The role of diabetes co-morbidity for tuberculosis treatment outcomes: a prospective cohort study from Mwanza, Tanzania

Chronic and infectious diseases often co-exist due to mutual risk factors as well as direct interactions between the diseases. One of the major challenges is the double burden of diabetes and pulmonary tuberculosis (TB) [1]. With the on-going diabetes epidemic in low-income countries already burdened by TB [2], diabetes may threaten the control of TB.

Previous studies have found that diabetes may impair sputum conversion and cure [3‐5] and increase the risk of relapse [6]. However, the studies focus on the treatment outcome related to clearance of the TB bacteria and do not take into account the impact of diabetes on the outcome of other factors such as body composition, functional recovery, as well as other clinical parameters affected by disease. We have previously demonstrated a 10 kg weight deficit among newly diagnosed TB patients compared to non-TB individuals [7], thus the regain of lean and fat mass is an important part of TB recovery, since rapid build-up of fat mass may lead to metabolic syndrome [8]. Also, TB patients often experience inflammation-induced anaemia as a consequence of the TB disease [9], thus a rise in haemoglobin during TB treatment can be considered a marker of recovery. We recently reported from Tanzania that while diabetes was associated with a higher risk of TB [10], diabetes had little consequences for the clinical manifestations of newly diagnosed TB [11]. In this paper we report the changes in anthropometry, grip strength, and clinical parameters over a five months follow-up period, to assess the role of diabetes on recovery during TB treatment.

Diabetes data were available for 1205 (96.4%) of the 1250 patients enrolled and included in the analyses. Of the 1205 TB patients 197 (16.3%) were categorized as having diabetes, which has previously been reported for PTB + patients only (n = 803) [10]. The mean (standard deviation) age was 36.6 (13.0) years, 40.9% were females, and 48.9% were HIV co-infected. There were no differences in background characteristics between TB patients with and without diabetes (Table 1).

The changes in anthropometric measurements during TB treatment are shown in table 2. Within the initial two months of TB treatment, TB patients with diabetes co-morbidity experienced a 1.3 kg (CI 95% 0.5; 2.0, p = 0.001) lower weight gain compared to the non-diabetes group. The delayed weight gain sustained at five months of TB treatment, with a 1.0 kg (CI 95% 0.3; 1.7, p = 0.007) lower weight gain among TB patients with diabetes co-morbidity (Table 2, Figure 1a). There was no baseline difference in the mean MUAC (22.9 vs. 23.3 cm, p = 0.185) and TST (7.2 vs. 7.3, p = 0.581) between those with and without diabetes. However, the increase in MUAC was higher in the non-diabetes group after two (Δ 0.3 g/dL, CI 95% 0.04; 0.6 p = 0.027) and five months (Δ 0.3 g/dL, CI 95% 0.02; 0.6 p = 0.036), whereas no difference was found for TST (two months: Δ 0.3 g/dL, CI 95% -0.2; 0.8 p = 0.288 and five months: Δ 0.3 g/dL, CI 95% -0.2; 0.8 p = 0.283). Although significant increases were seen for arm muscle area and arm fat area for both groups, there were no differences across diabetes status. Similarly, there were significant increases for waist circumference and grip strength, but the increase seemed to be unaffected by diabetes status.

The mean haemoglobin level was 10.7 g/dL at baseline, and was similar for non-diabetes and diabetes participants (Δ 0.03 g/dL, p = 0.851). However, the increase in haemoglobin was 0.6 g/dL (CI 95% 0.3; 0.9 p < 0.001) and 0.5 g/dL (CI 95% 0.2; 0.9 p = 0.004) lower after two and five months, respectively, among TB patients with diabetes co-morbidity (Table 3, Figure 1b). Diabetes did not affect the changes in the level of white blood cells and CD4 counts, and this was not modified by HIV status (data not shown).

Diabetes co-morbidity was associated with delayed recovery of weight and haemoglobin level within the first two months of TB treatment, and the accumulated difference persisted after five months. However, the functional recovery based on grip strength assessment was not affected by diabetes.

Being enrolled in a nutritional intervention study ensured that all participants had access to some nutritional support during the first two months of TB treatment. We recently reported that smear-positive TB was associated with a 10 kg weight loss, which was both reflected in large deficits in arm fat area and especially arm muscle area [7], suggesting that nutritional support to facilitate optimal recovery of lean body mass is needed during the treatment. As reported here, there was a considerable delayed weight gain in those with diabetes. On average the participants gained three and five kg over the two and five months treatment period, respectively, but participants with diabetes had a one kg weight deficit compared to the non-diabetes patients at both time points. Interestingly, this weight difference was built up during the first two months, and sustained at the same level after five months. Also MUAC increased at a slower pace in the diabetes group, whereas TST did not. That MUAC and TST did not behave similarly was reflected in the derived parameter arm muscle area, which also seemed to be increasing slower in the diabetes group. This could imply that people with diabetes have a slower muscle build-up, but this was not backed up by the functional measurement grip strength.

The low levels of haemoglobin at baseline are primarily inflammation-induced anaemia from the on-going HIV and TB infections [9, 25]. Regardless of the underlying cause, the haemoglobin level is expected to rise during recovery, which we also found with reasonable increases at two and five months. The slower increase in haemoglobin in those with diabetes could be the consequence of sooner improvement in the non-diabetes group. In parallel with the replenishment of iron to haemoglobin, there may also be a direct association between haemoglobin and lean body mass; either caused by mutual factors improving both lean body mass and haemoglobin levels, or local hypoxia due to low haemoglobin may be the delimiting factor in the build-up of lean body mass in the diabetes group.

The differences we found did not depend on TB status, since the diabetes-associated differences were present among both PTB + and PTB- participants. As suggested, the delayed increase in weight gain and haemoglobin levels in the diabetes group could partly be explained by a slower TB recovery. From a study in severely acute malnourished (marasmic) adults it has been shown that the daily increase in body weight during replenishment is app. 6 g per kg body weight [26]. Thus, any delay in TB recovery may interfere with body mass recovery. However, the slower improvement observed in our study could also be a consequence of poorly controlled diabetes, which is known to be associated with protein degradation and leucine oxidation [27, 28]. Finally, the association between diabetes and slow recovery could be explained by reverse causality; i.e. those with slower recovery may have more severe TB disease, and this could give rise to non-diabetes stress-hyperglycaemia [21, 22], which may have been misclassified as diabetes. However, this is not likely to be a major factor in this study, since we have observed very little, and probably not clinically important, baseline differences in the acute phase response between diabetes and non-diabetes participants [11], indicating similar baseline severity of TB in the two groups, and, furthermore, since the differences observed were not confounded by the acute phase response. We have previously reported fluctuations in the CD4 level during TB treatment with increases over the initial two months of treatment and with a subsequent decrease [29]. However, the data from this study show that the fluctuations were not affected by diabetes co-morbidity.

All patients diagnosed with diabetes were referred to the local diabetes clinics to be retested and treated accordingly. Data on anti-diabetic treatment has not been available for the present study, however, patients with a reconfirmation of diabetes have most likely started out with advice on lifestyle changes, and therefore medical intervention is unlikely to be confounding the data.

TB patients initiating TB treatment with diabetes co-morbidity may experience slower recovery from their TB disease. While previous studies have primarily focused on treatment outcomes related to the TB culture (or smear) intensity, conversion, cure and mortality, this study looked at general outcomes, such as anthropometry and haemoglobin, which are important for the functional recovery. A quick functional recovery leads to a sooner return to work, and thus, the delay may not only have beneficial health outcomes, but also economically consequences for low-income families burdened by TB.