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IMMUNOLOGIC BIOMARKERS IN PERIPHERAL BLOOD OF PERSONS WITH TUBERCULOSIS AND ADVANCED HIV
Author
Queiroz, Artur T. L
Pereira, Mariana Araújo
Duarte, Beatriz Barreto
Silva, Adriano Gomes
Costa, Allyson G
Andrade, Alice M. S
Pinto, João Pedro Miguez
Gomes, Renata Spener
Souza, Alexandra B
Benjamin, Aline
Sant’Anna, Flavia
Figueiredo, Marina C
Mave, Vidya
Salgame, Padmini
Ellner, Jerrold J
Sterling, Timothy R
Santos, Marcelo Cordeiro dos
Andrade, Bruno B
Rolla, Valeria C
Pereira, Mariana Araújo
Duarte, Beatriz Barreto
Silva, Adriano Gomes
Costa, Allyson G
Andrade, Alice M. S
Pinto, João Pedro Miguez
Gomes, Renata Spener
Souza, Alexandra B
Benjamin, Aline
Sant’Anna, Flavia
Figueiredo, Marina C
Mave, Vidya
Salgame, Padmini
Ellner, Jerrold J
Sterling, Timothy R
Santos, Marcelo Cordeiro dos
Andrade, Bruno B
Rolla, Valeria C
Affilliation
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal do Rio de Janeiro. Programa de Pós-graduação em Clínica Médica. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States.
Byramjee-Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site (BJGMC-JHU CRS). Pune, India / School of Medicine, Johns Hopkins University. Baltimore, MD, United States.
Rutgers-New Jersey Medical School. Center for Emerging Pathogens. Newark, NJ, United States.
Rutgers-New Jersey Medical School. Center for Emerging Pathogens. Newark, NJ, United States.
Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal do Rio de Janeiro. Programa de Pós-graduação em Clínica Médica. Rio de Janeiro, RJ, Brasil / Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States / Escola Bahiana de Medicina e Saúde Pública. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal do Rio de Janeiro. Programa de Pós-graduação em Clínica Médica. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States.
Byramjee-Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site (BJGMC-JHU CRS). Pune, India / School of Medicine, Johns Hopkins University. Baltimore, MD, United States.
Rutgers-New Jersey Medical School. Center for Emerging Pathogens. Newark, NJ, United States.
Rutgers-New Jersey Medical School. Center for Emerging Pathogens. Newark, NJ, United States.
Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States.
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil.
Instituto Gonçalo Moniz. Fundação Oswaldo Cruz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Universidade Salvador. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal do Rio de Janeiro. Programa de Pós-graduação em Clínica Médica. Rio de Janeiro, RJ, Brasil / Division of Infectious Diseases. Department of Medicine. Vanderbilt University School of Medicine. Nashville, TN, United States / Escola Bahiana de Medicina e Saúde Pública. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.
Abstract
Introduction: Tuberculosis (TB) is a common opportunistic infection among people living with HIV. Diagnostic tests such as culture, Xpert-MTB-RIF, and ULTRA have low sensitivity in paucibacillary TB disease; a blood biomarker could improve TB diagnostic capabilities. We assessed soluble factors to identify biomarkers associated with TB among persons with advanced HIV. Methods: A case-control (1:1) study was conducted, with participants from Rio de Janeiro and Manaus, Brazil. People living with HIV presenting with CD4 count ≤100 cells/mm3 were eligible to participate. Cases had culture-confirmed TB (N=15) (positive for Mycobacterium tuberculosis [Mtb]); controls had HIV-infection only (N=15). Study visits included baseline, month 2 and end of TB therapy, during which samples of peripheral blood were obtained. A panel containing 29 biomarkers including cytokines, chemokines and growth factors was utilized to assess candidate biomarkers using Luminex technology in cryopreserved EDTA plasma samples. We used neural network analysis, based on machine learning, to identify biomarkers (single or in combination) that best distinguished cases from controls. Additional multi-dimensional analyses provided detailed profiling of the systemic inflammatory environment in cases and controls. Results: Median CD4 count and HIV-1 RNA load values were similar between groups at all timepoints. Persons with TB had lower body mass index (BMI) (median=19.6, Interquartile Range [IQR]=18.6-22.3) than controls (23.7; IQR: 21.8 = 25.5, p=0.004). TB coinfection was also associated with increased frequency of other comorbidities. The overall profile of plasma cytokines, chemokines and growth factors were distinct between the study groups at all timepoints. Plasma concentrations of IL-15 and IL-10 were on average lower in TB cases than in controls. When used in combination, such markers were able to discriminate between TB cases and controls with the highest degree of accuracy at each study timepoint. Conclusion: Among persons with advanced HIV, plasma concentrations of IL-15 and IL-10 can be used in combination to identify TB disease regardless of time on anti-TB treatment.
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