Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition

Study Overview
=================
Brief Summary
-----------------
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).

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.

Official Title
-----------------
Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition

Conditions
-----------------
Tuberculosis, Severe Acute Malnutrition

Intervention / Treatment
-----------------
* Other: Development of a score and algorithm for TB treatment decision in hospitalised children with SAM.


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 59 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: TB-Speed SAM is a multicentric, prospective diagnostic cohort study assessing several diagnostic tests that could result in the development of a score and algorithm for TB treatment decision in hospitalised children with SAM.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prospective cohort<br>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.<br>* 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.<br>|

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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 |