Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition (TB-Speed SAM)

TB-Speed SAM is a multicentric, prospective diagnostic cohort study conducted in three countries with high and very high TB incidence (Sierra Leone, Uganda, and Zambia). It aims at assessing several diagnostic tests that could result in the development of a score and algorithm for TB treatment decision in hospitalised children with severe acute malnutrition (SAM).

Study Overview

• Status: Unknown
• Conditions: Tuberculosis; Severe Acute Malnutrition
• Intervention / Treatment: Other: Development of a score and algorithm for TB treatment decision in hospitalised children with SAM.

Detailed Description

There is now strong evidence that undiagnosed and untreated TB increases the risk of death in children, especially those severely malnourished who are highly vulnerable. Specific decision-making tools are therefore urgently needed to guide clinicians from high TB burden and low-income countries to initiate treatment quickly in children with SAM with suspected TB.

A diagnostic prediction score and algorithm was recently proposed by the investigators for TB treatment decision in HIV-infected children with presumptive TB (developed in the ANRS 12229 PAANTHER 01 study). Based on easily collected clinical features, chest X-Ray (CXR), Xpert MTB/RIF, and abdominal ultrasonography, the score aims to help clinicians make a same-day treatment decision. Such a prediction score improving TB diagnosis and shortening time to treatment initiation would be a key benefit in children with SAM.

Based on this experience, the investigators are proposing a diagnostic cohort study enrolling hospitalized severely malnourished children. The study will include the evaluation of several diagnostic tests that could be integrated in the development of a prediction model and subsequent score for the diagnosis of TB in hospitalized children with SAM. This will include Xpert MTB/RIF Ultra performed on one nasopharyngeal aspirate (NPA) and one stool sample, CXR, Quantiferon (QFT) Interferon-Gamma Release Assay (IGRA), Monocyte-to-lymphocyte ratio (MLR), and ultrasonography, which has shown its interest for the diagnosis of TB in both HIV-infected adults and children. In the PAANTHER study, it detected abdominal lymphadenopathy in 50% of culture confirmed TB cases and 35% of all confirmed and unconfirmed cases, with a specificity of 85%.

Using logistic regression, a score will be developed for TB diagnosis, considering confirmed and unconfirmed TB as reference diagnosis, in hospitalized children with SAM. As a secondary objective, and in order to reduce costs, sample collection, and complexity of the diagnostic process, a first-step screening score (excluding Ultra, abdominal ultrasound, and CXR if possible) will be developed to identify children with presumptive TB who would benefit from further diagnostic testing.

Both scores will be internally validated using resampling and will be incorporated in a stepwise algorithm to guide practical implementation of the screening and diagnosis process. The stepwise algorithm will be discussed with local clinicians involved in the study to better adapt it for future use in their routine practice.

The study will be implemented at inpatient nutrition centres from three selected tertiary hospitals in Uganda, and Zambia. A total of 720 children <5 years old with WHO-defined severe acute malnutrition will be enrolled with an equal distribution between sites, that is 240 participants per hospital.

• Study Type: Interventional
• Enrollment (Anticipated): 720
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Recruiting
    • Mulago National Referral Hospital
    • Contact: Country Principal Investigator; Email: ewobudeya@mujhu.org
    • Contact: Country co-Principal Investigator; Email: Juliet.MWANGA@epicentre.msf.org
• Zambia
  • Lusaka, Zambia
    • Recruiting
    • Lusaka University Teaching Hospital
  • Ndola, Zambia
    • Not yet recruiting
    • Arthur Davidson Children Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children aged < 5 years
• Severe acute malnutrition defined as weight-for-height Z score (WHZ) < -3 standard deviation (SD) or mid-upper arm circumference (MUAC) < 115 mm or clinical signs of bilateral pitting oedema in children aged <5 years [2]
• Hospitalized per hospital clinician's decision
• Parent/guardian informed consent

Exclusion Criteria:

- Ongoing TB treatment or history of intake of anti-TB drugs in the last 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Prospective cohort; Children included in the cohort will all be in the same arm. The patients will benefit from standard-of-care TB diagnosis with additional diagnostic methods.

Other: Development of a score and algorithm for TB treatment decision in hospitalised children with SAM.; The diagnostic strategy will include an initial clinical, radiographic and bacteriological evaluation of all enrolled children: TB contact history; Suggestive TB symptoms in the previous 4 weeks; Physical examination; Clinical, anthropometric and biochemical assessment of malnutrition; Clinical assessment for other non-dietary causes of malnutrition; Digitalized CXR; Ultra performed on NPA and stool samples, and one gastric aspirate (GA); Mycobacterial culture performed on two GAs; Abdominal ultrasonography; QuantiFERON®-TB Gold IGRA; Monocyte-to-Lymphocyte Ratio (MLR); C-Reactive Protein (CRP) TB diagnosis will be made according to national TB guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity of the score obtained	Sensitivity of the score obtained using predicted probability cut-off with the prediction model for the diagnosis of TB, defined as either confirmed or unconfirmed using the updated Clinical Case Definition for Classification of Intrathoracic Tuberculosis	6 months
Specificity of the score obtained	Specificity of the score obtained using predicted probability cut-off with the prediction model for the diagnosis of TB	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of children with NPA and stool samples collected as per study protocol	Feasibility of NPA and stool samples collection in HIV-infected children defined as the proportion of children with NPA and stool samples collected as per study protocol	6 months
Proportion of NPA-related adverse events (AEs)	Safety of NPA collection defined as proportion of AEs (vomiting, nose bleeding, low oxygen saturation, respiratory distress) occurring during NPA	6 months
Prevalence of TB among hospitalized children with SAM	Proportion of confirmed and unconfirmed TB in the study population	6 months
Clinical characteristics of TB disease in hospitalized children with SAM	Signs and symptoms of children with tuberculosis (confirmed and unconfirmed)	6 months
Bacteriological characteristics of TB disease in hospitalized children with SAM	Bacteriological characteristics (mycobacterial culture and drug susceptibility testing) of children with tuberculosis (confirmed and unconfirmed)	6 months
Biological characteristics of TB disease in hospitalized children with SAM	Haematological and immunological characteristics (full blood count, transaminases, CRP, IFN gamma) of children with tuberculosis (confirmed and unconfirmed)	6 months
Radiological characteristics of TB disease in hospitalized children with SAM	Radiological features (chest X-ray and abdominal US) of children with tuberculosis (confirmed and unconfirmed)	6 months
Estimated time to TB treatment decision in hospitalized children with SAM	Estimated time to TB treatment decision in hospitalized children with SAM, with and without presumptive TB based on the first-step screening prediction score	6 months
Diagnostic accuracy measures: 1/ Sensitivity of the different tests evaluated for the diagnosis of TB	Sensitivity of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP	6 months
Diagnostic accuracy measures: 2/ Specificity of the different tests evaluated for the diagnosis of TB	Specificity of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP	6 months
Diagnostic accuracy measures: 3/ Negative predictive value of the different tests evaluated for the diagnosis of TB	Negative predictive value of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP	6 months
Diagnostic accuracy measures: 4/ Positive predictive value of the different tests evaluated for the diagnosis of TB	Positive predictive value of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP)	6 months
Diagnostic accuracy measures: 5/ AUROC of diagnostic prediction models with and without the different tests results	Area Under the Receiver Operating Characteristics curve	6 months
Diagnostic accuracy of Ultra performed on one NPA and one stool sample against mycobacterial culture performed on gastric aspirates	Proportion of NPAs and stool samples with mycobacterium tuberculosis detected using Ultra	6 months
Tolerability of NPA collection: 1/ Discomfort/pain/distress experienced by the child as assessed by the child	Discomfort/pain/distress experienced by the child during NPA collection, as assessed by the child using the Wong-Baker face scale (in a subset of children). Scale range: 0 (no hurt) - 5 (hurts worst)	Within 3 days of inclusion
Tolerability of NPA collection: 2/ Discomfort/pain/distress experienced by the child as assessed by the parents	Discomfort/pain/distress experienced by the child during NPA collection, as assessed by the parents using the visual analog scale (in a subset of children). Scale range: 0 (no pain) - 10 (pain as bad as it could possibly be)	Within 3 days of inclusion
Tolerability of NPA collection: 3/ Discomfort/pain/distress experienced by the child as assessed by the nurse	Discomfort/pain/distress experienced by the child during NPA collection, as assessed by the nurses using the "Face Legs Activity Cry Consolability" behavioral pain scale (in a subset of children). Total score range: 0 (relaxed and comfortable) - 10 (severe discomfort/pain). Each item of the FLACC scale - Face, Legs, Activity, Cry, Consolability - has 3 possible quotes: 0 or 1 or 2, with a precise description provided to help with the rating. The total score is obtained by adding individual item scores.	Within 3 days of inclusion
Mortality at 6 months	Mortality at 6 months in children with SAM, with or without TB treatment	6 months
Percentage weight gain 6 months	Weight gain and WHZ at 6 months in children with SAM, with or without anti-TB treatment	6 months
TB treatment outcomes	TB treatment outcomes as defined per WHO guidelines (Cured, Treatment completed, Treatment failed, Died, Lost to follow-up, Not evaluated, Treatment success)	6 months

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: UNITAID

Publications and helpful links

Helpful Links

• TB-Speed project official website

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 4, 2019
• Primary Completion (ANTICIPATED): November 4, 2020
• Study Completion (ANTICIPATED): November 4, 2020

Study Registration Dates

• First Submitted: October 24, 2019
• First Submitted That Met QC Criteria: January 22, 2020
• First Posted (ACTUAL): January 27, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 22, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Nutrition Disorders; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Malnutrition; Severe Acute Malnutrition
• Other Study ID Numbers: C18-28

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No