TB and DM burden in Brazil and Peru
The overall distribution of TB and DM cases using the most updated report containing estimated data from both countries, performed in 2019, is shown in Figure 18,18. Brazil led the burden of TB in South and Central America, with a total of 96,000 TB cases reported and a rate of 46 cases per 100,000 inhabitants, while Peru had a total of 39,000 TB cases estimated and a rate of 119/100,000. Regarding DM distribution, more than 16.8 million cases were reported among Brazilians, with a rate of 80 cases per 100,000 estimated in 2019 1 and among Peruvian approximately 22 cases per 100,000 19. Furthermore, the cohort explored in the present study was located in state of Bahia, represented in the map with an incidence of TB-DM of 9 cases per 100 inhabitants. Similarly, the Province of Lima, from where our Peruvian cohort was followed, had an incidence of 10 cases per 100 inhabitants of TB-DM comorbidity in 2019. Therefore, our cohorts are originated from relevant endemic areas with relatively high burden of both TB and DM.
Characteristics of the study populations
Brazilian participants were significantly older than the Peruvians, (median age [IQR]: 45 [31–55] vs. 29 [IQR: 23–45], respectively; p < 0.01) (Table 1). Distribution of sex was similar between the cohorts (Table 1). With respect to clinical presentation, we found that Brazilian participants presented more frequently with cough (p<0.01), fever (<0.01) and weight loss (p=0.03), whereas individuals from Peru more often had hemoptysis (p<0.01) and lack of appetite (p=0.02) (Table 1 and Supplementary Figure 1). Moreover, Peruvians exhibited higher FPG levels (median [IQR] 95 [88.4–102.1] vs 91 [81–106]; p = 0.02), while Brazilian displayed more elevated HbA1c values (p<0.01). There was no difference in median OGTT level among the two populations (Table 1). Smoking history was more commonly reported in patients from Brazil (39.7% vs 21.5%, p< 0.01), while current illicit drug use and alcohol consumption were more frequent in Peruvians (p< 0.01) (Table 1). Metformin use was more frequently documented in Peruvian participants than that in those from Brazil (11.4% vs 1.3%, p< 0.01). Finally, Peruvians more often were BCG vaccinated than Brazilians (93.3% vs 75.4%, p<0.01). Additional comparisons are depicted in Table 1.
Distribution of TB cases according to glycemic status in Brazil and Peru
We next stratified the study participants in both countries based on the final diagnosis of the glycemic status (e.g., normoglycemic, PDM and DM). In Brazil, 42.2% of the PWTB had also DM and 41.4% had PDM (Table 2). In contrast, in Peru, 13.9% of the PWTB had comorbid DM, followed by 31% who had PDM (Table 2). DM was associated with older age in both countries and the group with highest median age were Brazilians individuals with DM (50.1 [IQR: 45–59], p <0.01) (Table 2). Among the TB clinical symptoms, hemoptysis was more prevalent in Peruvian patients with DM (47.4%; p <0.01) (Table 2). When all the TB patients were considered, we found HbA1c (p <0.01) and OGTT (p <0.01) values higher in Brazil, while FPG levels (p <0.01) higher in Peru (Table 2). Sputum culture grade values tended to be higher following hyperglycemia degree, with Brazilian patients exhibiting a greater frequency of higher culture grades (p <0.01).
Heterogeneity in values from the glycemic screening laboratory tests between persons with TB from Brazil and Peru
FPG and HbA1c value distribution in patients from both countries are shown in Figure 2. To better understand the value distribution obtained in the distinct screening tests in the study populations, we initially segregated participants in two groups, including: (i) those with normoglycemia and (ii) individuals with dysglycemia (PDM or DM). Dysglycemia was more prevalent among Brazilian participants (83.6%) (Figure 2A). However, FPG levels in this group showed that most individuals with dysglycemia presented values under the reference baseline, whereas, in Peru, 70.5% of patients with DM/PDM exhibited values above the limit for dysglycemia with this marker (Figure 2A). Comparison of FPG median values also displayed differences between countries (p<0.05), with higher levels found in the Peruvian cohort (Figure 2C). On the other hand, HbA1c levels had an inverse distribution in both populations (Figure 2B), in which Brazilians presented the vast majority of values above the reference for DM/PDM diagnosis. In addition, the median values of HbA1c showed to be significantly increased among Brazilians in comparison with Peru (p<0.001) (Figure 2D). These results suggest that the glycemic screening methods showed a distinct behavior according to the country.
Glycemic screening methods among TB cases
Next, we aimed to evaluate FPG and HbA1c level distribution according to the following groups: TB, TB-DM and TB-PDM. (Figure 3). Using a demographic density analysis with histograms, we found a similar distribution of FPG values and HbA1c percentage on both countries, where TB normoglycemic participants demonstrated a peak curve in lower FPG levels, followed by TBPDM (Figure 3A). Of note, our findings revealed that the TBDM group displayed wider distribution in both country curves (Figure 3A).
To better understand the differences in the glycemic markers according to TB-DM comorbidity between the two countries, we compared the levels of FPG and HbA1c in TB, TB-PDM and TB-DM groups in Brazil and Peru (Figure 3B). In all clinical groups, levels of FPG were higher among the Peruvians, whereas Brazilians displayed higher HbA1c values, except for the TBDM group (Figure 3B).
Distinct accuracy of glycemic screening methods in dysglycemia diagnosis among TB South American individuals.
In order to extend our investigations concerning the discriminative performance of glycemic markers to diagnose dysglycemia in TB patients, a receiver operating characteristic (ROC) curve analysis using values of the glycemic markers was employed in each country (Figure 4). HbA1c exhibited a good performance to identify dysglycemia the Brazilian cohort, with an area under curve (AUC) of 0.98 (CI: 0.93-1.00) (Figure 4A), whereas FPG demonstrated superior performance among Peruvians (AUC: 0.90; CI, 0.84-0.95) (Figure 4B). We next compared the different cohorts with regard to the performance of the FPG or HbA1c tests in distinguishing dysglycemia and found substantial differences between the AUC (p=0.0089 and p<0.0001 correspondingly) (Figure 4C). This finding reinforces the idea that there are important discrepancies in the overall accuracy of the FPG and of HbA1c tests to identify individuals with prediabetes or diabetes between Brazilians and Peruvians.
Finally, additional comparisons were made to narrow down the concordance between HbA1c and FGP to detect diabetes or prediabetes in the study populations. We noted that the FPG test had a good degree of agreement in the Peruvian cohort for identification of dysglycemia cases (k=0.77) or PDM (k=0.6), and very good degree for identification of DM individuals (k=0.96). Interestingly, for Brazilian cohort the degree of concordance for identification of dysglycemia or PDM was poor (k=0.20 and k=0.08, correspondingly) and for DM it was moderate (k=0.11) (Figure 4D). In contrast, the HbA1c test exhibited a very good agreement in the Brazilian cohort to detect dysglycemia (k=0.83), DM (k=0.98) or PDM (k=0.84). Meanwhile, in the Peruvian cohort, the agreement for dysglycemia was moderate (k=0.44), for DM it was very good (k=0.97) and for PDM it was just fair (k=0.35).