Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease: A Diagnostic Accuracy Study for Pediatric Tuberculosis

Abstract

Introduction: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study. Methods: This prospective diagnostic accuracy study evaluating several candidate tests for TB was set out to recruit 1000 children <15 years with presumptive TB in 5 countries (Malawi, Mozambique, South Africa, Tanzania, India). Assessments at baseline included documentation of TB signs and symptoms, TB history, radiography, tuberculin skin test, HIV testing and spirometry. Respiratory samples for reference standard testing (culture, Xpert Ultra) included sputum (induced/spontaneous) or gastric aspirate, and nasopharyngeal aspirate (if <5 years). For novel tests, blood, urine and stool were collected. All participants were followed up at months 1 and 3, and month 6 if on TB treatment or unwell. The primary endpoint followed NIH-consensus statements on categorization of TB disease status for each participant. The study was approved by the sponsor’s and all relevant local ethics committees. Discussion: As a diagnostic accuracy study for a disease with an imperfect reference standard, Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease (RaPaed-TB) was designed following a rigorous and complex methodology. This allows for the determination of diagnostic accuracy of novel assays and combination of testing strategies for optimal care for children, including high-risk groups (ie, very young, malnourished, children living with HIV). Being one of the largest of its kind, RaPaed-TB will inform the development of improved diagnostic approaches to increase case detection in pediatric TB.

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

“…The study protocol and methods are published elsewhere. 16 The study was performed in accordance with the Declaration of Helsinki. 17 The protocol and informed consent documents were approved by institutional review boards at all sites and the coordinating site (Division of Infectious Diseases and Tropical Medicine, Ludwig Maximilian University of Munich, Munich, Germany).…”

“…Children were excluded if they weighed less than 2 kg, had received three or more doses of tuberculosis medication, or if study procedures were considered an undue risk to the child. 16 Parents or guardians provided written informed consent, and participants provided written assent when they were older than the locally specified age for doing so.…”

“…After extensive training of all site staff, a standardised clinical, radiological, and laboratory workup was performed; monitoring and retraining, if necessary, was performed every 6 months. 16 For the two respiratory specimens (spontaneous or induced sputum at African sites, or gastric lavage at the Indian site) obtained from each participant, solid and liquid media cultures (Mycobacteria Growth Indicator Tube; Becton Dickinson, Sparks, NJ, USA) were inoculated and one Ultra was performed. Children younger than 5 years underwent nasopharyngeal aspirate for a second Ultra.…”

“…Diagnostic classifications were adapted from the US National Institutes of Health consensus statement for paediatric tuberculosis diagnostic evaluation studies. 2 , 16 Clinical case definitions were used to derive reference standards for diagnostic accuracy estimation, which are described in detail in the appendix (p 3) . Briefly, we defined a strict reference standard (SRS) including only children with culture or cultures positive for M tuberculosis as confirmed tuberculosis, compared with children with unlikely tuberculosis.…”

Pediatric Tuberculosis: A Review of Evidence-Based Best Practices for Clinicians and Health Care Providers

“…A recent monograph focuses on some of the key gaps and implementation challenges in TB care for children and adolescents, outlines the critical role of multisectoral partnerships, and discusses and provides examples of facilitating integration of innovations into routine programs [148]. Research and development specifically for children has led to an increasingly rich pipeline of new tools and methods to address gaps in TB prevention, diagnosis, and treatment, as well as rich data from recently developed collaborative research platforms and multinational trials that evaluate impact in a range of diverse settings (e.g., SHINE [32], TB-Speed [149], RaPaed-TB [150], and TB CONTACT [151]). Also of particular note are research efforts related to TB vaccine candidates and novel specimen types to aid in TB diagnosis.…”