Understanding NIH clinical case definitions for pediatric intrathoracic TB by applying them to a clinical trial

Abstract

Setting and Objective Currently, standardized clinical case definitions represent the best option for pediatric tuberculosis (TB) disease diagnosis and classification. We applied clinical case definitions for intrathoracic TB classification, developed by an expert panel for use in reporting diagnostic studies with passive case finding, to TB suspects from IMPAACT P1041, a trial of INH prophylaxis in healthy HIV-exposed, BCG vaccinated infants which employed active surveillance, to assess novel application of these guidelines in this setting. Methods P1041 TB suspects were retrospectively cross-classified by protocol-defined and NIH classifications and agreement assessed. Results Of 219 TB suspects, 166 had signs/symptoms (S/S), with 158 considered TB (21 confirmed, 92 probable, 45 possible) and 8 not TB (6 TB unlikely, 2 alternative diagnoses). Weight loss and failure to thrive represented the majority of observed S/S. Among those with S/S, agreement between definitions was poor. Additionally, 53 TB suspects were without S/S, including 33 classified by the P1041 protocol as TB. Conclusion The poor agreement between P1041 and NIH classifications reflects cases that are identified through active versus passive surveillance, the latter reflecting the intended use of NIH definitions. Given the interest in having standardized definitions for broader application, future efforts could focus on expanding TB disease classification for detection and classification of suspects identified through active surveillance.

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update

“…Definitions will need to be developed for different scenarios such as involving active case finding, for example, during household contact studies, but this is outside the present scope of work. Evaluation of data from active case-finding studies, one as a cohort study with active follow-up [23] and the other as a community-based tuberculosis contact investigation study [24], have reported that 12% and 65%, respectively, of children with confirmed tuberculosis did not have clinical features consistent with the standardized "clinical signs/symptoms suggestive of tuberculosis" used to categorize clinical, unconfirmed cases. Active case finding is likely to identify cases at an earlier stage of disease and a much shorter duration of symptoms compared with children investigated for tuberculosis at the referral level.…”

Incident Tuberculosis Diagnoses in Children at High Risk for Disease

“…When appropriate, investigators may wish to improve specificity by combining these case definitions with data from a clinical evaluation or prescription of treatment. One potential contributor to the observed discrepancies between NIH case definitions and clinical decision-making is that the NIH case definitions were not designed for the setting of active case finding [ 13 , 14 ], and some of children presented to health facilities following contact tracing activities. Another consideration is that NIH case definitions apply equal weight to each criterion, while clinicians may implicitly or explicitly weigh factors differently or consider factors beyond those noted in case definitions (eg, access to care).…”

Estimating Malaria Vaccine Efficacy in the Absence of a Gold Standard Case Definition: Mendelian Factorial Design

“…As it has been demonstrated in MR, using many ostensible Mendelian factors where some are invalid may have the potential to improve the robustness of MFD analysis (Kang et al, 2016). Finally, the application of MFD to the study of vaccines against other childhood diseases that have unspecific symptoms and no gold-standard case definition, such as pediatric tuberculosis (Beneri et al, 2016) The World Health Organization (WHO) recommends that the primary endpoint in pivotal…”