The Effect of Diabetes and Prediabetes on Mycobacterium tuberculosis Transmission to Close Contacts

Abstract

Background: It is unknown whether dysglycemia is associated with Mycobacterium tuberculosis transmission.

Methods: We assessed epidemiological and clinical characteristics of patients with culture-confirmed pulmonary tuberculosis and their close contacts, enrolled in a multicenter prospective cohort in Brazil. Contacts were investigated at baseline and 6 months after enrollment. QuantiFERON positivity at baseline and conversion (from negative to positive at month 6) were compared between subgroups of contacts according to glycemic status of persons with tuberculosis (PWTB) as diabetes mellitus (DM) or prediabetes. Multivariable mixed-effects logistic regression models were performed to test independent associations with baseline QuantiFERON positive and QuantiFERON conversion.

Results: There were 592 PWTB (153 DM, 141 prediabetes, 211 normoglycemic) and 1784 contacts, of whom 658 were QuantiFERON-positive at baseline and 106 converters. Multivariable analyses demonstrated that tuberculosis-prediabetes cases, acid-fast bacilli-positive, pulmonary cavities, and living with someone who smoked were independently associated with QuantiFERON positive in contacts at baseline. DM, persistent cough, acid-fast bacilli-positive, and pulmonary cavities in tuberculosis source cases were associated with QuantiFERON conversion.

Conclusions: Contacts of persons with pulmonary tuberculosis and dysglycemia were at increased risk of being QuantiFERON positive at baseline or month 6. Increased focus on such close contacts could improve tuberculosis control.

Keywords: Mycobacterium tuberculosis; diabetes; interferon-γ releasing assay; prediabetes; quantiFERON.

Figure 1.

Study flow chart. The main objective of the study was to compare incident tuberculosis (TB) infection among contacts from pulmonary tuberculosis patients with or without dysglycemia. Data were obtained from 1038 individuals diagnosed with culture-confirmed pulmonary tuberculosis enrolled into the RePORT Brazil study protocol. Of those, 592 (57%) had close contacts (average of 3 contacts per tuberculosis index case) who enrolled and were included in the analyses. During the clinical and laboratory evaluation (hemoglobin A1c levels) of the tuberculosis index cases, 141 had prediabetes (PDM), 153 had type-2 diabetes (DM), and 211 were normoglycemic. In 609 contacts of 198 tuberculosis-normoglycemic patients and 1186 contacts of 294 tuberculosis-dysglycemic patients the first QuantiFERON (QTF) test was performed. The close contacts enrolled of each tuberculosis index case were evaluated, and screening for Mycobacterium tuberculosis infection was performed with clinical and radiographic examination as well as with QTF testing. Those who had negative QTF result at baseline underwent repeat QTF testing at 6 months to assess for QTF conversion. For the present study, individuals whose QTF result was indeterminate (ind; first or second QTF) or those who did not have a second QTF test performed at month 6 of follow-up were excluded from the analysis.

Figure 2.

Characteristics of contacts of patients with active tuberculosis (TB) stratified by glycemic status. A, Characteristics of the close contacts of pulmonary tuberculosis patients stratified according to the presence of diabetes (DM) or prediabetes (PDM) were compared with those from patients with normoglycemia using the Fisher exact test (additional comparisons are displayed in Supplementary Table 3). B, Sankey diagram shows number of close contacts of pulmonary tuberculosis patients stratified based on QuantiFERON (QTF) test result. Number of individuals who developed incident tuberculosis during the follow-up is also highlighted (blue font) in each indicated subgroup. C, Frequency of tuberculosis contacts who tested positive in the first QTF result (prevalent latent tuberculosis infection) stratified based on the glycemic status of the tuberculosis index case. D, Frequency of tuberculosis contacts who were QTF negative in the first examination and tested positive in the second evaluation (QTF conversion, incident tuberculosis infection), stratified based on the glycemic status of the PWTB. C and D, Data were compared using the Fisher exact test. A, C, and D, P values were adjusted for clustering by index case. Abbreviation: CI, confidence interval.

Figure 3.

Factors associated with tuberculosis infection in contacts of pulmonary tuberculosis patients with diabetes and prediabetes. A, Characteristics of the close contacts of pulmonary tuberculosis patients stratified according to the QTF test result were compared using the Fisher exact test (additional comparisons are displayed in Supplementary Table 3). B, Frequency of indicated characteristics of the pulmonary tuberculosis index cases stratified based on the QTF results of the contacts was compared using the Pearson χ ² test. C, Left, scatter plot shows distribution of age (median and interquartile range) among the subgroups of contacts of persons with tuberculosis based on the QTF result. Data were compared using the Kruskal-Wallis test with Dunn multiple comparisons ad hoc test. The difference in median age values between the groups of positive QTF and of QTF conversion was statistically significant. Right, frequency of close tuberculosis contacts with the indicated characteristics was compared between the subgroups based on the QTF result was compared using the Pearson χ ² . D, A multivariable mixed-effects logistic regression with a random effect per “tuberculosis case” (to decrease the possible selection bias, because 1 “tuberculosis case” can have more than 1 contact, with different QTF results) was used to test association between indicated characteristics of pulmonary tuberculosis index patients or of the tuberculosis close contacts and positivity of the baseline QTF test or conversion of the QTF result in tuberculosis contacts. Variables included in the adjusted model exhibited univariate P values≤.2 (see Supplementary Table 4 for details). A, B, and C, P values were adjusted for clustering by index case. Passive smoking was defined as living with someone who smokes. Persistent cough was defined as patients who reported cough at the initial evaluation (month 0) and also at the month 2 visit. Abbreviations: AFB, acid-fast bacilli; CI, confidence interval; DM, diabetes; HIV, human immunodeficiency virus; NA, not applicable; nd, not detected; PDM, prediabetes; QTF, QuantiFERON; TB, tuberculosis.

Figure 4.

Factors associated with QTF conversion in contacts of pulmonary tuberculosis patients. A multivariable mixed-effects logistic regression with a random effect per “tuberculosis case.” Estimates are bias-corrected based on 1000 bootstrap iterations to account for the small sample size. Estimates (in terms of odds ratios) reflect associations between indicated characteristics of pulmonary tuberculosis index patients or of the tuberculosis close contacts and conversion of the QTF result (incident tuberculosis infection) in tuberculosis contacts. Variables included in the adjusted model exhibited univariate P values ≤.2 (see Supplementary Table 4 for details). Persistent cough was defined as patients who reported cough in the initial evaluation interview (month 0) and also in the month 2 visit. Abbreviations: AFB, acid-fast bacilli; CI, confidence interval; QTF, QuantiFERON; TB, tuberculosis.