Consensus statement on diagnostic end points for infant tuberculosis vaccine trials.

BACKGROUND  Definition of clinical trial end points for childhood tuberculosis is hindered by lack of a standard case definition. We aimed to identify areas of consensus or debate on potential end points for tuberculosis vaccine trials among human immunodeficiency virus-uninfected children. METHODS  Thirty-eight opinion leaders participated in a Consensus Workshop at the Second Global Forum on TB Vaccines (Estonia, 2010). Outcomes were categorized as unanimity, modified consensus, or lack of consensus. Individual reservations were noted. RESULTS  Modified consensus was achieved on 3 issues: (1) unsuitability of historical BCG trial end points as sole primary end points for modern infant trials; (2) symptomatic, complicated intrathoracic tuberculosis as an uncommon but clinically relevant disease phenotype; (3) primary complex tuberculosis in younger children as a common, high-risk phenotype, with a high rate of spontaneous resolution. Participants agreed that radiologic diagnosis of intrathoracic tuberculosis would be based primarily on hilar lymphadenopathy. Lack of consensus was noted for (1) significance of isolated culture of Mycobacterium tuberculosis and (2) the need for evidence of prior tuberculosis exposure to support a diagnosis of tuberculosis disease. Reservations were expressed regarding use of interferon-γ release assays and the clinical relevance, and potential for misclassification, of primary complex tuberculosis. CONCLUSIONS  The Workshop did not achieve consensus on a single primary end-point definition. Tuberculosis disease phenotypes with optimal diagnostic certainty will be uncommon in the study population. Criteria for composite or multiple end points were identified, and we propose a hierarchy of end-point criteria, based on rate of occurrence, clinical relevance, and diagnostic certainty.