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Impact of Systematic Tuberculosis Detection on Mortality in Young Children with Severe Pneumonia in High Tuberculosis Incidence Countries – A Stepped Wedge Cluster Randomized Trial

28 Pages Posted: 7 Sep 2022

See all articles by Olivier Marcy

Olivier Marcy

University of Bordeaux

Hélène Font

University of Bordeaux

Aurelia Vessière

University of Bordeaux

Laurence Borand

Institut Pasteur du Cambodge, Epidemiology & Public Health Unit

Chishala Chabala

University of Cape Town (UCT) - Division of Clinical Pharmacology

Celso Khosa

University of North Carolina (UNC) at Chapel Hill - National Institute of Health

Jean-Voisin Taguebue

Chantal Biya Foundation - Mother and Child Center

Raoul Moh

Universite Félix Houphouet Boigny - University of Felix Houphouet Boigny - Teaching Unit of Dermatology and Infectiology

Juliet Mwanga-Amumpaire

Epicentre (Mbarara)

Mannon Lounnas

affiliation not provided to SSRN

Veronica Mulenga

University of Zambia (UNZA)

Sandra Mavale

Eduardo Mondlane University (UEM) - Maputo Central Hospital

Josina Chilundo

Eduardo Mondlane University (UEM) - Maputo Central Hospital

Dalila Rego

affiliation not provided to SSRN

Bwendo Nduna

Makerere University - Johns Hopkins University Research Collaboration

Perfect Shankalala

University of Zambia (UNZA)

Uzima Chirwa

University of Zambia (UNZA)

Agathe De Lauzanne

Institute Pasteur du Cambodge - Epidemiology and Public Health Unit

Bunnet Dim

Institute Pasteur du Cambodge - Epidemiology and Public Health Unit

Emeline Tiogouo Ngouana

affiliation not provided to SSRN

Madeleine Folquet Amorrissany

affiliation not provided to SSRN

Lassina Cisse

affiliation not provided to SSRN

Flore Amon Tanoh Dick

affiliation not provided to SSRN

Eric Auguste Komena

University Hospital of Treichville - PACCI ANRS Research Programme

Sylvie Kwedi Nolna

affiliation not provided to SSRN

Gerald Businge

affiliation not provided to SSRN

Naome Natukunda

Epicentre (Mbarara)

Saniata Cumbe

Instituto Nacional de Saúde.

Prossy Mbekeka

affiliation not provided to SSRN

Ang Kim

affiliation not provided to SSRN

Chanrithea Keang

affiliation not provided to SSRN

Sokha Pol

affiliation not provided to SSRN

Elizabeth Maleche-Obimbo

University of Nairobi

James Seddon

Imperial College London

Tan Eang Mao

Royal Government of Cambodia - National Center for Tuberculosis and Leprosy Control (CENAT)

Stephen M. Graham

The University of Melbourne

Christophe Delacourt

affiliation not provided to SSRN

Eric Wobudeya

MU-JHU Care Ltd - MUJHU Research Collaboration

Maryline Bonnet

University of Montpellier - Translational Research in HIV and Infectious Diseases (TransVIHMI)

TB-Speed Pneumonia Study Group

Independent

More...

Abstract

Background: Tuberculosis diagnosis may be delayed or missed in children with severe pneumonia, as it is usually only considered in case of prolonged symptoms or antibiotic failure. Systematic tuberculosis screening at hospitalization could increase case detection and reduce mortality.

Methods: We did a stepped-wedge cluster-randomized trial in 16 hospitals from six high-tuberculosis incidence countries. Children <5 years with WHO-defined severe pneumonia received either the standard of care (SOC; control) or SOC plus Xpert MTB/RIF Ultra (Ultra) on nasopharyngeal aspirates (NPA) and stool samples (intervention). Hospitals were randomly switched from control to intervention at 5-week intervals. We assessed the impact on 12-week mortality using generalized linear mixed effect models. We analyzed endpoints in the two groups of children with and without severe acute malnutrition.

Findings: From March 2019 to March 2021, we enrolled 1401 and 1169 children in the control and the intervention arms, respectively. In the intervention, 1007 (97·4%) children had NPA and 850 (82·2%) had stool collected; 24 (2·1%) had positive Ultra. At 12 weeks, 110 (7·9%) and 90 (7·7%) children had died [adjusted OR: 0·95 (95%CI 0·58 – 1·58)] and 71 (5·1%) and 87 (7·4%) children had tuberculosis diagnosed in the control and intervention groups, respectively. In children with severe acute malnutrition, 57/240 (23·8%) and 53/297 (17·8%) died, 36/240 (15·0%) and 56/297 (18·9%) were diagnosed with tuberculosis, in the control and the intervention arm, respectively.

Interpretation: Systematic tuberculosis screening with Ultra at hospital admission did not reduce mortality in children with severe pneumonia but could be beneficial for children with severe acute malnutrition.

Trial Registration Details: This study is registered with clinicaltrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (https://pactr.samrc.ac.za/; PACTR202101615120643).

Funding Information: This study was supported by Unitaid and L’Initiative.

Declaration of Interests: All authors declared no conflicts of interest.

Ethics Approval Statement: The study was approved by the WHO Ethics Review Committee, the sponsor’s (Inserm) institutional review committee and the national Ethics Review Committees of participating countries, as well as relevant national authorities and Institutional Review Boards, WHO Research Ethics Review Committee (WHO ERC) Inserm - Comité d'évaluation éthique de l'Inserm (CEEI-IRB) National Ethics Committee for Health Research National Ethics Committee on Human Health Research National d'Ethique de la Recherche Comité Institucional de Bioética para Saude do INS Comité Nacional de Bioética para a Saude (CNBS) Uganda National Council for Science and Technology Joint Clinical Research Center REC University of Zambia Biomedical Research Ethics Committee National Research Health Authority.

Keywords: Children, severe pneumonia, tuberculosis, molecular diagnosis, mortality, malnutrition.

Suggested Citation

Marcy, Olivier and Font, Hélène and Vessière, Aurelia and Borand, Laurence and Chabala, Chishala and Khosa, Celso and Taguebue, Jean-Voisin and Moh, Raoul and Mwanga-Amumpaire, Juliet and Lounnas, Mannon and Mulenga, Veronica and Mavale, Sandra and Chilundo, Josina and Rego, Dalila and Nduna, Bwendo and Shankalala, Perfect and Chirwa, Uzima and De Lauzanne, Agathe and Dim, Bunnet and Tiogouo Ngouana, Emeline and Folquet Amorrissany, Madeleine and Cisse, Lassina and Amon Tanoh Dick, Flore and Komena, Eric Auguste and Kwedi Nolna, Sylvie and Businge, Gerald and Natukunda, Naome and Cumbe, Saniata and Mbekeka, Prossy and Kim, Ang and Keang, Chanrithea and Pol, Sokha and Maleche-Obimbo, Elizabeth and Seddon, James and Mao, Tan Eang and Graham, Stephen M. and Delacourt, Christophe and Wobudeya, Eric and Bonnet, Maryline and Group, TB-Speed Pneumonia Study, Impact of Systematic Tuberculosis Detection on Mortality in Young Children with Severe Pneumonia in High Tuberculosis Incidence Countries – A Stepped Wedge Cluster Randomized Trial. Available at SSRN: https://ssrn.com/abstract=4165612 or http://dx.doi.org/10.2139/ssrn.4165612

Olivier Marcy (Contact Author)

University of Bordeaux ( email )

Avenue Léon Duguit
Bordeaux, 33000
France

Hélène Font

University of Bordeaux ( email )

Aurelia Vessière

University of Bordeaux ( email )

Laurence Borand

Institut Pasteur du Cambodge, Epidemiology & Public Health Unit ( email )

Chishala Chabala

University of Cape Town (UCT) - Division of Clinical Pharmacology ( email )

Celso Khosa

University of North Carolina (UNC) at Chapel Hill - National Institute of Health ( email )

Chapel Hill, NC
United States

Jean-Voisin Taguebue

Chantal Biya Foundation - Mother and Child Center ( email )

Raoul Moh

Universite Félix Houphouet Boigny - University of Felix Houphouet Boigny - Teaching Unit of Dermatology and Infectiology ( email )

Juliet Mwanga-Amumpaire

Epicentre (Mbarara) ( email )

Mannon Lounnas

affiliation not provided to SSRN ( email )

No Address Available

Veronica Mulenga

University of Zambia (UNZA) ( email )

Department of Plant Science
LUSAKA
Zambia

Sandra Mavale

Eduardo Mondlane University (UEM) - Maputo Central Hospital ( email )

Mozambique

Josina Chilundo

Eduardo Mondlane University (UEM) - Maputo Central Hospital ( email )

Mozambique

Dalila Rego

affiliation not provided to SSRN ( email )

No Address Available

Bwendo Nduna

Makerere University - Johns Hopkins University Research Collaboration ( email )

Perfect Shankalala

University of Zambia (UNZA) ( email )

Department of Plant Science
LUSAKA
Zambia

Uzima Chirwa

University of Zambia (UNZA) ( email )

Department of Plant Science
LUSAKA
Zambia

Agathe De Lauzanne

Institute Pasteur du Cambodge - Epidemiology and Public Health Unit ( email )

Bunnet Dim

Institute Pasteur du Cambodge - Epidemiology and Public Health Unit ( email )

Emeline Tiogouo Ngouana

affiliation not provided to SSRN ( email )

No Address Available

Madeleine Folquet Amorrissany

affiliation not provided to SSRN ( email )

No Address Available

Lassina Cisse

affiliation not provided to SSRN ( email )

No Address Available

Flore Amon Tanoh Dick

affiliation not provided to SSRN ( email )

No Address Available

Eric Auguste Komena

University Hospital of Treichville - PACCI ANRS Research Programme ( email )

Sylvie Kwedi Nolna

affiliation not provided to SSRN ( email )

No Address Available

Gerald Businge

affiliation not provided to SSRN ( email )

No Address Available

Naome Natukunda

Epicentre (Mbarara) ( email )

Saniata Cumbe

Instituto Nacional de Saúde. ( email )

Prossy Mbekeka

affiliation not provided to SSRN ( email )

No Address Available

Ang Kim

affiliation not provided to SSRN ( email )

No Address Available

Chanrithea Keang

affiliation not provided to SSRN ( email )

No Address Available

Sokha Pol

affiliation not provided to SSRN ( email )

No Address Available

Elizabeth Maleche-Obimbo

University of Nairobi ( email )

4139-40200
Nairobi, 40200
Kenya

James Seddon

Imperial College London ( email )

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Tan Eang Mao

Royal Government of Cambodia - National Center for Tuberculosis and Leprosy Control (CENAT) ( email )

Phnom Penh
Cambodia

Stephen M. Graham

The University of Melbourne ( email )

Christophe Delacourt

affiliation not provided to SSRN ( email )

No Address Available

Eric Wobudeya

MU-JHU Care Ltd - MUJHU Research Collaboration ( email )

Maryline Bonnet

University of Montpellier - Translational Research in HIV and Infectious Diseases (TransVIHMI) ( email )