Combination of Mycobacterium tuberculosis immunodominant peptides and serum host response biomarkers for the diagnosis of tuberculosis
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1
IMSS, UNIDAD DE INVESTIGACION BIOMEDICA DE ZACATECAS, Mexico
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2
Servicios de Salud de Zacatecas, SSA, COORDINACION DE INVESTIGACION EN SALUD, Mexico
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3
UNIVERSIDAD CENTRAL DE VENEZUELA, INSTITUTO DE BIOMEDICINA, Venezuela
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4
FUNDACION INSTITUTO INMUNOLOGIA DE COLOMBIA, DEPARTAMENTO DE BIOLOGIA MOLECULAR E INMUNOLOGIA , Colombia
Tuberculosis (TB), despite being a curable disease, continues to be a major public health threat. From 8.6 million people who developed TB in 2012, over one-third were not diagnosed, being the lack of a biomarker-based, low-cost, non-sputum-base test for TB diagnostics an important issue to solve. Efficient, rapid and accurate diagnosis is critical for timely initiation of treatment and control of the disease. Given none commercial ELISA assays have acceptable performance to diagnose TB, the recent WHO policy statement encouraged further work in biomarkers for TB diagnosis research, including serologic assays that directly detect antibodies to MTB antigens or antigen detection assays that specifically detect mycobacterial derived compounds or antigens. Indeed, TB control programs around the world still require the validation of biomarkers for diagnosis not only for active TB, but also for the diagnosis of latent infected individuals who are at the highest risk of TB reactivation.
From previous studies, a group of protein serum biomarkers from a transcriptional signature that distinguishes active tuberculosis individuals (TBA) from latent infected (LTB) and from non-TB infected (CTR), was identified in subjects selected under strict clinical and laboratory criteria, including clinical diagnosis, tuberculin test, Quantiferon-Gold®, blood count, blood chemistry, AFB, Mycobacterium tuberculosis (MTB) culture and chest X-ray. On the other hand, ELISA assays with a group of immunodominant TB peptides, showed that TBA patients have serum specific antibodies that react with some of these synthetic peptides. In this study, three selected TB host response biomarkers (B1, B2 and B3) and antibodies to four TB immunodominant peptides (P1, P2, P3 and P4), were evaluated in a combined serial diagnosis tests for active TB by standardized ELISA assays, in serum of non-infected subjects, TB infected individuals, and in TB active patients.
Differences in levels of biomarkers and peptides among TBA, TBL, and CTR individuals were analyzed for multiple comparisons test. No differences were found between the TBL and CTR (NonTBA groups) and were considered as a single Non-TBA group for comparison to TBA subjects by Linear discriminant analysis (LDA) and ROC curves analysis. Several cutoff points were considered and results of validity (sensitivity, specificity), security (predictive values), risk (likelihood ratio) and overall value (Youden index) were analyzed by testing single or multiple (serial and parallel) diagnostic test.
Results of LDA indicate that P2, P3, B1, and B2 have the greatest discriminatory power and in combination they correctly classify 88.5% of cases with a sensitivity of 95.6 % and a specificity of 71.4%. According ROC analysis, B1 has an AUC of 0.9, followed by P3 with 0.88, B2 with 0.86 and P2 with 0.66. Quantification of P3 with a cutoff equal or greater than 0.34 DO showed the greatest overall value (Youden index 0.7); however B1 gave the highest possible sensitivity (100%) but low specificity (58.8%). A serial diagnostic test was calculated for B1 as a first test and P3 as a second test. The result show sensitivity 92%, specificity 91%, Likelihood ratio positive 10, Likelihood ratio negative 11, PPV 79%, and NPV 97%; however these values should be adjusted according to the prevalence of the disease in each region. Overall, the identification of both molecules has efficiency as a TBA diagnosis test of 83%, according to Youden index.
A rapid serial diagnosis test based on the combined use of serum biomarkers and serum antibodies to MTB specific synthetic peptides is useful for the development of a low-cost, non-sputum-base test for TB diagnosis, because of its high sensitivity and specificity to discriminate TBA subjects from healthy non-infected TB controls and TBL individuals.
Acknowledgements
This project was supported by CONACYT, Mexico, Grant 215380, PDCPN2013-01. JAEM is a Scholar of Fundacion IMSS. Noe Macias Segura recived a scholarship from CONACYT, MEXICO.
Keywords:
Tuberculosis,
diagnosis,
biomarkers,
ELISA,
Antigenic peptides
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Poster Presentation
Topic:
Infectious and parasitic diseases
Citation:
ENCISO-MORENO
J,
CUEVAS CORDOBA
B,
MACIAS-SEGURA
N,
GANDARA-JASSO
B,
ARAUJO-GARCIA
Z and
PATARROYO
M
(2015). Combination of Mycobacterium tuberculosis immunodominant peptides and serum host response biomarkers for the diagnosis of tuberculosis.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00199
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Received:
15 May 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
PhD. JOSE ANTONIO ENCISO-MORENO, IMSS, UNIDAD DE INVESTIGACION BIOMEDICA DE ZACATECAS, ZACATECAS, ZACATECAS, 98000, Mexico, enciso_2000@yahoo.com