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Objective Diabetes is associated with pulmonary tuberculosis (TB), possibly due to impaired immunity, and diabetes may exacerbate the clinical manifestations of TB. Our aim was to assess the role of diabetes in the clinical manifestations of TB.
Methods We studied 1250 patients with pulmonary TB in an urban population in a cross-sectional study in Tanzania. All participants were tested for diabetes and HIV co-infection, and TB culture intensity was assessed. Levels of white blood cells, haemoglobin, acute phase reactants, CD4 count and HIV viral load were measured, and a qualitative morbidity questionnaire was used to identify the prevalence of disease-related symptoms.
Results Tuberculosis patients with diabetes had a higher neutrophil count (B 0.5 × 109 cells/l, 95% CI 0.2; 0.9, P = 0.001) than non-diabetic TB patients. Serum C-reactive protein (B 18.8 mg/l, CI 95% 8.2; 29.4, P = 0.001) and alpha-1-acid glycoprotein (B 0.2 g/l, CI 95% 0.03; 0.3, P = 0.02) were similarly higher in patients with diabetes. Diabetes did not affect culture intensity or HIV status, but self-reported fever was three times higher among participants with diabetes than in those without diabetes (OR 2.9, CI 95% 1.5; 5.7, P = 0.002).
Conclusion Diabetes is associated with small changes in the manifestations of TB, but may have little clinical significance.
Objectif: L’association entre le diabète et la tuberculose (TB) pulmonaire est probablement liée à un déficit immunitaire et le diabète peut aggraver les manifestations cliniques de la TB. Notre objectif était d’évaluer le rôle du diabète dans les manifestations cliniques de la TB.
Méthodes: Nous avons étudié 1250 patients atteints de TB pulmonaire dans une population urbaine dans le cadre d’une étude transversale en Tanzanie. Tous les participants ont été testés pour le diabète et la coinfection VIH, et le rendement de la culture de TB a étéévalué. Les taux de globules blancs, l’hémoglobine, les réactants de phase aiguë, la numération des CD4 et la charge virale VIH ont été mesurés. Un questionnaire qualitatif sur la morbidité a été utilisé pour déterminer la prévalence des symptômes liés à la maladie.
Résultats: Les patients TB diabétiques avaient un nombre plus élevé de neutrophiles (B 0,5 x 109 cellules/L, IC95%: 0,2 - 0,9; p = 0,001) que les patients TB non-diabétiques. Le CRP (B 18,8 mg/L, IC95%: 8,2 - 29,4; p = 0,001) et AGP (B 0,2 g/L, IC95%: 0,03 - 0,3; p = 0,02) sériques étaient aussi plus élevés chez les patients diabétiques. Le diabète n’avait pas d’influence sur le rendement de la culture ou le statut VIH, mais la fièvre auto-déclarée était trois fois plus élevée chez les patients atteints de diabète que chez ceux sans diabète (OR: 2,9, IC95%: 1,5 - 5,7; p = 0,002).
Conclusion: Le diabète est associéà de petits changements dans les manifestations de la TB, mais pourrait n’avoir que peu de signification clinique.
Objetivo: La diabetes está asociada con la tuberculosis (TB) pulmonar, posiblemente debido a una inmunidad comprometida, y puede exacerbar las manifestaciones clínicas de la TB. Nuestro objetivo era evaluar el papel de la diabetes en las manifestaciones clínicas de la TB.
Métodos: Hemos estudiado a 1250 pacientes con TB pulmonar durante un estudio crosseccional en población urbana de Tanzania. A todos los participantes se les realizaron pruebas para diabetes y VIH, y se evaluó la intensidad del cultivo de TB. Se midieron los niveles de leucocitos, hemoglobina, reactivos de fase aguda, conteo de CD4 y carga viral de VIH, y se utilizó un cuestionario cualitativo de morbilidad para identificar la prevalencia de los síntomas relacionados con la enfermedad.
Resultados: Los pacientes con TB y diabetes tenían un mayor conteo de neutrófilos (B 0.5 × 109 células/L, 95% CI 0.2;0.9, p = 0.001) que los pacientes no diabéticos-TB. La proteína C-reactiva en suero (B 18.8 mg/L, IC 95% 8.2; 29.4, p = 0.001) y la alfa-1 glicoproteína ácida (B 0.2 g/L, IC 95% 0.03;0.3, p = 0.02) eran igualmente altos en pacientes con diabetes. La diabetes no afectaba la intensidad de cultivo o el estatus de VIH, pero la fiebre autoreportada era tres veces mayor entre los participantes con diabetes que entre aquellos sin diabetes (OR 2.9, IC 95% 1.5; 5.7, p = 0.002).
Conclusión: La diabetes está asociada con pequeños cambios en las manifestaciones de la TB, pero pueden tener poco significado clínico.
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Diabetes (type II) is increasingly common in low-income countries previously dominated by communicable diseases (Mohan et al. 2006). Diabetes is known to increase the risk of infections (Joshi et al. 1999; Muller et al. 2005) possibly due to impaired cellular immunity and neutrophil function (Pozzilli & Leslie 1994; Delamaire et al. 1997; Calvet & Yoshikawa 2001). In low-income populations, highly exposed to tuberculosis (TB), diabetes may contribute considerably to the incidence of TB. Furthermore, hyperglycaemia per se can lead to infectious complications as well as increased mortality (McCowen et al. 2001). Diabetes may also exacerbate the clinical manifestations of TB, although it has only been addressed in few studies from low-income settings and none from the African continent. However, studies from Taiwan and from the US–Mexican border, based on register data, have reported that people with diabetes experience worse clinical manifestations of TB, that is, fever, haemoptysis, lower lung infiltration, higher mycobacterial burden and delayed conversion (Wang et al. 2005, 2009; Alisjahbana et al. 2007; Restrepo et al. 2007).
We recently found that diabetes among urban Tanzanians was associated with a fourfold increased risk of active TB (Faurholt-Jepsen et al. 2011). Based on the data already available on the impaired immunity in patients with diabetes, we therefore hypothesised that TB patients with diabetes initially would present with more severe clinical manifestations compared to TB patients without diabetes. In this article, we report the role of diabetes on the clinical manifestations of TB, as well as on paraclinical parameters including haematology, acute phase response and sputum culture intensity.
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Of 1250 patients with pulmonary TB recruited, 1205 (96.4%) had complete blood glucose data and were included in the analyses. Mean (standard deviation) age and BMI were 36.6 years (13.0) and 18.8 kg/m2 (3.0), respectively, and 493 (40.9%) were women. HIV infection was present in 60.6% and 43.8% of women and men (P < 0.001), respectively, and 12.6% of HIV-infected patients used ART prior to the study. Nearly 803 (66.6%) were diagnosed as PTB+, and among those with a PTB+ diagnosis, 735 (92%) were culture-positive and 68 (8%) were diagnosed as PTB+ using smear microscopy owing to either a contaminated or missing culture sample. The overall prevalence of anaemia was 78.1%. The mean (standard deviation) total white blood cell count was 6.5 × 109 (2.6 × 109) cells/l, of which 4.2 × 109 (2.2 × 109) cells/l (64.6%) were neutrophil granulocytes and 1.9 × 109 (0.9 × 109) cells/l (29.9%) were lymphocytes, and 89.4% had an acute phase response elevated above the reference level. Of the 1205 patients with TB, 444 (36.9%) had impaired glycaemia, including 197 (16.4%) with diabetes. Demographic characteristics of the population are shown in Table 1.
Table 1. Background characteristics of 1205 patients with tuberculosis stratified by diabetes status*
| ||Non-diabetes (n = 1008)||Diabetes (n = 197)||P|
|Female sex (%)||40.1||45.2||0.18|
|Age (year)||36.3 (12.8)||38.0 (13.6)||0.08|
|Ethnic group (%)|
| Mhaya||7.4||7.1|| |
| Mjita||4.6||5.1|| |
| Mnyamwezi||6.0||4.1|| |
| Mkurya||5.2||7.1|| |
| Other||31.4||28.9|| |
| Married/cohabiting||52.8||55.4|| |
| Separated/divorced/widow||22.3||23.1|| |
| Businessman/employed||35.4||37.8|| |
| Other||25.5||24.0|| |
| Muslim||22.1||19.3|| |
| Other||4.3||2.0|| |
|HIV co-infection (%)||49.7||50.8||0.79|
There was no difference in Mycobacterium tuberculosis culture status (OR 1.2, CI 95% 0.9; 1.8, P = 0.26) and HIV status (OR 1.0, CI 95% 0.7; 1.4, P = 0.98) across diabetes status. The associations between diabetes and clinical and paraclinical parameters were assessed using linear regression models adjusted for age and sex (Table 2). Patients with diabetes had 0.4 × 109 cells/l higher white blood cell count (95% CI 0.02; 0.8, P = 0.04) and 0.5 × 109 cells/l higher neutrophil count (95% CI 0.2; 0.9, P = 0.001), whereas no difference was found for the level of lymphocytes. There was an interaction between diabetes and the TB diagnosis (PTB+ vs. PTB−) for the acute phase reactants CRP (P = 0.004) and AGP (P = 0.04); the association between diabetes and acute phase reactants was present among PTB+ patients only. PTB+ patients with diabetes had 18.8 mg/l (CI 95% 8.2; 29.4, P = 0.001) and 0.2 g/l (CI 95% 0.003; 0.3, P = 0.02) higher levels of CRP and AGP, respectively, compared to PTB+ patients without diabetes. Diabetes did not affect the levels of CD4 count and HIV viral load.
Table 2. Clinical and paraclinical status of 1205 patients with pulmonary TB with and without diabetes
| ||Patients without diabetes (n = 1008)||Patients with diabetes (n = 197)||Difference, crude||P||Difference, adjusted*||P|
| Women||10.1 (2.3)||9.9 (2.5)||−0.2 (−0.8; 0.3)||0.43||−0.3 (−0.8; 0.2)||0.27|
| Men||11.2 (2.4)||11.3 (2.8)||0.04 (−0.5; 0.5)||0.89||0.04 (−0.5; 0.6)||0.88|
|WBC total (×109/l)||6.4 (2.6)||6.8 (2.6)||0.4 (−0.04; 0.8)||0.08||0.4 (0.02; 0.8)||0.04|
| Neutrophils (×109/l)||4.1 (2.2)||4.6 (2.3)||0.5 (0.2; 0.8)||0.004||0.5 (0.2; 0.9)||0.001|
| Lymphocytes (×109/l)||2.0 (0.9)||1.9 (0.8)||−0.1 (−0.2; 0.1)||0.26||−0.1 (−0.2; 0.1)||0.27|
|C-reactive protein (mg/l)†|
| PTB−||51.4 (57.4)||41.6 (45.2)||−9.7 (−24.8; 5.3)||0.20||−7.5 (−22.4; 7.3)||0.32|
| PTB+||88.3 (55.6)||106.1 (61.3)||17.8 (7.2; 28.4)||0.001||18.8 (8.2; 29.4)||0.001|
|Alpha-1-acid glycoprotein (g/l)‡|
| PTB−||1.9 (0.8)||1.8 (0.9)||−0.1 (−0.4; 0.1)||0.31||−0.1 (−0.3; 0.2)||0.50|
| PTB+||2.6 (0.7)||2.8 (0.7)||0.2 (0.02; 0.3)||0.03||0.2 (0.03; 0.3)||0.02|
|CD4 count (cells per μl)|
| HIV-negative||553.5 (339.8)||540.4 (335.1)||−13.1 (−86.8; 60.7)||0.73||−12.3 (−86.2; 61.6)||0.74|
| HIV-positive||292.2 (206.4)||271.8 (0.37)||−20.5 (−64.8; 23.9)||0.37||−14.9 (−59.1; 29.2)||0.51|
|HIV viral load (RNA copies/ml) (log10)||4.3 (1.39)||4.1 (1.5)||−0.2 (−0.5; 0.1)||0.28||−0.2 (−0.5; 0.1)||0.29|
|Handgrip strength (kg)||25.8 (8.3)||24.5 (7.8)||−1.3 (−2.6; −0.03)||0.04||−0.8 (−1.9; 0.4)||0.18|
The distribution of symptoms typically indicative of TB and diabetes is shown in Table 3. In a logistic regression model adjusted for age and sex, the proportion of self-reported fever was almost three times (OR 2.9, CI 95% 1.5; 5.7, P = 0.002) higher among PTB+ participants with diabetes than among PTB+ participants without diabetes, whereas no association was found for PTB− participants (interaction, P = 0.02). The association between diabetes and fever was not confounded by the levels of acute phase reactants and white blood cells (data not shown).
Table 3. Reported morbidity among 1205 patients with pulmonary TB with and without diabetes
| ||Patients without diabetes (n = 1008)||Patients with diabetes (n = 197)||Difference, crude OR (95% CI)||P||Difference, adjusted* OR (95% CI)||P|
|Disease-related symptoms (%)|
| Fever (yes)†|
| PTB−||78.4||77.8||1.0 (0.5; 1.8)||0.91||1.0 (0.5; 1.9)||0.97|
| PTB+||80.9||92.5||2.9 (1.5; 5.7)||0.002||2.9 (1.5; 5.7)||0.002|
| Ulcers, leg/feet (yes)||5.9||2.6||0.4 (0.2; 1.1)||0.07||0.4 (0.2; 1.1)||0.06|
| Visual impairment (yes)||21.8||23.2||1.1 (0.8; 1.6)||0.66||1.0 (0.7; 1.5)||0.94|
| Polydipsia (yes)||50.9||48.2||0.9 (0.7; 1.2)||0.49||0.9 (0.7; 1.2)||0.53|
| Polyuria (yes)||59.7||52.3||0.7 (0.5; 1.0)||0.053||0.7 (0.5; 1.0)||0.06|
| Weight loss (yes)||80.7||77.2||0.7 (0.4; 1.1)||0.11||0.7 (0.4; 1.1)||0.14|
| Cough (yes)||96.6||96.5||0.9 (0.4; 2.2)||0.90||0.9 (0.4; 2.1)||0.88|
| Haemoptysis (yes)||22.3||21.3||0.9 (0.7; 1.4)||0.76||1.0 (0.7; 1.4)||0.89|
| Night sweat (yes)||75.4||79.2||1.2 (0.9; 1.8)||0.26||1.2 (0.9; 1.8)||0.25|
|Medical history (%)|
| TB relapse (yes)||7.2||10.7||1.5 (0.9; 2.6)||0.10||1.6 (0.9; 2.6)||0.09|
| Relatives with diabetes (yes)||5.6||8.1||1.5 (0.8; 2.7)||0.17||1.5 (0.8; 2.7)||0.17|
| ARV treatment for HIV (yes)||6.0||9.1||1.6 (0.9; 2.8)||0.10||1.5 (0.9; 2.6)||0.16|
None of the other self-reported diabetes-related symptoms were different between diabetes and non-diabetes TB patients. However, the seemingly higher proportion with TB relapse, and lower proportion with weight loss, ulcers on the extremities and polyuria in those with diabetes were not statistically significant. Except for the above mentioned, no other interactions between diabetes and HIV as well as between diabetes and TB diagnosis were found for paraclinical parameters or symptoms.
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Among patients with pulmonary TB, the presence of diabetes was associated with minor alterations in clinical and paraclinical manifestations. Although TB patients with diabetes had slightly higher levels of neutrophil granulocytes and acute phase response and more often had fever, most symptoms and paraclinical tests were similar to TB patients without diabetes. In particular, there was no difference in culture intensity and HIV viral load.
It has previously been reported that TB patients with diabetes may have higher mycobacterial burden, higher TB culture intensity and altered radiographic patterns (Hendy & Stableforth 1983; Mboussa et al. 2003; Wang et al. 2005, 2009). We did indeed find a higher acute phase response, including elevated levels of neutrophil granulocytes, among TB patients with diabetes. In a study from Indonesia, leucocyte count and CRP levels were reported, but there was no statistical difference between patients with and without diabetes co-morbidity, but in contrast to our data, the median level of both measures seemed to be lower in the diabetes group (Alisjahbana et al. 2007). The TB diagnosis (PTB−vs. PTB+) affected the level of the acute phase reactants, causing a higher level of CRP and AGP among the PTB+ participants, in which group those with diabetes had the highest levels. The higher acute phase response in PTB+ patients with diabetes indicates that diabetes does affect the clinical manifestations of TB, but the differences are so small that they may not be clinically relevant. Also, the higher acute phase response seen in the diabetes group could possibly be associated with stress hyperglycaemia, indicating that the glucose levels in patients with more severe TB could be elevated to such extent that the patients fullfiled the criteria for diabetes. We did not see this association among patients with PTB−, but the PTB− diagnosis embrace a group of patients, which is rather heterogeneous, and may include a large proportion of severely ill patients not capable of producing an adequate acute phase response. Finally, our data do not support higher culture intensity among patients with diabetes, and neither was the proportion of PTB− and PTB+ affected by diabetes. This finding is in contrast to other studies, where diabetes has been associated with more severe bacterial status on sputum microscopy and culture (Restrepo et al. 2007; Wang et al. 2009).
In accordance with previous studies from the US–Mexican border and Taiwan (Restrepo et al. 2007; Wang et al. 2009), we found that the proportion of reported fever was three times as high in those with diabetes as in those without diabetes. The elevated neutrophil count and acute phase reactants seen in the patients with diabetes could be mediated by cytokines also responsible for fever (Exton 1997), and the cytokines responsible for fever are also associated with reduced appetite, which we reported elsewhere (PrayGod et al. 2011b). Because of these circumstances, it is likely that people with diabetes experience accelerated weight loss caused by the TB disease and subsequently delayed weight gain during the course of the anti-TB treatment. Some of the patients diagnosed with diabetes may have stress hyperglycaemia; a state common in severely ill patients (i.e. trauma, surgery and intensive care unit) (Başoğlu et al. 1999; Gearhart & Parbhoo 2006). The mechanisms behind stress hyperglycaemia are primarily caused by the activation of the hypothalamic–pituitary–adrenal axis, leading to insulin resistance and hyperglycaemia (Gearhart & Parbhoo 2006). Severe TB infection could potentially lead to hyperglycaemia in this population. Therefore, the association between diabetes and reported fever might partly be mediated by stress hyperglycaemia, and only a repeated diabetes diagnosis after 6 months of anti-TB treatment could reveal to what extent stress hyperglycaemia was present in this population. We do know that the prevalence of diabetes in a comparable non-TB population from the same city was very high (9%; Faurholt-Jepsen et al. 2011), and because there is growing evidence of the association between habitual diabetes and increased risk of incident TB, non-diabetic stress hyperglycaemia is likely to represent a minority of the diabetes diagnosed in the present study. Furthermore, owing to the inclusion criteria from the nutritional study, wherefrom the participants were recruited, patients with TB with severe or terminal illness were excluded from the study; thus, those at highest risk of stress hyperglycaemia were already excluded. Nevertheless, interpretation of glucose parameters, without taking stress-induced hyperglycaemia in patients with infectious diseases into account, should be carried out with precaution, and the diabetes diagnosis should preferably be confirmed after the elimination of the infection. Also, the two diseases may share risk factors, and socio-economic circumstances in early life could lead to a higher risk of both diabetes and TB in later life, thus reducing the biological interaction between the two diseases as they co-occur.
HIV is the strongest risk factor for TB (Lönnroth et al. 2010) and interferes markedly with the clinical presentation of TB causing more extra-pulmonary and disseminated forms of TB. Despite a higher prevalence of diabetes among HIV uninfected compared to HIV-infected (Faurholt-Jepsen et al. 2011) groups, no interaction was found between HIV infection and diabetes in relation to the manifestations of TB. One of eight HIV-infected patients received ART, which potentially could cause metabolic dysfunction (Butt et al. 2009), but no differences were identified between the users of ART and ART-naïve HIV-infected participants (data not shown). Because this study is the first to be conducted in a TB population heavily co-infected with HIV, it is encouraging that we did not experience a worsened clinical status among patients with both diabetes and HIV co-morbidity. However, the nature of the cross-sectional data does not allow commenting upon prognosis, but because diabetes (Young et al. 2009) and HIV (Swaminathan et al. 2010) individually impairs treatment outcome of TB, the combination of diabetes and HIV co-morbidity may further worsen TB treatment outcome.
It is unfortunate that we did not have access to detailed descriptions of X-rays, because other studies found altered radiographic patterns among patients with diabetes co-morbidity (Hendy & Stableforth 1983; Wang et al. 2005, 2009), but we chose a broad spectrum of paraclinical parameters as well as a qualitative morbidity interview to investigate the impact of diabetes on the clinical manifestations of TB. Even though the definitions for normal and elevated blood glucose levels are widely used in non-TB patient populations, the group with low fasting blood glucose is quite heterogeneous and may not necessarily identify the healthiest group of patients seen from a metabolic point of view. Also, many of the patients diagnosed with diabetes had blood glucose levels in the lower end of the range for diabetes, which could underestimate the role of diabetes on the clinical manifestations, because the manifestations are likely to be more pronounced in patients with advanced diabetes. More biomarkers related to inflammation, insulin, glycosylated haemoglobin measurements as well as a repeated diabetes screening after TB recovery are highly needed. Also, this being a cross-sectional study, we may have failed to show that people with diabetes have severe clinical presentation of TB, because those with severe manifestation died or failed to seek treatment at the hospitals, or were excluded from the study owing to the exclusion criteria about severe disease.
In conclusion, although diabetes is a risk factor for pulmonary TB in an urban Tanzanian population, it does not seem to considerably increase the severity of TB.