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Keywords:

  • tuberculosis;
  • diabetes;
  • mortality;
  • Africa;
  • prospective cohort study

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Objective

Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment.

Methods

A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined.

Results

There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5-month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co-infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates.

Conclusion

Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival.

Objectif

Des preuves solides suggèrent que le diabète pourrait être associé à la tuberculose (TB) et pourrait influencer les résultats du traitement antituberculeux. Nous avons évalué le rôle du diabète dans la conversion des cultures d'expectorations et sur la mortalité chez les patients sous traitement de la TB.

Méthodes

Au total 1250 patients tanzaniens atteints de TB ont été suivis prospectivement pendant le traitement de la TB avec une culture des crachats au bout de 2 et 5 mois. L’état de survie a été évalué au moins un an après le début du traitement. Au départ, tous les participants ont subi des tests pour le diabète et le VIH, et la concentration sérique de glycoprotéine alpha-1 (AGP) de la phase aiguë a été déterminée.

Résultats

Il n'y avait pas de différences entre les participants avec et sans diabète, concernant la proportion de cultures positives à 2 (3,8 vs. 5,8%) et à 5 (1,3 vs. 0,9%) mois (> 0,46). Cependant, chez les patients avec une culture TB positive, relativement plus de patients atteints de diabète sont décédés avant les 5 mois de suivi. Au cours des 100 premiers jours de traitement de la TB, le diabète était associé à un risque cinq fois plus élevé de mortalité (RR: 5,09; IC95%: 2,36–11,02; P < 0,001) chez les patients non infectés par le VIH et deux fois plus élevé chez les patients coinfectés avec le VIH (RR: 2,33, IC95%: 1,20–4,53; P = 0,012), tandis que le diabète n’était pas associé à la mortalité à long terme. Un ajustement supplémentaire selon l’AGP n'a pas modifié les estimations.

Conclusion

Le diabète augmente considérablement le risque de mortalité précoce au cours du traitement de la TB. L'effet ne peut pas être expliqué par la sévérité accrue de la TB, mais pourrait être dû à une réponse au traitement défaillant de la TB. Des recherches supplémentaires sont nécessaires pour clarifier le mécanisme et évaluer si le contrôle glycémique améliore la survie.

Objetivo

Hay evidencia que sugiere que la diabetes podría estar asociada con la tuberculosis (TB) y podría influenciar el resultado de su tratamiento. Hemos evaluado el papel de la diabetes sobre la conversión del cultivo de esputo y la mortalidad en pacientes recibiendo tratamiento para la TB.

Métodos

Se siguió de forma prospectiva a un total de 1250 pacientes Tanzanos con TB, realizándoseles un cultivo de esputo tras 2 y 5 meses. El estatus de supervivencia se evaluó al menos un año después de iniciar el tratamiento. Al comienzo del estudio a todos los participantes se les practicaron pruebas para diabetes y VIH, y se determinó la concentración en suero de la Alfa-1 glicoproteína (AGP), reactivo de fase aguda.

Resultados

No había diferencias entre los participantes con y sin diabetes con respecto a la proporción de cultivos positivos a los 2 (3.8 vs. 5.8%) y 5 (1.3 vs. 0.9%) meses (> 0.46). Sin embargo, entre aquellos pacientes con un cultivo positivo para TB, un número relativamente mayor de pacientes con diabetes murió antes de los 5-meses de seguimiento. Dentro de los 100 días iniciales de tratamiento de la TB, la diabetes estaba asociada con un aumento de cinco veces el riesgo de mortalidad (RR 5.09, IC 95% 2.36; 11.02, < 0.001) entre aquellos pacientes sin infección por VIH, y un aumento del doble entre los pacientes coinfectados con VIH (RR 2.33 IC 95% 1.20; 4.53, = 0.012), mientras que la diabetes no estaba asociada con una mortalidad a largo plazo. Un ajuste posterior con respecto al AGP no afectó los resultados.

Conclusión

La diabetes aumenta considerablemente el riesgo de una mortalidad temprana durante el tratamiento para la TB. El efecto podría no explicarse por un aumento en la severidad de TB, pero podría estar relacionado con un deterioro en la respuesta al tratamiento para la TB. Es necesario investigar para clarificar el mecanismo y evaluar si el control de la glicemia mejora la supervivencia.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The double burden of infectious and chronic diseases in low-income countries is becoming a global health problem. Due to the nutrition and lifestyle transition, that is, increased intake of refined sugar and fat in combination with physical inactivity (Kuhnlein & Receveur 1996; Torun et al. 2002; Yajnik 2004), even among the poor, those already burdened by infectious diseases are now also at risk of chronic metabolic diseases.

In 2011, around 366 million people had diabetes, of whom 4 million died of diabetes-related causes (Roglic & Unwin 2010; Whiting et al. 2011). By 2030, the number of people with diabetes is projected to reach 552 million (Whiting et al. 2011). The increase is mainly driven by changes in low- and middle-income countries, which also harbour 95% of the global burden of TB. This is of particular concern, as there is evidence to suggest that diabetes increases the risk of TB (Jeon & Murray 2008; Young et al. 2009), which will further encumber already burdened TB control programmes.

Diabetes may also worsen the clinical manifestations and treatment outcomes of TB (Dooley & Chaisson 2009; Ruslami et al. 2010a; Baker et al. 2011). More specifically, a couple of studies have reported more severe manifestations of TB in people with diabetes (Wang et al. 2005, 2009; Restrepo et al. 2007; Faurholt-Jepsen et al. 2012) and prolonged time to TB culture conversion and cure (Güler et al. 2007; Dooley et al. 2009; Wang et al. 2009), which may cause more frequent recurrence of TB (Sasaki et al. 2003). Finally, although diabetes has been associated with increased mortality in retrospective studies (Patel et al. 1977; Oursler et al. 2002; Dooley et al. 2009; Wang et al. 2009), only one small study reports mortality data from a low-income country (Mboussa et al. 2003). An inherent limitation of the available studies is that TB to some extent causes stress hyperglycaemia (Başoğlu et al. 1999; Gearhart & Parbhoo 2006), which may affect the diagnosis of diabetes. Hence, the associations between diabetes and TB found in case–control studies, the associations between diabetes and severe clinical manifestations based on cross-sectional studies and between diabetes and poor treatment outcomes, could be affected by reverse causality.

Based on studies in Mwanza, Tanzania, we have recently reported that diabetes was strongly associated with incident TB (Faurholt-Jepsen et al. 2011). However, in contrast to previous studies, in this case–control study, an attempt was made to adjust for the acute phase response to reduce the significance of stress hyperglycaemia. Based on follow-up data, we now present data on the role of diabetes on treatment outcome (i.e. sputum culture conversion and mortality) among patients undergoing TB treatment.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Subjects and study design

Newly diagnosed pulmonary TB patients from Mwanza, Tanzania, were invited to participate in the study during from April 2006 to October 2008. Patients below 15 years of age, pregnant or lactating women, patients terminally ill from TB or HIV (judged unlikely to survive >48 h), patients suffering from other severe diseases and non-residents of Mwanza City were excluded. The study was nested in the framework of two larger nutritional intervention studies (PrayGod et al. 2011, 2012).

All participants were followed up for treatment outcome at 2 and 5 months (i.e. culture conversion) and for survival status at least 1 year after TB treatment started. Trained research personnel used tracing information provided at recruitment to locate the participants. The survival information was collected using a structured questionnaire on survival status, including information on recurrence of TB within the first year after TB treatment. If the participant had experienced recurrence of TB, the information was confirmed using the patient records from the TB health facilities. Of those confirmed to be dead (all-cause mortality), data on date and place of death were obtained. Moreover, mortality information was ascertained using either a death certificate or any other official document. If the survival information could not be obtained, the date of last known contact was used. Diabetes and HIV testing were not repeated; thus, the baseline diagnosis was used at all time points.

Measurements

Sputum smear microscopy was performed at the recruiting health facility and at the Zonal TB Reference Laboratory at Bugando Medical Centre. Using the spot-morning-spot procedure (IUATLD 2000), the smears were graded according to the presence of acid fast bacilli (AFB) as either negative (no AFB) or positive: 1–9 in 100 fields, 1+ (10–99 AFB in 100 fields), 2+ (1–10 AFB pr. field in >50 fields) or 3+ (>10 pr. field in >20 fields). Additionally, early morning sputum samples were collected in a sterile universal bottle for culture of Mycobacterium tuberculosis on Lowenstein Jensen solid media and graded as either negative (no growth of colonies) or positive: 1–19 colonies, 1+ (20–100 colonies), 2+ (innumerable discrete colonies) or 3+ (confluent growth). A positive test result was defined as sputum positive pulmonary TB (PTB+), and the final TB diagnosis relied on culture status; microscopy results were only used if the culture result was missing. However, the diagnosis sputum smear negative pulmonary TB (PTB−) was used for patients with a negative sputum result, but with clinical suspicion of TB, patient history, lack of clinical improvement after treatment with a broad spectrum antibiotic and chest X-ray suggestive of TB based on the WHO guidelines available when the study was conducted ().

Sputum for culture was collected again after 2 months from those with a baseline PTB+ diagnosis, and similarly, a retest was carried out after 5 months. The grading of the culture at 2 and 5 months was identical to the baseline procedure.

HIV diagnosis was based on two rapid tests: Determine HIV 1/2 (Inverness Medical Innovations, Inc., Delaware, DE, USA) and Capillus HIV-1/HIV-2 (Trinity Biotech Plc., Wicklow Ireland). Samples with discordant results on the two rapid tests were retested by 3rd generation Vironostika HIV Uniform II plus O (Biomeriux, Boxtel, the Netherlands) at the NIMR, Mwanza laboratories.

Fasting blood glucose (FBG) was determined on capillary whole blood using point-of-care diagnostic instruments (HemoCue Glucose System 201+, HemoCue, Sweden). As the FBG in TB participants might be affected by the infection (non-diabetes stress hyperglycaemia; Başoğlu et al. 1999; Gearhart & Parbhoo 2006), the indication for offering a standard 75 g 2-h oral glucose tolerance test (OGTT) was expanded from the commonly used FBG 5.6–6.0 mm to 5.1–11.0 mm. Final diabetes diagnosis was based on either a FBG > 6.0 mm or a 2 h blood glucose > 11.0 mm (WHO 2006). The diabetes diagnosis was obtained after the TB diagnostics, and thus, the TB diagnosis was independent from the diabetes status. Participants already known to have diabetes were only classified as such in the study if the diagnosis could be reproduced by our methods.

Statistical analysis

Data were double entered, and all statistical analyses were performed using Stata 12.0 (StataCorp LP, College Station, TX, USA). The chi-square-test was used to test for differences in the distribution of TB culture grading as well as sputum culture conversion stratified by diabetes status. We used Kaplan–Meier plot to present the time-to-death data. Cox proportional hazards analysis was used to assess predictors of mortality in a multivariate analysis (Table 3, model 1) including status of diabetes (diabetes vs. non-diabetes), TB culture status (PTB− vs. PTB+) and HIV (HIV infected vs. HIV uninfected) and further adjusted for body mass index, sex and age (centred on the median age, 34 years) (model 2). The proportional hazards assumption was uncertain with regard to the diabetes variable; the score process test (Lin et al. 1993) was significant with P = 0.02, thus rejecting the Cox model. We therefore allowed the effect of this variable to change after an initial period of 100 days, and this revised model was accepted.

Ethics statement

Ethical permission was obtained from the Medical Research Coordinating committee of the National Institute for Medical Research (NIMR) in Tanzania, and consultative approval was given by The Danish National Committee on Biomedical Research Ethics. Written and oral information was presented to all eligible participants by the health staff before written informed consent was obtained. Written consent was obtained from parents/legal guardians of any participants under 18 years of age. Counselling prior to HIV testing was compulsory, and post-test counselling was offered to all who tested HIV positive. Participants with diagnosed HIV and/or diabetes were referred to the respective clinics for care and management.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Of the 1250 TB patients recruited for the nutritional intervention studies, 40.8% (n = 510) were women, mean (SD) age was 36.5 years (12.9), 50.6% (n = 633) were HIV co-infected, and 16.4% (n = 197) were diagnosed with diabetes as previously reported (Faurholt-Jepsen et al. 2011; PrayGod et al. 2011, 2012). Background characteristics are shown in Table 1.

Table 1. Background characteristics of 1250 patients with pulmonary tuberculosis (TB)
  1. Data are n (%) unless otherwise indicated.

  2. a

    Diabetes data were available for 1205 (96.4%) participants.

Age, years [mean (SD)]36.5 (12.9)
Female sex510 (40.8)
Ethnic group
Msukuma tribe570 (45.6)
Other tribes679 (54.4)
Marital status
Single308 (24.8)
Married/cohabiting658 (53.1)
Separated/divorced/widow274 (22.1)
Occupation
Farmer/Fisherman488 (39.1)
Businessman/Employed450 (36.1)
Housewife146 (11.7)
Unemployed62 (5.0)
Other101 (8.1)
Religion
Christian931 (74.5)
Muslim268 (21.5)
Other50 (4.0)
Alpha-1 glycoprotein, g/l [mean (SD)]2.4 (0.9)
TB status
Sputum negative pulmonary TB (PTB−)427 (34.2)
Sputum positive pulmonary TB (PTB+)823 (65.8)
HIV infected633 (50.6)
Diabetesa197 (16.4)

Of 1102 (88.2%) patients with diabetes and TB culture data available, 735 (66.7%) had positive sputum cultures at baseline. Among these PTB+ patients, 5.5% and 1.0% continued to be culture positive after 2 and 5 months of TB treatment, respectively. There were no differences between participants with and without diabetes regarding the proportion and intensity of positive cultures at any time point (Table 2). However, among those with a positive culture at baseline, 10 and 19 patients with or without diabetes, respectively, had died before the 5-months follow-up visit. Thus, if these deaths were due to treatment failure and considered culture positive at 5 months, then the proportion of TB patients with a positive culture at 5 months would have been higher among those with diabetes comorbidity (12.6% vs. 5.0%. P = 0.01). Participants with diabetes more often had missing culture data – due to either missing sample or contamination – at both 2 (26.9% vs. 18.9%, P = 0.010) and 5 months (28.4% vs. 20.7%, P = 0.203).

Table 2. Tuberculosis culture grading and conversion among 735 tuberculosis (TB) patients with available baseline diabetes and TB culture data stratified by diabetes status
 Patients without diabetesPatients with diabetes P
(n = 617)(n = 118)
  1. Data are based on chi-square test, n (column%).

  2. a

    Culture data available for 542 patients (73.7%) and 39 patients (5.3%) had died.

  3. b

    Culture data available for 521 patients (70.9%) and 90 patients (12.2%) had died.

Baseline TB culture grading, n (column%)
+1 (incl. 1–19 colonies)103 (16.7)26 (22.0)0.373
+287 (14.1)15 (12.7)
+3427 (69.2)77 (65.3)
Follow-up TB culture grading, n (column%)
2 monthsa
Negative436 (94.2)76 (96.2)0.465
Total positive TB culture (non-conversion)27 (5.8)3 (3.8)
+1 (incl. 1–19 colonies)25 (5.4)1 (1.3)
+20 (0.0)0 (0.0)
+32 (0.4)2 (2.5)
5 monthsb
Negative440 (99.1)76 (98.7)0.741
Total positive TB culture (non-conversion)4 (0.9)1 (1.3)
+1 (incl. 1–19 colonies)0 (0.0)0 (0.0)
+21 (0.2)0 (0.0)
+33 (0.7)1 (1.3)

Complete survival data up to at least 12 months were available for 1239 (99.1%) participants and were included in the mortality analyses. Median (interquartile range) follow-up time was 647 (492–833) days, and 172 (13.9%) died within the study period. Half of the study participants died in hospital, the other half died at home. Of the 172 (13.9%) deaths, 39 (3.1%) occurred within the first 60 days, 64 (5.2%) within 100 and 138 (11.1%) within 365 days. Within the first 60 days, 10 of 39 (25.6%) patients reported that the deceased had unknown diabetes status. Among the 1205 with available diabetes data, the proportion of deaths involving a patient with diabetes was 41.4, 34.0, and 24.4% after 60, 100 and 365 days, respectively.

In univariate Cox proportional hazards analysis, diabetes did not seem to be associated with mortality (crude RR 1.35, 95% CI 0.91; 2.00, P = 0.14), but this was due to a time-dependant association (score process test, P = 0.02) with excess mortality risk exclusively within the initial 100 days of treatment (crude RR 2.70, 95% CI 1.53; 4.77, P = 0.001). After the initial 100 days, diabetes was not associated with excess mortality (RR 0.80, 95% CI 0.45; 1.43, P = 0.45). Furthermore, PTB− compared to PTB+ (crude RR 2.47, 95% CI 1.83; 3.33, P < 0.001) and HIV infected compared to HIV uninfected (crude RR 3.04, 95% CI 2.16; 4.29, P < 0.001) were associated with mortality.

The association between major morbidities (i.e. diabetes, TB, HIV) and risk of mortality was assessed in (i) a Kaplan–Meier survivor function (Figure 1, diabetes and HIV only), (ii) in a multivariate Cox proportional hazards analysis (Table 3, model 1), and (iii) in a multivariate analysis further adjusted for age (centred on the median, 34 years) and sex (Table 3, model 2). There was an interaction between diabetes and HIV (model 1: P = 0.02; model 2: P = 0.07), which was due to a higher diabetes-associated risk of mortality among HIV uninfected, and, similarly, the highest HIV-associated risk of mortality among non-diabetes participants. In the adjusted model (model 2), diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected and within the initial 100 days of treatment. Diabetes was also associated with mortality in HIV infected individuals during the first 100 days, but not later. PTB− was associated with a twofold increased mortality risk compared to PTB+. Due to an interaction between age and HIV (P < 0.001), the model was centred on the median age (34 years). Thus, the HIV-associated mortality risk of RR 2.23 (95% CI 1.01; 4.90, P = 0.046) and 4.86 (95% CI 2.93; 8.05, P < 0.001) among participants with and without diabetes, respectively, reflects the risk for participants aged 34 years. Further, adjustment with AGP did not affect the estimates (model 3).

Table 3. Relative risk for death during tuberculosis treatment among 1239 patients with pulmonary tuberculosis (TB)
 Model 1aModel 2bModel 3c
RR95% CI P RR95% CI P RR95% CI P
  1. a

    Multivariate Cox proportional hazards analysis with diabetes, HIV and culture negative pulmonary tuberculosis as predictors (Interaction: HIV–diabetes, P = 0.02).

  2. b

    Multivariate Cox proportional hazards analysis further adjusted for age, sex and body mass index (Interactions: HIV–diabetes P = 0.07, HIV-age P < 0.001). The model is centred on the median age (34 years).

  3. c

    Multivariate Cox proportional hazards analysis further adjusted for alpha-1 glycoprotein (Interactions: HIV–diabetes P = 0.06, HIV-age P < 0.001). The model is centred on the median age (34 years).

  4. d

    The diabetes risk is time dependent; the score process test was significant with P = 0.02. Diabetes data were available for 1195 (96.4%) participants.

Diabetes (<100 days)d
HIV negative5.482.56; 11.72<0.0015.092.36; 11.02<0.0014.952.28; 10.76<0.001
HIV positive1.951.01; 3.760.0482.331.20; 4.530.0122.181.11; 4.410.024
Diabetes (>100 days)d
HIV negative1.600.74; 3.450.2291.370.62; 3.060.4351.410.64; 3.130.396
HIV positive0.590.29; 1.110.1000.630.32; 1.250.1870.620.31; 1.240.180
HIV
Non-diabetes3.142.06; 4.79<0.0014.862.93; 8.05<0.0014.862.93; 8.06<0.001
Diabetes1.120.55; 2.270.7622.231.01; 4.900.0462.140.97; 4.760.061
Tuberculosis culture status
Culture positive (PTB+)Ref.–; ––; –Ref.–; –
Culture negative (PTB−)1.881.36; 2.58<0.0012.021.44; 2.82<0.0011.911.33; 2.770.001
image

Figure 1. Mortality among 1239 pulmonary tuberculosis patients with and without diabetes and HIV. TB, tuberculosis; DM-, non-diabetes; DM+, diabetes; HIV-, HIV uninfected; HIV+, HIV infected.

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The analysis used in model 2 also revealed that men had a 53% higher mortality risk compared to women (RR 1.53, 95% CI 1.09; 2.16, P = 0.015). The role of the nutritional intervention was tested in a stratified analysis, but had no effect on the risk of mortality or any of the other covariates and was therefore not included in the final model. Also, treatment with ART known to cause metabolic changes (Carr et al. 1999) did not alter the estimates of the Cox regression (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

We have recently reported that diabetes is strongly associated with risk of pulmonary TB in Tanzania, and here, we show that diabetes is highly associated with mortality during the first 100 days of TB treatment. The main methodological issue in this and other studies on the role of diabetes in relation to risk of TB, severity of manifestations, treatment outcomes and survival is that often diabetes status is assessed after development and diagnosis of TB disease. The acute phase response caused by serious infections comprises hyperglycaemia (Başoğlu et al. 1999; Gearhart & Parbhoo 2006). It is therefore possible that some of the pulmonary TB patients with blood glucose values suggestive of diabetes (Alberti et al. 1998) have non-diabetes stress-induced hyperglycaemia rather than diabetes. Therefore, estimates of the associations between diabetes and risk of TB, severity of TB, treatment outcomes and mortality may be affected by reverse causality, that is, that pulmonary TB causes non-diabetes stress hyperglycaemia misclassified as diabetes. Recently, a systematic review reported decreasing levels of hyperglycaemia during TB treatment (Jeon et al. 2010), indicating the existence of stress hyperglycaemia at the start of TB treatment. Therefore, we measured serum concentrations of the acute phase reactant AGP and adjusted the survival analysis for elevated levels to see whether the diabetes-associated mortality was simply due to a higher inflammatory response. However, this adjustment had no effect on any of the mortality estimates.

If TB patients with more severe disease, accompanied by an acute phase response that leads to stress hyperglycaemia, are incorrectly diagnosed with diabetes, this leads to an overestimation of the true association between diabetes and mortality. In this situation, adjustment for elevated AGP is intended to reduce the significance of this reverse causality. If diabetes disease leads to more severe TB, which is accompanied by an acute phase response and cause mortality, then adjustment for elevated AGP is expected to remove or reduce the estimate of a true causal association between diabetes and mortality. However, after the adjustments, we still found that a diagnosis of diabetes was associated with increased risk of dying. This suggests that the association found is neither due to reverse causality nor more advanced TB disease. Thus, the current data do not explain why diabetes comorbidity was a major risk factor for mortality within the early phase of treatment and why diabetes was not a long-term risk factor.

We recently reported that diabetes had little, and possibly no clinical relevant, impact on the clinical presentation of TB, when the patients were enrolled in the study (Faurholt-Jepsen et al. 2012). Despite few baseline effects, our findings reflect that diabetes has a negative effect on treatment outcome. Also, our analyses suggest that treatment failure attributable to diabetes might mediate an effect of diabetes on mortality. In fact, several studies have reported that pulmonary TB patients with diabetes had more advanced TB disease than patients without diabetes and that diabetes was associated with delayed sputum conversion and reduced cure rate (Wang et al. 2005, 2009; Alisjahbana et al. 2007; Restrepo et al. 2007). Indeed, the latter could be explained by an effect of diabetes on absorption and metabolism of TB drugs, as a study from Indonesia found lower plasma levels of rifampicin in TB patients with diabetes during the continuation phase of treatment (Nijland et al. 2006). The effect on absorption could possibly be mediated through increased body weight and differences in hepatic induction. However, the study found no indication of a diabetes-associated rifampicin difference during the initial phase of TB treatment (Ruslami et al. 2010b). In our study, those with a diagnosis of diabetes had only slightly elevated serum acute phase reactants and neutrophil counts (Faurholt-Jepsen et al. 2012), but due to the high early mortality rate before the 2-month follow-up among patients with diabetes, it is possible that there was a larger proportion of non-converters in this group. From a study in Maryland, USA, it was reported that diabetes delayed time to conversion from 39 to 49 days, but with similar conversion rates after 60 days (Dooley et al. 2009). Also, in an Indonesian study, diabetes was associated with a positive culture at the end of treatment (Alisjahbana et al. 2007). As we did not follow sputum conversion during the intensive phase (<60 days), we cannot exclude the possibility that the apparent effect of diabetes on mortality was explained by early impairment of the treatment effect. Besides, while one of six patients was diagnosed with diabetes at baseline, almost half of the deaths occurring during the first 60 days involved a patient with diabetes. Thus, it is possible that death among those with diabetes was due to treatment failure. Furthermore, the diabetes status of 10 patients dying in this period was unknown, and we can only speculate whether diabetes was involved in these deaths.

There are divergent data on the role of diabetes on TB mortality, and few data are available from low-income countries (Baker et al. 2011), which harbour the largest burden of TB. Two studies from Indonesia and Saudi Arabia found no differences in mortality risk among TB patients with or without diabetes (Singla et al. 2006; Alisjahbana et al. 2007), whereas three smaller, retrospective studies, two from the USA and one from Taiwan, reported increased mortality risk among patients with diabetes (Oursler et al. 2002; Dooley et al. 2009; Wang et al. 2009). The study from Indonesia (Alisjahbana et al. 2007), a lower-middle-income country, was the only available prospective study and used similar methods, but based their diabetes diagnosis solely on FBG and excluded all patients with impaired fasting glycaemia. However, the study had very little mortality, and this was not associated with diabetes (Alisjahbana et al. 2007). As in our study, they did not find baseline differences on bacteriological examination between patients with or without diabetes, but diabetes comorbidity was associated with a higher treatment failure (not cured) at the end of treatment. Despite more severe TB among those with diabetes, only two deaths were reported from the study at the end of treatment, both of which had diabetes comorbidity.

The remaining four studies were all retrospective, with the largest study reporting no effect of diabetes on mortality among TB inpatients (Singla et al. 2006). In one study from Maryland, USA, the overall reported mortality was 9% with the odds of death twice as high among TB patients with diabetes and with increasing risk after adjustment for HIV status (Dooley et al. 2009). The patients were considered to have diabetes, if they had a history of elevated random non-fasting samples or from medical records; thus, the diagnosis was not obtained during the study. Also from another TB population from Maryland the reported deaths were 21% with the risk of mortality being almost seven times higher among patients with diabetes (Oursler et al. 2002). However, there is no indication of how the diabetes diagnosis was obtained, whether the patients were treated or suffered from insulin-dependent diabetes (type I). Also, it is surprising that the mortality in general was very high in the US studies, but the reason for this remains unclear. Finally, in a retrospective study from Taiwan with 217 in- and outpatients without HIV comorbidity, 11.1% were reported dead with the odds of dying being more than seven times higher among patients with diabetes comorbidity (Wang et al. 2009). The diabetes diagnosis was based on historical records or FBG suggestive of diabetes, whereas patients who did not have elevated FBG were chosen as controls. None of the previous studies have reported a time-dependent mortality risk among patients with diabetes comorbidity. If diabetes in general is associated with early TB mortality, timing of the diabetes diagnosis as well as subsequent treatment may be essential for survival. By splitting the data at 100 days, it seems as if this period is the most vulnerable for the TB patients. We also tested the data by splitting at 60 and 80 days, which similarly was accepted by the model (not shown), but we chose reporting the effect as we did to ensure future interventions based on data like ours would not end prematurely.

Ideally, patients with a test result compatible with diabetes should have a confirmatory diabetes test, after the acute phase response has faded. If confirmed, then lifestyle changes or medical intervention could be introduced. However, if indeed diabetes increases early mortality, then there is a need for diagnostic tools to distinguish between stress hyperglycaemia and diabetes and for studies to determine the effects of glycaemic control among diabetics during TB treatment.

In most low-income settings, people do not know whether they have diabetes or not. If diabetes (or hyperglycaemia) is associated with excess mortality, a routine glucose screening at the TB clinics may be necessary to identify those at increased risk of death due to diabetes. As we missed the blood glucose screening in 10 of 39 deaths in the first 60 days, it may be necessary to improve the timing and give the blood glucose test high priority immediately after TB diagnosis. In addition to the identification of patients at risk, it is equally important to improve the management of such patients; better supervision of TB treatment and more frequent routine visits during the initial treatment phase could be one approach, whereas a medical intervention to normalise the blood glucose levels should be tested under safe conditions. The use of intensive insulin therapy to control hyperglycaemia in severe illness has proven difficult to manage (Griesdale et al. 2009) and may not even be feasible in a resource poor setting.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Diabetes considerably increases the risk of dying during TB treatment, and this effect is not explained by greater severity of TB disease at the start of treatment. As there is evidence to suggest that diabetes also increases the risk of developing TB, the ongoing diabetes epidemic is a major threat to TB control programmes. While prevention of diabetes is crucial, it is also important to identify TB patients at risk of diabetes comorbidity to improve care and possibly reduce morbidity and mortality.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

We thank all health service providers at the TB clinics and study participants involved in the study. The study was supported by the Danish Council for Independent Research, by Danida and by the University of Copenhagen. The funding bodies had no role in the study design, data collection, data analysis, data interpretation or decision to publish the findings.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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