Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition (TB-Speed SAM)
- Conditions
- TuberculosisSevere Acute Malnutrition
- Registration Number
- NCT04240990
- Lead Sponsor
- Institut National de la Santé Et de la Recherche Médicale, France
- Brief Summary
TB-Speed SAM is a multicentric, prospective diagnostic cohort study conducted in two countries with high and very high TB incidence (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, that is approximately 240 participants per hospital.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 603
- Children aged 2 to 59 months
- Severe acute malnutrition defined as weight-for-height Z score (WHZ) < -3 standard deviation (SD) or mid-upper arm circumference (MUAC) < 115 mm (in children over 6 months) or clinical signs of bilateral pitting oedema
- Hospitalized per hospital clinician's decision
- Parent/guardian informed consent
- Ongoing TB treatment or history of intake of anti-TB drugs in the last 3 months
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method Specificity of the score obtained 6 months Specificity of the score obtained using predicted probability cut-off with the prediction model for the diagnosis of TB
Sensitivity of the score obtained 6 months 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
- Secondary Outcome Measures
Name Time Method Biological characteristics of TB disease in hospitalized children with SAM 6 months Haematological and immunological characteristics (full blood count, transaminases, CRP, IFN gamma) of children with tuberculosis (confirmed and unconfirmed)
Radiological characteristics of TB disease in hospitalized children with SAM 6 months Radiological features (chest X-ray and abdominal US) of children with tuberculosis (confirmed and unconfirmed)
Diagnostic accuracy measures: 3/ Negative predictive value of the different tests evaluated for the diagnosis of TB 6 months 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)
Prevalence of TB among hospitalized children with SAM 6 months Proportion of confirmed and unconfirmed TB in the study population
Clinical characteristics of TB disease in hospitalized children with SAM 6 months Signs and symptoms of children with tuberculosis (confirmed and unconfirmed)
Bacteriological characteristics of TB disease in hospitalized children with SAM 6 months Bacteriological characteristics (mycobacterial culture and drug susceptibility testing) of children with tuberculosis (confirmed and unconfirmed)
Sensitivity of the score obtained 6 months Sensitivity of the score obtained using predicted probability cut-off with the screening prediction model for the identification of children with presumptive TB requiring further diagnostic evaluation
Specificity of the score obtained 6 months Specificity of the score obtained using predicted probability cut-off with the screening prediction model for the identification of children with presumptive TB requiring further diagnostic evaluation
Estimated time to TB treatment decision in hospitalized children with SAM 6 months Estimated time to TB treatment decision in hospitalized children with SAM, with and without presumptive TB based on the first-step screening prediction score
Diagnostic accuracy measures: 1/ Sensitivity of the different tests evaluated for the diagnosis of TB 6 months Sensitivity of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP)
Diagnostic accuracy measures: 2/ Specificity of the different tests evaluated for the diagnosis of TB 6 months Specificity of the different tests evaluated for the diagnosis of TB (Ultra performed on NPA and stools, CXR, abdominal ultrasound, QFT, MLR, CRP)
Diagnostic accuracy measures: 4/ Positive predictive value of the different tests evaluated for the diagnosis of TB 6 months 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)
Diagnostic accuracy measures: 5/ AUROC of diagnostic prediction models with and without the different tests results 6 months Area Under the Receiver Operating Characteristics curve
Diagnostic accuracy of Ultra performed on one NPA and one stool sample against a specific microbiological reference standard including Ultra and mycobacterial culture from gastric aspirates 6 months Proportion of NPAs and stool samples with mycobacterium tuberculosis detected using Ultra
Proportion of children with NPA and stool samples collected as per study protocol 6 months Feasibility of NPA and stool samples collection defined as the proportion of children with NPA and stool samples collected as per study protocol
Proportion of NPA-related adverse events (AEs) 6 months Safety of NPA collection defined as proportion of AEs (vomiting, nose bleeding, low oxygen saturation, respiratory distress) occurring during NPA
Tolerability of NPA collection: 1/ Discomfort/pain/distress experienced by the child as assessed by the child Within 3 days of inclusion 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)Tolerability of NPA collection: 2/ Discomfort/pain/distress experienced by the child as assessed by the parents Within 3 days of inclusion 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)Tolerability of NPA collection: 3/ Discomfort/pain/distress experienced by the child as assessed by the nurse Within 3 days of inclusion 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.Mortality at 6 months 6 months Mortality at 6 months in children with SAM, with or without TB treatment
Percentage weight gain 6 months 6 months Weight gain and WHZ at 6 months in children with SAM, with or without anti-TB treatment
TB treatment outcomes 6 months TB treatment outcomes as defined per WHO guidelines (Cured, Treatment completed, Treatment failed, Died, Lost to follow-up, Not evaluated, Treatment success)
Trial Locations
- Locations (3)
Mulago National Referral Hospital
🇺🇬Kampala, Uganda
Lusaka University Teaching Hospital
🇿🇲Lusaka, Zambia
Arthur Davidson Children Hospital
🇿🇲Ndola, Zambia
Mulago National Referral Hospital🇺🇬Kampala, Uganda