Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial - 23/02/23

Doi : 10.1016/S1473-3099(22)00668-5

Olivier Marcy, MD ^a,⁎ , Eric Wobudeya, MD ^b, Hélène Font, PhD ^a, Aurélia Vessière, PhD ^a, Chishala Chabala, MD ^c, Celso Khosa, MD ^d, Jean-Voisin Taguebue, MD ^e, Raoul Moh, MD ^f,^g, Juliet Mwanga-Amumpaire, MMED ^h, Manon Lounnas, PhD ⁱ, Veronica Mulenga, MD ^c, Sandra Mavale, ProfMD ^k, Josina Chilundo, MD ^k, Dalila Rego, MD ^l, Bwendo Nduna, MD ^m, Perfect Shankalala, MD ^c, Uzima Chirwa, MD ^j, Agathe De Lauzanne, MD ⁿ, Bunnet Dim, MD ⁿ, Emeline Tiogouo Ngouana, MD ^o, Madeleine Folquet Amorrissani, ProfMD ^p, Lassina Cisse, ProfMD ^q, Flore Amon Tanoh Dick, ProfMD ^r, Eric A Komena, MD ^f,^g, Sylvie Kwedi Nolna, PhD ^ae, Gerald Businge, MD ^b, Naome Natukunda, MSc ^h, Saniata Cumbe, MD ^d, Prossy Mbekeka, MD ^s, Ang Kim, ProfMD ^t, Chanrithea Kheang, MD ^u, Sokha Pol, MD ^v, Elizabeth Maleche-Obimbo, ProfMD ^w, James A Seddon, MD ^x,^y, Tan Eang Mao, MD ^z, Stephen M Graham, ProfMD ^aa,^ab,^ac, Christophe Delacourt, ProfMD ^ad, Laurence Borand, PharmD ⁿ, Maryline Bonnet, MD ^ae
for the
TB-Speed Pneumonia Study Group^{^†}
Members listed in appendix 2

Olivier Marcy, Angeline Serre, Anne Badrichani, Manoa Razafimanantsoa, Julien Poublan, Aurélia Vessière, Clémentine Roucher, Estelle Occelli, Aurélie Beuscart, Aurélie Charpin, Gemma Habiyambere, Salomé Mesnier, Eric Balestre, Bandana Bhatta, Anne-Laure Maillard, Joanna Orne-Gliemann, Emmanuelle Baillet, Nicolas Koskas, Marc D’Elbée, Delphine Gabillard, Hélène Font, Minh Huyen, Maryline Bonnet, Manon Lounnas, Hélène Espérou, Sandrine Couffin-Cadiergues, Alexis Kuppers, Benjamin Hamze, Laurence BORAND, Agathe de LAUZANNE, Bunnet DIM, Chanthy Keang, Long PRING, Song YIN, Channimol SARITH, Chanvirak PHAN, Sovann NHEUONG, Socheat LY, Sanary KAING, Vouchleang SRENG, Elen LUN, Leakhena SAY, Sophea SUOM, Romyka FERHY, Dina SO, Sorunna BORN, Sophea PAL, Boraneath NANG, Tan Eang MAO, Ang KIM, Viso Srey, Piseth Kan, leakhena Hout, Samnang Ith, Sophany Oum, Sokunvadhana Sau, Kim Heang Ho, Daronic Kith, Nathara Nuch, Chhun Leang Horm, Cheameas Sophon, Bosba Roeungdeth, Chhay MENG, Ravin RITH, Samnang PHY, Chanchetra SOR, Voleak SAO, Sophea KHAT, Bunthoeun MAK, Angkeaborin UY, Sreyny KHAY, Kimsan SOM, rongvirak HACH, Hay SOK, Sotheavy KUON, Synatt HENG, Amara SENG, Sopheak NIM, Reach PAN, Srean KIM, Keo SREY LEAP, Bormey NET, Viccheka NOUN, Daven LAY, Chhaing MANY, Socheata Seng, Vuthy Ly, Saran So, Sovutthik Oun, Sopheap CHEY, Rattany CHHEA, Lydeth BAONG, Vanna THOUNG, Chanrithea KHEANG, Borady BY, Vathanak Nguon, Eksophea MEACH, Sopheak Tek, Sina Ngeav, Tetra Lun, Deth HEM, Nayreang CHUT, Setha SARIK, Hgekkoung NANG, Mengnean MEACH, Sopal SRENG, Dara SAR, Rathana KIN, Phoran ROS, Chenda DORN, Chansy KAK, Srey Leak Sambath, Leakhena Son, Linda Bin, Eangnay Pengong, Sokha Pol, Samnang Khutsorn, Sorsophea Seang, Virak Soun, Vuthy Vong, Chandara Khoeung, Panha Um, Sokunthea Bou, Sarin Song Pich, Puthy Nim, Sopheak Khat, Nuon Ban Si, Sovannodom Ream, Sim Ing, Phanith Chann, Samrith Ngeth, Marina Sun, Sokea Chhoeung, Soeun Sean, Ratanak Prak, Jean-Voisin Taguebue, Sylvie Kwedi Nolna, Audrey Amboua Schouame Onambele, Numfor Hycenth, Bernard Melingui, Angeline Nkembe Medounmga, Luciole Hougnang Tatmi, Nathalie Etemgoua, Vanessa Kouesso, Jean Bugin, Celestine Nzedjom, Roger Ngoya, Jules Eyike, Elyse Loudjom, Roger Lonsti, Ladi Dang, Edward Bintar, Chantal Njayong, Cinthia Ngonsoa O, Isabelle Ndzeukap, Pascaline Dzoyem, Clémentine Dzokou, Berthe Dindo, Raoul Moh, Eric Auguste Komena, Roger Aka Bony, Christian Kouadio, Serge Danho, Melissa Goli, Madeleine Folquet, Max Valère Itchy, Abdel Sidibé, Lancina Cissé, Joseph Ouattara, Mamadou Konaté, Flore Amon-Tanoh Dick, Melissa Cardena, Laurence Adonis-Koffi, Djabia Eugenie, Ferdinand Kouamé, Hervé Menan, André Inwoley, Timothée Ouassa, Marcelle Sandrine Nguessan, Celso Khosa, Saniata Cumbe, Emelva Manhiça, Alcina Zitha, Valter Chiúle, Eva Muxanga, Irene Gune, Yara Lima, Jorge Ribeiro, Sandra Mavale, Josina Chilundo, Felismina Maxanguana, Natália Morais, Julieta Manhiça, Josefina Give, Jafito Atumane, Gelson Lucas, Arsénio Thai, Adélio Chave, Dalila Rego, Lúcia Guambe, Faiaz Issa, Rosa Carneiro, Neusa Pene, Natércia Florindo, Dália Machel, Cecília Cumbane, Helena Mendes, Mule Kitungwa, Valdo Muianga, Humberto Tamele, Adelino Sulude, Roda Mabota, Herquéria Comandante, Abelardo Massangaie, Eric Wobudeya, Gerald Bright Businge, Faith Namulinda, Robert Sserunjogi, Rashidah Nassozi, Charlotte Barungi, Hellen Aanyu, Doreen Muwonge, Eva Kagoya, Serene Aciparu, Sophia Chemutai, Samuel Ntambi, Amir Wasswa, Juliet Nangozi, Abner Tagoola, Prossy Mbekeka, Sajja Kenneth, John Paul Lubega, Aidah Nassali, Jessica Tagobera, Christine Agwang, Florence Kalembe, Annet Ajambo, Elizabeth Aguti, Samuel Kasibante, Henry Matende, Israel Owen Odongo, Juliet Mwanga Amumpaire, Naome Natukunda, Gertrude Ngabirano, Paul Kakwenza, Simpson Nuwamanya, Miria Nyangoma, Jane Nabbuto, Florence Abok, Rinah Arinaitwe, Diana Birungi, Evans Mwesigwa, Daniel Atwine, Hassan Mbega, Patrick Orikiriza, Ivan Taremwa, Esther Turyashemererwa, Hope Derrick, Dan Nyehangane, Rodney Kaitano, Susan Logoose, Steven Businge, Charles Ntambi, Jerome Mugabi, John Mzee, Julius Besigye, Saul Kanzira, Phionah Turyatemba, Florence Twebaze, Chishala Chabala, Veronica Mulenga, Perfect Shankalala, Chimuka Hambulo, Vincent Kapotwe, Marjory Ngambi, Kunda Kasakwa, Uzima Chirwa, Chifunda Kapula, Susan Zulu, Grace Nawakwi, Teddy Siasulingana, Jessy Chilonga, Maria Chimbini, Mutinta Chilanga, Bwendo Nduna, Muleya Inambao, Mwate Mwambazi, Barbra Halende, Wyclef Mumba, Endreen Mankunshe, Maureen Silavwe, Moses Chakopo, Roy Moono

^a Inserm UMR 1219, IRD EMR 271, University of Bordeaux, Bordeaux, France

^b Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda

^c University of Zambia School of Medicine, University Teaching Hospital, Lusaka, Zambia

^d Instituto Nacional de Saúde, Marracuene, Mozambique

^e Mother and Child Center, Chantal Biya Foundation, Yaoundé, Cameroon

^f Teaching Unit of Dermatology and Infectiology, UFR of Medical Sciences, Felix-Houphouet Boigny University, Abidjan, Côte d’Ivoire

^g Programme PAC-CI, CHU de Treichville, Abidjan, Côte d’Ivoire

^h Epicentre Mbarara Research Centre, Mbarara, Uganda

ⁱ MIVEGEC, University of Montpellier, CNRS, IRD, Montpellier, France

^j Children’s Hospital, University Teaching Hospital, Lusaka, Zambia

^k Paediatrics Department, Maputo Central Hospital, Maputo, Mozambique

^l Paediatrics Department, José Macamo General Hospital, Maputo, Mozambique

^m Arthur Davidson’s Children, Ndola, Zambia

ⁿ Epidemiology and Public Health Unit, Clinical Research Group, Institut Pasteur du Cambodge, Phnom Penh, Cambodia

^o Byem Assi Hospital, Yaoundé, Cameroon

^p Paediatrics Department, Cocody University Teaching Hospital, Abidjan, Côte d’Ivoire

^q Paediatrics Department, Treichville University Teaching Hospital, Abidjan, Côte d’Ivoire

^r Mother and Child Department, Angré University Hospital, Abidjan, Côte d’Ivoire

^s Jinja Regional Referral Hospital, Jinja, Uganda

^t Pulmonology Department, National Pediatric Hospital, Phnom Penh, Cambodia

^u Paediatrics Department, Kompong Cham Provincial Hospital, Kompong Cham, Cambodia

^v Paediatrics Department, Takeo Provincial Hospital, Takeo, Cambodia

^w Department of Paediatrics & Child Health, University of Nairobi, Nairobi, Kenya

^x Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South Africa

^y Department of Infectious Disease, Imperial College London, London, UK

^z National Center for Tuberculosis and Leprosy, Ministry of Health, Phnom Penh, Cambodia

^aa University of Melbourne Department of Paediatrics and Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia

^ab International Union Against Tuberculosis and Lung Disease, Paris, France

^ac Burnet Institute, Melbourne, VIC, Australia

^ad Department of Paediatric Pulmonology, Necker University Teaching Hospital, Paris, France

^ae IRD UMI233, Inserm U1175, University of Montpellier, Montpellier, France

^* Correspondence to: Dr Olivier Marcy, Université de Bordeaux, Bordeaux Population Health Centre U1219, Bordeaux 33076, France Université de Bordeaux Bordeaux Population Health Centre U1219 Bordeaux 33076 France

Summary

Background

Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality.

Methods

We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d’Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643).

Findings

From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597–1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696–2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO₂ less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO₂ less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial.

Interpretation

Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition.

Funding

Unitaid and L’Initiative.

Translation

For the French translation of the abstract see Supplementary Materials section.

Le texte complet de cet article est disponible en PDF.

Plan

Introduction

Methods

Study design and participants

Randomisation and masking

Procedures

Outcomes

Statistical analysis

Role of the funding source

Results

Discussion

Data sharing

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Vol 23 - N° 3

P. 341-351 - mars 2023 Retour au numéro

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Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial - 23/02/23

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