesia, 737 patients with pulmonary TB were screened for DM and were followed up prospectively during TB treatment. Clinical characteristics and outcome were compared between patients with TB who had DM and patients with TB who did not have DM.

Results.DM was diagnosed in 14.8% of patients with TB and was associated with older age and a greater body weight. On presentation, diabetic patients with TB had more symptoms but had no evidence of more-severe TB. After 2 months, results of sputum microscopic examination was more often positive in diabetic patients (18.1% vs. 10.0%). After 6 months, 22.2% of cultured sputum specimens from diabetic patients were positive for Mycobacterium tuberculosis (adjusted odds ratio, 7.65; P = .004).

Conclusion.DM seems to have a negative effect on the outcome of TB treatment. The underlying mechanisms for the different response to treatment in diabetic patients with TB must be explored. Screening for DM and subsequent glycemic control may improve the outcome of TB treatment.

Diabetes mellitus (DM) was a well-known risk factor for tuberculosis (TB) in the past [1, 2], but this was largely forgotten during the second half of the 20th century, with the advent of widely available treatment for both diseases. Now, with the current global increase in cases of type 2 DM [3], the association between TB and DM is re-emerging. The greatest increase in cases of type 2 DM will occur in developing countries, where TB is highly endemic [3]. As a result, a growing number of patients with TB worldwide will present with DM. Indeed, recent studies show that 10%–30% of patients with TB may also have DM [4,5,6,7,8–9]. We have confirmed the association between DM and TB in Indonesia, which has the third highest number of patients with TB [10] and the fourth highest number of persons with DM worldwide [3]. We previously found type 2 DM in 13.3% of patients with TB and 3.2% of age-matched control subjects (OR, 4.7; 95% CI, 2.7–8.1) [4].

With regard to the possible effects of DM on the presentation and outcome of TB, recent data are more scarce. In the era before insulin therapy, patients with DM appeared to be doomed to die of pulmonary TB if they survived the diabetic coma [2]. After the introduction of insulin in 1922, TB remained a serious and deadly threat to patients with DM [1], but with effective anti-TB treatment, their prognosis improved dramatically [11]. More recent studies exploring the possible effects of DM on the presentation and outcome of TB have had conflicting results [7, 9, 12]. In a prospective cohort study in an Indonesian region, we examined whether DM was associated with more-severe TB or with a less favorable response to treatment.

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Methods

Study design and patient population.In a prospective cohort study, we included consecutive new patients with pulmonary TB who were aged ⩾15 years and who presented at 3 outpatient TB clinics in Jakarta and Bandung in Indonesia from October 2000 through December 2005. Diagnosis of TB was made on the basis of clinical presentation and chest radiograph findings and was confirmed by microscopic detection of acid-fast bacilli. All patients with confirmed TB were screened for DM by measurement of fasting blood glucose (FBG) concentrations. No anti-DM agents were received within 48 h before blood samples were obtained, and DM was diagnosed if the FBG concentration was >126 mg/dL at 2 different time points; FBG concentrations of 110–126 mg/dL were considered to indicate impairment, in accordance with international criteria [13]. In all patients, we measured FBG concentrations before and after 1 month of anti-TB treatment. TB treatment consisted of a standard regimen of daily rifampicin, isoniazid, pyrazinamid, and ethambutol for 2 months (the intensive phase) and rifampicin and isoniazid for another 4 months (the continuation phase), according to World Health Organization guidelines [14]. In accordance with national guidelines, patients in whom DM was established initiated oral anti-DM drugs after 2–4 weeks of TB treatment. No patient received insulin. Written informed consent was obtained from all subjects, and the study was approved by the ethical committee of the Faculty of Medicine, University of Indonesia, Jakarta, and the Faculty of Medicine, Padjadjaran University, Hasan Sadikin Hospital, Bandung, Indonesia.

Patient characterization and follow-up.Signs and symptoms were recorded before the initiation of TB treatment, and additional history was obtained for the presence of DM or DM treatment, previous TB treatment, TB contacts, other comorbidities, and medication use. A symptom score (0–6) was calculated on the basis of the presence of cough, hemoptysis, dyspnea, fever, night sweats, and weight loss (1 point for each item). Patients with a symptom score >4 were classified as having highly symptomatic disease. The performance status of each patient was determined by field physicians, using the Karnofsky index, based on questioning of the patient and, if possible, the patient's family or friends [15]. A Karnofsky score of 80% corresponds with the inability to do work or perform normal daily activities. For evaluating disease severity, we used sputum mycobacterial load measurements, chest radiograph findings, and anemia and blood inflammatory markers. Microscopic examination of Ziehl-Neelsen–stained sputum slides was performed for acid-fast bacilli, and sputum mycobacterial load was graded as +, ++, or +++ [14]. Culture for Mycobacterium tuberculosis was performed on Ogawa 3% medium, and M. tuberculosis drug-susceptibility testing for rifampicin and isoniazid was performed using an absolute concentration method with supranational control. This method has shown to have an accuracy of 96%–100% in 10 rounds of World Health Organization/International Union Against Tuberculosis and Lung Disease proficiency testing [16]. Examination of blood samples included a C-reactive protein level measurement, complete blood count, liver and kidney function testing, and HIV testing (Determine dipsticks; Abbott). Anemia was defined as a hemoglobin concentration <12 mg/dL (in female patients) or <13 mg/dL (in male patients). Chest radiographs were read independently by 2 experienced professionals, and abnormalities were classified as mild, moderate, or severe [17]. Persons involved in clinical scoring, microscopic examination reading, and chest radiograph examination were unaware of the patients' DM classifications.

We followed up with patients biweekly during the intensive phase and monthly thereafter. History, physical examination, blood testing, and microscopic examination and culture of sputum samples were repeated after the intensive phase (at 2 months) and at the end of treatment (at 6 months). We measured adherence by interview and pill count. In accordance with the national TB program, specific definitions were used to classify treatment response and outcome [10].

Data analysis and statistics.We compared findings for patients with TB who had DM with findings for patients with TB who did not have DM. We used Pearson's χ2 test to compare ratios, Student's t test for normally distributed continuous variables, and nonparametric Mann-Whitney U test for nonnormally distributed continuous variables. Univariate and multivariate logistic regression were used to calculate ORs for factors associated with disease presentation and bacteriological response at 2 and 6 months after initiation of TB treatment. Study site and patient age, sex, and body mass index (BMI; calculated as the weight in kilograms divided by the square of height in meters; which is associated with DM), as well as parameters that are logically related to the end points analyzed, were included as independent variables in logistic regression models. Data were analyzed using SPSS, version 12.01 (SPSS).

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Results

Patient characteristics.Of 737 new patients with TB who were screened, 15 were excluded because of HIV seropositivity (n = 7), other comorbidity (n = 7), or missing data (n = 1). An additional 88 patients were excluded because of FBG concentrations indicating impairment (110–126 mg/dL; n = 29) or undetermined status of DM (1 measurement only; n = 59). All of the remaining 634 patients had positive sputum microscopic examination results. Five hundred thirty-four (92.1%) of 580 patients had culture results that were positive for M. tuberculosis. Of 634 patients, 540 had normal FBG concentrations, and 94 patients (14.8%) received diagnoses of concomitant DM. The prevalence of DM among patients with TB was 17.1% in Jakarta and 11.6% in Bandung. DM was newly diagnosed in 57 patients (61.3%) and was confirmed to be type 2 DM. No insulin deficiency was found in 14 randomly selected diabetic patients (data not shown), and among patients with a history of DM, none were using insulin. As expected, patients with TB who had type 2 DM were older and had a higher BMI (table 1).

Table 1
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Table 1

Characteristics of patients with tuberculosis (TB) who had diabetes (DM) and patients with TB who did not have DM.

Disease presentation.There was a slight difference in disease presentation between patients with TB who had DM and patients with TB who did not have DM (table 1). Patients with TB who had DM presented with more symptoms and a lower performance status (according to the Karnofsky index). Symptom score and Karnofsky index did not show a statistically significant correlation. After adjustment for possible confounding factors, including age, sex, chest radiograph abnormalities (mild, moderate, or severe), sputum mycobacterial load (+, ++, or +++), and BMI, DM remained associated with a Karnofsky index ⩽80% (adjusted OR, 3.04; P < .001) and a symptom score >4 (adjusted OR, 2.90; P = .001; table 1).

Although patients with TB who had DM were more symptomatic, blood testing and bacteriological and radiological examination did not reveal more-severe disease in patients with TB who had DM (table 1). Diabetic patients revealed less anemia in univariate analysis, but after adjustment for other factors, including age, sex, BMI, and duration of disease, this association was no longer statistically significant (adjusted OR, 0.53; 95% CI, 0.27–1.03). Diabetic patients also had fewer pulmonary cavities and a slightly lower sputum mycobacterial load (table 1), but after adjustment for other factors, neither cavities (adjusted OR, 0.76; 95% CI, 0.39–1.48) nor mycobacterial load (OR, 1.71; 95% CI, 0.90–3.25) were significantly associated with DM. table 2 displays crude and adjusted ORs for all predictive factors examined for the Karnofsky index, symptom score, pulmonary cavities, anemia, and sputum mycobacterial load.

Table 2
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Table 2

All dependent variables at disease presentation examined in multivariate regression analysis.

Initial response to TB treatment.Twenty-four patients (3.8%) defaulted and 11 (1.7%) were transferred during the intensive phase of TB treatment. Among the remaining 599 patients, 2 patients with DM died within 2 months after initiation of treatment. Symptomatic improvement, weight gain, and reduction of blood inflammatory markers were similar in both groups (not shown). Treatment adherence was estimated to be 98% in the group of patients with TB who had DM and 91% in the group of patients with TB who did not have DM on the basis of patients' reports and pill counts. Microscopic examination of sputum samples at 2 months was performed for 593 patients; 18.1% of diabetic patients and 10% of nondiabetic patients had positive results (table 3). However, after adjustment for age, sex, BMI, study site, chest radiograph abnormalities, and sputum mycobacterial load before initiation of treatment, the association between DM and sputum smear positivity was no longer statistically significant (table 3). Sputum culture at 2 months, performed for 413 patients, was not associated with DM in either univariate or multivariate analysis (table 3).

Table 3
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Table 3

Treatment response and outcome of patients with tuberculosis (TB) with and without diabetes mellitus (DM).

Outcome after 6 months of treatment.During the continuation phase of TB treatment, 42 additional patients (7.0%) defaulted, and 11 (1.8%) were transferred. Adherence was similar in diabetic and nondiabetic patients (not shown). No more deaths were witnessed, and symptomatic improvement was similar in both groups. Microscopic examination of sputum samples at 6 months, performed for 532 patients, revealed positive results for 3.1% of control patients and was not associated with DM in univariate analysis or after adjustment for age, sex, BMI, sputum examination results at 2 months, drug resistance, and adherence (table 3). Severe chest radiograph abnormalities and positive sputum microscopic examination results at 2 months were the only factors that were significantly associated with positive sputum microscopic examination results at 6 months (table 4).

Table 4
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Table 4

All dependent variables at follow-up examined in multivariate regression analysis.

Sputum cultures after 6 months were performed for 360 (66.3%) of 543 patients; 6 patients with DM (22.2%) and 32 control patients (6.9%) still receiving treatment had positive culture results at this point. DM was significantly associated with positive sputum culture results after 6 months of treatment; this association remained after adjustment for age, sex, BMI, chest radiograph abnormalities, sputum mycobacterial load after 2 months, noncompliance, and drug resistance (adjusted OR, 7.65; P = .004; table 3). Besides DM, only sputum examination results at 2 months remained significantly associated with sputum culture results at 6 months (table 4).

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Discussion

In our study in Indonesia, we found type 2 DM in a significant proportion of patients with TB. Before the initiation of TB treatment, diabetic patients had more symptoms but had no evidence of more-severe TB on blood testing and on bacteriological and radiological examination. At the end of 6 months of TB treatment, DM was strongly associated with positive sputum culture results—even more so after adjustment for possible confounding factors.

Type 2 DM increases the risk of developing active TB [4,5–6, 18], but less is known about the possible effects of DM on the severity and outcome of TB. Recently, a number of studies have compared disease presentation between diabetic and nondiabetic patients with TB. Studies in Malaysia [19], Saudi Arabia [9], and Turkey [12] did not find major differences in presenting symptoms, but a recent, large study in the Mexico-Texas border region reported a higher rate of fever and hemoptysis among diabetic patients [7]. Of note, in that particular study, DM was self-reported, and patients were not systematically screened for the disease. Unlike our study, the cited studies provided relatively little information about possible confounding factors, which is unfortunate, because presentation is influenced by many factors, including age, sex, nutritional status, accessibility to health care (resulting in a delay in patient presentation), and comorbidity. We were able to correct for most of these factors and still found that diabetic patients had more symptoms than nondiabetic patients. Some of the symptoms should, therefore, be ascribed to DM itself (which was often untreated and poorly controlled). Similar to previous studies, we found a higher frequency of “atypical” images with fewer cavities in patients with DM [20,21–22], although other researchers have reported a higher frequency of pulmonary cavities in patients with DM [7, 23, 24].

The second hypothesis that we examined in our cohort was whether DM is associated with a less favorable response to TB treatment. Indeed, after 2 months of treatment, 2 patients with DM had died, and sputum microscopic examination results were more frequently positive among diabetic patients. However, after adjustment for possible confounding factors, the association between sputum microscopic examination results and DM was no longer statistically significant, and culture results at 2 months (a more important parameter) were not significantly associated with DM. The 2-month data should, therefore, be interpreted with caution. At 6 months, more than twice as many diabetic patients as nondiabetic patients had a sputum culture result that was positive for M. tuberculosis and DM remained a strong and independent prognostic factor after adjustment for possible confounding factors. Previous studies dealing with this subject have had conflicting results. Some studies found no effect of DM on TB cure rates [9, 19], and others did report significant effects on treatment outcome [25,26,27–28]. Similar to our findings, a recent large retrospective study involving the Texas-Mexico border region revealed a significantly higher rate of sputum smear positivity during the first months of treatment among patients with self-reported DM [7]. Importantly, none of these studies have used sputum culture results after treatment as an end point. Of note, other factors that may be related to treatment outcome, including incarceration, and drug or alcohol use [29], were absent in our cohort.

The conclusions of studies like ours very much depend on the quality of case definitions and proper evaluation of end points. We used strict definitions to establish or exclude DM. Diagnosis of DM in patients with pulmonary TB can be confounded by disease activity, but DM was confirmed by repeated measurement of FBG concentration during TB treatment and measurement of insulin in a subset of patients. In a recent study in the same region, the mean HbA1c was 10.5 for diabetic patients and 5.6 for nondiabetic patients (J. Stalenhoef, personal communication). We previously found that only 3% of cases of DM in patients with TB reverse after TB treatment [4].

With regard to end points, careful data collection was performed. Drop-out rates were very low, especially considering the region of this study. Sputum microscopic examination results were available for 93.8% of patients at 2 months and 84% of patients at 6 months. For sputum culture, which is not routinely performed in this region, results were available for 61.5% of patients at 2 months and 57.8% of patients at 6 months. On the basis of sputum microscopic examination results, the treatment failure rate was 3.1% in the control group; 5.9% of control patients who completed 6 months of treatment had a positive sputum culture result. These figures are comparable to results in a recent large trial in Africa that used a similar regimen [30]. All patients were tested for HIV infection, and HIV-seropositive patients were excluded from analysis. Possible confounding factors were recorded in detail and were accounted for. Unfortunately, no follow-up was performed after completion of treatment to see if DM was also associated with increased relapse rates.

If DM indeed has a negative effect on TB treatment, what could be the possible mechanism(s)? Noncompliance may lead to treatment failure, but treatment adherence was actually better among diabetic patients. Drug-resistance, another strong determinant of treatment failure in TB, was also lower among diabetic patients. We speculated about other possible explanations. In this respect, pharmacokinetic aspects of TB treatment may be relevant. The available evidence suggests that the efficacy of rifampicin is dependent on exposure to the drug or on the maximum drug concentrations achieved [31]. We have recently found that exposure (area under the curve, 0–6 h) to rifampicin was 2-fold lower in patients with TB who had DM than in patients who did not have DM [32]. Similar differences were found for the maximal plasma concentrations of rifampicin; the maximal plasma concentration of rifampicin was above the target concentration of 8 mg/L [33] in 6% of patients with TB who had DM, compared with 47% of patients who did not have DM. These pharmacokinetic differences might lead to easier acquisition of drug resistance and might explain the lower bacteriological response in diabetic patients with TB. Additional studies are needed to clarify these issues.

To summarize, we have examined the effect of type 2 DM on the presentation and outcome of pulmonary TB in an Indonesian region. DM was associated with more symptoms but not with increased severity of TB and had a negative effect on the outcome of anti-TB treatment. The findings of this study underline the need to improve the care of patients with concomitant DM and TB, especially in developing countries. Therefore, we advocate to screen patients with TB for DM, especially those aged >35 years. Prospective studies are needed to determine the effects of tighter glycemic control on TB treatment and outcome.

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Acknowledgments

We thank Dr. H. Danusantorso and Dr. M. Pangaribuan (Central Jakarta Tuberculosis Association Clinic, Jakarta, Indonesia), Prof. C. B. Sudjana Prawira (Hasan Sadikin General Hospital, Bandung, Indonesia), and Dr. H. B. Sampoerno (Bandung Tuberculosis and Lung Clinic, Bandung, Indonesia), for encouraging and accommodating research in their institutions. We are grateful for the assistance of Dr. M. den Heijer, H. Straetman, and C. Tack (Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands), for their consultation and input in the preparation of this manuscript.

Financial support.Royal Academy of Arts and Sciences (The Netherlands).

Potential conflicts of interest.All authors: no conflicts.

  • Received November 9, 2006.
  • Accepted March 24, 2007.
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  1. Clin Infect Dis. (2007) 45 (4): 428-435. doi: 10.1086/519841
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