Biomarcadores séricos: ferramenta para o diagnóstico diferencial entre tuberculose latente e tuberculose pulmonar em crianças e adolescentes

Abstract

Children are estimated to account for 10% of tuberculosis (TB) cases worldwide.However, bacteriological confirmation in this group remains a challenge, as they most often develop paucibacillary forms of pulmonary TB (PTB). Additionally, the tuberculin skin test (TST) and interferon gamma release assays (IGRAs) present diagnostic limitations and do not differentiate LTBI from active TB. Serum biomarkers have been proposed as a potential alternative for use in rapid tests such as point of care (POC) tests. The cell wall of Mycobacterium tuberculosis is composed of lipids and proteins capable of stimulating the synthesis of antibodies in the host. This cross-sectional study, with prospective inclusions from August 2014 to June 2017, had the objective of evaluating whether serum levels of the biomarkers are capable of differentiating LTBI from pulmonary TB in children and adolescents. The participants were included at health units of six municipalities in the state of Rio de Janeiro, Brazil and divided into 3 groups: control -TB contacts, asymptomatic, with normal chest radiography and negative TST; LTBI - TB contacts, asymptomatic, with normal chest radiography and positive TST; and pulmonary TB - patients with signs, symptoms, laboratory and radiological findings suggestive of active disease. Serum anti-cardiolipin, -sulfatide, -mycolic acid, and -Mce1A IgM, and anti-Mce1A IgGwere assayed by the ELISA method. Statistical analysis was performed using GraphPadPrism (version 5.0). The Kruskal-Wallis test was used to compare biomarkers levels, followed by the Dunn test or the Mann-Whitney test and the T test when indicated. Categorical variables were analyzed using chi-square tests. The level of significance was set at p <0.05. Sensitivity and specificity were assessed by analysis of the ROC curve. Of the 107 participants, 20 were classified as control, 44 as LTBI and 43 as PTB. The median age was 7 years (interquartile range = IQR: 4.3 - 9) in the control group, 8.5 years in the LTBI (IQR: 4 - 11) and 11 years in the PTB (IQR: 1.9 - 15), with p= 0.47. There was no difference between genders. In all age groups, the anti-Mce1A IgG titer was higher in those with PTB compared to those with LTBI. Analysis across the curve showed the AUC = 0.73 with p= 0.0002. For the cut-off of 0.26 OD (95% CI = 0.628-0.88), sensitivity was 72.09% and specificity was 63.64%. When comparing the BACT+ PTB group with LTBI, sensitivity was 73.7% and specificity was 63.7% (cut-off = 0.26) and for the comparison of BACT+ PTB vs control, 73.7% and 70 % respectively. Anti-cardiolipin, sulfatide, mycolic acid and Mce1A IgM did not discriminate LTBI and PTB,and their levels were higher in the control group. Anti-Mce 1A IgG levels were higher in children and adolescents with PTB compared to those with LTBI, showing the potential use of these biomarkers as a tool for the diagnosis of TB in the pediatric group