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The association of diabetes (DM) with tuberculosis (TB) is a re-emerging problem because of the rapid rise worldwide of type 2 DM.1–7 There is evidence that TB patients with DM may have higher bacillary loads than patients with TB without DM, but others have not confirmed these observations.8–12 The impact of DM on reduction in bacillary load during TB treatment and the potential for transmission is also unclear. In the light of this uncertainty, we sought to determine whether TB patients with DM patients were more likely to take longer to clear the bacterium from sputum during the first phase of treatment than TB patients without DM.
We accessed a large retrospective dataset containing sociodemographic and culture data from all TB patients reported to south Texas between 1996 and 2002 and selected all TB patients recorded with positive sputum culture. Ethical approval for the study was obtained from all participating institutions.7 All patients received standard "directly observed therapy, short course" (DOTS): isoniazid (5–10 mg/kg), rifampin (10 mg/kg), pyrazinamide (15–30 mg/kg), and ethambutol (15–25 mg/kg) during the first 2 months (first phase) and isoniazid and rifampin for the following 4 months (second phase). At 2–4 weeks, most patients are switched from daily to twice weekly dosing. Sputum specimens were taken at the time of diagnosis and monthly thereafter, provided the patient had a productive cough. Culture was performed on Lowenstein-Jensen medium and either Bactec radiometric method or the mycobacteria growth indicator tube (MGIT; Becton-Dickinson, Franklin Lakes, NJ). Demographic information, self-reported social and medical risk factors for TB, clinical and radiological characteristics of TB disease at diagnosis, and treatment outcome for each TB patient were recorded. Microbiology records were generated by the laboratory only when a specimen was received.
Because our preliminary data indicated that impaired clearance in TB patients with DM was concentrated in the first phase of DOTS, we focused on the first 60 days of treatment.7 The dates of treatment initiation and the dates of collection of specimens that yielded the last positive and first negative cultures for a given patient were established.7 We calculated the time (in days) for culture conversion from positive to negative (time to clearance [TTC]) for each patient (days between the treatment initiation date and the date of collection of the first negative culture, provided there were no subsequent positive cultures; no censoring). When records showed only positive cultures or the last culture was positive, the data were censored, and the TTC was calculated as the number of days between the last positive culture and the treatment start date. We removed 69 patients with positive HIV serology because this infection independently impairs clearance and 66 non-compliant patients who did not complete treatment for the same reason. The dataset thus generated contained 469 adult TB patients (age 
20 years).7
All data analyses were performed using SAS version 9.1 (Cary, NC). We first used descriptive statistics to compare TB patients with DM and TB patients without DM, followed by the Kaplan-Meier method and the log-rank test to compare the distribution of TTC between the two groups.13 Potential associations between the culture TTC and other independent variables were also explored. Because TTC is not normally distributed, and estimation of means may be biased because of censoring, we report median TTC. The Cox proportional hazard mode was used to identify any interactions and potential associations after adjusting for other covariates.14 Variables entered into the final model included age, sex, and any variable from the univariate analysis with P < 0.1. We conducted stepwise removal of the least significant independent variable, leaving only those with P < 0.05. We estimated adjusted hazard ratios and their 95% confidence intervals (CIs) as a measure of association between DM status and culture TTC.
The characteristics of the TB patients did not differ from those described previously (Table 1
).7 Briefly, DM patients were more likely to be older women with no classic social risks for TB (e.g., jail, drug and alcohol abuse) and were also more likely to be smear positive at diagnosis. Table 2 shows the comparison of median time to clearance using univariate and a stepwise multiple regression model. During the first 60 days of treatment, the median culture TTC was longer for patients with DM (42 days for TB patients with DM versus 37 days for TB patients without DM; P = 0.03; Table 2; Figure 1). DM status continued to be significantly associated with delayed bacterial clearance in TB patients with DM compared with TB patients without DM (Table 2), after controlling for possible confounders.
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Our findings are consistent with our previous observation and those of others, of higher bacterial load in patients with TB patients with DM at diagnosis and during the first or second months of treatment but not thereafter.7,21 It is likely that the observed delay in TTC during the first 2 months of treatment among DM patients is related to the increased likelihood of them being smear positive at diagnosis (a well-recognized predictor of delayed bacterial clearance during treatment).20–22 Consistent with this observation, we found that TB patients who did not clear until the second month were more likely to have DM (P = 0.001) and be smear positive (P = 0.02) than those who cleared in the first month. Indeed, the association of smear positivity with delayed TTC was so strong that it masked all other effects. For this reason, we excluded smear positivity from our final model so that we could determine the importance of DM as an underlying pathology.
Possible biological explanations for delayed TTC in the first phase of treatment in DM patients include higher bacterial burden at diagnosis, which could be related to slower kinetics in the immune response in DM patients. Delayed interferon (IFN)-
response has been observed in a mouse model of TB and DM and in TB patients with DM.23–25 Altered metabolism of rifampin in TB patients with DM is also a possible explanation.26
We examined the effect of multi-drug resistant (MDR)-TB, but in patients who clear M. tuberculosis within 2 months, rates of MDR-TB did not differ by diabetes status. Not unexpectedly, however, if we look at the effect of MDR-TB between 2 and 9 months of initiation of treatment, we do see significant delay in M. tuberculosis clearance among patients with MDR-TB (data not shown). A report from Indonesia found a delay in culture clearing in TB patients with DM patients at 6-month follow-up, but they took no account of MDR-TB, which may have biased their results.4
The major limitation of this study is that it used retrospective data, in which DM classification is based on self-reporting. However, this would likely lead to some undiagnosed DM patients being included in the group not reporting DM. This would tend to reduce the observed difference. Missing follow-up data were also a limitation for survival analysis, particularly the fact that failure to produce sputum as the patient improved was not recorded. Nevertheless, we censored < 50% of the data, which is acceptable for survival analysis for estimating the median TTC. Shorter time intervals between specimens would also have provided more precision.
Despite the goal of global TB eradication by the year 2050, in 2004, there were an estimated 8.9 million new cases of TB worldwide.27 Our data showed that DM seems to interfere with sterilization of pulmonary TB by drug therapy. By 2030, it is estimated that 336 million of the worlds’ population will have DM, many in TB-endemic countries.1 DM on this scale may impact TB control. Prospective studies are needed to define more clearly the consequences for transmission among DM patients and the measures that might be taken to lessen the effect.
Received November 13, 2007. Accepted for publication June 26, 2008.
Acknowledgments: The authors thank the members of the NSTT (www.nstt.info) in south Texas and the members of the Division of Tuberculosis Elimination at the Texas Department of State Health Services who contributed to this study by collecting and entering data and by processing and reporting routine microbiological reports. We also acknowledge the statistical consulting work performed on this paper through a subcontract with Universal Statistical Technology and Training (USTAT), based in Okemos, Michigan.
Financial support: This study was supported by NIAID 1 R21 AIO56207-01 and by the Hispanic Health Research Center EXPORT Grant NIHMHD P20 MD000170 020.
* Address correspondence to Susan P. Fisher-Hoch, Division of Epidemiology, University of Texas School of Public Health, Brownsville, 80 Fort Brown, Brownsville, TX 78520. E-mail: susan.p.fisher-hoch{at}utb.edu 
Authors’ addresses: Blanca I. Restrepo, University of Texas Health Science Center Houston-School of Public Health, University of Texas at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, Tel: 956-882-5172, Fax: 956-882-5152, E-mail: Blanca.I.Restrepo{at}utb.edu. Susan P. Fisher-Hoch, University of Texas Health Science Center Houston-School of Public Health, University of Texas at Browns-ville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, Tel: 956-882-5167, Fax: 956-882-5152, E-mail: susan.p.fisher-hoch{at}utb.edu. Brian Smith, Texas Department of State and Health Services, Region 11, 601 W. Sesame Dr., Harlingen, TX 78550, Tel: 956-444-3202, Fax: 956-444-3298, E-mail: Brian.Smith{at}dshs.state.tx.us. Shangchoon Jeon, Nursing Research Center, 426B W Fee Hall, Michigan State University, East Lansing, MI 48823, Tel: 517-355-1851, Fax: 517-355-5002, E-mail: Sangchoon.Jeon{at}hc.msu.edu. Mohammed H. Rahbar, Center for Clinical and Translational Sciences, UT Professional Building, Room 1100.21, 6410 Fannin Street, Houston, TX 77030, Tel: 713-500-7901, Fax: 713-500-0766, E-mail: Mohammad.H.Rahbar{at}uth.tmc.edu. Joseph B. McCormick, University of Texas Health Science Center Houston-School of Public Health, University of Texas at Brownsville, 80 Fort Brown, SPH Bldg, Brownsville, TX 78520, Tel: 956-882-5166, Fax: 956-882-5152, E-mail: joseph.b. mccormick{at}utb.edu.
This article has been cited by other articles:
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  K. E. Dooley, T. Tang, J. E. Golub, S. E. Dorman, and W. Cronin Impact of Diabetes Mellitus on Treatment Outcomes of Patients with Active Tuberculosis Am J Trop Med Hyg, April 1, 2009; 80(4): 634 - 639. [Abstract] [Full Text] [PDF]
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