Two proposals submitted to the RePORT in Maternal Health and Pediatrics (RePORT Peds) were selected for award in 2016. Funding is provided by the National Institute of Allergy and Infectious Diseases (NIAID) will support two projects up to three years for a maximum of $325,000 per year.

 

Background and Purpose

Improved diagnosis and treatment for children and pregnant women is important for global health. TB in pregnant women and children is different than TB in nonpregnant adults and has been vastly understudied. The natural history of TB in childhood is complex, heavily influenced by the age of primary infection, and distinct from that in adults. The clinical spectrum of TB in children is diverse and includes latent infection, a wide range of complicated and uncomplicated intrathoracic disease, and diverse manifestations of extrathoracic or disseminated disease that range from superficial lymphadenopathy to miliary disease with or without central nervous system involvement. The presence of HIV co-infection further complicates diagnosis and can alter the natural history of TB in older children, resembling the more disseminated disease found in the very youngest age groups. These variances from adult TB necessitate the exclusive study of children in order to address research gaps in childhood TB. Similarly, TB in pregnancy presents diagnostic challenges due to the nonspecific nature of the early symptoms, many of which may be attributed to pregnancy. TB most often affects women when they are economically and reproductively active. The risk of developing active TB nearly doubles during pregnancy and immediately postpartum. This unique period of vulnerability surrounding pregnancy and its causation are poorly understood. In areas of high HIV prevalence, women of child-bearing age (15-24) are disproportionately affected by TB. TB in pregnant women living with HIV greatly increases the risk of maternal and infant mortality, requiring more study in this population.

 

Vision and Objectives

  • Build and enhance biomedical, clinical, and implementation research capacity for the population of children and pregnant women by establishing prospective longitudinal cohorts of pregnant women and children with suspected, probable, or confirmed TB and their contacts (or other high TB risk patients) for studies using state-of-the-art research tools.
  • Address crucial TB research gaps for children and pregnant women while leveraging resources from an existing infrastructure that is currently mostly focused on research for nonpregnant adults.

Similar cohorts have been and are being established in high burden countries including the RePORT Consortia, the umbrella program supporting this research initiative. RePORT represents several bilateral, multi-organizational collaborative efforts comprising a global network of cohort research units (CRUs) that undertake coordinated research to better understand similarities and differences in the TB epidemic in high burden countries and to facilitate a broad array of biomedical TB research.

 

The two proposals are described below:

A combination of oral swabs and highly sensitive nucleic acid amplification testing for the diagnosis of pulmonary tuberculosis in HIV-infected and uninfected children. The principal investigator is Mark Nicol, University of Cape Town, South Africa. The proposed study will work to develop a diagnostic test to detect TB in young children.  The microbiological diagnosis of pulmonary tuberculosis (PTB) is challenging due to a low microbiologic yield from current methods and difficulty in collecting appropriate specimens from children. The proposed study is an extension of the team’s current TB-RePORT study, which involves testing a highly sensitive nucleic acid amplification assay, “Ultra,” using induced sputum specimens collected from children with suspected PTB. They hypothesize that microbiologic confirmation of PTB may be made by using Ultra on an oral swab, an easier and less invasive method for collecting specimens. The proposed study aims to test Ultra on oral swabs and to compare the yield to Ultra and culture on induced sputum.  It will also compare the accuracy of Ultra for diagnosing PTB in HIV-infected and uninfected children. Accuracy will be determined by comparing the Ultra assay test results with a combination of microbiological testing and clinical diagnosis as a gold standard. This study will build upon the current TB-RePORT study conducted at the South Africa site by including collection of the oral swab specimens and extending recruitment to include an additional cohort of children to increase the number of samples needed to determine test accuracy.    

 

Enhancing diagnostics and improving outcomes in childhood tuberculosis (EDICT study). The principal investigator is Sanjay Lala, Wits Health Consortium, South Africa. Childhood TB is an urgent global public health priority but childhood TB research is extremely difficult primarily due to the difficulty of confirming a diagnosis of childhood TB. In parallel with measures to improve the sensitivity of tests that are used to confirm a diagnosis of M.tuberculosis infection in children, such as nucleic acid amplification tests and culture, biomarker(s) that can assist in the diagnosis and response to treatment in childhood TB are urgently required. As part of the RePORT consortium, the proposed study will contribute biological samples (principally blood and urine) taken from children with TB, as well as from a control group of children with lower respiratory tract infection (LRTI), to help develop urgently needed diagnostic tests for childhood TB. Because TB disease most commonly presents with features indistinguishable from acute bacterial or viral lower respiratory tract infections (LRTI) in this setting – and is often missed in children with LRTI – a biorepository from children with LRTI is an essential control group. Additionally, two site-specific studies will be undertaken: one determining if TB-affected children with nonreactive tuberculin skin tests (TST) are at risk of poorer nutritional outcomes following the completion of TB treatment and the second will determine whether hospital-based source case investigation (SCI) for TB disease and/or HIV infection should be urgently implemented for caregivers of children with TB and LRTI.