Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of <i>Mycobacterium tuberculosis</i> Infection
Authors: Elisa Nemes, Virginie Rozot, Hennie Geldenhuys, Nicole Bilek, Simbarashe Mabwe, Deborah Abrahams, Lebohang Makhethe, Mzwandile Erasmus, Alana Keyser, Asma Toefy, Yolundi Cloete, Frances Ratangee, Thomas Blauenfeldt, Morten Ruhwald, Gerhard Walzl, Bronwyn Smith, Andre G. Loxton, Willem A. Hanekom, Jason R. Andrews, Maria D. Lempicki, Ruth Ellis, Ann M. Ginsberg, Mark Hatherill, Thomas J. Scriba, Susan Rossouw, Carolyn Jones, Elisma Schoeman, Yolande Gregg, Elizabeth Beyers, Sandra Kruger, Helen Veltdsman, Sophie Keffers, Sandra Goliath, Mariana Mullins, Michele Tameris, Angelique Luabeya, Ashley Veldsman, Humphrey Mulenga, Angelique Hendricks, Fajwa Opperman, Elma Van Rooyen, Julia Noble, Samentra Braaf, Rose Ockhuis, Emerencia Vermeulen, Alessandro Companie, Xoliswa Kelepu, Maigan Ratangee, Abraham Pretorius, Henry Issel, Phumzile Langata, Ilse Davids, Roxanne Herling, Hadn Africa, Marcia Steyn, Lungisa Nkantso, Noncedo Xoyana, Bongani Diamond, Margareth Erasmus, Jane Hughes, Denise van der Westhuizen, Lydia Makunzi, Natasja Botes, Julia Amsterdam, Clive Maqubela, Portia Dlakavu, Pamela Mangala, Charmaine Abrahams, Petrus Tyambetyu, Diann Gempies, Cindy Elbring, Elizabeth Hamilton, Fadia Alexander, Sindile Wiseman Matiwane, Cashwin September, Christel Petersen, Yulande Herselman, Johanna Hector, Terence Esterhuizen, Lauren Mactavie, Elize van der Riet, Debbie Pretorius, Carolyn Jones, Justin Shenje, Anne Swarts, Eunice Sinandile, Janelle Botes, Terence Esterhuizen, Constance Schreuder, Jateel Kassiem, Onke Xasa, Boitumelo Mosito, Rodney Raphela, Denis Arendsen, Palesa Dolo, Elizabeth Filander, Hassan Mahomed, Fazlin Kafaar, Leslie Workman, Humphrey Mulenga, Rodney Ehrlich, Sizulu Moyo, Sebastian Gelderbloem, Michele Tameris, Gregory Hussey
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability.To improve the consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion.Sources of QuantiFERON-TB variability were assessed, and optimal procedures were identified. Distributions of IFN-γ response levels were analyzed in healthy adolescents, Mtb-unexposed control subjects, and patients with pulmonary tuberculosis.Individuals with no known Mtb exposure had IFN-γ values less than 0.2 IU/ml. Among individuals with IFN-γ values less than 0.2 IU/ml, 0.2-0.34 IU/ml, 0.35-0.7 IU/ml, and greater than 0.7 IU/ml, tuberculin skin test positivity results were 15%, 53%, 66%, and 91% (P < 0.005), respectively. Together, these findings suggest that values less than 0.2 IU/ml were true negatives. In short-term serial testing, "uncertain" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/ml), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFN-γ values from less than 0.2 to greater than 0.7 IU/ml had 10-fold higher tuberculosis incidence rates than those who maintained values less than 0.2 IU/ml over 2 years (P = 0.0003). By contrast, "uncertain" converters were not at higher risk than nonconverters (P = 0.229). Eighty-seven percent of patients with active tuberculosis had IFN-γ values greater than 0.7 IU/ml, suggesting that these values are consistent with established Mtb infection.Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-γ <0.2 to >0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease.