WHO Consolidated On Tuberculosis: Guidelines

WHO
consolidated
guidelines on
tuberculosis
Module 5: Management
of tuberculosis in children
and adolescents
WHO
consolidated
guidelines on
tuberculosis
Module 5: Management
of tuberculosis in children
and adolescents
WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents
ISBN 978–92–4-004676–4 (electronic version)

ISBN 978–92–4-004677–1 (print version)
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Design by Inis Communication

Contents
Acknowledgements v
Abbreviations ix
Definitions xi
Executive summary xvii
1. Introduction 1
1.1. Background 1
1.2. Rationale for the development of the 2022 consolidated guidelines 2
1.3. Objectives of the 2022 consolidated guidelines 2
1.4. Target audience 2
1.5. WHO recommendations relevant to the management of TB in children and adolescents 2
1.6. Scope of the guideline update 3
1.7. Publication, dissemination, evaluation and expiry 6
1.8. Document structure 6
2. TB screening and contact investigation 9

3. Prevention of TB 11
4. Diagnostic approaches for TB in children and adolescents 17
4.1. The use of the Xpert MTB/RIF Ultra assay in gastric aspirate and stool specimens for
the diagnosis of pulmonary TB and rifampicin resistance 18
4.2. Treatment decision algorithms for the diagnosis of pulmonary TB in children aged
below 10 years of age 22
iii
4.3. Consolidated recommendations on TB diagnostics and diagnostic approaches relevant
to children and adolescents 26
5. Treatment of TB disease in children and adolescents 31

5.1. Treatment shortening in children and adolescents with non-severe TB 32
5.2. Treatment regimens for TB meningitis in children and adolescents 37
5.3. Treatment of multi-drug and rifampicin resistant TB in children 41
5.4. Consolidated recommendations on TB treatment for children and adolescents 53
6. Models of TB care for case detection and provision of TPT in children and
adolescents 57
6.1. Decentralized and family-centred, integrated models of care to deliver child and
adolescent TB services 58
6.2. Consolidated recommendations on models of TB care relevant to children and
adolescents 63
7. Special situations 65
8. Research priorities 69
9. References 73
Annex 1. WHO recommendations incorporated in the guidelines on the
management of TB in children and adolescents 81
Annex 2. Supplementary table 83
Web annexes:
Web annex 1: Methods and Expert Panels
https://apps.who.int/iris/bitstream/handle/10665/352507/9789240046788-eng.pdf
Web annex 2: GRADE Summary of Findings Tables
Web annex 3: GRADE Evidence to Decision Tables
Web annex 4: Summaries of unpublished data
Web annex 5: Overview of consolidated WHO recommendations
iv
Acknowledgements
The production and writing of the WHO consolidated guidelines on tuberculosis. Module 5: management
of tuberculosis in children and adolescents, 2022 was coordinated by Sabine Verkuijl, Annemieke Brands,
Kerri Viney and Tiziana Masini, under the guidance of Farai Mavhunga, head of the TB Vulnerable
Populations, Communities and Comorbidities unit and the overall direction of Tereza Kasaeva, Director
of the World Health Organization (WHO) Global Tuberculosis (TB) Programme. Colleagues from the
Prevention, Diagnosis, Treatment, Care and Innovation Unit, Global TB Programme, WHO, under
the leadership of Matteo Zignol, also contributed to these guidelines. The WHO Global Tuberculosis
Programme gratefully acknowledges the contribution of all experts involved in the development of
these guidelines.1
Guideline Development Group

The Guideline Development Group (GDG) was composed of Susan Abdel-Rahman (Children’s Mercy
Research Institute, United States of America (United States)), Deepak Agrawal (Aarogyam Paediatrics
Hospital, India), Shakil Ahmed (Dhaka Medical College, Bangladesh), Elie Akl (American University
of Beirut and Center for Systematic Reviews of Health Policy and Systems Research, Lebanon),
Valentina Aksenova (Research Institute of Phthisiopulmonology of the First M.I. Sechenov Moscow
State Medical University, Russian Federation), Farhana Amanullah (Indus Hospital, Pakistan), Grace Bolie
(National TB Programme, Democratic Republic of the Congo), Chishala Chabala (University Teaching
Hospital, Zambia), Gunta Dravniece (PATH, Ukraine), Connie Erkens (KNCV Tuberculosis Foundation,
Netherlands), Betina Mendez Alcântara Gabardo (Clinical Hospital Federal University of Paraná,
Brazil), Stephen Graham (University of Melbourne, Australia), Patrik Hummel (Friederich-Alexander
University, Germany), Amir M. Khan (Association for Social Development, Pakistan), Margaret Nasil Kal
(National TB Programme, Papua New Guinea), Tamara Kredo (South African Cochrane Centre, South
African Medical Research Council, South Africa), Susan Maloney (Centers for Disease Control and
Prevention, United States), Anna Mandalakas (Baylor College of Medicine; Texas Children’s Hospital,
United States), Sushant Mane (Grant Government Medical College and Sir J.J. Group of Hospitals, India),
Lindsay McKenna (Treatment Action Group, United States), Imran Pambudi (National TB Programme,
Indonesia), Phan Huu Phuc (National Paediatric Hospital, Vietnam), Moorine Sekadde (National TB
and Leprosy Programme, Uganda), Kathryn Snow (University of Melbourne, Australia) and Sabira
Tahseen (National TB Reference Laboratory, Pakistan).
Elie Akl, Farhana Amanullah, Stephen Graham and Tamara Kredo co-chaired the GDG meeting.
External Review Group

The external reviewers for these guidelines were Martina Casenghi (Elizabeth Glaser Pediatric AIDS
Foundation, Switzerland), Anthony Enimil (Komfo Anokye Teaching Hospital, Ghana), Malgorzata
Grzemska (former WHO staff member, Poland), Catherine Hewison (Médecins Sans Frontières, France),
Devan Jaganath (University of California San Francisco, United States), Kobto Ghislain Koura (The
International Union Against TB and Lung Disease, France), Celia Martínez de Cuellar (Hospital de
Clínicas, Universidad Nacional de Asunción, Paraguay), Ya Diul Mukadi (United States Agency for
1
For more information about the areas of expertise, the gender and geographical distribution of participants as well as declarations of
interests and the management of potential conflicts for members of the GDG and External Review Group, see Web annex 1.
Acknowledgements v
International Development (USAID), United States), Rahab Mwaniki (Kenya Aids NGOs Consortium
(KANCO), Kenya), Marc Nicol (University of Western Australia, Australia), Elizabeth Maleche Obimbo
(University of Nairobi, Kenya), Peter Owiti (Wote Youth Development Project, Kenya), Nyan Win Phyo
(Civil Society Taskforce; World Vision, Thailand), Ramatoulaye Sall (Independent Consultant, Senegal),
Rina Triasih (Universitas Gadyah Mada, Indonesia) and Eric Wobudeya (Mulago National Referral
Hospital, Uganda; Makerere University – Johns Hopkins University (MU-JHU) Research Collaboration,
Uganda).
Evidence reviewers
The following persons contributed to the reviews and summarized evidence for the guidelines using
the Population, Intervention, Comparator and Outcomes (PICO) framework (see section 1.3 for more
information about the PICO questions).
PICO question 1 (TB screening in children): Bryan Vonasek (Baylor College of Medicine, United
States; University of Wisconsin, United States); Tara Ness, Alexander W Kay, Anna Mandalakas (Baylor
College of Medicine, United States); Yemisi Takwoingi (University of Birmingham, United Kingdom
of Great Britain and Northern Ireland (United Kingdom)); Susan S van Wyk (Stellenbosch University,
South Africa); Laura Ouellette (Texas Medical Center Library, United States); Ben J Marais (Marie Bashir
Institute for Infectious Diseases; University of Sydney, Australia); Karen R Steingart (Liverpool School
of Tropical Medicine, United Kingdom).
PICO question 2a (Integrated treatment decision algorithms to diagnose pulmonary TB): Ted Cohen
and Kenneth S Gunasekera (Yale School of Public Health, United States); James A Seddon (Imperial
College London, United Kingdom; Stellenbosch University, South Africa).
PICO question 2b (Use of Xpert Ultra in gastric aspirate or stool to diagnose pulmonary TB and
rifampicin resistance): Alexander W Kay and Tara Ness (Baylor College of Medicine, United States);
Yemisi Takwoingi (University of Birmingham, United Kingdom), Karen R Steingart (Liverpool School of
Tropical Medicine, United Kingdom).
PICO question 3 (Treatment shortening in children and adolescents with non-severe drug-susceptible
TB): Anna Turkova, Genevieve H Wills, Louise Choo, Krissy LeBeau, Margaret J Thomason, Angela
M Crook, Diana M Gibb (University College London, United Kingdom); Chishala Chabala (University
Teaching Hospital, Zambia), Helen McIlleron (University of Cape Town, South Africa), Paul Revill, James
Love-Koh (University of York, United Kingdom), Graeme Hoddinott (Stellenbosch University, South
Africa), Hayley Jones (University of Bristol, United Kingdom).
PICO question 4a and 4b (Use of bedaquiline and delamanid in children with MDR/RR-TB, aged
below 6 years (bedaquiline) and below 3 years (delamanid)): Pharmacokinetic (PK) and safety analysis:
Susan M. Abdel-Rahman (Children’s Mercy Research Institute, United States); Paediatric drug-resistant
(DR)-TB individual patient dataset (IPD): Anthony Garcia-Prats (Stellenbosch University, South Africa;
University of Wisconsin, United States); Vivian Cox, Rory Dunbar, Tina Sachs, Jessica Workman, Rose
Brown, Anneke C. Hesseling (Stellenbosch University, South Africa); Maria Garcia-Cremades, Kendra
Radtke, Alexander Floren, Rada Savic (University of California San Francisco, United States), Tamara
Kredo, Funeka Bango (South African Medical Research Council, South Africa).
PICO question 5 (Treatment of TB meningitis in children and adolescents): Giorgia Sulis (McGill
University, Canada), Gamuchirai Tavaziva, Andrea Benedetti and Faiz Ahmad Khan (McGill University,
Canada), Geneviève Gore (McGill University, Canada), Regan Solomons and Ronald van Toorn
(Stellenbosch University, South Africa), Stephanie Thee (Charité-Universitätsmedizin Berlin, Germany),
Jeremy Day (University of Oxford, United Kingdom), Silvia S Chiang (Alpert Medical School of Brown
University, United States; Rhode Island Hospital, United States).
PICO question 6 (Models of care for TB case detection and TB prevention in high TB burden settings):
Yael Hirsch-Moverman (Columbia University, United States), Hamidah Hussain (Interactive Research
vi WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
and Development (IRD) Global, Singapore), Daria Szkwarko (Brown University, United States), Courtney
Yuen (Harvard Medical School, United States).
Background question 1 (Socioeconomic impact of TB on affected families): Salla Atkins (Karolinska
Institutet, Sweden; Tampere University, Finland), Kristi Sidney-Annerstedt and Knut Lönnroth (Karolinska
Institutet, Sweden), Lauri Heimo, Maria Ribas Closa (Tampere University, Finland), Lieve Vanleeuw (South
African Medical Research Council, South Africa), Peter Wambi (Uganda Tuberculosis Implementation
Research Consortium, Uganda), Louisa Chenciner (Royal Free London NHS Foundation Trust, United
Kingdom), Uzochukwu Egere (Liverpool School of Tropical Medicine, United Kingdom), Daniel J Carter
and Delia Boccia (London School of Hygiene and Tropical Medicine, United Kingdom), Tom Wingfield
(Liverpool School of Tropical Medicine, United Kingdom; Liverpool University Hospital NHS Foundation
Trust, United Kingdom; Karolinska Institutet, Sweden). (Patient cost surveys): Nobuyuki Nishikiori
(WHO, Switzerland).
Background question 2 (Engaging adolescents with TB, or at risk of TB, in their care): Silvia S.
Chiang (Alpert Medical School of Brown University, United States; Rhode Island Hospital, United
States), Patricia Moscibrodzki (London School of Hygiene and Tropical Medicine, United Kingdom),
Leslie A Enane (Indiana University School of Medicine, United States). Contributors: Margaux Amara,
Meredith B Brooks, Virginia Byron, Jennifer Furin (Harvard Medical School, United States), Sarah
Bernays (University of Sydney, Australia; London School of Hygiene and Tropical Medicine, United
Kingdom), Yaroslava Bondarenko (Bogomolets National Medical University, Ukraine), Márcia Cortez
Bellotti de Oliveria (Universidade Federal do Rio de Janeiro, Brazil), Andrea T. Cruz (Baylor College of
Medicine, United States), Hernán Del Castillo Barrientos (Instituto Nacional de Salud del Niño-Breña,
Peru), Anthony Enimil (Kwame Nkrumah University of Science and Technology, Ghana; Komfo Anokye
Teaching Hospital, Ghana), Vivian Faith (Network of TB Champions in Kenya, Kenya), Gabriella Ferlazzo
(Médecins Sans Frontières, South Africa), Rashida Abbas Ferrand (Rhode Island Hospital, United States;
Biomedical Research and Training Institute, Zimbabwe), Graeme Hoddinott (Stellenbosch University,
South Africa), Petros Isaakidis (Médecins Sans Frontières, South Africa), Evgenia Karayeva (Brown
School of Public Health, United States), Katharina Kranzer (Rhode Island Hospital, United States;
Biomedical Research and Training Institute, Zimbabwe), Homa Mansoor (Médecins Sans Frontières,
India), Ben J Marais (Marie Bashir Institute for Infectious Diseases; University of Sydney, Australia), Lily
Meyersohn (Rhode Island Hospital, United States), Victoria Oliva Rapoport (Alpert Medical School
of Brown University, United States), Erika Mohr-Holland (Médecins Sans Frontières, South Africa),
Anh Phuong Nguyen (TB Patients Community of Vietnam, Hanoi, Vietnam), Joshua Ochieng Oliyo
(Committee of African Youth Advisors, Kenya), Clemax Couto Sant’Anna (Universidade Federal do
Rio de Janeiro, Brazil), Saning’o Saruni (Haydom Lutheran Hospital, Tanzania), Susan M Sawyer (Royal
Children’s Hospital and Murdoch Children’s Research Institute, Australia; University of Melbourne,
Australia), H. Simon Schaaf (Stellenbosch University, South Africa), James A Seddon (Imperial College
London, United Kingdom; Stellenbosch University, South Africa), Sangeeta Sharma (National Institute
of Tuberculosis and Respiratory Diseases, India), Alena Skrahina (The Republican Research and Practica
Centre for Pulmonology and TB, Belarus), Jeffrey R Starke (Baylor College of Medicine, United States),
Tania A Thomas (University of Virginia, United States), Rina Triasih (Universitas Gadjah Mada and Dr
Sardjito Hospital, Indonesia), Bazarragchaa Tsogt (Mongolian Tuberculosis Coalition, Mongolia), Henry
Welch (Baylor College of Medicine, United States; The University of Papua New Guinea, Papua New
Guinea), Olga Zvonareva (Maastricht University, the Netherlands).
Evidence reviewers for contextual factors: Olivier Marcy (Université de Bordeaux, France); Maryline
Bonnet and Manon Lounnas (Institut de Recherche pour le Développement, France), Eric Wobudeya
(Mulago National Referral Hospital, Uganda; Makerere University – Johns Hopkins University (MU-JHU)
Research Collaboration, Uganda); Pamela Nabeta (FIND, Switzerland), Claudia M Denkinger and
Mary Gaeddert (University of Heidelberg, Germany); Sushant Mukherjee, Mario JP Songane, Jean-
François Lemaire and Martina Casenghi (Elizabeth Glaser Pediatric AIDS Foundation, Switzerland);
Nyashadzaishe Mafirakureva and Peter J Dodd (University of Sheffield, United Kingdom); Nancy Medley
and Melissa Taylor (Liverpool School of Tropical Medicine, United Kingdom), Susanna S van Wyk
Acknowledgements vii
(Stellenbosch University, South Africa), Sandy Oliver (University College London, United Kingdom; and
University of Johannesburg, South Africa), Joanna Orne-Gliemann (Université de Bordeaux, France).
WHO Steering Group

The WHO guidelines Steering Group comprised Annabel Baddeley, Lice Gonzalez Angulo, Ernesto
Jaramillo, Avinash Kanchar, Charalambos Sismanidis (WHO Global Tuberculosis Programme); Martina
Penazzato (WHO Global HIV, Hepatitis and Sexually Transmitted Infections Programme); Bernadette
Cappello, Lorenzo Moja (WHO Department of Health Products, Policy and Standards); Marie Valentin
(WHO Department of Regulation and Prequalification); Corinne Simone Collette Merle (WHO Special
Programme for Research and Training in Tropical Diseases); Valentina Baltag, Wilson Milton Were
(WHO Department of Maternal, Newborn, Child & Adolescent Health & Ageing); Lina Mahy (WHO
Department of Nutrition and Food Safety); Chiara Servili (WHO Department of Mental Health and
Substance Use); Sarah Rylance (WHO Department of Non Communicable Diseases Management);
Ogtay Gozalov (WHO Regional Office for Europe); Mukta Sharma (WHO Regional Office for South-
East Asia); Kyung Hyun Oh (WHO Regional Office for the Western Pacific Region); Pedro Avedillo (Pan
American Health Organization); Kenza Bennani, Martin van den Boom (WHO Regional Office for the
Eastern Mediterranean Region); André Ndongosieme (WHO Regional Office for Africa).
Other contributors
Pete Dodd (Sheffield University, United Kingdom), Anneke Hesseling (Stellenbosch University, South
Africa), Oliver Marcy (University of Bordeaux, France), Nicole Salazar-Austin (Johns Hopkins University,
United States), James Seddon (Imperial College London, England) served as technical resource persons
during the GDG meeting.
The following persons participated as observers during the GDG meeting: Draurio Barreira Cravo
Neto (Unitaid, Switzerland), Charlotte Colvin (USAID, United States), Anne Detjen (UNICEF, United
States), Thomas Gradel (Unitaid, Switzerland), Brian Kaiser (Stop TB Partnership Global Drug Facility,
Switzerland), Michael McCaul (Stellenbosch University, South Africa), Lawrence Mbuagbaw (St Joseph’s
Healthcare, Canada), Celeste Naude (Stellenbosch University, South Africa), Oxana Rucsineanu (TB
Community Advisory Board), Anna Scardigli (Global Fund to Fight AIDS, Tuberculosis and Malaria,
Switzerland), Cherise Scott (Unitaid).
The Global Tuberculosis Programme also thanks the WHO Guidelines Review Committee for their
review and approval of the guidelines.
Funder
This update was funded by grants provided to WHO by Unitaid and the United States Agency for
International Development.
viii WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Abbreviations
AIDS acquired immunodeficiency syndrome
ANC antenatal care
ART antiretroviral treatment
BCG bacille Calmette-Guérin
C(A)LHIV children (and adolescents) living with HIV infection
CHW community health worker
CXR chest X-ray or chest radiography
DR-TB drug-resistant tuberculosis
DS-TB drug-susceptible tuberculosis
DST drug susceptibility testing
DTG dolutegravir
E ethambutol
EPTB extrapulmonary TB
Eto ethionamide
FDC fixed-dose combination (medicines)
GDF Stop TB Partnership Global Drug Facility
GDG Guideline Development Group
GRADE Grading of Recommendations Assessment, Development and Evaluation
GUV germicidal ultraviolet
H isoniazid
HEPA high-efficiency particulate air
HIV human immunodeficiency virus
KSP Knowledge Sharing Platform
iCCM integrated community case management
IGRA interferon-gamma release assay
IMCI integrated management of childhood illness
IPD individual patient data (or dataset)
IPT isoniazid preventive therapy
LAMP loop-mediated isothermal amplification
LF-LAM lateral flow lipoarabinomannan assay
LPA line-probe assay
M moxifloxacin
MDR-TB multidrug-resistant tuberculosis
NAATs nucleic acid amplification tests
Abbreviations ix
NPA nasopharyngeal aspirate
NRTIs nucleoside reverse transcriptase inhibitors
NTLP National TB and Leprosy Control Programme
NTP National Tuberculosis Programme
OSF optimized sucrose flotation
PHC primary health care
PICO Population, Intervention, Comparator and Outcomes
PK pharmacokinetic(s)
PTB pulmonary tuberculosis
R rifampicin
RAL raltegravir
RR-TB rifampicin-resistant tuberculosis
SAGE Strategic Advisory Group of Experts on Immunisation
SAM severe acute malnutrition
SDGs Sustainable Development Goals
SL-LPA second-line line-probe assay
SOS simple one step (stool processing method)
SPK stool processing kit
TB tuberculosis
TBM tuberculous meningitis
TPT TB preventive treatment
TST tuberculin skin test
UNGA United Nations General Assembly
US FDA United States Food and Drug Administration
WHO World Health Organization
XDR-TB extensively drug-resistant tuberculosis
Z pyrazinamide
x WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Definitions
Unless otherwise specified, the terms defined here apply as used in this document. They may have
different meanings in other contexts.
Active (tuberculosis) case-finding: Provider-initiated screening and testing in communities by
mobile teams, often using mobile X-ray and rapid molecular tests. The term is sometimes used
synonymously with “systematic screening”.
Adherence: Extent to which a person’s behaviour (e.g. taking medicines, following a particular diet,
changing lifestyle) corresponds with agreed recommendations from a health care provider.
Advanced HIV disease: For adolescents and children aged 5 years and over, this is defined as a
CD4 cell count below 200 cells/mm3 or a WHO clinical stage 3 or 4 event at presentation for care.
All children aged under 5 years living with HIV should be considered as having advanced disease
at presentation.
Adverse event: Any untoward medical occurrence that may present in a person with TB during
treatment with a pharmaceutical product but that does not necessarily have a causal relationship
with the treatment.
Age groups: Unless stated otherwise in the text, the following definitions apply to the terms used
in this document:
• Infant: aged under 1 year (12 months).
• Child: aged under 10 years.
– Young child: aged under 5 years.
• Adolescent: aged 10–19 years (inclusive).
– Young adolescent: aged 10–14 years.
– Older adolescent: aged 15–19 years.
• Adult: aged 20 years or over.
Background HIV and tuberculosis drug resistance prevalence: Settings with high HIV prevalence
are defined as those in which the HIV prevalence is 1% or higher among adult pregnant women, or
5% or higher among people with TB. WHO does not intend to establish thresholds for low, moderate
or high levels of prevalence of isoniazid resistance. National TB programmes will establish definitions
for their own countries.
Bacteriologically confirmed tuberculosis: TB diagnosed in a biological specimen by a WHO-
approved rapid test such as Xpert® MTB/RIF or LF-LAM, smear microscopy or culture.
Contact: Any person exposed to a person with TB.
Contact investigation: Systematic identification of people, including children and adolescents, with
previously undiagnosed TB disease and TB infection among the contacts of an index TB patient in the
household and in comparable settings in which transmission occurs. It consists of identification, clinical
evaluation and/or testing and provision of appropriate TB treatment (for people with confirmed TB)
or TB preventive treatment (for people without TB disease).
Decentralization: Depending on the standard in the research settings used for the comparator, this
includes provision of, access to or capacity for child and adolescent TB services at a lower level of
Definitions xi
the health system than the lowest level where this is currently routinely provided. In most settings,
decentralization applies to the district hospital (first referral level hospital) level and/or primary health
care level and/or community level. Interventions for decentralization include capacity-building of
various cadres of health care workers, expanding access to diagnostic services, ensuring availability
of TB medicines for children and adolescents, and follow-up of children and adolescents with TB or
on TB preventive treatment.
Differentiated HIV service delivery model: Person-centred approach to simplify provision of HIV
services across the cascade in ways that better serve the needs of people living with HIV and reduce
unnecessary burdens on the health system.
Drug susceptibility testing (DST): In vitro testing using either molecular genotypic techniques
to detect resistance-conferring mutations, or phenotypic methods to determine susceptibility to a
medicine.2
Extensive (or advanced) pulmonary tuberculosis disease: Presence of bilateral cavitary disease
or extensive parenchymal damage on chest radiography (CXR). In children aged under 15 years,
advanced disease is usually defined by the presence of cavities or bilateral disease on CXR.
Extensively drug-resistant tuberculosis (XDR-TB):3
• Pre-XDR-TB: TB caused by Mycobacterium tuberculosis strains that fulfil the definition of multidrug-
resistant TB (MDR-TB) or rifampicin-resistant TB (RR-TB) and that are also resistant to any
fluoroquinolone.4
• XDR-TB: TB caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and that are
also resistant to any fluoroquinolone and at least one additional Group A medicine.5
Extrapulmonary tuberculosis (EPTB) (classification): Any bacteriologically confirmed or clinically
diagnosed case of TB involving organs other than the lungs (e.g. pleura, peripheral lymph nodes,
abdomen, genitourinary tract, skin, joints and bones, meninges).6
Family-centred, integrated care: Family-centred models of care refer to interventions selected on the
basis of the needs, values and preferences of the child or adolescent and their family or caregiver. This
can include health education, communication, material or psychological support. Integrated services
refer to approaches to strengthen collaboration, coordination, integration and harmonization of child
and adolescent TB services with other child health-related programmes and services. This can include
integration of models of care for TB screening, prevention, diagnosis and treatment with other existing
service delivery platforms for maternal and child health (e.g. antenatal care, integrated community
case management, integrated management of childhood illnesses) and other related services (e.g.
HIV, nutrition, immunization). Other examples include evaluation of children and adolescents with
common comorbidities (e.g. meningitis, malnutrition, pneumonia, chronic lung disease, diabetes, HIV)
for TB and community health strategies integrating child and adolescent TB awareness, education,
screening, prevention and case-finding into training and service delivery activities.
2
Implementing tuberculosis diagnostics: a policy framework. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/
handle/10665/162712, accessed 11 March 2022).
3
Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis, 27–29 October 2020.
Geneva: World Health Organization; 2021 (https://www.who.int/publications/i/item/meeting-report-of-the-who-expert-consultation-
on-the-definition-of-extensively-drug-resistant-tuberculosis, accessed 11 March 2022).
4
The fluoroquinolones include levofloxacin and moxifloxacin as currently recommended by WHO for inclusion in shorter and
longer regimens.
5
Group A medicines are currently levofloxacin or moxifloxacin, bedaquiline and linezolid; therefore, XDR-TB is MDR/RR-TB that is
resistant to a fluoroquinolone and either bedaquiline or linezolid (or both). Group A medicines could change in the future. Therefore,
the terminology “Group A” is appropriate here and will apply to any Group A medicines in the future.
6
Following a WHO expert consultation in September 2021, intrathoracic lymph node TB is now classified as pulmonary TB in children.
xii WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Grading of Recommendations Assessment, Development and Evaluation (GRADE): System for
rating quality of evidence and strength of recommendations. This approach is explicit, comprehensive,
transparent and pragmatic.7
High tuberculosis transmission setting: Setting with a high frequency of people with undetected
or undiagnosed TB disease, or where people with infectious TB are present and there is a high risk
of TB transmission. People with TB are most infectious when they are untreated or inadequately
treated. Spread is increased by aerosol-generating procedures and by the presence of highly
susceptible people.
Household contact: Person who shared the same enclosed living space as the index case for one
or more nights or for frequent or extended daytime periods during the 3 months before the start of
current treatment.
Index case (index patient) of tuberculosis: Initially identified person of any age with new or
recurrent TB in a specific household or other comparable setting in which others may have been
exposed. An index case is the person on which a contact investigation is centred but is not necessarily
the source case.
Inpatient health care setting: Health care facility where people are admitted and assigned a bed
while undergoing diagnosis and receiving treatment and care, for at least one overnight stay.
Integrated treatment decision algorithm: Flowchart allocating evidence-based scores to
microbiological, clinical and radiological features that allow clinicians to make decisions regarding
starting TB treatment in children.
Interferon-gamma release assay (IGRA): Blood test used to test for Mycobacterium tuberculosis
infection by measuring the body’s immune response to TB bacteria.
Multidrug-resistant tuberculosis (MDR-TB): TB caused by Mycobacterium tuberculosis strains that
are resistant to at least both rifampicin and isoniazid.
New case: Newly registered episode of TB in a person who has never been treated for TB or has
taken TB medicines for less than 1 month.
Non-severe pulmonary tuberculosis for the purpose of determining treatment duration
for drug-susceptible tuberculosis: Intrathoracic lymph node TB without airway obstruction;
uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease confined to one lobe of
the lungs and without a miliary pattern.
Number needed to screen: Number of people who need to undergo screening in order to diagnose
one person with TB disease.
Operational research or implementation research: In the context of this document, applied
research that aims to develop the critical evidence base that informs the effective, sustained and
embedded adoption of interventions within a health system to improve health or patient outcomes.
Such research deals with the knowledge gap between efficacy, effectiveness and current practice to
produce the greatest gains in disease control.8 Operational research also provides decision-makers
with information to enable them to improve the performance of their health programmes.9
7
GRADE is a transparent framework for developing and presenting summaries of evidence. It provides a systematic approach for making
clinical and public health practice recommendations. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ. 2008;336:924.
8
Guide to operational research in programs supported by the Global Fund. Geneva: Global Fund to Fight AIDS, Tuberculosis and Malaria;
2007 (https://www.who.int/hiv/pub/operational/or_guide_gf.pdf, accessed 11 March 2022).
9
Expanding capacity for operations research in reproductive health: summary report of a consultative meeting. Geneva: World Health
Organization; 2003 (https://apps.who.int/iris/bitstream/handle/10665/67936/WHO_RHR_02.18.pdf?sequence=1&isAllowed=y, accessed
11 March 2022).
Definitions xiii
Outpatient health care setting: Health care facility where people are undergoing diagnosis
and receiving treatment and care but are not admitted for overnight stays (e.g. ambulatory clinic,
dispensary).
Passive case-finding: Patient-initiated pathway to TB diagnosis involving a person with TB disease
who experiences symptoms that they recognize as serious; the person having access to and seeking
care, and presenting spontaneously at an appropriate health facility; a health worker correctly assessing
that the person fulfils the criteria for presumptive TB; and successful use of a diagnostic algorithm
with sufficient sensitivity and specificity to diagnose TB.
People who use drugs: People who engage in the harmful or hazardous use of psychoactive
substances that could impact negatively on their health, social life, resources or legal situation.
Presumptive tuberculosis: Person who presents with symptoms or signs suggestive of TB.
Previously treated: People who have previously received 1 month or more of TB medicines. Previously
treated people may have been treated with a first-line regimen for drug-susceptible TB or a second-
line regimen for drug-resistant forms.
Programmatic management of tuberculosis preventive treatment: All coordinated activities by
public and private health caregivers and the community aimed at scaling up TB preventive treatment
to people who need it.
Pulmonary tuberculosis (PTB) (classification): Any bacteriologically confirmed or clinically
diagnosed case of TB involving the lung parenchyma or the tracheobronchial tree, including tuberculous
intrathoracic lymphadenopathy (mediastinal and/or hilar), without radiographic abnormalities in the
lungs.10 Miliary TB is classified as PTB because there are lesions in the lungs. A person with both PTB
and extrapulmonary TB should be classified as having PTB.
Rifampicin-resistant tuberculosis (RR-TB): TB caused by Mycobacterium tuberculosis strains
resistant to rifampicin. These strains may be susceptible or resistant to isoniazid (i.e. MDR-TB) or
resistant to other first-line or second-line TB medicines. In these guidelines and elsewhere, MDR-TB
and RR-TB cases are often grouped together as MDR/RR-TB and are eligible for treatment with an
MDR-TB regimen.
Rifampicin-susceptible, isoniazid-resistant tuberculosis: TB caused by Mycobacterium tuberculosis
strains resistant to isoniazid and susceptible to rifampicin.
Serious adverse event: Adverse event that can lead to death or a life-threatening experience,
to hospitalization or prolongation of hospitalization, to persistent or significant disability, or to a
congenital anomaly. Serious adverse events that do not immediately result in one of these outcomes
but that require an intervention to prevent such an outcome from happening are included. Serious
adverse events may require a drastic intervention, such as termination of the medicine suspected of
having caused the event.
Severe acute malnutrition: Presence of oedema of both feet or severe wasting (weight-for-height/
length less than −3 standard deviations/Z-scores or mid-upper arm circumference less than 115 mm).11
Severe extrapulmonary tuberculosis: Presence of miliary (disseminated) TB or TB meningitis.
In children and young adolescents aged under 15 years, extrapulmonary forms of disease other
than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are
considered to be severe.
10
Following a WHO expert consultation in September 2021, intrathoracic lymph node TB is now classified as pulmonary TB in children.
11
Pocket book of hospital care for children: guidelines for the management of common childhood illnesses, 2nd edition. Geneva:
World Health Organization; 2013 (https://apps.who.int/iris/bitstream/handle/10665/81170/9789241548373_eng.pdf, accessed
27 September 2021).
xiv WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Severe pneumonia: Cough or difficulty in breathing plus at least one of the following:
• central cyanosis or oxygen saturation <90% on pulse oximetry;
• severe respiratory distress (e.g. grunting, nasal flaring, very severe chest indrawing);
• signs of pneumonia with a general danger sign (inability to breastfeed or drink, persistent vomiting,
lethargy or unconscious, convulsions, stridor in a calm child, severe malnutrition).8
Source case: Person with TB disease who infected others in a new setting. This could be the index
patient or another person who was not identified.
Systematic screening for tuberculosis disease: Systematic identification of people at risk for TB
disease in a predetermined target group by assessing symptoms and using tests, examinations or
other procedures that can be applied rapidly. For those who screen positive, the diagnosis needs
to be established by one or several diagnostic tests and additional clinical assessments. This term is
sometimes used interchangeably with “active tuberculosis case-finding”. It should be distinguished
from testing for TB infection (with a TB skin test or interferon-gamma release assay).
Treatment outcomes and relapse: Categories for treatment outcomes used in this document and
the term “relapse” were applied according to the definitions agreed for use by TB programmes, unless
otherwise specified.12,13
Tuberculin skin test (TST): Intradermal injection of a combination of mycobacterial antigens that
elicit an immune response (delayed-type hypersensitivity), represented by induration, which can be
measured in millimetres. TST is used to diagnose TB infection.
Tuberculosis (TB): Disease state due to Mycobacterium tuberculosis. In this document, it is commonly
referred to as “TB disease” to distinguish it from “TB infection”.
Tuberculosis infection: State of persistent immune response to stimulation by Mycobacterium
tuberculosis antigens with no evidence of clinically manifest TB disease. This is referred to as “TB
infection” as distinct from “TB disease”. There is no gold standard test for direct identification of M.
tuberculosis infection in humans. Most infected people have no signs or symptoms of TB but are at
risk for TB disease. The term “latent TB infection” has been replaced by the term “TB infection”.
Tuberculosis preventive treatment (TPT): Treatment offered to people considered at risk of TB
disease to reduce that risk. Also referred to as “treatment of TB infection” or “TB preventive therapy”.
Underweight: Among adolescents, this usually refers to a body mass index below 18.5. Among
children aged under 10 years, it usually refers to a weight-for-age Z-score below −2 standard deviations.
12
Definitions and reporting framework for tuberculosis – 2013 revision. Geneva: World Health Organization; 2013 (WHO/ HTM/TB/2013.2;
http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf, accessed 11 March 2022).
13
Meeting report of the WHO expert consultation on drug-resistant tuberculosis treatment outcome definitions, 17–19 November 2020.
Geneva: World Health Organization; 2021 (https://apps.who.int/iris/rest/bitstreams/1336957/retrieve, accessed 11 March 2022).
Definitions xv
xvi WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Executive summary
Introduction
Children and young adolescents (aged below 15 years) represent about 11% of all people with
tuberculosis (TB) globally. This means that 1.1 million children become ill with TB every year, almost
half of them below five years of age. National TB programmes (NTPs) only notify less than half of
these children, meaning that there is a large case detection gap (1). The reasons for this gap include
challenges with specimen collection and bacteriological confirmation of TB in young children, due
to the paucibacillary nature of TB disease in this age group and the lack of highly sensitive point-of-
care tests. In 2020, the COVID-19 pandemic had an additional negative impact on TB notifications
in children. In addition to the case detection gap, only one third of child contacts below five years of
age eligible for TB preventive treatment (TPT) received it in 2020. Young children are at higher risk of
developing TB disease, including severe forms of TB, after TB infection, and the majority do so within
a few months following exposure and infection (2, 3). In addition to children and young adolescents,
over half a million older adolescents (aged 15–19 years) are estimated to develop TB every year (4).
The United Nations Sustainable Development Goal (SDGs) (5) and the World Health Organization
(WHO) End TB Strategy (6) include targets to reduce TB incidence by 80% and TB deaths by 90% to
be achieved by the year 2030, relative to baseline levels in 2015. In addition, to accelerate progress
towards these global targets, the Resolution adopted by the United Nations General Assembly at the
High-Level Meeting on the fight against tuberculosis in September 2018 commits to diagnosing and
treating 40 million people with TB (including 3.5 million children), and 1.5 million people with drug-
resistant TB (DR-TB) (including 115 000 children) by 2022. It also commits to providing at least 30
million people (including 4 million child contacts under five years of age), 20 million other household
contacts (including children aged five years and above) and 6 million people living with HIV (including
children) with TPT by 2022 (7).
Rationale
To support countries in preventing and managing TB in children and adolescents, WHO’s Global
Tuberculosis Programme published the WHO Guidance for national tuberculosis programmes on the
management of tuberculosis in children (second edition) in 2014 (8). Since the publication of the second
edition, new evidence related to diagnostic approaches for TB, treatment for drug-susceptible TB,
DR-TB and TB meningitis, as well as models of care relevant to children and adolescents has become
available. The WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis
in children and adolescents (2022) is a consolidated guideline of new and existing recommendations
(see annex 1), and replaces the 2014 guidance. It complements existing WHO guidelines on the
management of TB, recognizing the unique characteristics and needs of these groups, as well as those
of their parents, caregivers and families. The guidelines are complemented by the WHO operational
handbook on tuberculosis. Module 5: Management of tuberculosis in children and adolescents, which
provides guidance on how to implement the recommendations in the guidelines.
Executive summary xvii

Objectives
The objectives of the 2022 consolidated guidelines are: to provide policy-makers and implementing
partners with evidence-based recommendations on the cascade of care for children and adolescents;
to support the implementation of activities to prevent TB among children and adolescents at risk;
to improve TB case detection and treatment outcomes in children and adolescents with TB using
effective models of care; and to contribute to reductions in TB related morbidity and mortality in
children and adolescents in line with global targets including those in the SDGs (5), the WHO End
TB Strategy (6) and the Political declaration of the UN General Assembly High-Level Meeting on the
fight against tuberculosis (7).
Target audience
The target audience for these consolidated guidelines consists primarily of NTPs, primary health
care (PHC) programmes, maternal and child health programmes, national AIDS programmes (or
their equivalents in health ministries) and other health policy-makers. They also target generalist
and specialist paediatricians, clinicians and health practitioners working on TB, HIV and/or infectious
diseases in public and private sectors, the educational sector, nongovernmental, civil society and
community-based organizations, as well as technical and implementing partners.
Recommendations on the management of TB in

children and adolescents
A WHO convened Guideline Development Group (GDG) meeting held in 2021 led to eight new
recommendations on the management of TB in children and adolescents (Table 1). A summary of
the recommendations consolidated in this guideline are listed in Table 2 below.
A summary of all new and consolidated recommendations can be found in web annex 5.
Table 1: New recommendations in the WHO consolidated guidelines on tuberculosis.

Module 5: management of tuberculosis in children and adolescents, 2022
Diagnostic approaches
1 In children with signs and symptoms of pulmonary TB, Xpert Ultra should be used
as the initial diagnostic test for TB and detection of rifampicin resistance on sputum,
nasopharyngeal aspirate, gastric aspirate or stool, rather than smear microscopy/culture
and phenotypic drug susceptibility testing (DST).
(UPDATED: strong recommendation, moderate certainty of evidence for test accuracy in
stool and gastric aspirate; low certainty of evidence for test accuracy in sputum; very low
certainty of evidence for test accuracy in nasopharyngeal aspirate)
2 In children with presumptive pulmonary TB attending health care facilities, integrated
treatment decision algorithms may be used to diagnose pulmonary TB.
(NEW: interim, conditional recommendation, very low certainty of evidence)
Treatment regimens
3 In children and adolescents between 3 months and 16 years of age with non-severe TB
(without suspicion or evidence of multidrug- or rifampicin-resistant TB (MDR/RR-TB), a
4-month treatment regimen (2HRZ(E)/2HR) should be used.
(NEW: strong recommendation, moderate certainty of evidence)
xviii WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
4 In children with MDR/RR-TB aged below 6 years, an all-oral treatment regimen containing
bedaquiline may be used.
(NEW: conditional recommendation, very low certainty of evidence)14
5 In children with MDR/RR-TB aged below 3 years delamanid may be used as part of longer
regimens.
(NEW: conditional recommendation, very low certainty of evidence)15
6 In children and adolescents with bacteriologically confirmed or clinically diagnosed TB
meningitis (without suspicion or evidence of MDR/RR-TB), a 6-month intensive regimen
(6HRZEto) may be used as an alternative option to the 12-month regimen (2HRZE/10HR).
(NEW: conditional recommendation, very low certainty of evidence)
Models of TB care
7 In high TB burden settings, decentralized TB services may be used in children and
adolescents with signs and symptoms of TB and/or in those exposed to TB.
8 Family-centred, integrated services in addition to standard TB services may be used in
children and adolescents with signs and symptoms of TB and/or those exposed to TB.
Table 2: Recommendations in the WHO consolidated guidelines on tuberculosis. Module 5:

management of tuberculosis in children and adolescents, 2022, by chapter and topic
Chapter Topic
Screening Screening for TB in targeted populations
and contact
investigation Tools for screening for TB
HIV counselling and testing for household and close contacts of people with TB
Prevention TB infection prevention and control: administrative controls
TB infection prevention and control: environmental controls
TB infection prevention and control: respiratory protection
BCG vaccination: BCG vaccination at birth vs at six weeks
BCG vaccination: Selective BCG vaccination
BCG vaccination: Need for revaccination
BCG vaccination: BCG vaccination for HIV-infected infants
14
This recommendation applies to and complements the 2020 WHO recommendations on shorter and longer regimens that contain
bedaquiline: A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended in eligible patients with
confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) who have not been exposed to treatment with second-line TB
medicines used in this regimen for more than one month, and in whom resistance to fluoroquinolones has been excluded (Conditional
recommendation, very low certainty in the evidence); bedaquiline should be included in longer multidrug-resistant TB (MDR-TB) regimens
for patients aged 18 years or more (Strong recommendation, moderate certainty in the estimates of effect); bedaquiline may also be
included in longer MDR-TB regimens for patients aged 6–17 years; (Conditional recommendation, very low certainty in the estimates
of effect) (9).
15
This recommendation complements the 2020 WHO recommendation on longer regimens that contain delamanid: Delamanid may be
included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens (Conditional recommendation, moderate
certainty in the estimates of effect) (9).
Executive summary xix

TB preventive treatment: Identifying populations for TB infection testing and TB
preventive treatment – People living with HIV
preventive treatment – Household contacts (regardless of HIV status)
preventive treatment – Other people at risk
TB preventive treatment: Algorithms to rule out TB disease
TB preventive treatment: Testing for TB infection
TB preventive treatment: TB preventive treatment options
Diagnostic Use of commercial serodiagnostics
approaches
Xpert MTB/RIF and Xpert Ultra as initial tests in adults and children with signs
and symptoms of pulmonary TB
Xpert MTB/RIF and Xpert Ultra as initial tests in adolescents and children with
signs and symptoms of extrapulmonary TB
Xpert MTB/RIF and Xpert Ultra repeated testing in children and adolescents
with signs and symptoms of pulmonary TB
Xpert MTB/RIF and Xpert Ultra as initial tests for pulmonary TB in adults in the
general population either with signs and symptoms of TB or chest radiography
with lung abnormalities or both
Truenat MTB, MTB Plus and Truenat MTB-RIF Dx in adults and children with
signs and symptoms of pulmonary TB
Moderate complexity automated nucleic acid amplification tests (NAATs) for
detection of TB and resistance to rifampicin and isoniazid
Loop-mediated isothermal amplification
Lateral flow urine lipoarabinomannan (LF-LAM) assay
Low complexity NAATs for detection of resistance to isoniazid and second-line
TB agents
First-line line-probe assay (LPAs)
Second-line line-probe assays (SL-LPAs)
High complexity reverse hybridization-based NAATs for detection of
pyrazinamide resistance
xx WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Treatment Treatment of severe forms of pulmonary TB in children
Treatment of infants aged 0–3 months with TB
Treatment of osteoarticular TB in children
Use of thrice weekly dosing and fixed dose combination tablets
Use of corticosteroids in TB meningitis
A 4-month treatment regimen composed of isoniazid, rifapentine, moxifloxacin
and pyrazinamide for treatment of drug-susceptible pulmonary TB
Regimen for rifampicin-susceptible and isoniazid-resistant TB
Shorter all-oral bedaquiline-containing regimen for multidrug- or rifampicin-
resistant TB (MDR/RR-TB)
Longer regimens for MDR/RR-TB
The bedaquiline, pretomanid and linezolid (BPaL) regimen for MDR-TB with
additional fluoroquinolone resistance
Monitoring patient response to MDR-TB treatment using culture
Models of TB Health education and counselling
care
Treatment adherence interventions
Treatment administration options
Ambulatory care for persons with MDR-TB
Decentralized model of care for persons with MDR-TB
Special Routine HIV testing for persons with presumptive and diagnosed TB
situations
Co-trimoxazole prophylaxis for infants, children and adolescents living with HIV
General recommendations on eligibility for ART
Timing of ART for children and adolescents with TB
First-line ART regimens
Second-line ART regimens
Management of severe acute malnutrition (SAM)
Management of moderate undernutrition
Contact investigation
Based on these guidelines, tools to support implementation have been developed, including new
integrated treatment decision algorithms and an updated table on dosing of second-line TB medicines.
In accordance with the process for updating WHO guidelines, a systematic and continuous process
of identifying and bridging evidence gaps following guideline dissemination will be employed. If new
evidence that could potentially impact the current evidence base for any of the recommendations
is identified, it will be reviewed with a view to updating the recommendation. WHO welcomes
suggestions regarding additional questions for inclusion in future updates of the guideline.16
16
The WHO Global Tuberculosis Programme can be contacted at gtbprogramme@who.int.
Executive summary xxi

Main changes to the 2014 guidance in the 2022
update
The 2014 WHO Guidance for national tuberculosis programmes on the management of tuberculosis in
children (second edition) (8) included 28 recommendations on the management of TB in children. The
2022 consolidated guidelines incorporate: recommendations from the 2014 guidelines that remain
valid (mainly topics that remain key components of high-quality TB care for which no new evidence
was assessed), relevant recommendations that have since been published in other WHO guidelines,
and new recommendations published in 2022. A summary of the changes to the 2014 guidance is
provided in the supplementary table in annex 2. Also, the focus of the 2022 consolidated guidelines
is on children and adolescents aged 0–19 years, whereas the previous guidelines focused on children
and to a lesser extent, younger adolescents (aged 10–14 years).
xxii WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
1. Introduction
1.1. Background
Children and young adolescents (aged below 15 years) represent about 11% of all people with TB
globally. This means that close to 1.1 million children become ill with TB every year, almost half of them
below five years of age. National TB programmes (NTPs) only notify less than half of these children,
meaning that there is a large case detection gap (1). The reasons for this gap include challenges with
specimen collection and bacteriological confirmation of TB in young children, due to the paucibacillary
nature of TB disease in this age group and the lack of highly sensitive point-of-care tests (10). In 2020,
the COVID-19 pandemic had an additional negative impact on TB notifications in children, with a 24%
decrease in notifications compared to 2019 (in comparison, notifications in people aged 15 years
and above decreased by 18%). In addition to the case detection gap, only one third of child contacts
below five years of age eligible for TB preventive treatment (TPT) actually received it in 2020 (1).
Young children are at higher risk of developing TB disease, including severe forms of TB, than older
age groups, after TB infection, and the majority do so within a few months following exposure and
infection (2, 3). In addition to children and young adolescents, over half a million older adolescents
(15–19 years) are estimated to develop TB every year (4).
The United Nations Sustainable Development Goal (SDGs) (5) and the World Health Organization
(WHO) End TB Strategy (6) include targets to reduce TB incidence by 80% and TB deaths by 90%
to be achieved by the year 2030, relative to baseline levels in 2015. In addition, the Resolution
adopted by the United Nations General Assembly (UNGA) at the High-Level Meeting on the fight
against tuberculosis in September 2018 commits to diagnosing and treating 40 million people with
TB (including 3.5 million children), and 1.5 million people with DR-TB (including 115 000 children) by
2022. It also commits to providing at least 30 million people (including 4 million child contacts under
five years of age), 20 million other household contacts (including children over the age of five years)
and 6 million people living with HIV (including children) with TPT by 2022 (7).
To support countries in preventing and managing TB in children and adolescents, WHO’s Global
Tuberculosis Programme published the WHO Guidance for national tuberculosis programmes on
the management of tuberculosis in children (second edition) in 2014. Since these guidelines were
published, new recommendations and guidance on the management of TB have been published
in WHO guidelines and other policy documents on TB prevention, screening, diagnosis, treatment,
management and models of care. Many of these recommendations are also applicable to children and
adolescents. In addition, new evidence related to the management of TB in children and adolescents
became available to WHO in 2021. Some of these data were received in response to a specific request
from WHO for data on the management of TB in children and adolescents, issued as an Expression
of Interest in July 2020,17 which was developed in consultation with the core team of the Child and
Adolescent TB Working group.18 Data from a randomized controlled trial on treatment shortening
for children with non-severe TB were made available to the WHO in 2021. Therefore, in 2021, the
WHO convened a Guideline Development Group (GDG) to review new evidence on the management
of TB in children and adolescents. This guideline update includes new recommendations that were
17
WHO public call for data on the management of TB in children and adolescents. 24 July 2020. WHO [website] (https://www.who.int/
news-room/articles-detail/who-public-call-for-data-on-the-management-of-tb-in-children-and-adolescents, accessed 20 January 2022).
18
Child and Adolescent TB Working Group (https://www.stoptb.org/wg/dots_expansion/childhoodtb/, accessed 20 January 2022).
1. Introduction 1
issued at the GDG meeting in May-June 2021 as well as current recommendations from other WHO
guidelines that are relevant to the management of TB in children and adolescents (including those
that are in the previous guidelines on the management of TB in children that have been validated).
This update consolidates all recommendations in one guideline.
1.2. Rationale for the development of the 2022

consolidated guidelines
Since the publication of the WHO Guidance for national tuberculosis programmes on the
management of tuberculosis in children (second edition) (2014) (8), there have been numerous studies,
including reviews, randomized controlled trials, observational studies, pharmacokinetic (PK) and
pharmacodynamic studies, qualitative research and cost-effectiveness research, which have evaluated
the impact of various interventions. These are related to diagnostic approaches for TB, treatment for
drug-susceptible TB (DS-TB), drug-resistant TB (DR-TB) and TB meningitis (TBM), as well as models
of TB care, relevant to children and adolescents. Therefore, it was timely to review this new evidence
and to update the recommendations from 2014. Other recommendations in the 2014 guidance were
reviewed for their continued relevance. It was agreed that the new guidelines should be consolidated,
bringing together new recommendations as well as existing recommendations with relevance to
children and adolescents.
1.3. Objectives of the 2022 consolidated guidelines

The objectives of the 2022 consolidated guidelines on the management of TB in children and
adolescents are to:
1. provide policy-makers and implementing partners with evidence-based recommendations on the
entire cascade of care for children and adolescents to support the implementation of activities
to prevent TB among children and adolescents at risk, and to improve TB case detection and
treatment outcomes in children and adolescents with TB, using effective models of care; and
2. contribute to reductions in TB-related morbidity and mortality in children and adolescents in
line with global targets including those in the SDGs (5), the End TB Strategy (6) and the Political
declaration of the UN General Assembly High-Level Meeting on the fight against tuberculosis (7).
1.4. Target audience

The target audience for these consolidated guidelines consists primarily of NTPs, primary health
care (PHC) programmes, maternal and child health programmes, national AIDS programmes (or
their equivalents in health ministries) and other health policy-makers. They also target generalist
and specialist paediatricians, clinicians and health practitioners working on TB, HIV and/or infectious
diseases in public and private sectors, the educational sector, nongovernmental, civil society and
community-based organizations, as well as technical and implementing partners.
1.5. WHO recommendations relevant to the

management of TB in children and adolescents
The 2022 consolidated guidelines represent a significant update compared to the previous guidelines
issued in 2014. They include: (i) new recommendations based on the review of newly available
evidence related to the Population, Intervention, Comparator and Outcomes (PICO) questions that
were developed for this guideline update; (ii) recommendations with relevance to children and
adolescents from other WHO TB guidelines issued since 2014; and (iii) a few recommendations from
2 WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
the 2014 guidance that remain unchanged. These latter recommendations cover key components
of high-quality TB care for which a review of the evidence was either not done (such as HIV testing
for persons with presumptive TB and TB disease), or for which no new evidence was available. A
summary of the changes to the 2014 guidance is provided in the supplementary table in annex 2.
The full details of the new recommendations, including evidence and justification, subgroup and
implementation considerations and monitoring and evaluation, are provided in this guideline. Other
WHO recommendations relevant to the management of TB in children and adolescents have been
consolidated in tables in the relevant chapters. It is important to note that the original wording of
the recommendations based on the source guidelines has been included. In some source guidelines,
age groups have been defined differently compared to the 2022 consolidated guidelines on the
management of TB in children and adolescents, and the adult age group may include adolescents
aged 15 years and above. Where this is the case, it has been indicated in the tables. Users of this
guideline update are advised to refer to the original guideline for full information related to the
recommendation. In addition, all WHO recommendations on TB are now included in the WHO TB
Knowledge Sharing Platform (KSP)19 which can be searched by population (e.g. children or people
living with HIV) or by topic (e.g. diagnosis or treatment). Refer to section 1.7 for further details.
For ease of reference, a full overview of all new and consolidated recommendations is included in
web annex 5.
1.6. Scope of the guideline update

The population of interest in these guidelines is children and adolescents, defined as:
• A child is a person under 10 years of age.
• An adolescent is a person 10–19 years of age (inclusive).
The pathway of TB infection and disease in an individual child or adolescent, and the interface with
and retention across sequential stages of care (termed the ‘cascade of care’) was used as the analytic
framework during the scoping process for this guideline update (Figure 1) (10). This pathway involves
multiple steps from exposure to a person with an infectious form of TB, leading to subsequent TB
infection and, for some, progression to TB disease. Each of the steps in the cascade of care requires
evidence-based interventions to reduce TB transmission, prevent TB, enable early and accurate
diagnosis of TB and optimize treatment outcomes for children with drug-susceptible or DR-TB.
In addition, child-, adolescent- and family-friendly services are needed to optimize access to high
quality care.
19
WHO TB Knowledge Sharing Platform (https://extranet.who.int/tbknowledge)
1. Introduction 3
Figure 1: Cascade of care in children and adolescents exposed to and with TB, with
broad topics of PICO questions with corresponding numbers as per section 1.3.1
Diagnostic approaches Treatment of
(PICO 2 a and b) DS-TB, DR-TB
and TBM
Accessed (PICO 3, 4a
health care and 4b, and 5)
Feeling ill system Diagnosed Treated
Diseased
Did NOT
access health
care system
Models of Care TB case

detection and TB prevention
Exposed (PICO 6 a and b)
Infected Un/misdiagnosed
Susceptible Accessed health care system

Screening in health care
facilities (PICO 1)
Preventive treatment
Source: Roadmap towards ending TB in children and adolescents. Second edition. Geneva: World Health Organization; 2018.
DS/DR-TB: drug-susceptible/drug-resistant TB; TBM: TB meningitis.
Based on this understanding of the cascade of TB care in children and adolescents, the potential
contribution of interventions targeting different steps in this cascade is summarized in the following
logic model (which was the model used to frame these guidelines) with the potential contribution of
the evidence to short-term and long-term outcomes (Figure 2).
Figure 2: The logic model used for the guidelines on the management of TB in children
and adolescents
Inputs Activities Short-term Long-term

outcomes* outcomes*
• Stakeholder • Contact investigation • Earlier and increased • Reduced TB incidence

engagement from all • TB screening activities detection of DS- and and prevalence in
sectors in the • Diagnostic DR-TB in children and children and
community approaches for adolescents (1, 2, 6) adolescents (1, 2, 6)
• Financial resources relevant forms of DS- • Improved TB • Reduced TB mortality
• Human resources and DR-TB treatment outcomes in children and
• Equipment and • Optimal treatment (3, 4, 5) adolescents (1, 3, 4, 5, 6)
supplies regimens for the • Increase in TB • Reduced post-TB
• Participation by treatment of DS- and preventive treatment sequelae in children
families with children DR-TB coverage in children and adolescents (4, 5)
and adolescents • Innovative models of and adolescents (6) • Reduced financial
exposed to or with care to deliver TB • Improved quality of losses due to TB, for
(presumptive) TB services to children child and adolescent families and for the
• Community and adolescents TB care (6) community (1, 2, 3, 6)
participation • Capacity building of
• Infection control at health care workers at
community level all levels
• Evidence from • Demand generation at
research community level
*The numbers under short- and long-term outcomes refer to the PICO questions in section 1.6.1.
DS/DR-TB: drug-susceptible/drug-resistant TB.
A WHO Steering Group drafted a series of PICO (questions, which were discussed and agreed
upon by the GDG during a preparatory webinar. Systematic reviews or other studies were sought or
commissioned for each of the PICO questions. In addition, two priority background questions were
formulated to provide additional insight into implementation considerations related to TB care for
children and adolescents. After a review of preliminary data, the GDG recommended that one PICO
question (PICO question 1 on TB screening) should not be further pursued as the evidence for this
question overlapped directly with the evidence reviewed for the WHO consolidated guidelines on
tuberculosis. Module 2: screening – systematic screening for tuberculosis disease, published in 2021 (11).
Therefore, this PICO question was not considered by the GDG at their meeting in May-June 2021.
1.6.1. PICO questions

PICO question 1: TB screening approaches in children <10 years of age
Which screening tools should be used to screen systematically for TB disease in children aged below
10 years accessing health care?
a. In children aged below 10 years accessing health care in high TB prevalence settings, should
systematic screening for PTB using chest radiography (CXR) be used against a composite reference
standard?
b. In children aged below 10 years accessing health care in high TB prevalence settings, should
systematic screening for pulmonary TB using symptom screen be used against a composite
reference standard?
PICO question 2: TB diagnostic approaches in children

a. In children aged below 10 years with presumptive pulmonary TB attending health care facilities,
should integrated treatment-decision algorithms be used to diagnose pulmonary TB, compared
to a microbiological or composite reference standard?
b. In children aged below 10 years with signs and symptoms of pulmonary TB, seeking care at health
care facilities, should Xpert Ultra in gastric aspirate or stool be used to diagnose pulmonary TB
and rifampicin resistance, as compared with a microbiological/composite reference standard?
i. What is the diagnostic accuracy of Xpert Ultra in gastric aspirate and stool for pulmonary
TB in children aged below 10 years, as compared with a microbiological and composite
reference standard?
ii. What is the diagnostic accuracy of Xpert Ultra in gastric aspirate and stool for rifampicin
resistance in children aged below 10 years, as compared with a microbiological and composite
reference standard?
PICO question 3: Treatment shortening in children and adolescents with non-severe drug-
susceptible TB
In children and adolescents with non-severe TB, should a 4-month intervention regimen versus the
standard 6-month regimen conforming to WHO guidelines be used?
PICO question 4: Treatment of rifampicin-resistant/multidrug resistant TB (MDR/RR-TB)
a. In MDR/RR-TB patients aged below 6 years, should an all-oral treatment regimen containing
bedaquiline versus other regimens conforming to WHO guidelines without bedaquiline be used?
b. In MDR/RR-TB patients aged below 3 years, should an all-oral treatment regimen containing
delamanid versus other regimens conforming to WHO guidelines without delamanid be used?
1. Introduction 5
PICO question 5: Treatment of paediatric TB meningitis
In children and adolescents with presumed or bacteriologically confirmed drug-susceptible TB
meningitis, should a 6-month intensive regimen, compared to the 12-month regimen that conforms
to current WHO guidelines be used?
PICO question 6: Models of care for TB case detection and TB prevention settings with a
prevalence of TB in the general population of 100 per 100 000 or more:
a. In children and adolescents with signs and symptoms of TB, should decentralization of child and
adolescent TB services versus centralized child and adolescent TB services (at referral or tertiary
hospital level) be used?
b. In children and adolescents exposed to TB, should decentralization of child and adolescent TB
prevention and care services versus centralized prevention and care services (at referral or tertiary
hospital level) be used to increase coverage of TPT in eligible children and adolescents?
c. In children and adolescents with signs and symptoms of TB, should family-centred, integrated
services versus standard, non-family-centred, non-integrated services be used?
d. In children and adolescents exposed to TB, should family-centred, integrated services versus
standard, non-family-centred, non-integrated services be used to increase coverage of TPT in
eligible children and adolescents?
1.6.2. Background questions

a. What is the socioeconomic impact of TB on children and adolescents and their families?
b. How can adolescents with TB or eligible for TPT be optimally engaged in their care?
1.7. Publication, dissemination, evaluation and expiry

The electronic version of the consolidated guidelines on the management of TB in children and
adolescents will form part of the WHO TB KSP, which features the following components for each TB
module: (i) consolidated guidelines, (ii) operational handbooks with implementation guidance; as well
as (iii) a catalogue of WHO e-learning materials.
Further dissemination strategies include global, regional and country webinars and consultations,
development of training materials based on the guideline and the operational handbook, and technical
support for countries during programme reviews and other in-country missions, as well as review of
national strategic plans and funding applications.
Data collected for the annual global TB reports will be evaluated to monitor TB notification rates for
children (0–4 and 5–9 years) and adolescents (10–14 and 15–19 years), the proportion of notified TB
cases that are children and young adolescents under 15 years (for both DS-TB and DR-TB, and TB
treatment coverage rates for children under 5 years, children and young adolescents 5–14 years of
age. Other indicators that will be monitored include TB treatment outcomes for children and young
adolescents under the age of 15 years as well as coverage of TPT among eligible contacts under the
age of 5 years, as well as older contacts.
The recommendations included in the 2022 consolidated guidelines will be considered for updating
in five years’ time, or earlier if new evidence becomes available. For the interim recommendation
on the use of treatment decision algorithms, new data will be generated and reviewed within a two-
year time period.
1.8. Document structure

A summary of the structure of the guidelines including a brief description of the contents is provided
in Box 1.
Box 1: Structure of the 2022 consolidated guidelines
Î Chapter 1 is the introduction and provides background information, an overview of the

scope (including PICO and background questions), the rationale, objectives and target
audience for the guidelines.
Î Chapter 2 includes WHO recommendations on TB screening and contact investigation
that are relevant to children and adolescents. While no new recommendations were made
in these areas by the GDG on the management of TB in children and adolescents, new
recommendations on TB screening in children and adolescents were issued by WHO in
2021. These include recommendations on the populations to be screened (persons living
with HIV infection and close contacts) and the screening tools that can be applied. The
other recommendations in this chapter relate to contact investigation.
Î Chapter 3 focuses on TB prevention. It includes existing recommendations on TB infection
prevention and control as well as TPT. The recommendations on TPT relate to the identification
of populations who should be tested for TB infection, algorithms to rule out TB disease,
tests for TB infection and TPT regimens. This chapter also includes recommendations on
BCG vaccination that were published in a WHO position paper in 2018.
Î Chapter 4 includes WHO recommendations on diagnostic approaches. Two new
recommendations were made in the 2021 GDG meeting on: (i) the use of Xpert Ultra
in gastric aspirate and stool specimens to diagnose pulmonary TB and rifampicin
resistance; and (ii) the use of integrated treatment decision algorithms in children with
presumptive pulmonary TB. Other recommendations in this chapter include existing WHO
recommendations on rapid diagnostic tests including Xpert MTB/RIF, Xpert Ultra, Truenat
MTB, MTB Plus and Truenat MTB-RIF Dx, lateral flow urine lipoarabinomannan (LF-LAM)
assays, low complexity automated nucleic acid amplification tests, line probe assays and
high complexity reverse hybridization-based nucleic acid amplification tests.
Î Chapter 5 focuses on TB treatment. Four new recommendations were made by the
child and adolescent TB GDG on TB treatment: (i) a 4-month regimen for children and
adolescents 3 months to 16 years of age with non-severe drug-susceptible TB; (ii) a
6-month intensive regimen to treat TB meningitis composed of isoniazid, rifampicin,
pyrazinamide and ethionamide; (iii) use of bedaquiline as part of shorter or longer
regimens for children of all ages to treat MDR/RR-TB; and (iv) use of delamanid as part
of longer regimens for children of all ages to treat MDR/RR-TB. A summary of other
valid treatment recommendations is also consolidated in this chapter, including for drug
susceptible and DR-TB and for severe forms of EPTB.
Î Chapter 6 includes WHO recommendations on models of care. Two new recommendations
on models of care arose in 2021 including one on decentralized care and another on
integrated family-centred care. Other WHO recommendations in this chapter include
existing recommendations on health education and counselling, treatment adherence
interventions, treatment support and decentralized care for people with MDR/RR-TB.
Î Chapter 7 includes existing WHO recommendations on several specific situations such
as care of the child or adolescent living with TB and HIV, care of children with TB and
malnutrition, and optimal feeding of infants born to mothers with TB. The recommendations
on HIV include those on HIV testing, eligibility for and timing of antiretroviral therapy (ART),
co-trimoxazole prophylaxis and treatment regimens for ART.
Î Chapter 8 describes research priorities that were identified at the GDG meeting in 2021.
These signal areas where additional evidence is needed to improve the prevention,
management and care of TB in children and adolescents.
1. Introduction 7
2. TB screening and contact
investigation
This chapter includes current WHO recommendations that apply to children and adolescents on TB
screening and contact investigation. They have been consolidated from current WHO guidelines
on systematic screening for TB disease and contact investigation, namely the WHO consolidated
guidelines on tuberculosis. Module 2: screening – systematic screening for tuberculosis disease (11)
and Guidance for national tuberculosis programmes on the management of tuberculosis in children
(second edition) (8). For more information on each recommendation including the remarks, source
of evidence, justification, subgroup, implementation and monitoring and evaluation considerations,
the source guidelines or WHO TB KSP should be consulted.
Table 3: WHO recommendations on TB screening and contact investigation relevant to

WHO consolidated guidelines on tuberculosis. Module 2: screening – systematic

screening for tuberculosis disease (11)
Screening for TB in targeted populations
Household contacts and other close contacts of individuals with TB disease should be
systematically screened for TB disease.
(Strong recommendation, moderate certainty of evidence)
People living with HIV should be systematically screened for TB disease at each visit to a health
facility.
(Strong recommendation, very low certainty of evidence)
Systematic screening for TB disease may be conducted among subpopulations with structural
risk factors for TB. These include urban poor communities, homeless communities, communities
in remote or isolated areas, indigenous populations, migrants, refugees, internally displaced
persons and other vulnerable or marginalized groups with limited access to health care.
(Existing recommendation: conditional recommendation, very low certainty of evidence).
Tools for screening for TB
Among individuals aged 15 years and older in populations in which TB screening is
recommended, systematic screening for TB disease may be conducted using a symptom
screen, chest X-ray or molecular WHO-recommended rapid diagnostic tests, alone or in
combination.
(Conditional recommendation, very low certainty of evidence for test accuracy)
2. TB screening and contact investigation 9

Among individuals aged 15 years and older in populations in which TB screening is
recommended, computer-aided detection software programmes may be used in place of
human readers for interpreting digital chest X-rays for screening and triage for TB disease.
(Conditional recommendation, low certainty of evidence)
Among adults and adolescents living with HIV, systematic screening for TB disease should be
conducted using the WHO-recommended four symptom screen and those who report any one
of the symptoms of current cough, fever, weight loss or night sweats may have TB and should
be evaluated for TB and other diseases.
Among adults and adolescents living with HIV, C-reactive protein using a cut-off of >5 mg/L
may be used to screen for TB disease.
(Conditional recommendation, low certainty of evidence for test accuracy)
Among adults and adolescents living with HIV, chest X-ray may be used to screen for TB disease.
(Conditional recommendation, moderate certainty of evidence for test accuracy)
Among adults and adolescents living with HIV, molecular WHO-recommended rapid diagnostic
tests may be used to screen for TB disease.
Adult and adolescent inpatients with HIV in medical wards where the TB prevalence is >10%
should be tested systematically for TB disease with a molecular WHO-recommended rapid
diagnostic test.
(Strong recommendation, moderate certainty of evidence for test accuracy)
Among individuals younger than 15 years who are close contacts of someone with TB,
systematic screening for TB disease should be conducted using a symptom screen including
any one of cough, fever or poor weight gain; or chest radiography; or both.
(Strong recommendation, moderate to low certainty of evidence for test accuracy)
Among children younger than 10 years who are living with HIV, systematic screening for TB
disease should be conducted using a symptom screen including any one of current cough,
fever, poor weight gain or close contact with a TB patient.
(Strong recommendation, low certainty of evidence for test accuracy)
Guidance for national tuberculosis programmes on the management of tuberculosis in
children. Second edition (8)
In settings of high HIV prevalence, all household and close contacts of people with TB should
be counselled and tested for HIV.
In settings of low HIV prevalence, all household members and close contacts of people with TB
who have symptoms compatible with TB disease may be offered counselling and testing for HIV
as part of their clinical evaluation.
(Conditional recommendation, very low certainty of evidence)
All household contacts of an index case who is a person living with HIV should be counselled
and tested for HIV.
3. Prevention of TB
This chapter includes current WHO recommendations that apply to children and adolescents on TB
prevention. They have been consolidated from current WHO guidelines on TB infection, prevention
and control, a BCG position paper and guidelines on TPT, namely the WHO guidelines on tuberculosis
infection prevention and control, 2019 update (12), the BCG vaccines: WHO position paper (published in
the Weekly Epidemiological Record) (13) and the WHO consolidated guidelines on tuberculosis. Module 1:
prevention – tuberculosis preventive treatment (14). For more information on each recommendation
including the remarks, source of evidence, justification, subgroup, implementation and monitoring
and evaluation considerations, the source guidelines or WHO TB KSP should be consulted.
Table 4: WHO recommendations on TB infection prevention and control, BCG

vaccination and TPT relevant to children and adolescents
TB infection prevention and control: WHO guidelines on tuberculosis infection

prevention and control, 2019 update (12)
Administrative controls
Triage of people with TB signs and symptoms, or with TB disease, is recommended to
reduce M. tuberculosis transmission to health workers (including community health workers
(CHW)), persons attending health care facilities or other persons in settings with a high risk of
transmission.
(Conditional recommendation, very low certainty in the estimates of effects)
Respiratory separation/isolation of people with presumed or demonstrated infectious TB is
recommended to reduce M. tuberculosis transmission to health workers or other persons
attending health care facilities.
Prompt initiation of effective TB treatment of people with TB disease is recommended to reduce
M. tuberculosis transmission to health workers, persons attending health care facilities or other
persons in settings with a high risk of transmission.
(Strong recommendation, very low certainty in the estimates of effects)
Respiratory hygiene (including cough etiquette) in people with presumed or confirmed TB is
recommended to reduce M. tuberculosis transmission to health workers, persons attending
health care facilities or other persons in settings with a high risk of transmission.
(Strong recommendation, low certainty in the estimates of effects)
Environmental controls
Upper-room germicidal ultraviolet (GUV) systems are recommended to reduce M. tuberculosis
transmission to health workers, persons attending health care facilities or other persons in
settings with a high risk of transmission.
(Conditional recommendation, moderate certainty in the estimates of effects)
Ventilation systems (including natural, mixed-mode, mechanical ventilation and recirculated
air through high-efficiency particulate air (HEPA) filters) are recommended to reduce M.
tuberculosis transmission to health workers, persons attending health care facilities or other
persons in settings with a high risk of transmission.
Respiratory protection
Particulate respirators, within the framework of a respiratory protection programme, are
recommended to reduce M. tuberculosis transmission to health workers, persons attending
health care facilities or other persons in settings with a high risk of transmission.
BCG vaccination: BCG vaccines: WHO position paper, 2018 (13)
Bacillus Calmette-Guérin (BCG) vaccination at birth vs at 6 weeks
In countries or settings with a high incidence of TB and/or leprosy, a single dose of BCG vaccine
should be given to neonates at birth, or as soon as possible thereafter, for prevention of TB
and leprosy disease. If it cannot be given at birth, it should be given at the earliest opportunity
thereafter and should not be delayed. Any delay in vaccination may lead to opportunities for
known or unknown exposure to TB or leprosy-infected contacts.
Co-administration of BCG with the hepatitis B birth dose is safe and strongly recommended. In
order to avoid missed opportunities for neonatal vaccination, BCG multi-dose vials should be
opened and used despite any wastage of unused vaccine.
If the birth dose was missed, catch-up vaccination of unvaccinated older infants and children
is recommended since evidence shows it is beneficial. Catch-up vaccination should be done at
the earliest convenient encounter with the health care system to minimize known or unknown
exposure to TB or leprosy infected contacts.
Selective BCG vaccination
Countries with a low incidence of TB or leprosy may choose to selectively vaccinate neonates
in recognized risk groups for developing disease. High-risk groups to be considered for BCG
vaccination include the following:
• Neonates to parents (or other close contacts/relatives) with previous TB or leprosy
• Neonates in households with contacts to countries with high incidence of TB and/or leprosy
• Neonates in any other locally identified risk group for TB and/or leprosy
In a few countries with low TB incidence, BCG vaccination is largely replaced by intensified case
detection, contact tracing and supervised early treatment.
Need for revaccination
Studies show minimal or no evidence of any additional benefit of repeat BCG vaccination
against TB or leprosy. Therefore, revaccination is not recommended even if the TST reaction or
result of an IGRA is negative. The absence of a BCG scar after vaccination is not indicative of a
lack of protection and is not an indication for revaccination.
BCG vaccination for HIV-infected infants
Children who are HIV-infected when vaccinated with BCG at birth are at increased risk of
developing disseminated BCG disease. However, if HIV-infected individuals including children,
are receiving ART, are clinically well and immunologically stable (CD4% >25% for children aged
<5 years or CD4 count ≥200 if aged >5 years) they should be vaccinated with BCG.
• In general, populations with high prevalence of HIV infection also have the greatest burden of
TB; in such populations the benefits of potentially preventing severe TB through vaccination
at birth are outweighed by the risks associated with the use of BCG vaccine. Therefore, it is
recommended that in such populations:
– Neonates born to women of unknown HIV status should be vaccinated as the benefits of
BCG vaccination outweigh the risks.
– Neonates of unknown HIV status born to HIV-infected women should be vaccinated if they
have no clinical evidence suggestive of HIV infection, regardless of whether the mother is
receiving ART.
– Although evidence is limited, for neonates with HIV infection confirmed by early virological
testing, BCG vaccination should be delayed until ART has been started and the infant
confirmed to be clinically and immunologically stable (CD4% >25%).
TB preventive treatment: WHO consolidated guidelines on tuberculosis. Module 1 –
prevention – tuberculosis preventive treatment, 2020 (14)
Identifying populations for TB infection testing and TPT – people living with HIV
Adults and adolescents living with HIV who are unlikely to have TB disease should receive TB
preventive treatment as part of a comprehensive package of HIV care. Treatment should also
be given to those on antiretroviral treatment, to pregnant women and to those who have
previously been treated for TB, irrespective of the degree of immunosuppression and even if TB
infection testing is unavailable.
(Strong recommendation, high certainty in the estimates of effect)
Infants aged <12 months living with HIV who are in contact with a person with TB and who
are unlikely to have TB disease on an appropriate clinical evaluation or according to national
guidelines should receive TB preventive treatment.
(Strong recommendation, moderate certainty in the estimates of effect)
Children aged ≥12 months living with HIV who are considered unlikely to have TB disease on
an appropriate clinical evaluation or according to national guidelines should be offered TB
preventive treatment as part of a comprehensive package of HIV prevention and care if they
live in a setting with high TB transmission, regardless of contact with TB.
(Strong recommendation, low certainty in the estimates of effect)
All children living with HIV who have successfully completed treatment for TB disease may
receive TB preventive treatment.
(Conditional recommendation, low certainty in the estimates of effect)
Identifying populations for TB infection testing and TB preventive treatment – household
contacts (regardless of HIV status)
Children aged <5 years who are household contacts of people with bacteriologically confirmed
pulmonary TB and who are found not to have TB disease on an appropriate clinical evaluation
or according to national guidelines should be given TB preventive treatment even if TB infection
testing is unavailable.
(Strong recommendation, high certainty in the estimates of effect)
Children aged ≥5 years adolescents and adults who are household contacts of people with
bacteriologically confirmed pulmonary TB who are found not to have TB disease by an
appropriate clinical evaluation or according to national guidelines may be given TB preventive
treatment.
In selected high-risk household contacts of patients with multidrug-resistant tuberculosis,
preventive treatment may be considered based on individualized risk assessment and a sound
clinical justification.
(Conditional recommendation, very low certainty in the estimates of effect)
Identifying populations for TB infection testing and TB preventive treatment – other
people at risk
(these populations may include children and adolescents)
People who are initiating anti-TNF20 treatment, or receiving dialysis, or preparing for an organ
or haematological transplant, or who have silicosis should be systematically tested and treated
for TB infection.
(Strong recommendation, low to very low certainty in the estimates of effect)
Systematic TB infection testing and treatment may be considered for prisoners, health workers,
immigrants from countries with a high TB burden, homeless people and people who use drugs.
(Conditional recommendation, low to very low certainty in the estimates of effect)
Systematic TB infection testing and treatment is not recommended for people with diabetes,
people who engage in the harmful use of alcohol, tobacco smokers and underweight people
unless they also belong to other risk groups included in the above recommendations.
Algorithms to rule out TB disease
Adults and adolescents living with HIV should be screened for TB according to a clinical
algorithm. Those who do not report any of the symptoms of current cough, fever, weight loss
or night sweats are unlikely to have TB disease and should be offered preventive treatment,
regardless of their antiretroviral treatment (ART) status.
Adults and adolescents living with HIV who are screened for TB according to a clinical algorithm
and who report any of the symptoms of current cough, fever, weight loss or night sweats may
have TB disease and should be evaluated for TB and other diseases and offered preventive
treatment if TB disease is excluded.
Chest radiography may be offered to people living with HIV on ART and preventive treatment
given to those with no abnormal radiographic findings.
Infants and children living with HIV who have poor weight gain, fever or current cough or who
have a history of contact with a person with TB should be evaluated for TB and other diseases
that cause such symptoms. If TB disease is excluded after an appropriate clinical evaluation
or according to national guidelines, these children should be offered TB preventive treatment,
regardless of their age.
(Strong recommendation, low certainty in the estimates of effect)
20
TNF: tumour necrosis factor
The absence of any symptoms of TB and the absence of abnormal chest radiographic findings
may be used to rule out TB disease among HIV-negative household contacts aged ≥5 years
and other risk groups before preventive treatment.
Testing for TB infection
Either a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to test
for TB infection.
(Strong recommendation, very low certainty in the estimates of effect)
TB preventive treatment options
The following options are recommended for the treatment of TB infection regardless of HIV
status: 6 or 9 months of daily isoniazid, or a 3-month regimen of weekly rifapentine plus
isoniazid,21 or a 3-month regimen of daily isoniazid plus rifampicin.
(strong recommendation, moderate to high certainty in the estimates of effect).
A 1-month regimen of daily rifapentine plus isoniazid22 or 4 months of daily rifampicin alone
may also be offered as alternatives.
(Conditional recommendation, low to moderate certainty in the estimates of effect)
In settings with high TB transmission, adults and adolescents living with HIV who have an
unknown or a positive TB infection test, and are unlikely to have TB disease, should receive
at least 36 months of daily isoniazid preventive therapy (IPT). Daily IPT for 36 months
should be given whether or not the person is on ART, and irrespective of the degree of
immunosuppression, history of previous TB treatment and pregnancy in settings considered to
have a high TB transmission as defined by national authorities.
21
In children 2 years and above.
22
In children 13 years and above.
4. Diagnostic approaches for TB
in children and adolescents
Of the estimated 1.1 million children who developed TB annually, only 399 000 (36.5%) were notified
to NTPs in 2020. Under-notification is worst among children below 5 years of age, with only 27.5% of
children with TB being notified (1). These ‘missing’ children are not diagnosed and/or not reported.
TB-related mortality among children below 15 years of age was estimated at 226 000 for 2020 (1).
Modelling has shown that 80% of TB-related deaths are among children under 5 years of age, and
that 96% of children who die of TB, did not access treatment (15).
The low case detection rate among (young) children is due to several factors including: the fact that
young children have paucibacillary TB and do not excrete enough bacilli to be detectable by available
bacteriological tests; the lack of a sensitive point-of-care diagnostic test; difficulties in collecting suitable
respiratory samples for bacteriological confirmation; and misdiagnosis due to the overlap of non-
specific symptoms of TB with other common childhood diseases. Children often first access care at
the PHC level, where there may be little or no awareness and capacity to diagnose and manage
children with TB (this includes capacity for sample collection, access to bacteriological tests and CXR,
as well as capacity and confidence in making a clinical diagnosis when bacteriological testing is not
available or is negative). In addition, paediatric TB services are often highly centralized at secondary
or tertiary levels of the health system and managed in a vertical, non-integrated way. TB screening
is often not systematically incorporated into clinical algorithms for child health (10).
This chapter contains two new recommendations relevant to the diagnosis of TB in children and
adolescents as well as other valid WHO recommendations that apply to children and adolescents
on TB diagnosis. The two new recommendations relate to the use of the Xpert Ultra assay in gastric
aspirate and stool specimens for the diagnosis of PTB and detection of rifampicin resistance among
children, and the use of integrated treatment decision algorithms23 for the diagnosis of PTB in children.
Prior to 2022, Xpert Ultra had already been recommended for use in nasopharyngeal aspirate (NPA)
and sputum specimens; hence, the 2022 recommendation widens the number of specimens that can
be used and aligns this with the WHO recommendation on Xpert MTB/RIF (which WHO recommends
for use in gastric aspirate, NPA, sputum and stool specimens to diagnose PTB and detect rifampicin
resistance) (16). The two new recommendations are described in detail in this chapter.
Section 4.3 consolidates recommendations from current WHO guidelines on rapid diagnostic tests and
the use of commercial serodiagnostic tests, namely the WHO consolidated guidelines on tuberculosis.
Module 3: diagnosis – rapid diagnostics for tuberculosis detection, 2021 update (16) and the Commercial
serodiagnostic tests for diagnosis of tuberculosis: policy statement (17). For more information on each
recommendation including the remarks, source of evidence, justification, subgroup, implementation
and monitoring and evaluation considerations, the source guidelines or WHO’s TB KSP should be
consulted.
The WHO convened an expert consultation on the classification of intrathoracic TB disease among
children in September 2021. The experts reviewed evidence from the point of view of pathophysiology,
23
Treatment decision algorithms are defined as: A flow chart allocating evidence-based scores to microbiological, clinical and radiological
features that allow clinicians to make a decision regarding starting TB treatment in children.

clinical and surveillance, and advised the WHO to update the classification of intrathoracic TB
lymphadenopathy in children as PTB.
4.1. The use of the Xpert MTB/RIF Ultra assay

in gastric aspirate and stool specimens for the
diagnosis of pulmonary TB and rifampicin resistance
Recommendation:
In children with signs and symptoms of pulmonary TB, Xpert Ultra should be used as the
initial diagnostic test for TB and detection of rifampicin resistance on sputum, nasopharyngeal
aspirate, gastric aspirate or stool, rather than smear microscopy/culture and phenotypic drug
susceptibility testing (DST).
(Strong recommendation, moderate certainty of evidence for test accuracy in stool and gastric
aspirate; low certainty of evidence for test accuracy in sputum; very low certainty of evidence for
test accuracy in nasopharyngeal aspirate).
Remarks
• The recommendation on the use of Xpert Ultra to detect rifampicin resistance in stool
and gastric aspirate was extrapolated from existing recommendations on its use in other
sample types.
• Considerations regarding the acceptability and feasibility of implementation of both stool and
gastric aspirate specimens need to be taken into account.
4.1.1. Justification and evidence

The development of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, United States of America (United
States)) was a significant step forward in improving the diagnosis of TB and the detection of rifampicin
resistance globally. However, Xpert MTB/RIF sensitivity is suboptimal, particularly among people
(including children) with smear-negative TB and people (including children) living with HIV. The Xpert
MTB/RIF Ultra (Cepheid, Sunnyvale, United States), hereafter referred to as Xpert Ultra, was developed
by Cepheid as the next-generation assay to overcome these limitations. Xpert Ultra has a lower limit
of detection than the Xpert MTB/RIF, with an additional “trace” semi-quantitative category. It uses
the same GeneXpert® platform as the Xpert MTB/RIF. Xpert MTB/RIF is strongly recommended as
the initial diagnostic test for TB and rifampicin-resistance detection in sputum (including induced and
spontaneously expectorated sputum), gastric aspirate, NPA and stool specimens rather than smear
microscopy/culture and phenotypic DST in children aged below 15 years with signs and symptoms
of PTB. The Xpert Ultra assay is recommended in the same population as the initial diagnostic test
for TB and detection of rifampicin resistance in sputum or NPA, rather than smear microscopy/culture
and phenotypic DST (16).
The 2020 rapid diagnostics guidelines and 2021 update listed the evaluation of the diagnostic accuracy
of Xpert Ultra in gastric aspirate or stool specimens for PTB in children as a research priority. Therefore,
a systematic review and meta-analysis were conducted to evaluate the use of the Xpert Ultra assay in
two paediatric specimens, namely gastric aspirate and stool, for which insufficient data were available
at the time of the GDG meeting on molecular assays in December 2019 (18).
PICO question: In children aged below 10 years of age with signs and symptoms of pulmonary
TB seeking care at health care facilities, should Xpert Ultra in gastric aspirate or stool be used to
diagnose pulmonary TB and rifampicin resistance, as compared with a microbiological/composite
reference standard?
Evidence: In preparation for the GDG meeting on the management of TB in children and adolescents,
an update of the review on the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for TB disease
in children (18) was performed. A systematic search of the literature was carried out in January 2021.
This update focused specifically on the diagnostic accuracy of Xpert Ultra in gastric aspirate or
lavage specimens and stool specimens for the diagnosis of PTB and rifampicin resistance in children
below 10 years of age. Nine studies that evaluated the diagnostic accuracy of Xpert Ultra in gastric
aspirate and/or stool specimens in children were identified. For the meta-analysis, six studies (653
participants) provided data for gastric specimens (19–24) and six studies (1278 participants) for stool
specimens (20, 23–27). The review found that for gastric aspirate, Xpert Ultra sensitivity was 64% in
children 0–9 years, against a microbiological reference standard and specificity was 95%. For stool,
Xpert Ultra sensitivity was 53% in children 0–9 years, against the microbiological reference standard
and specificity was 98%. Sensitivity estimates against a composite reference standard were lower for
both specimen types. There were no studies that evaluated the diagnostic accuracy of Xpert Ultra
for detection of rifampicin resistance using gastric aspirate or stool specimens.
Of the nine studies, eight (89%) reported the proportion of Xpert Ultra positive results that were trace
results. In these eight studies, of the total Xpert Ultra positive results, the proportion (expressed as a
percentage) of Ultra trace results ranged from 0% to 66% (median 52%) in studies evaluating gastric
specimens and from 0% to 84% (median 52%) in studies evaluating stool specimens.
GDG considerations: The GDG members discussed that all TB tests, including the microbiological
reference standard (usually culture or Xpert Ultra on respiratory samples) have suboptimal sensitivity
in children, due to the paucibacillary nature of TB disease in this age group. Therefore, the panel
highlighted that a positive test accurately determines a case of TB disease, but a negative test does not
exclude TB disease. As no studies assessed the diagnostic accuracy for Xpert Ultra for the detection
of rifampicin resistance in children, conclusions related to the use of Xpert Ultra for the diagnosis of
rifampicin resistance were based on data in adults, evaluated for the 2020 rapid diagnostic guidelines.
The GDG members agreed that the desirable effects from the test in both specimens are moderate,
but large for the detection of rifampicin resistance, because of the large impact on the choice of
effective treatment when rifampicin resistance is detected. The panel noted that false-negative results
should be interpreted within the context of the clinical picture, and clinicians should not solely use a
negative test to rule out disease. The GDG judged that the balance of effects favours the intervention
(considering both the moderate desirable effects and small undesirable effects), based on moderate
certainty evidence for both gastric aspirate and stool samples.
The GDG judged that more time and training-related resources would be required to collect gastric
aspirate specimens, and that the procedure would also often require hospital admission. Stool
processing may result in some additional time requirement to prepare the sample, depending on
the processing method. The panel decided upon comparing the cost of doing the tests on the sample
types versus not doing the test. The panel then concluded that the costs for both specimen types vary.
While there were no studies on the cost-effectiveness of gastric aspirate, a cost-effectiveness study
compared stool testing against clinical diagnosis at PHCs in Uganda, assuming that no respiratory
samples would be collected without referral to the hospital or without invasive sampling (see web
annex 4). Compared to that standard of care, stool testing was more effective, but also more costly.
The GDG members discussed that an Xpert Ultra test on stool samples becomes cost-effective even at
a TB prevalence level of 3% at a zero discount rate (the practice of discounting future health effects).
Implementation aspects such as the importance of obtaining microbiological confirmation and the
detection of rifampicin resistance would further favour cost-effectiveness of stool testing. The panel
therefore concluded that the evidence probably favours Xpert Ultra testing on stool samples.
In terms of acceptability, although the gastric aspirate sample collection was found to be an invasive
procedure (that could be uncomfortable to children), the panel felt that the procedure is probably
acceptable to children, caregivers and health care workers (HCW), considering the role of this procedure
to obtain bacteriological confirmation at higher level facilities. The GDG noted the importance of

non-invasiveness of stool samples for bacteriological testing for the diagnosis of TB in children and
agreed that this sample type was acceptable to all relevant stakeholders, including HCWs, laboratory
technicians, parents and children.
The panel agreed that, despite the requirements of training and skills, using Xpert Ultra on gastric
aspirate is probably feasible to implement, especially at higher levels of the health care system. The
majority of the panel felt that Xpert Ultra on stool samples is feasible to implement at all levels of the
health care system (see web annex 3).
4.1.2. Subgroup considerations

Children with severe acute malnutrition (SAM): four studies (with 259 participants, of whom 9
had TB disease) were identified for children with SAM using Xpert Ultra on gastric aspirates and three
studies (428 participants, 19 with TB) using Xpert Ultra on stool specimens. The meta-analysis on stool
samples in children with SAM showed similar accuracy as in the overall analysis (sensitivity 63.2%,
specificity 98.5%). A meta-analysis on gastric aspirates could not be performed due to insufficient data.
Children living with HIV infection: four studies (99 participants, 8 with TB disease) were identified
for children living with HIV using Xpert Ultra on gastric aspirates and two studies (100 participants, 3
with tuberculosis) using Xpert Ultra on stool specimens. A meta-analysis on stool or gastric aspirate
samples could not be conducted for children living with HIV due to paucity of data.
Age subgroups: analyses on age subgroups were conducted by systematic reviewers.
• For gastric aspirate samples from children aged below 1 year, Xpert Ultra pooled sensitivity
and specificity (95% CI) were 67.3% (43.5 to 84.6) and 94.0% (84.7 to 97.8) respectively (5 studies,
182 participants; low-certainty (sensitivity) and moderate-certainty (specificity) evidence). From
children aged 1 to 4 years, Xpert Ultra pooled sensitivity and specificity (95% CI) were 71.5% (40.0
to 90.4) and 94.0% (73.8 to 98.9), respectively (4 studies, 327 participants; low-certainty evidence).
• For stool samples from children aged below 1 year, Xpert Ultra pooled sensitivity and specificity
(95% CI) were 65.2% (33.7 to 87.3) and 96.2% (88.9 to 98.7), respectively (4 studies, 295 participants;
very low-certainty (sensitivity) and moderate-certainty (specificity) evidence). From children aged
1 to 4 years, Xpert Ultra pooled sensitivity and specificity (95% CI) were 43.3% (27.1 to 61.2) and
97.1% (74.8 to 99.7), respectively (3 studies, 331 participants; very low-certainty (sensitivity) and
low-certainty (specificity) evidence). The small number of children aged below 1 year and in the
1–4 years age group for both samples limited the confidence in the precision of the estimates for
these age groups.
The systematic review did not identify studies that evaluated Xpert Ultra in gastric aspirate or stool
samples of children with severe pneumonia.
Xpert Ultra on gastric aspirate, stool, NPA and sputum (expectorated or induced) samples can be
used in all paediatric comorbidity and age subgroups mentioned in this section as the preferred initial
test for the diagnosis of PTB in children.
4.1.3. Implementation considerations

Specimen collection and the quality thereof needs to be ensured to optimize accurate diagnosis for
all specimen types.
Gastric aspirate samples: Gastric aspirate sample collection in children requires trained staff and
access to supplies. It may also require hospitalization and may therefore not be feasible at lower
levels of the health system. It is considered an invasive procedure, requires fasting and may be
uncomfortable and less acceptable to children and caregivers, or have adverse effects. Referral
systems need to be functional to ensure that children who need to be tested using gastric samples
reach the appropriate level of care.
Stool samples: Stool sampling has the advantage of being non-invasive, with the collection generally
perceived as easy and feasible by HCWs and caregivers, irrespective of the clinical condition of the
child. The possible drawback is that children may not be able to pass stool on command causing delay
in sample collection. Enhancing awareness and sensitizing caregivers on stool as a suitable sample
for TB testing is important, to enhance acceptability and implementation. Stool processing is also
an acceptable procedure for laboratory technicians and regarded as a good alternative to sputum
samples. Relatively high rates of non-determinate Xpert Ultra results (including error, invalid, or no
results) were reported in the studies included in the systematic review. These rates varied from less
than 1% to 10% and may depend on the stool processing method used.
Stool processing methods: An analysis of preliminary results of a head-to-head comparison of
three centrifuge-free stool processing methods combined with Xpert Ultra was conducted to inform
implementation considerations on the use of Xpert Ultra in stool samples. The three processing
methods were optimized sucrose flotation (OSF) (28), simple one step stool (SOS) (29) and stool
processing kit (SPK) (25). The results at the time of the GDG meeting showed a similar performance
of Xpert Ultra in combination with the three stool processing methods, in terms of sensitivity and
specificity. All methods were found to be easy to process by laboratory staff at the reference laboratory
level and had a high ease-of-use score. However, most users considered that these methods cannot
be performed by non-laboratory personnel (such as nurses or HCWs) in PHC settings without access
to a laboratory. Overall, the SOS method appeared to be the preferred method as it does not require
additional equipment and is comparable to sputum processing using Xpert Ultra. The SPK is still at
prototype stage but will not be commercialized; the optimized sucrose flotation is still under validation,
and its development into a kit format to simplify some of the steps is envisaged in the near future.
Therefore, either of the available centrifuge-free stool processing methods may be used, depending
on local preference and laboratory infrastructure.
Xpert Ultra trace results: Trace results are common with the use of Xpert Ultra in all paediatric
specimen types, reflecting the paucibacillary nature of TB disease in children. For children as well as
people living with HIV who are being evaluated for PTB, and for persons being evaluated for EPTB,
the “M. tuberculosis complex (MTBC) detected trace” Ultra result is considered as bacteriological
confirmation of TB (30). This is an important implementation consideration, in view of the risk of
morbidity and mortality in these populations. Trace results will have an indeterminate result for
rifampicin resistance; therefore, alternative specimens may need to be collected for Xpert Ultra
processing in persons with a high likelihood of drug resistance.
4.1.4. Monitoring and evaluation

Local monitoring of specimen collection by specimen type, diagnostic test, result and clinical diagnosis
in a TB Laboratory Register (or equivalent) is recommended. Results should be recorded in a TB
Register.
Routine recording and reporting of child and adolescent notifications in five-year age brackets (i.e.
0–4, 5–9, 10–14, 15–19 years) is recommended by WHO for countries with case-based electronic
recording and reporting systems.

4.2. Treatment decision algorithms for the diagnosis
of pulmonary TB in children aged below 10 years
of age
Interim recommendation
In children with presumptive pulmonary TB attending health care facilities, integrated treatment
decision algorithms may be used to diagnose pulmonary TB.
(Conditional recommendation, very low certainty of evidence).
Remarks
• Presumptive TB refers to a person who presents with symptoms and/or signs suggestive of
TB.24
• Bacteriological confirmation should be sought as part of the integrated treatment decision
algorithms whenever possible, using WHO recommended rapid diagnostic tests and
appropriate paediatric specimens (including stool, nasopharyngeal aspirate, induced or
expectorated sputum or gastric aspirate).
• In follow-up to the GDG meeting, new integrated treatment decision algorithms for specific
populations and settings, have been developed and internally validated. These algorithms are
detailed with practical guidance on their use in the operational handbook on the management
of tuberculosis in children and adolescents.25 National TB and other health programmes are
encouraged to use these evidence-based algorithms.
• This interim recommendation will remain valid for a period of 24 months after the publication
of these guidelines, after which new evidence will be reviewed.

TB diagnosis in children relies on a thorough assessment of all evidence derived from a careful history
of exposure, clinical examination and relevant investigations. While various algorithms and scoring
systems for TB diagnosis in children exist, these have not been systematically evaluated. There is a
need for evidence-based, practical treatment decision algorithm(s), ideally for different settings with
varying access to diagnostic tests and CXR.
PICO question: In children aged below 10 years with presumptive pulmonary TB attending health
care facilities, should integrated treatment-decision algorithms be used to diagnose pulmonary TB,
compared to a microbiological or composite reference standard?
Evidence: To address the need for evaluating and developing evidence-based, integrated treatment
decision algorithm(s), ideally for different settings with varying access to diagnostic tests and CXR, an
individual participant dataset (IPD) meta-analysis was conducted. For this analysis, an IPD meta-cohort
was developed, consisting of diagnostic evaluations data from children aged below 10 years, to infer
the sensitivity and specificity of treatment-decision algorithms (or scores) in identifying pulmonary TB,
using the updated clinical case definitions for the classification of intrathoracic TB among children (31).
Data were requested from investigators in February 2021. Data for the IPD was sourced from several
studies carried out within a geographically diverse set of TB high-burden countries. Algorithm sensitivity
and specificity in classifying TB was evaluated against the Union Desk Guide Algorithm (32), which
24
Definitions and reporting framework for tuberculosis – 2013 revision (updated December 2014 and January 2020). Geneva: World
Health Organization; 2013.
25
WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents (https://apps.who.
int/iris/bitstream/handle/10665/352523/9789240046832-eng.pdf ).
was developed in an attempt to operationalize the 2014 WHO guidance (8) by outlining the steps
that a health care worker should take in evaluating a child with presumptive PTB.
To make full use of available data for comparing the performance of these algorithms in different
settings, missing variables were imputed, heterogeneous definitions of variables were collapsed, and
slight modifications were made to the algorithms or scores to enable the use of the variables available
in the IPD. A total of 14 studies, comprising 5494 records were included, of which 4811 records were
included in this analysis (26, 33–47). Studies from 13 countries (including 12 high TB, TB/HIV and/or
MDR-TB burden countries) within 5 of the 6 WHO regions were included. The cohort in the meta-
analysis used to inform this recommendation had a median age of 26 months (interquartile range
13.4–58.3); 38% of the children had TB, of which 30% was bacteriologically confirmed; 20% of the
children were living with HIV infection; and 14% had SAM.
Seven algorithms or scoring systems were identified for evaluation, comprising the Uganda National
TB/Leprosy Control Program (NTLP) algorithm (48), the Brazilian Ministry of Health Child PTB Scoring
System (49), the Gunasekera et al. 2021 algorithm (50), the Keith Edward score (51), the Marcy et al.
2019 algorithm (52), the Stegen-Toledo score (53), and the Marais et al. 2006 criteria (54). The pooled
estimates of the sensitivity and specificity of each algorithm/score were compared to the standard of
care algorithm (i.e. The Union Desk Guide Algorithm, which constituted the reference standard (32))
for children aged below 10 years, for children living with HIV, for children with SAM and for children
aged below 1 year.
For the overall population of children under the age of 10 years, the pooled sensitivity of the seven
algorithms or scoring systems ranged from 16% (Marais et al. criteria) to 95% (Gunasekera et al.
algorithm), while the pooled specificity ranged from 9% (Gunasekera et al. algorithm) to 89% (Marais
et al. criteria) (see web annex 3).
GDG considerations: The GDG felt that algorithms with clinical criteria have an important role to
play in making decisions on starting children on TB treatment, particularly at peripheral levels of the
health care system. There was strong consensus among the GDG members about the need and
importance of working on treatment decision algorithms to improve the gaps in TB case detection in
children. An important advantage of evidence-based algorithms (as it allocates a modelled weight to
features of clinical evaluation), is that this modelling process allows for specification of the weight of
certain clinical features, rather than being based solely on expert opinion. The panel highlighted that
data in the IPD were mainly from tertiary settings where the proportion of children with confirmed
TB is higher than at district hospital or PHC level. It was acknowledged that the IPD had a high level
of heterogeneity. Conducting a meta-regression analysis by level of the health care system was not
possible because of the limited number of studies.
The GDG concluded that none of the evaluated algorithms were optimal in terms of either sensitivity
or specificity, combined with the very low certainty of evidence. The GDG also noted that algorithms
with a high sensitivity (i.e. low number of false negatives) generally have a low specificity (i.e. a high
number of false positives) and vice versa. The panel reflected on the consequences of false negative
and false positive conclusions based on integrated treatment decision algorithms and agreed that
it was most important to avoid missing a TB diagnosis in a child who has TB, considering the large
case detection gap and the consequences of a missed diagnosis of TB.
During the GDG deliberations, the following options that emerged from the evidence review were
discussed: (i) choose one of the algorithms reviewed for a possible recommendation; (ii) make a
generic recommendation on the use of integrated treatment decisions algorithms and present new
evidence-based algorithms in the operational handbook; (iii) make a statement about the need for
further research on treatment decision algorithms, affirming the need for such algorithms.
The GDG judged the available evidence as inappropriate to support a recommendation for any specific
algorithm; and instead decided to make a generic recommendation on the use of treatment decision

algorithms, and to describe newly developed algorithms for relevant subgroups and/or settings in the
operational handbook. The decision for a generic recommendation considers the current practice of
HCWs making decisions on starting TB treatment in children based on a combination of clinical signs
and symptoms, history of TB contact and investigations, and the need to develop evidence-based
approaches for this practice. In addition, an interim conditional recommendation was deemed most
appropriate, considering the need to reduce the TB case detection gap in children and the need for
additional evidence on the use of integrated treatment decision algorithms in programmatic settings.
The GDG also prioritized the need to reduce false negative results, while accepting a certain degree
of over-diagnosis, as well as limiting unnecessary referrals and tests for children. The GDG members
judged that a general recommendation with operational guidance on the use of evidence-based
algorithms integrating the use of rapid diagnostics with clinical features would empower HCWs,
including those in settings with limited access to diagnostic tools, to make decisions on starting TB
treatment in children.
The GDG concluded that a period of 24 months for the interim conditional recommendation would be
needed to: set up and conduct studies to generate new data, including studies to externally validate
the algorithms, implementation/operational research, modelling studies to determine the potential
impact of the treatment decision algorithms and qualitative research into feasibility and acceptability
for health care workers and families (refer to chapter 8 on detailed research priorities).

For HIV-infected children under the age of 10 years, the pooled sensitivity of the algorithms
reviewed ranged from 24% (Marais et al. criteria) to 92% (Uganda NTLP algorithm), and the pooled
specificity from 15% (Uganda NTLP algorithm) to 87% (Stegen-Toledo score, cut-off 5).
For children with SAM the pooled sensitivity varied between 33% (Marais et al. criteria) and 93%
(Uganda NTLP algorithm and Keith Edward score), while the pooled specificity varied between 10%
(Keith Edward score) and 88% (Stegen-Toledo score, cut-off 5).
For infants aged below 1 year the pooled sensitivity ranged from 17% (Marais et al. criteria) to 93%
Gunasekera et al. algorithm) and the pooled specificity from 13% (Gunasekera et al. algorithm) to
86% (Stegen-Toledo score, cut-off 5).
The GDG members highlighted the need for the development of specific evidence-based treatment
decision algorithms for specific subgroups at high risk of rapid progression of TB disease, including
children living with HIV, children with SAM and infants, if possible.

Algorithms included in the operational handbook: In the follow-up to the GDG meeting, new
integrated treatment decision algorithms for specific populations and settings have been developed
and internally validated, using regression modelling with pre-determined cut-off values for sensitivity
and specificity against the reference standard (using updated clinical case definitions to define
pulmonary TB, outlined in Graham S et al. (31)), based on the individual patient data set used for
the evidence review conducted to answer this PICO question. The algorithms are described in the
operational handbook and cover the diagnosis of PTB among children under the age of 10 years,
including intrathoracic lymphadenopathy. The algorithms are not suitable for the diagnosis of EPTB.
Implementation at peripheral levels of the health system: Integrated treatment decision algorithms
allow treatment decisions to be made at more decentralized levels of care, where children generally
present earlier, with less severe disease and lower bacteriological confirmation rates. Algorithms
integrating clinical criteria have an important role to play at these levels of the health system.
The decision to start treatment is linked to other recommendations in these guidelines, such as
shortening of the treatment duration for children with non-severe forms of TB and on decentralization
of TB services. Once a decision to start TB treatment has been made, the severity of disease needs
to be assessed to inform the duration of treatment. Detailed criteria for assessing severity of disease
are described in the operational handbook.
Referral: Defining the criteria for referral of children evaluated for PTB at peripheral levels of the
health care system using the algorithms is important. Examples of subgroups in need of referral
include infants, children with presumptive severe forms of EPTB (such as TBM, disseminated TB and
osteoarticular TB) and children with presumptive DR-TB in regions with a high prevalence of DR-TB.
Children presenting with severe acute pneumonia need referral to the appropriate level of care for
oxygen supplementation, while children with SAM need to be provided with appropriate nutritional
support. A high index of suspicion is important among infants with acute symptoms who are contacts
of people with bacteriologically confirmed TB, to make a treatment decision as soon as possible rather
than wait for symptoms to persist. This is due to the potential for rapid deterioration in the clinical
condition of infants and development of severe TB disease.
Clinical monitoring of children started on TB treatment: It is important to acknowledge that the
preference for sufficient sensitivity of the algorithms to detect and treat children with TB will mean
that some children who do not have TB will be treated with TB treatment. The risk of severe drug-
related toxicity in children is very low, and shorter regimens for non-severe TB (see chapter 5) will
further reduce the risks related to treatment. However, it will be critical to monitor children started on
TB treatment and to refer them for evaluation for other diseases and appropriate treatment if they
fail to respond to TB treatment within 1 month.
Implementation in high DR-TB burden settings: Integrated treatment decision algorithms may
be implemented in settings with a high burden of DR-TB. Seeking bacteriological confirmation using
appropriate paediatric samples and WHO recommended rapid diagnostic tests (such as Xpert MTB/
RIF or Ultra) is critical among children who have a history of contact with a source case with confirmed
or highly likely DR-TB (including a TB patient not responding to treatment, or a source case who died
of TB while on treatment). Once a decision to treat a child without bacteriological confirmation for TB
has been made based on the algorithm, risk factors for the child having DR-TB need to be assessed.
Clinicians need to keep a high index of suspicion for DR-TB in these children and ensure they are
tested and managed for DR-TB as appropriate (see chapter 5).

The integrated treatment decision algorithms need to be monitored and evaluated for their impact
on case notifications and treatment outcomes.
Clinical monitoring of people with TB started on treatment based on clinical criteria is equally important,
such as the need to monitor response to treatment (to identify an alternative diagnosis for children
who may be misdiagnosed as having TB), adverse events and deterioration in the clinical condition.

4.3. Consolidated recommendations on TB
diagnostics and diagnostic approaches relevant to
Table 5: WHO recommendations on diagnostic approaches relevant to children and
adolescents
WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics

for tuberculosis detection, 2021 update (16)
Recommendations on Xpert MTB/RIF and Xpert Ultra as initial tests in adults and
children with signs and symptoms of pulmonary TB (Note that in these guidelines, adults
refer to persons aged 15 years and above and children aged below 15 years, therefore the
adult population includes older adolescents):
In adults* with signs and symptoms of pulmonary TB, Xpert MTB/RIF should be used as an
initial diagnostic test for TB and rifampicin-resistance detection in sputum rather than smear
microscopy/culture and phenotypic drug susceptibility testing (DST).
(Strong recommendation, high certainty of evidence for test accuracy; moderate certainty of
evidence for patient-important outcomes)
* Adults and adolescents from 15 years
In children with signs and symptoms of pulmonary TB, Xpert MTB/RIF should be used as an
initial diagnostic test for TB and rifampicin-resistance detection in sputum, gastric aspirate,
nasopharyngeal aspirate and stool rather than smear microscopy/culture and phenotypic DST.
(Strong recommendation, moderate certainty for accuracy in sputum; low certainty of evidence
for test accuracy in gastric aspirate, nasopharyngeal aspirate and stool)
In adults* with signs and symptoms of pulmonary TB and without a prior history of TB
(≤5 years) or with a remote history of TB treatment (>5 years since end of treatment), Xpert
Ultra should be used as an initial diagnostic test for TB and for rifampicin-resistance detection in
sputum, rather than smear microscopy/culture and phenotypic DST.
(Strong recommendation, high certainty of evidence for test accuracy)
In adults* with signs and symptoms of pulmonary TB and with a prior history of TB and an end
of treatment within the last 5 years, Xpert Ultra may be used as an initial diagnostic test for TB
and for rifampicin-resistance detection in sputum, rather than smear microscopy/culture and
phenotypic DST.
(Conditional recommendation, low certainty of evidence for test accuracy)
Recommendations on Xpert MTB/RIF and Xpert Ultra as initial tests in adolescents and
children with signs and symptoms of extrapulmonary TB
In adults and children with signs and symptoms of TB meningitis, Xpert MTB/RIF or Xpert Ultra
should be used in cerebrospinal fluid (CSF) as an initial diagnostic test for TB meningitis rather
than smear microscopy/culture.
(Strong recommendation, moderate certainty of evidence for test accuracy for Xpert MTB/RIF; low
certainty of evidence for test accuracy for Xpert Ultra)
In adults and children with signs and symptoms of extrapulmonary TB, Xpert MTB/RIF may
be used in lymph node aspirate, lymph node biopsy, pleural fluid, peritoneal fluid, pericardial
fluid, synovial fluid or urine specimens as the initial diagnostic test for respective form of
extrapulmonary TB rather than smear microscopy/culture.
(Conditional recommendation, moderate certainty of evidence for test accuracy for pleural fluid;
low certainty for lymph node aspirate, peritoneal fluid, synovial fluid, urine; very low certainty for
pericardial fluid, lymph nodes biopsy)
In adults and children with signs and symptoms of extrapulmonary TB, Xpert Ultra may be used
in lymph node aspirate and lymph node biopsy as the initial diagnostic test for lymph nodes TB
rather than smear microscopy/culture.
In adults and children with signs and symptoms of extrapulmonary TB, Xpert MTB/RIF or Xpert
Ultra should be used for rifampicin-resistance detection rather than culture and phenotypic DST.
(Strong recommendation, high certainty of evidence for test accuracy for Xpert MTB/RIF; low
certainty of evidence for Xpert Ultra)
In HIV-positive adults and children with signs and symptoms of disseminated TB, Xpert MTB/RIF
may be used in blood, as an initial diagnostic test for disseminated TB.
Recommendations on Xpert MTB/RIF and Xpert Ultra repeated testing in children and
adolescents with signs and symptoms of pulmonary TB
In adults* with signs and symptoms of pulmonary TB who have an Xpert Ultra trace positive
result on the initial test, repeated testing with Xpert Ultra may not be used.
Remark: Xpert Ultra trace results in adolescents will require follow-up, including reassessing
clinical symptoms and information on prior history of TB. In the case of suspected rifampicin
resistance, repeated testing may provide additional benefit for detection as well as an initial
attempt to assess rifampicin resistance. For interpretation of trace results in children, see
section 4.1.3.
In children with signs and symptoms of pulmonary TB in settings with pretest probability below
5% and an Xpert MTB/RIF negative result on the initial test, repeated testing with Xpert MTB/RIF
in sputum, gastric fluid, nasopharyngeal aspirate or stool specimens may not be used.
(Conditional recommendation, low certainty of evidence for test accuracy for sputum; and very
low for other specimen types)
In children with signs and symptoms of pulmonary TB in settings with pretest probability 5% or
more and an Xpert MTB/RIF negative result on the initial test, repeated testing with Xpert MTB/
RIF (for total of two tests) in sputum, gastric fluid, nasopharyngeal aspirate and stool specimens
may be used.
(Conditional recommendation, low certainty of evidence for test accuracy for sputum; and very
low for other specimen types)
In children with signs and symptoms of pulmonary TB in settings with pretest probability below
5% and an Xpert Ultra negative result on the initial test, repeated testing with Xpert Ultra in
sputum or nasopharyngeal aspirate specimens may not be used.

In children with signs and symptoms of pulmonary TB in settings with pretest probability 5% or
more and an Xpert Ultra negative result on the first initial test, repeated one Xpert Ultra test (for
a total of two tests) in sputum and nasopharyngeal aspirate specimens may be used.
Recommendations on Xpert MTB/RIF and Xpert Ultra as initial tests for pulmonary
TB in adults in the general population either with signs and symptoms of TB or chest
radiograph with lung abnormalities or both
In adults* in the general population who had either signs or symptoms of TB or chest
radiograph with lung abnormalities or both, the Xpert MTB/RIF or Xpert Ultra may replace
culture as the initial test for pulmonary TB.
(Conditional recommendation, low certainty of the evidence in test accuracy for Xpert MTB/RIF;
and moderate certainty for Xpert Ultra)
In adults* in the general population who had either a positive TB symptom screen or chest
radiograph with lung abnormalities or both, one Xpert Ultra test may be used rather than two
Xpert Ultra tests as the initial test for pulmonary TB.
(Conditional recommendation, very low certainty of evidence for test accuracy).
Truenat MTB, MTB Plus and Truenat MTB-RIF Dx in adults and children with signs and
symptoms of pulmonary TB (specimen type: sputum)
In children and adults* with signs and symptoms of pulmonary TB, the Truenat MTB or MTB
Plus may be used as an initial diagnostic test for TB rather than smear microscopy/culture.
In children and adults* with signs and symptoms of pulmonary TB and a Truenat MTB or MTB
Plus positive result, Truenat MTB-RIF Dx may be used as an initial test for rifampicin resistance
rather than culture and phenotypic DST.
Moderate complexity automated nucleic acid amplification tests (NAATs) for detection of
TB and resistance to rifampicin and isoniazid
In people with signs and symptoms of pulmonary TB, moderate complexity automated NAATs
may be used on respiratory samples for the detection of pulmonary TB, and of rifampicin and
isoniazid resistance, rather than culture and phenotypic DST.
(Conditional recommendation, moderate certainty of evidence for diagnostic accuracy)
Loop-mediated isothermal amplification
TB-LAMP may be used as a replacement test for sputum-smear microscopy for diagnosing
pulmonary TB in adults* with signs and symptoms consistent with TB.
(Conditional recommendation, very low certainty evidence)
TB-LAMP may be used as a follow-on test to smear microscopy in adults* with signs and
symptoms consistent with pulmonary TB, especially when further testing of sputum smear-
negative specimens is necessary.
Lateral flow urine lipoarabinomannan assay
In inpatient settings, WHO strongly recommends using LF-LAM to assist in the diagnosis of TB
disease in HIV-positive adults and children:
a. with signs and symptoms of TB (pulmonary and/or extrapulmonary) (strong recommendation,
moderate certainty in the evidence about the intervention effects) or
b. with advanced HIV disease or who are seriously ill (strong recommendation, moderate
certainty in the evidence about the intervention effects); or
c. irrespective of signs and symptoms of TB and with a CD4 cell count of less than 200 cells/
mm3 (strong recommendation, moderate certainty in the evidence about the intervention effects).
In outpatient settings, WHO suggests using LF-LAM to assist in the diagnosis of TB disease in
HIV-positive adults and children:
a. with signs and symptoms of TB (pulmonary and/or extrapulmonary) or seriously ill
(conditional recommendation, low certainty in the evidence about test accuracy); and
b. irrespective of signs and symptoms of TB and with a CD4 cell count of less than
100 cells/mm3 (conditional recommendation, very low certainty in the evidence about
test accuracy)
In outpatient settings, WHO recommends against using LF-LAM to assist in the diagnosis of TB
disease in HIV-positive adults and children:
a. without assessing TB symptoms (strong recommendation, very low certainty in the evidence
about test accuracy);
b. without TB symptoms and unknown CD4 cell count or without TB symptoms and CD4 cell
count greater than or equal to 200 cells/mm3 (strong recommendation, very low certainty in the
evidence about test accuracy); and
c. without TB symptoms and with a CD4 cell count of 100–200 cells/mm3 (conditional
recommendation, very low certainty in the evidence about test accuracy).
Low complexity NAATs for detection of resistance to isoniazid and second-line TB agents
In people with bacteriologically confirmed pulmonary TB, low complexity automated NAATs
may be used on sputum for the initial detection of resistance to isoniazid and fluoroquinolones,
rather than culture-based phenotypic DST.
(Conditional recommendation, moderate certainty of evidence for diagnostic accuracy)
In people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low
complexity automated NAATs may be used on sputum for the initial detection of resistance to
ethionamide, rather than DNA sequencing of the inhA promoter.
(Conditional recommendation, very low certainty of evidence for diagnostic accuracy)
In people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low
complexity automated NAATs may be used on sputum for the initial detection of resistance to
amikacin, rather than culture-based phenotypic DST.
(Conditional recommendation, low certainty of evidence for diagnostic accuracy)

First-line line-probe assay (LPAs)
For persons with a sputum smear-positive specimen or a cultured isolate of Mycobacterium
tuberculosis complex (MTBC), commercial molecular LPAs may be used as the initial test instead
of phenotypic culture-based DST to detect resistance to rifampicin and isoniazid.
(Conditional recommendation, moderate certainty in the evidence for the test’s accuracy)
Second-line line-probe assays (SL-LPAs)
For patients with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of
phenotypic culture-based DST, to detect resistance to fluoroquinolones.
(Conditional recommendation, moderate certainty in the evidence for test accuracy for direct
testing of sputum specimens; low certainty in the evidence for test accuracy for indirect testing of
Mycobacterium tuberculosis cultures)
For patients with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of
phenotypic culture-based DST, to detect resistance to the second-line injectable drugs.
(Conditional recommendation, low certainty in the evidence for test accuracy for direct testing
of sputum specimens; very low certainty in the evidence for test accuracy for indirect testing of
Mycobacterium tuberculosis cultures)
High complexity reverse hybridization-based NAATs for detection of pyrazinamide
resistance
In people with bacteriologically confirmed TB, high complexity reverse hybridization-based
NAATs may be used on M. tuberculosis culture isolates for detection of pyrazinamide resistance
rather than culture-based phenotypic DST.
(Conditional recommendation, very low certainty of evidence for diagnostic accuracy)
Commercial serodiagnostic tests for diagnosis of tuberculosis: policy statement, 2011 (17)
Commercial serodiagnostics should not be used in children suspected of active pulmonary or
extrapulmonary TB, irrespective of their HIV status.
(Strong recommendation, very low certainty of evidence for the use of
commercial serodiagnostics)
5. Treatment of TB disease in
This chapter contains four new recommendations (published for the first time and described in full
detail here) relevant to the treatment of TB disease in children and adolescents as well as other valid
WHO recommendations that apply to the treatment of TB in children and adolescents (section 5.4).
The four new recommendations concern drug-susceptible TB (DS-TB): (i) a four-month regimen for
children and adolescents below 16 years of age with non-severe drug-susceptible TB (section 5.1);
(ii) a six-month intensive regimen to treat TBM composed of isoniazid, rifampicin, pyrazinamide and
ethionamide (section 5.2); (iii) use of bedaquiline as part of shorter or longer regimens for children
of all ages to treat MDR/RR-TB (section 5.3.1); and (iv) use of delamanid as part of longer regimens
for children of all ages to treat MDR/RR-TB (section 5.3.2).
The recommendations in this chapter have been consolidated from current WHO guidelines on
TB treatment, namely the WHO consolidated guidelines on tuberculosis. Module 4: treatment –
drug-susceptible tuberculosis treatment, 2022 update (55) and the WHO consolidated guidelines on
tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment, 2020 update (9). Where
appropriate, details on recommendations from the 2014 Guidance for national tuberculosis programmes
on the management of tuberculosis in children (second edition) (8), and Rapid advice: treatment of
tuberculosis in children (56), which remain relevant have been included. For more information on each
recommendation including the remarks, source of evidence, justification, subgroup, implementation
and monitoring and evaluation considerations, the source guidelines or WHO TB KSP should be
consulted.

5.1. Treatment shortening in children and
adolescents with non-severe TB
Recommendation:
In children and adolescents between 3 months and 16 years of age with non-severe TB (without
suspicion or evidence of MDR/RR-TB), a 4-month treatment regimen (2HRZ(E)/2HR) should
be used.
Remarks
• Non-severe TB is defined as: Peripheral lymph node TB; intrathoracic lymph node TB without
airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary disease,
confined to one lobe of the lungs, and without a miliary pattern.
• Children and adolescents who do not meet the criteria for non-severe TB should receive the
standard six-month treatment regimen (2HRZE/4HR), or recommended treatment regimens
for severe forms of extrapulmonary TB.
• The use of ethambutol in the first two months of treatment is recommended in settings with a
high prevalence of HIV,26 or of isoniazid resistance.27

The majority of children with TB have less severe forms of the disease than adults. Treatment regimens
that are shorter than those for adults may be effective in treating children with TB, however solid
evidence to substantiate this has been lacking to date. Shorter treatment regimens can result in lower
costs to families and health services, potentially less toxicity, lower risks of drug-drug interactions in
children living with HIV, and fewer problems with adherence. Shorter, safe and effective treatment
regimens for children with both drug-susceptible and DR-TB benefit children with TB and their families,
and are a key intervention to achieve the End TB Strategy targets, as well as targets related to children
set during the UNGA High-Level Meeting on the fight against tuberculosis in 2018. New evidence
from a recently completed trial on the shortened treatment of drug-susceptible TB in children and
adolescents has paved the way for new recommendations on shorter regimens for this group.
The SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children) was the first and only large
phase three trial to evaluate the duration of TB treatment in children with non-severe drug-susceptible
TB. Therefore, evidence from the trial rather than a systematic review, was used to answer this
PICO question (57). The SHINE trial was a multi-centre, open-label, parallel-group, non-inferiority,
randomized, controlled, two-arm trial comparing 4-month (16 weeks) versus the standard 6-month
(24 weeks) treatment durations in children under 16 years of age with symptomatic non-severe
TB. Children and young adolescents aged below 16 years were treated with rifampicin, isoniazid,
pyrazinamide with or without ethambutol using WHO recommended doses, appropriate for paediatric
dosing (58).
PICO question: In children and adolescents with non-severe TB, should a 4-month intervention
regimen versus the standard 6-month regimen conforming to WHO guidelines be used?
26
Defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is
≥1% or among TB patients is ≥5% in the 2014 Guidance for national tuberculosis programmes on the management of tuberculosis in
children (second edition) (8).
27
WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance; NTPs will establish
definitions for their own countries.
Evidence: In the SHINE trial, the primary efficacy outcome was a composite of treatment failure
(including an extension of treatment beyond the replacement of missed doses, TB treatment drug
changes or restarts due to suspected treatment failure), on-treatment loss-to-follow-up, TB recurrence
or death by 72 weeks (from randomization), excluding children not reaching 16 weeks follow-up
(modified-intention-to-treat). The non-inferiority margin for the primary efficacy outcome was 6%.
The primary safety outcome was grade 3–5 adverse events recorded while on TB treatment.
The SHINE trial definition of non-severe TB was: peripheral lymph node TB or respiratory TB (including
uncomplicated intrathoracic lymph node disease) confined to one lobe without cavities, no significant
airway obstruction, uncomplicated pleural effusion, and no miliary TB.
The SHINE trial inclusion criteria were: children and young adolescents aged <16 years; weight ≥3 kg;
no known drug resistance; symptomatic but non-severe TB; smear negative on gastric aspirate or other
respiratory sample (an Xpert MTB/RIF positive, rifampicin susceptible result was allowed);28 clinician’s
decision to treat with a standard first-line regimen; not treated for TB in the previous two years; known
HIV status (positive or negative). Trial exclusion criteria were: respiratory sample acid fast bacilli smear-
positive (a smear-positive peripheral lymph node sample was allowed); premature birth (<37 weeks)
and aged under 3 months; miliary TB, spinal TB, TBM, osteoarticular TB, abdominal TB, congenital TB;
pre-existing, non-tuberculous disease likely to prejudice the response to, or assessment of, treatment
(such as liver or kidney disease, peripheral neuropathy or cavitation); any known contraindication to
taking TB drugs; known contact with a drug-resistant adult source case (including mono-resistant
TB); known drug-resistance in the child; being severely ill; pregnancy.
A total of 1204 children were enrolled in the trial between July 2016 and July 2018. The median age of
enrolled children was 3.5 years (range: 2 months – 15 years), 52% were male, 11% had HIV-infection,
and 14% had bacteriologically confirmed TB. Retention in the trial by 72 weeks and adherence29 to
allocated TB treatment were 95% and 94%, respectively. Sixteen (2.8%) versus 18 (3.1%) children
reached the primary efficacy outcome (treatment failure) in the 16- versus 24-week arms respectively,
with an unadjusted difference of -0.3% (95% CI: -2.3, 1.6). Treatment success was reported in 97.1%
of participants receiving the 16-week regimen versus 96.9% in those receiving the 24-week regimen
(relative risk (RR): 1.00, 95% CI: 0.98–1.02). Non-inferiority of the 16-week regimen was consistent
across all intention-to-treat, per-protocol and key secondary analyses. This included restricting the
analysis to the 958 (80%) children that were independently adjudicated to have TB at baseline by
the trial Endpoint Review Committee. A total of 7.8% of children experienced a grade 3–5 adverse
event in the 16-week arm, versus 8.0% in the 24-week arm (RR: 0.98, 95% CI: 0.67–1.44). There were
115 on-treatment grade ≥3 adverse events in 95 (8%) children, 47 (8%) in the 16-week and 48 (8%)
in the 24-week arm, most common being pneumonia or other chest infections (29 (25%)) or liver-
related events (11 (10%)) across both arms. There were 17 grade 3 or 4 adverse reactions (considered
possibly, probably or definitely) related to trial drugs, including 11 hepatic events; all adverse reactions
except three occurred in the first eight weeks of treatment.
GDG considerations: The GDG judged that while the desirable effects related to this PICO question
are related to treatment outcomes, shortening the duration of treatment is also important and
desirable (as reducing the length of treatment could make treatment easier for children and caregivers
as well as reduce cost for families and the health system). The GDG discussed that since the SHINE
trial was a non-inferiority trial, no difference in unfavourable outcomes between the two arms is what
the trial aimed to detect. Therefore, both desirable and undesirable effects were judged by most GDG
members as trivial. Since non-inferiority of the 4-month regimen was demonstrated in the trial, the
balance of effects was judged to not favour either the shorter or the longer duration of treatment.
28
In the SHINE trial, children with Xpert MTB/RIF results had very low or low semi-quantitative results, or a negative result. Xpert Ultra
was not used in the SHINE trial.
29
In the SHINE trial, adherence was defined as the proportion of children who received an adequate amount of treatment (as defined in
the statistical analysis plan for both the intervention and control regimens; generally, a cut off of 80% of the allocated doses was used,
within a certain time frame of starting each phase of treatment (i.e. intensive phase versus continuation phase).

However, the GDG noted that treatment duration is a critical issue which was further considered in
the context of issues such as cost, acceptability and feasibility.
The GDG also discussed that presumably, a shorter duration of treatment would reduce costs to
both the health care system and to children with TB and their families. The GDG ultimately agreed
on ‘moderate savings’ despite the varying views on the level of these savings. The GDG judged that
equity was probably increased with a shorter duration of treatment. Despite no direct evidence on
acceptability, the GDG judged that the shorter regimen was acceptable to stakeholders.
In addition, the GDG felt that, in the absence of exposure to DR-TB, access to CXR would help
distinguish between non-severe and severe disease. However, the panel recognized that access to
CXR is often limited or quality of CXR and capacity for interpretation is insufficient at lower levels
of the health care system, which may have equity implications. Therefore, feasibility was judged to
vary by setting. The GDG noted that it is critically important to clearly define “non-severe” disease
and that NTPs be encouraged to scale up access to quality CXR and train health care providers
in its interpretation. Overall, the GDG judged that if the severity of TB disease in children can be
adequately determined under programmatic conditions, then implementation of a 4-month regimen
is highly feasible.

Children with peripheral lymph node TB: Although the number of children with peripheral lymph
node TB in the SHINE trial were small (N=19 in the 16-week arm and N=21 in the 24-week arm), there
was no difference in the proportion of unfavourable outcomes between the two arms. The SHINE trial
also found that 16 weeks of treatment was non-inferior compared to 24 weeks of treatment among
children with both peripheral lymph node disease and pulmonary disease (N=182 in the 16-week
arm and N=171 in the 24-week arm). These results may provide reassurance to clinicians regarding
a seemingly delayed clinical response to TB treatment, frequently seen in children with peripheral
lymph node TB (where lymph nodes remain enlarged even after treatment).
Children and adolescents living with HIV infection (CALHIV): CALHIV were eligible for enrolment
in the SHINE trial; 65 (11%) CALHIV were enrolled in the 16-week arm and 62 (10%) in the 24-week
arm. 49% of CALHIV in the 16-week arm and 43% in the 24-week arm were on antiretroviral treatment
at the time of enrolment. 20% of CALHIV in both arms had a CD4 count of less than 200 cells per mm3.
51% of CALHIV in the 16-week arm and 63% in the 24-week arm were classified as severe as per the
WHO immunological classification for established HIV infection (59). In this subgroup, the 16-week
regimen was non-inferior as compared to the 24-week regimen, although the 95% confidence interval
for the risk difference was wide (risk difference -4.3, 95% CI -14.9 to 6.2).
In view of the limited evidence, clinicians may consider treating CALHIV with non-severe TB for 4
months, depending on the degree of immunosuppression and ART status, as well as the presence
of other opportunistic infections. These children and adolescents will need to be monitored closely,
especially at 4 months of treatment, and treatment extended to 6 months if there is insufficient
progress.
Children with SAM: In the SHINE trial, SAM was defined as weight-for-height Z-score (WHZ) <−3 or
MUAC <115 mm (60). Thirty children with SAM (5%) were included in the 16-week arm and 33 (5%)
in the 24-week arm. No separate subgroup analysis was therefore conducted for children with SAM.
In view of the insufficient evidence on this subgroup, and as SAM is defined as a danger sign, children
with SAM and non-severe TB should preferably receive 6 months of TB treatment.
Infants <3 months of age and/or weighing <3 kg: Infants <3 months of age and infants weighing
<3 kg (including premature birth (<37 weeks) were not eligible for inclusion in the SHINE trial. No
new data on the treatment of congenital TB and very young infants (aged 0–3 months) with TB
disease was received following a call for data. Therefore, infants aged 0–3 months with suspected or
confirmed PTB or tuberculous peripheral lymphadenitis should be promptly treated with the 6-month
treatment regimen (2HRZ(E)/4HR), as per the existing recommendation from the 2014 Guidance for
national tuberculosis programmes on the management of tuberculosis in children (second edition) (8).
Treatment may require dose adjustment to reconcile the effect of age and possible toxicity in young
infants. The decision to adjust doses should be taken by a clinician experienced in the management
of paediatric TB.
Children treated for TB in the past two years: Given the increased risk of treatment failure and
of drug resistance, children and adolescents treated in the preceding two years were not eligible for
inclusion in the SHINE trial; they should be treated with the 6-month treatment regimen (2HRZ(E)/4HR).

Assessing severity of disease: The feasibility of assessing the severity of TB disease, particularly in
settings without access to CXR or capacity for CXR interpretation and WHO-recommended diagnostic
tests was identified as a major implementation consideration. Chest radiography was identified by
the GDG as a critical tool to evaluate the severity of intrathoracic disease. As indicated under the
recommendation remarks, non-severe intrathoracic or PTB disease refers to: intrathoracic lymph
node TB without airway obstruction; uncomplicated TB pleural effusion or paucibacillary, non-cavitary
disease confined to one lobe of the lungs and without a miliary pattern. Extensive or advanced
disease in children under 15 years of age is usually defined by the presence of cavities or bilateral
disease on CXR (61). NTPs are encouraged to scale up access to quality CXR and provide training to
health care providers in its interpretation. Out-of-pocket expenses for CXR pose a potential barrier
to TB diagnosis and access to shorter regimen for eligible children and young adolescents. In the
SHINE trial, children who were Xpert MTB/RIF positive, but sputum smear-negative were eligible for
inclusion. The 85 children (7%) who were Xpert MTB/RIF positive (45 in the 4-month arm and 40 in
the 6-month arm), had very low or low semi-quantitative Xpert MTB/RIF results.
Detailed implementation guidance is provided in the Operational handbook on the management of
tuberculosis in children and adolescents, taking into consideration differences in the health care system
and country context, including the availability of diagnostic tools to make a diagnosis and to assess
disease severity. While access to CXR is an important implementation consideration, it should not be
a barrier for children and adolescents in lower resourced settings to benefit from the shorter regimen.
The implementation guidance in the operational handbook comprises criteria for assessing disease
severity, including clinical criteria in the absence of CXR or rapid diagnostics or other bacteriological
tests, to determine eligibility for the shorter regimen. Children with Xpert MTB/RIF or Ultra results
that are trace, very low or low, who meet radiographical or clinical criteria for non-severe TB, can be
treated with the 4-month regimen.
Continuum between TB infection and disease: An additional implementation consideration is
the concept that a continuum exists between TB infection, non-severe and more severe forms of
TB disease in children. Shorter treatment regimens for drug-susceptible TB are now very similar to
recently recommended shorter regimens for the treatment of TB infection, in terms of duration and
composition, in particular the regimen that consists of 3 months of daily isoniazid and rifampicin
(3HR) (14). This implies that incorrectly diagnosing a child who has TB infection as having non-severe
TB disease may not have severe consequences.
Contact investigation: Another implementation consideration is the scale-up of contact investigation
approaches, which can improve early identification of children with non-severe disease who may
benefit from the 4-month regimen.
Use of ethambutol in the intensive phase of treatment: Children and young adolescents with non-
severe TB who live in settings with low HIV prevalence or a low prevalence of isoniazid resistance and
those who are HIV negative can be treated with a three-drug regimen (HRZ) for 2 months, followed

by 2 months of HR. Children and young adolescents with non-severe TB who are living in settings
where the prevalence of HIV is high30 and/or the prevalence of isoniazid resistance is high31 should
be treated with HRZE for 2 months followed by HR for 2 months. In the SHINE trial, ethambutol
was used in line with these recommendations as per national guidelines and all CALHIV received
ethambutol as part of their treatment. For the 6-month regimen used to treat more severe forms of
TB, it is recommended to add ethambutol to the regimen (i.e. 4HRZE/2HR).
Child-friendly formulations: NTPs are encouraged to prioritize the use of child-friendly fixed dose
combination (FDC) formulations for TB treatment in children up to 25 kg body weight, such as: the
3-FDC HRZ 50/75/150 mg with or without the addition of dispersible ethambutol, and the 2-FDC HR
50/75 mg (available from the Stop TB Partnership Global Drug Facility (GDF)). Capacity building of
health care workers at all levels of the health system on diagnostic approaches (including treatment
decision algorithms), eligibility for the four-month regimen and monitoring of children on first-line TB
treatment will also be critical factors in the successful implementation of the shorter regimen.
Treatment of severe PTB in children and young adolescents: Children and young adolescents with
forms of PTB that do not meet the eligibility criteria for the four-month regimen should be treated
with a standard 6-month regimen that includes a fourth drug (ethambutol) in the intensive phase
(such as 2HRZE/4HR).
Treatment options for adolescents from 12 years of age: Another implementation consideration
is that adolescents aged 12 years and above with TB can benefit from the 4-month regimen that
consists of isoniazid, rifapentine, moxifloxacin and pyrazinamide (HPMZ), which is now conditionally
recommended by WHO (55). Adolescents aged between 12 and 16 years therefore have three
options for treatment: the 4-month HPMZ regimen, the 4-month 2HRZ(E)/2HR regimen, and the
standard 6-month 2HRZ(E)/4HR regimen. Adolescents from 16 years of age were not included in the
SHINE trial and therefore have two options: the 4-month HPMZ regimen and the standard 6-month
2HRZE/4HR regimen.
Choosing an appropriate regimen for this age group will depend on clinical factors (such as the
presence of severe disease or if living with HIV, ART status and CD4 count) as well as contextual factors
(including the availability of the HPMZ regimen in the country).

The clinical monitoring requirements for the shorter regimen remain the same as for the 6-month
regimen and treatment outcomes are determined at the end of the 4-month regimen.
Should there be insufficient clinical improvement after completion of the 4-month regimen, the clinician
may decide to extend treatment to 6 months while considering alternative diagnoses, including DR-TB.
Monitoring for potential relapse is a priority for shorter regimens especially when they are introduced
into programmatic settings. Therefore, follow-up of children and young adolescents for up to 12
months after completion of the 4-month regimen is important.
30
This level of resistance was defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence
among adult pregnant women is ≥1% or among TB patients is ≥5% in the 2014 Guidance for national tuberculosis programmes on the
management of tuberculosis in children (second edition) (8).
31
WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance; instead NTPs will
establish definitions for their own countries.
5.2. Treatment regimens for TB meningitis in children
and adolescents
Recommendation
In children and adolescents with bacteriologically confirmed or clinically diagnosed TB meningitis
(without suspicion or evidence of MDR/RR-TB), a 6-month intensive regimen (6HRZEto) may be
used as an alternative option to the 12-month regimen (2HRZE/10HR)
(Conditional recommendation, very low certainty of the evidence).
Remarks
• The shorter intensive regimen is suitable for children and adolescents who have no evidence of
drug resistance and in children and adolescents who have a low likelihood of drug-resistant TB,
e.g. those without risk factors for any form of drug-resistant TB.
• The recommendation from the Guidance for national tuberculosis programmes on the
management of tuberculosis in children (second edition, 2014) remains an option for the treatment
of children and adolescents with suspected or confirmed TB meningitis (TBM): Children and
adolescents with suspected or confirmed tuberculous meningitis should be treated with a four-
drug regimen (HRZE) for 2 months, followed by a two-drug regimen (HR) for 10 months, the total
duration of treatment being 12 months (Strong recommendation, low certainty of evidence).
• Due to a lack of data, the shorter intensive treatment regimen recommendation should not be
used in children and adolescents living with HIV who are diagnosed with TB meningitis.

Following M. tuberculosis infection, young children are at high risk of developing the most severe
forms of the disease, of which the most devastating form is TBM. This predominantly affects young
children with a peak age of onset of 2–4 years (2). Up to 15% of childhood TB may present as TBM
(62); with a decreasing incidence of bacterial meningitis attributed to other causes, TB is the leading
cause of bacterial meningitis in many settings (63). TBM is associated with significant mortality and
morbidity; in a systematic review and meta-analysis published in 2014, the risk of death among children
aged 0–14 years with TBM was estimated at 19.3% and the risk of neurological sequelae among TBM
survivors was estimated at 36.7% (64). Even among children without severe neurological sequelae,
attention deficit and behavioural disorders are common and the human cost and financial burden for
families and society are high. Diagnosis in the most advanced clinical stage, which occurred in almost
50% of children with TBM, was associated with worse outcomes based on the findings of the review.
WHO currently recommends a regimen of 12 months duration to treat TBM, consisting of isoniazid,
rifampicin, ethambutol and pyrazinamide given daily for the first 2 months, followed by isoniazid
and rifampicin given daily for 10 additional months (2HRZE/10HR) (8, 56). Recommended doses to
be used in this regimen are the same as those for the treatment of PTB (8).
The recommendation on the use of the 12-month regimen was based on a literature review (65)
and was first included in the 2010 Rapid advice: treatment of TB in children (56). This review included
46 studies with information on the efficacy of different regimens and dosages for the management
of TBM (25 studies included paediatric data and 21 included data on both adults and children). The
majority of these studies were non-randomized, non-comparative studies. The quality of the studies
ranged from low to very low and no clear conclusions could be drawn from the efficacy studies, given
that they differed widely in terms of design, drugs used and patient populations. None of the studies
from this review were entered into GRADE, given the lack of comparative data.
Shorter regimens to treat paediatric TBM are used in some settings. The South African National
TB Guidelines recommend a regimen composed of daily isoniazid, rifampicin, pyrazinamide and

ethionamide, given for 6 months (6HRZEto) (66). The recommendations in South Africa are based on
expert opinion, in particular with regards to replacing ethambutol with a drug (ethionamide) that has
more efficient blood-brain barrier penetration (65). A clinical trial is underway to compare a regimen
consisting of higher-dose isoniazid, higher-dose rifampicin, pyrazinamide and levofloxacin given
daily for 6 months, compared to the WHO-recommended regimen, but the results are not expected
until 2023 (SURE trial, ISRCTN40829906). Shorter regimens may be as effective and safe, and may
improve adherence and reduce the burden on persons with TBM and health care systems, but it is
not known how outcomes compare between the shorter regimens and the WHO-recommended
12-month regimen.
PICO question: In children and adolescents with presumed or bacteriologically confirmed drug-
susceptible TB meningitis, should a 6-month intensive regimen, compared to the 12-month regimen
that conforms to WHO guidelines be used?
Evidence: To inform recommendations on the treatment for child and adolescent TBM, a systematic
review and meta-analysis was conducted to compare the effectiveness of shorter regimens versus
the current WHO-recommended 12-month regimen (8). The primary intervention of interest was the
regimen currently used in South Africa (66); in secondary analyses, outcomes associated with other
shorter regimens were examined. The search criteria from an earlier systematic review and meta-
analysis conducted in 2014 were updated and the search was run in February 2021 (64). Studies with
available information on at least the composition and duration of treatment regimens were included.
Ineligible regimens included those without rifampicin, treatment regimens with a duration over 12
months other than the WHO regimen, intermittent regimens and non-intensive short regimens. Pooled
proportions were estimated across studies and within regimens through aggregate-level meta-analysis
using GLMM with Gauss-Hermite quadrature for the following outcomes: death by end of treatment;
loss to follow-up; treatment success; neurological sequelae (among survivors); and survival without
neurological sequelae (among those starting treatment). Subgroup analyses were planned but were
not feasible, due to insufficient data.
Of the 1820 unique citations screened, 149 full text papers were evaluated. Of these, five met inclusion
criteria for the systematic review. In addition, two unpublished cohorts were eligible for inclusion. In
total, four studies of intervention regimens (three published and one unpublished) (67–70), and three
studies of the comparator regimen (two published and one unpublished) (71–73) were identified. No
studies performing head-to-head comparisons of regimens were identified. Three of the four studies
of intervention regimens were conducted in a single referral centre in South Africa. As only one study
reported on outcomes from an 8-month regimen in Vietnam (69), it was excluded from the meta-
analysis. The two published studies of the comparator regimen were conducted at different sites in
India (71, 72), while data for the unpublished study were collected in various centres in Europe through
the Pediatric Tuberculosis Network European Trials Group (ptbnet) (73). A total of 837 patients with
TBM received intervention regimens with the median age in each study ranging from 2.3 to 5.5 years
(age range: 2 months to 15 years). Among the 282 patients treated with the comparator regimen,
the median age in the European study was 3.3 years, while summary data on age were not reported
in the studies from India.
The cumulative number of deaths was recorded at the end of treatment for each regimen (i.e. at 6
months after treatment initiation in studies of the intervention regimen; at 12 months after treatment
initiation in studies of the comparator regimen). Among studies of the intervention regimen, 0.0%–
9.6% of patients died within six months; most deaths occurred early after hospital admission and
primarily involved patients diagnosed in stage 3 at baseline. Among studies of the comparator
regimen (i.e. the standard of care), 7.1%–30.0% of patients died. In one of these studies, diagnosis
at stage 3 was most strongly associated with mortality, although stage-specific outcome data were
not reported. In a random effects meta-analysis, the pooled proportions of deaths were 6.0% (95%
confidence interval [CI] 2.0–13.0) and 24.0% (95% CI: 18.0–32.0) for children and adolescents who
received the intervention and comparator regimens, respectively. The percentage of patients with
treatment success were 78.5%–100.0%, with a random effects pooled proportion of 95.0% (95% CI:
74.0–99.0) among studies of the intervention regimen, and 70%–85.7%, with a random effects pooled
proportion of 75.0% (95% CI: 69.0–81.0) among studies of the comparator regimen. Neurological
sequelae were defined and assessed differently across studies. Among patients treated with the
intervention regimen, 50.0%–66.7% had neurological sequelae, mostly categorized as mild. The
vast majority of these were among patients diagnosed at stage 2 or 3. Among patients treated with
the comparator regimen, 31.9%–50.0% had neurological sequelae. In one study on the comparator
regimen from India, 17 of 29 (58.6%) cases were categorized as mild. The random effects pooled
proportions of neurological sequelae among survivors were 66.0% (95% CI: 55.0–75.0) and 36.0%
(95% CI: 30.0–43.0) for the intervention and comparator regimens, respectively. Among the 135 HIV-
negative and 13 HIV-positive patients who received the intervention regimen in South Africa, none
relapsed within two years of post-treatment. Other studies did not report on relapse.
Because of the non-comparative nature of the studies, which were all observational, narrative
descriptions reporting pooled proportions were provided rather than estimated measures of effect.
The certainty of evidence was deemed to be very low for all outcomes due to very serious risk of
bias, serious or very serious inconsistency within regimens, and very serious indirectness. Imprecision
could not be assessed due to the lack of comparative data.
The reviewers concluded that pooled estimates need to be interpreted with caution considering
the small number of studies, the potential for confounding by indication, other potential residual
confounding and between-study heterogeneity regarding the assessment of neurological sequelae.
GDG considerations: While the GDG members discussed evidence of benefits of the intervention
regimen and biological plausibility, they noted the very low certainty of the data. The GDG members
decided to choose that the balance of effects ‘does not favour either the intervention or the
comparison’. This decision reflects that both the desirable and undesirable effects varied, as well as
the very low certainty of the evidence overall. Recognizing how quickly the condition of children with
TBM can deteriorate, GDG members were not comfortable favouring one regimen over the other,
based on the very low certainty of the data.
The GDG members also noted that the feasibility of introducing the shorter intensive regimen
is dependent on the setting. Acceptability, affordability and access to the component medicines
(including the child-friendly ethionamide formulation, a 125 mg dispersible tablet) are important
contextual factors as well as any additional implementation considerations such as the necessity and
availability of monitoring tests that are needed with the shorter regimen. GDG members thought that
the short intensive regimen would probably be acceptable as it includes medicines that have been in
use for many years, including first line medicines and ethionamide. The intervention regimen is more
costly than the comparator regimen, but refers to the costs of medicines only; GDG members stated
that other costs (including to patients, families and the health system) were important.
The GDG acknowledged the limited data on alternative regimens to treat TBM and the need
for continued efforts to optimize and better understand treatment options for TBM, including
implementation considerations, such as dosing.

Children living with HIV infection: Most studies in the review were restricted to HIV-negative
children. HIV-positive children represented a small proportion of children with TBM overall, and all
received the intervention regimen. In the three studies using the intervention regimen included in
the evidence review, 11 children were identified as having HIV infection (of a total of 724 children).
Therefore, it was not possible to undertake analyses stratified by HIV infection. An additional small
study of 13 children from South Africa used an extended duration of the intervention regimen (i.e.
9 months of HRZEto). Therefore, the recommendation on the 6-month regimen does not apply to
HIV-infected children who are diagnosed with TBM.

Adolescents: The population in the PICO question included both children (aged 0–9 years) and
adolescents (aged 10–19 years). Based on the available information in the studies the median age of
patients in the three studies using the intervention regimen were: 35 months (range: 2 months–14
years), 28 months (range: 2 months–15 years) and 30 months (5–82 months). In the studies using the
comparator regimen, the age structure reported in two of the three studies was: <18 years and 3.3
years (range: 1–16 years). This recommendation therefore applies to both adolescents and children.
Other subgroup analyses: Several subgroup analyses were pre-planned by the systematic reviewers
(including subgroup analyses by: age group, for patients with DR-TB (including isoniazid-resistant
TB), for patients who were microbiologically confirmed versus those clinically diagnosed, by Medical
Research Council stage at diagnosis, and for patients with complications including tuberculoma and
hydrocephalus). However, these analyses could not be conducted due to insufficient data.

One key implementation consideration is the administration of the intervention regimen with the
correct dosages of the included medicines, using currently available child-friendly formulations,
including FDC formulations when possible. The regimen includes isoniazid, rifampicin, pyrazinamide
and ethionamide, and is dosed as follows:
• Isoniazid: 20 mg per kg, maximum 400 mg daily
• Rifampicin: 20 mg per kg, maximum 600 mg daily
• Pyrazinamide: 40 mg per kg, maximum 2000 mg daily
• Ethionamide: 20 mg per kg, maximum 750 mg daily
Historically, the regimen was dosed using a child-friendly FDC (dispersible tablet) of isoniazid and
rifampicin (60 mg/60 mg) with pyrazinamide and ethionamide added as single medicines. This 60/60
mg FDC has limited availability globally, while a 50/75 mg isoniazid/rifampicin dispersible tablet is
widely available through the Stop TB Partnership Global Drug Facility in over 100 countries (at the
time of the GDG meeting). Using this formulation, rifampicin is dosed at slightly higher mg per kg
doses as the drug ratio between isoniazid and rifampicin is 1:1.5 in the formulation. Higher doses of
rifampicin are being used in several other trials including the SURE trial, TBM Kids and OptiRif Kids.
Results from the SURE trial and TBM Kids are expected in the coming years while the results from
the OptiRif Kids trial (74) were published after the GDG meeting. The dosing of the shorter intensive
regimen was the subject of an expert consultation convened by the WHO after the GDG meeting
and information on dosing for this regimen is included in the Operational Handbook.
A dispersible paediatric formulation of ethionamide (125 mg) has been available from the Stop
TB Partnership GDF since March 2018. Although orders for ethionamide are received from high
MDR-TB burden countries consistently (this formulation was supplied by GDF to 41 countries between
2019 and 2021 at the time of the GDG meeting), the GDG members discussed that the paediatric
formulation of ethionamide may not be available in all countries or health care levels where it is
needed. Ethionamide is a component of the shorter all-oral bedaquiline-containing regimens to
treat MDR/RR-TB; however, at the time that the GDG meeting was held (May-June 2021) the shorter
regimen was only recommended for children aged 6 years and above.
The GDG members also noted that this regimen should ideally be used in children with TBM that is
bacteriologically confirmed as drug susceptible. However, it can also be used for children who are
clinically diagnosed, but there should be no suspicion of DR-TB, such as in children or adolescents
who have a history of contact with a patient with confirmed DR-TB (including isoniazid resistance,
rifampicin resistance or multi-drug resistance). In countries or areas with a high background prevalence
of DR-TB and where ethionamide is in use to treat DR-TB, programmes and clinicians need to consider
the risks and benefits of using this regimen. The current recommendation for the diagnosis of TBM is
that in adults or children with signs and symptoms of TBM, Xpert MTB/RIF or Xpert Ultra should be
used in cerebrospinal fluid as the initial diagnostic test rather than smear microscopy/culture (strong
recommendation, moderate certainty of evidence for test accuracy for Xpert MTB/RIF; low certainty
of evidence for test accuracy for Xpert Ultra (16).

Implementation of this recommendation should be subject to ongoing monitoring and evaluation
to ensure high quality implementation adapted to the local context. Uptake of the regimen and
monitoring of treatment outcomes among patients who receive this regimen are also of interest.
The overall incidence of TBM as a form of EPTB in children and adolescents reflects the ongoing
transmission of TB to children, as well as delays in the diagnosis of TB and is therefore important
information to monitor as well.
5.3. Treatment of multi-drug and rifampicin resistant

TB in children
Around 25 000–32 000 children are estimated to develop MDR/RR-TB every year (75–77). In 2018,
3398 children (aged below 15 years) were started on second-line treatment for MDR/RR-TB. After
increasing to 5586 in 2019, due to the impact of the COVID-19 pandemic, this number dropped back
to 3234 in 2020, representing only 2.5% of the total number of persons with MDR/RR-TB initiated on
treatment and only 10.1%–12.9% of the estimated number of children with incident MDR/RR-TB (78).
Treatment outcomes reported in a systematic review and individual patient data meta-analysis
conducted for the 2018 WHO DR-TB treatment guidelines, showed an overall successful treatment
outcome of 78% in children treated for MDR-TB (75% of confirmed and 89% of clinically diagnosed
children) (79). Appropriate treatment of children with MDR/RR-TB with a WHO recommended regimen
is an important step in ensuring a successful treatment outcome, as well as preventing the acquisition
of further drug resistance. Other measures to prevent drug resistance or limit its spread include
treatment of drug-susceptible TB with a WHO recommended regimen (to avoid misuse or overuse
of antibiotics), infection prevention and control, the use of WHO recommended molecular diagnostic
tests and patient support. Recommendations on each of these areas are included in this consolidated
guideline and on the WHO TB KSP. The implementation and use of new molecular diagnostic tools,
treatment decision algorithms and WHO recommended treatment regimens are vital components
to ensure antimicrobial stewardship.

5.3.1. The use of bedaquiline in children with MDR/RR-TB aged
below 6 years
Recommendation
In children with MDR/RR-TB aged below 6 years, an all-oral treatment regimen containing
bedaquiline may be used (conditional recommendation, very low certainty of the evidence).
Remarks
• This recommendation applies to and complements current WHO recommendations on shorter
and longer regimens that contain bedaquiline (9):
‒ A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended
in eligible patients with confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/
RR-TB) who have not been exposed to treatment with second-line TB medicines used in
this regimen for more than 1 month, and in whom resistance to fluoroquinolones has been
excluded. (Conditional recommendation, very low certainty in the evidence)
‒ Bedaquiline should be included in longer multidrug-resistant TB (MDR-TB) regimens
for patients aged 18 years or more. (Strong recommendation, moderate certainty in the
estimates of effect)
‒ Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6–17 years.
Justification and evidence

PICO question: In MDR/RR-TB patients aged below 6 years, should an all-oral treatment regimen
containing bedaquiline versus other regimens conforming to WHO guidelines without bedaquiline
be used?
Historical context: In 2012, for the first time in over 40 years, a new TB drug with a novel mechanism
of action – namely bedaquiline – was granted accelerated approval by the United States Food and
Drug Administration (US-FDA) for the treatment of MDR-TB among adults (≥18 years of age) for
whom an effective treatment regimen was not otherwise available (80). In 2013, following an expert
group meeting which reviewed available Phase IIb trial data on the efficacy and safety of bedaquiline,
the WHO issued an interim policy guidance comprising a conditional recommendation and based on
very low confidence in the estimates of effect, indicating that bedaquiline may be added to a WHO-
recommended regimen in adults with MDR-TB (≥18 years of age) under specific conditions (81).
In 2016, after the introduction and roll-out of bedaquiline in an increasing number of countries and
with more data available on its use, the WHO convened a GDG meeting to re-evaluate the added
benefit of bedaquiline in conjunction with a WHO-recommended longer regimen for the treatment
of MDR-TB. At this time, the GDG agreed that there was not enough evidence to prompt a change
in the 2013 recommendation (82).
In 2019, after a GDG meeting where new evidence was reviewed from the adult IPD and two ongoing
paediatric studies (TMC207-C211 and IMPAACT P1108), WHO issued the consolidated guidelines
on DR-TB treatment (83), where bedaquiline was recommended for inclusion in longer MDR-TB
regimens for persons aged 18 years or more (strong recommendation, moderate certainty in the
estimates of effect) and in longer MDR-TB regimens for children and adolescents aged 6–17 years
(conditional recommendation, very low certainty in the estimates of effects). Also in 2019, following
the review of available data on the programmatic implementation of a shorter, all oral treatment
regimen including bedaquiline in South Africa, the WHO recommended a shorter, all-oral bedaquiline
containing regimen of 9–11 months for eligible persons with confirmed MDR/RR-TB who were not
exposed to treatment with second-line TB medicines used in this regimen for more than 1 month,
and in whom resistance to fluoroquinolones was excluded (conditional recommendation, very low
certainty in the evidence) (9). This recommendation on the shorter all-oral bedaquiline-containing
regimen replaced earlier recommendations on shorter regimens which contained an injectable agent.
In a new IPD meta-analysis used as evidence for the 2020 WHO guidelines, bedaquiline use resulted
in significantly fewer episodes of treatment failure, relapse and death (84). At the time, there was
limited experience in the use of bedaquiline in children aged under 6 years, but experience of
its use in adolescents, patients with EPTB disease and people living with HIV was growing. Earlier
recommendations on the composition of longer regimens indicated that bedaquiline could also be
included in such regimens for patients aged 6–17 years; hence, the all-oral bedaquiline-containing
regimen was also conditionally recommended for use in eligible children and adolescents aged 6
years and above.
Gap: The recommendations that apply to children were based on extrapolation of efficacy data in
adults, in combination with PK and safety data from phase II trials in children aged 6–17 years. However,
a recommendation on the use of bedaquiline in children aged less than 6 years was not possible
in the past, due to a lack of evidence, particularly on PK, safety and tolerability. The medicines that
compose the shorter all-oral bedaquiline-containing regimen have been part of MDR-TB regimens
for many years, in similar combinations, for both adults and children. The associated adverse drug
reactions have been widely described and the drug dosages established. This however did not apply
to bedaquiline at the time of the 2019 GDG on DR-TB, and the use of bedaquiline for young children
in both shorter and longer regimens was therefore identified as a gap to be addressed as part of the
2021 update of the child and adolescent TB guidelines.
Evidence: To answer the PICO question on the use of bedaquiline in children under the age of 6
years, data from two phase II trials (TMC207-C211 and IMPAACT P1108) were reviewed by the GDG.
TMC207-C211 is a phase II, open-label, single-arm study to evaluate the PK, safety, tolerability and
anti-mycobacterial activity of bedaquiline in combination with a background regimen of MDR-TB
medications for the treatment of children and adolescents 0–17 years of age who have bacteriologically
confirmed or clinically diagnosed pulmonary and selected forms of extrapulmonary MDR-TB.32
IMPAACT P1108 is a phase I/II dose finding modified age de-escalation study to evaluate the PK,
safety and tolerability, of bedaquiline in combination with optimized individualized MDR-TB regimens
in HIV-infected and HIV-uninfected children with clinically diagnosed or confirmed pulmonary (intra-
thoracic) and selected forms of extrapulmonary MDR-TB.33
As data reviewed from TMC207-C211 corresponded to children aged 5–18 years and that from
IMPAACT P1108 included children aged 0–6 years, the review of PK and safety data focused mainly
on data from IMPAACT P1108. Although the sample size of the available interim data for review was
small (N= 12), the GDG concluded that in children 0–6 years of age, cardiac safety signals were not
distinct from those reported in adults. Population PK models from both studies suggest that drug
exposures observed in adults can be reached in most children receiving bedaquiline, although some
dose modification may be necessary depending on the age and weight of the child.
In addition, data from a paediatric MDR/RR-TB IPD were analysed descriptively (24 231 records from
all six WHO regions, the majority from India and South Africa). The search was conducted in April
2020. Just under 20 000 of these records were used for a matched analysis of treatment outcomes in
children being treated for DR-TB. The analysis included 40 children aged below 6 years and 68 children
aged 6–12 years who received bedaquiline. In the matched analysis, bedaquiline was significantly
associated with shorter treatment duration and a lower adjusted odds ratio of injectable TB drug use.
There was no statistically significant difference in successful treatment outcomes between children
aged less than 6 years receiving an all-oral bedaquiline-based regimen versus those not receiving
32
Pharmacokinetic study to evaluate anti-mycobacterial activity of TMC207 in combination with background regimen (BR) of multidrug
resistant tuberculosis (MDR-TB) medications for treatment of children/adolescents pulmonary MDR-TB (https://clinicaltrials.gov/ct2/
show/NCT02354014, accessed 21 January 2022).
33
P1108. A Phase I/II, open-label, single arm study to evaluate the pharmacokinetics, safety and tolerability of bedaquiline (BDQ) in
combination with optimized individualized multidrug-resistant tuberculosis (MDR-TB) therapy in HIV-infected and HIV-uninfected
infants, children and adolescents with MDR-TB disease (https://www.impaactnetwork.org/studies/p1108, accessed 21 January 2022).

bedaquiline (89% versus 97%, p=0.9). Residual confounding (including confounding by indication)
was thought to be likely.
A child-friendly formulation of bedaquiline (20 mg scored uncoated tablet) is being used in the Janssen
C211 study to dose children aged below 5 years and will also soon be used in an updated protocol
of IMPAACT study P1108 (this study has used the 100 mg formulation to date in all age groups). No
head-to-head studies were conducted to examine the bioequivalence of the 20 mg and the 100 mg
formulation of bedaquiline. Indirect bioequivalence testing showed that both tablets have the same
bioavailability and can be used interchangeably at the same total dose. Findings from the bedaquiline
crush study (85) also showed that bioavailability of bedaquiline tablets suspended in water was the
same as for tablets swallowed whole.
GDG considerations: The GDG discussed the desirable effects that were previously reported and
noted that including bedaquiline in all-oral regimens for children will allow the construction of regimens
that are more child- and family-friendly, with shorter durations (as shown by the IPD analysis, where
bedaquiline-containing regimens were usually shorter than those not including bedaquiline). The
GDG rated the desirable effects as moderate. The main concern noted by the panel was the lack of
data on long-term safety and adverse events. However, the GDG noted that clinical experience with
using bedaquiline in young children showed that the drug is tolerated well and often better than in
the adult population. Therefore, the GDG agreed that the undesirable effects were small. Overall,
the GDG determined that the balance between desirable and undesirable effects probably favours
the use of bedaquiline in children aged below 6 years. The GDG highlighted that the benefits may
vary depending on specific contexts and population characteristics, such as by nutritional status. The
GDG also noted that the potential higher cost of bedaquiline in an MDR/RR-TB treatment regimen
should be considered in the context of the benefits of shorter injectable free regimens (i.e. less travel,
reduced time spent in clinics and fewer adverse events). In addition, they judged that equity might
increase when bedaquiline becomes available to younger children, as its use would be acceptable to
the majority of stakeholders, and that one of the main feasibility aspects would be related to the need
for safety monitoring (i.e. access to ECG monitoring, as well as staff capacity for monitoring). However,
the panel judged that the use of bedaquiline in young children was probably feasible to implement.
Subgroup considerations
Children living with HIV: While trial TMC207-C211 has not yet enrolled children living with HIV, the
IMPAACT study P1108 study enrols HIV-infected and HIV-uninfected infants, children and adolescents
with MDR-TB disease (of the nine children aged below 6 years enrolled and with PK data at the time
of the GDG report, one was HIV-infected). In the paediatric IPD, 12 of the 40 children (30%) aged
below 6 years treated with a bedaquiline-containing regimen were HIV positive, as compared to 364
out of 1992 (20%) treated with DR-TB regimens not including bedaquiline.
The composition of treatment regimens for MDR/RR-TB does not usually differ substantially for people
living with HIV; bedaquiline may be used in all children, irrespective of HIV status. Known drug-drug
interactions, such as between bedaquiline and efavirenz, need to be avoided.
Extrapulmonary TB: The shorter, all oral bedaquiline-containing regimen is contraindicated in
children with extrapulmonary forms of TB other than TB lymphadenopathy (see implementation
considerations for the full eligibility criteria). Children with these forms of EPTB should be treated
with longer regimens, composed of medicines from groups A, B and C (9). Data on the penetration
of bedaquiline across the blood-brain barrier are sparse.
Implementation considerations
Eligibility for the shorter, all-oral, bedaquiline containing regimen: The removal of the age
restriction for the use of bedaquiline means that children of all ages with confirmed MDR/RR-TB and
without fluoroquinolone resistance may be offered the shorter, all-oral regimen with bedaquiline,
if they meet the eligibility criteria. This regimen is composed of bedaquiline (used for 6 months),
in combination with levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose),
pyrazinamide and clofazimine for four months (with the possibility of extending to 6 months if the
patient remains sputum smear positive at the end of four months); followed by 5 months of treatment
with levofloxacin/moxifloxacin, clofazimine, ethambutol and pyrazinamide. The eligibility criteria are:
• No extensive TB disease
• No severe EPTB (any forms other than TB lymphadenopathy)
• No resistance or suspected ineffectiveness of a medicine in the shorter regimen (except
isoniazid resistance)
• No exposure to previous treatment with second-line medicines in the regimen for more than one
month (unless susceptibility to these medicines is confirmed).
Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive
parenchymal damage on CXR in adults. In children aged under 15 years, advanced disease is usually
defined by the presence of cavities or bilateral disease on CXR. Severe EPTB refers to the presence of
miliary TB or TBM (i.e. disseminated disease) (61). In children aged under 15 years, extrapulmonary
forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without
compression) are considered as severe (86). The shorter regimen should not be used in the presence
of mutations in both the inhA promoter and katG on first-line LPA (MTBDRplus) in the child as this
suggests that both isoniazid at high dose and thioamides are not effective (87).
Promoting the use of bedaquiline in all-oral regimens for children will allow the construction of
regimens that are more child- and family-friendly and shorter, which may reduce the use of second-line
drugs with potentially more severe adverse events compared to bedaquiline (including, but not limited
to injectables). Implementation of shorter, all-oral regimens may also facilitate the implementation
of DR-TB treatment at peripheral levels of the health care system. NTPs and clinicians are therefore
discouraged from using injectable agents as part of treatment regimens for MDR/RR-TB in children
of all ages.
Regimen building for children not eligible for the shorter all-oral bedaquiline-containing
regimen: Children who do not have bacteriological confirmation of TB and/or resistance patterns but
who have a high likelihood of MDR/RR-TB (based on clinical signs and symptoms of TB, in combination
with a history of contact with a patient with confirmed MDR/RR-TB) are eligible to receive bedaquiline
as part of their treatment regimen. However, they do not meet the eligibility criteria for the shorter
all-oral bedaquiline-containing regimen, as this regimen may only be used in people with TB with at
least confirmation of rifampicin resistance in whom resistance to fluoroquinolones has been ruled out
(84). These children will benefit from an individualized longer treatment regimen, taking into account
the drug susceptibility (and/or mutation) pattern of the most likely source case, if this information is
available. Treatment duration will depend on the extent and severity of disease, as well as the response
to treatment. Shortening the total treatment duration to less than 18 months may be considered in
children without extensive disease (61). Children with a diagnosis of rifampicin resistance only without
further DST (such as a child diagnosed with Xpert MTB/RIF or Xpert Ultra testing on a stool sample
but no further DST on respiratory samples) could be treated with available bedaquiline-containing
regimens at the discretion of the treating clinician.
Guidance on how to construct optimal all-oral treatment regimens in children with MDR/RR-TB who
are not eligible for the shorter, all-oral bedaquiline-containing regimen is provided in the operational
handbook, considering their age, resistance patterns in the child or most likely source case and extent
of TB disease. The construction of these treatment regimens is aligned to the WHO consolidated
guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment, the priority
drug groupings in groups A, B and C as well as the minimum number of effective drugs required (61).
Duration of bedaquiline use: Evidence assessed by a GDG in November 2019 supported the
safe use of bedaquiline beyond 6 months in people with TB who received appropriate schedules

of baseline and follow-up monitoring. However, at that time the GDG was not able to assess the
relative effectiveness of prolonged bedaquiline use, owing to limited evidence and potential residual
confounding in the data. The regimen needs to have at least three effective agents if bedaquiline is
stopped at six months; thus, if after 6 months, one of the three remaining agents needs to be stopped
because of toxicity, then it needs to be replaced. The replacement medicine would be chosen from
either group B (unless both clofazimine and cycloserine or terizidone are already included) or group
C. The choice from group C is determined by the order in which the medicines are ranked, and the
individual circumstances of the patient and setting (9).
Concurrent use of bedaquiline and delamanid: The GDG held in November 2019 found insufficient
evidence to allow for a statement about the effectiveness of concurrent use of both medicines.
However, the group concluded that the safety data assessed in 2019 suggest no additional safety
concerns with regard to the concurrent use of bedaquiline and delamanid. Therefore, bedaquiline and
delamanid may be used in people with MDR/RR-TB who have limited options for other treatment,
i.e. for those with an insufficient number of other effective drugs included in their regimen, such
as due to an extensive drug-resistance profile or intolerance to other second-line TB medications.
Appropriate schedules of safety monitoring (at baseline and throughout treatment) should be in
place for these people with TB, including ECG and electrolyte monitoring, and clinicians should be
cognizant of other medicines in the regimen that can either prolong the QT interval or cause other
potential adverse events (9).
MDR/RR-TB case detection in children: Efforts to implement child-friendly DR-TB regimens including
bedaquiline should be implemented in parallel with increased efforts at the country level to close the
case detection gap. Evidence-based, integrated treatment decision algorithms (see chapter 4) that are
specific for different settings with varying access to diagnostic tests and CXR, apply to children with
presumptive MDR/RR-TB as well, and need to be widely implemented to ensure that MDR/RR-TB is
detected and effectively treated among children.
Administration of bedaquiline: Dosing guidance for the use of bedaquiline in children below 6
years of age is provided in the operational handbook, based on an expert consultation on dosing
that was conducted as a follow up to the GDG meeting. The guidance takes into account the child-
friendly formulation of bedaquiline that was approved by the US FDA in May 2020 and has been
available from the Stop TB Partnership GDF since June 2020, namely a 20 mg scored tablet which can
be taken whole or dispersed in water for patients who have difficulty swallowing intact tablets. This
formulation of bedaquiline has been included in the 8th WHO Essential Medicine List for Children
(EMLc), released in October 2021 (88). To aid with administration, the dispersed mixture in water can
be further mixed with a beverage or soft food or crushed and mixed with soft food immediately prior
to its use and administered (see below for more details). It should also be noted that the findings from
the bedaquiline crush study showed that bioavailability of bedaquiline tablets suspended in water
was the same as for tablets swallowed whole (85). Therefore, if the 20 mg formulation of bedaquiline
is not available, the crushed 100 mg formulation dissolved in water can be used to dose younger
children without compromising bioavailability.
Concomitant food intake is an important factor to consider when evaluating bioavailability. Bedaquiline
bioavailability was optimized in the trials when co-administered with a high-fat meal. In practice,
feeding frequency needs to be considered. In infants, feeding frequency is higher and favours the
administration with high-fat meals, but it should also be considered that buffering capacity increases
with increased feeding frequency. The paediatric bedaquiline formulation can be prepared and
administered with a variety of foodstuffs (including water, milk products, apple juice, orange juice,
cranberry juice, carbonated beverages, yoghurt, apple sauce, mashed banana and porridge) to
improve palatability. The formulation is also stable for eight hours if the preparation is stored in a
syringe. It should ideally be taken with a high-fat meal, and administration on an empty stomach
should be avoided as bedaquiline drug exposures are reduced.
Clinical monitoring: The risk of emergence of bedaquiline resistance should be a key consideration
when the drug is being used. Due to the difficulties in obtaining a suitable specimen from children
aged below 6 years, performing DST may be challenging. However, if there are concerns about
acquired drug resistance, every effort should be made to obtain a suitable sample, such as gastric
aspirate, sputum induction or NPA (stool is not a suitable sample for conducting DST).
In the IMPAACT P1108 study, none of the children aged below 6 years had QT prolongation in any
of the categories of 60 milliseconds and above. Almost all children also received clofazimine. Three
children (of 11; 27%) experienced QT prolongation of 30–60 milliseconds, which was described as mild
and insignificant. In general, the use of bedaquiline in populations with underlying cardiac conduction
abnormalities and concomitant medications that prolong QTc needs to be carefully considered. A
major implementation consideration includes the need for safety monitoring, as well as the need to
build staff capacity (training, capacity building) to ensure that appropriate safety monitoring is put in
place. Additional costs associated with wider implementation of bedaquiline (in addition to the higher
cost of the drug), include availability of ECG machines, appropriate monitoring and trained staff to
perform these activities. However, the GDG felt that savings related to potential shorter treatment
duration as well as the avoidance of additional resource requirements related to injectable use (such
as for monitoring with audiometry and implications for child development), outweigh the costs of
bedaquiline introduction and implementation.
Adaptation of the recommendation to the local context will require staff capacity building and training,
followed by supportive supervision and mentoring. Implementing all-oral treatment regimens will
facilitate decentralization of MDR-TB treatment services and may therefore improve access to patient-
centred care.
Monitoring and evaluation

People with TB, including children who receive a shorter or longer MDR-TB treatment regimen
need to be monitored for response to treatment and for safety during treatment using schedules
of relevant clinical and laboratory testing. This has been successfully applied in previous studies of
shorter regimens under field conditions and in the programmatic setting in South Africa.
The WHO framework for active drug safety monitoring (89) needs to be applied to people with TB
on any type of MDR-TB regimen, to ensure appropriate action and an acceptable level of monitoring
for and prompt response to adverse events – alongside monitoring for treatment outcomes.
Electrocardiography is indicated for children on regimens with two or three agents that are expected
to prolong the QT interval. Specific biochemical tests should also be made available according to the
agents included in the regimens.
In children, smear and culture monitoring of the response to treatment may be challenging, due to
difficulties in obtaining appropriate specimens for testing. However, in children with a bacteriologically
confirmed diagnosis, all reasonable efforts should be taken to demonstrate bacteriological conversion.
Once cultures have become negative or in children who never had a confirmed diagnosis, repeated
respiratory sampling may not be useful if the child is otherwise responding well clinically. Resolution
of clinical symptoms and weight gain can be used as indicators of improvement. All children should
have regular clinical follow-up, including weight and height monitoring. Drug dosages should be
adjusted with weight gain, as needed.
Recording and reporting of details on the diagnosis, treatment regimens, clinical monitoring and
treatment outcomes of children and adolescents with MDR/RR-TB is important to monitor the
programmatic implementation of newly recommended regimens as well as efforts to improve case
finding of children with DR-TB. Data from national programmes on the use of bedaquiline in children
of all ages is important to increase the evidence base.

5.3.2. The use of delamanid in children with MDR/RR-TB aged
below 3 years
Recommendation
In children with MDR/RR-TB aged below 3 years delamanid may be used as part of longer
regimens (conditional recommendation, very low certainty of evidence).
Remarks
• This recommendation complements the current WHO recommendation on longer regimens
that contain delamanid (9):
– Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more
on longer regimens (conditional recommendation, moderate certainty in the estimates of
effect).
Justification and evidence

PICO question: In MDR/RR-TB patients aged below 3 years, should an all-oral treatment regimen
containing delamanid versus other regimens conforming to WHO guidelines without delamanid
be used?
Historical context In 2014, the European Medicines Agency granted a conditional marketing
authorization for delamanid for the treatment of adults (≥18 years of age) with pulmonary infections
due to MDR-TB when an effective treatment regimen could not otherwise be devised for reasons of
resistance or tolerability (90). In the same year, following a WHO convened expert group meeting
that reviewed available data on efficacy and safety of delamanid, the WHO issued an interim policy
guidance comprising a conditional recommendation based on very low confidence in estimates of
effect, indicating that delamanid may be added to a WHO-recommended regimen in adults (≥18
years of age) with pulmonary MDR-TB (91).
In 2016, given more available data on the use of delamanid in children diagnosed with MDR-TB,
the WHO convened another expert panel to assess new data and develop an addendum to the
2014 interim guidance on delamanid, with specific recommendations for children with MDR-TB.
Based on the assessment of this evidence and recommendations from the expert panel, the WHO
recommended that delamanid may be added to the WHO-recommended longer regimen in children
and adolescents (6–17 years) (conditional recommendation, very low confidence in estimates of
effect) (92). The WHO interim guidance on delamanid was based on data from phase I and phase II
clinical trials (trials 242–12–232 and 242–12–233) and the results of other earlier studies. The use of
delamanid was conditionally approved by the WHO given the limited alternative treatment options
for people with MDR-TB, on the basis that the potential benefits probably outweighed the potential
risks. The WHO recommendations were also conditional upon longer-term effectiveness and safety
data becoming available in subsequent years, especially from phase III randomized controlled trials.
In 2016, the WHO convened a GDG meeting where the added benefit of delamanid was re-evaluated
in conjunction with a WHO-recommended longer regimen for the treatment of MDR-TB but at that
time, the GDG agreed that there was not enough evidence to prompt a change in the recommendation
included in the interim guidance (93). In 2019, after convening a GDG meeting where newly available
evidence from ongoing delamanid studies was reviewed, WHO issued the consolidated guidelines
on DR-TB treatment (83). With respect to the use of delamanid in children younger than 6 years,
the GDG judged that on the basis of findings in adults and on the pharmacological and safety data
reviewed, extrapolations on efficacy should be restricted to children aged 3–5 years but not to
children younger than 3 years, pending further evidence. Exposure profiles of children 3–5 years of
age were comparable to adults and no higher than in children aged 6 years and older, for whom
past GDGs convened by the WHO had already recommended the use of delamanid. Additionally,
based on the laboratory and cardiac data provided, no safety signals distinct from those reported
in adults were observed in children aged 3–5 years. Based on this, the WHO recommended that
delamanid may be included in the treatment of MDR/RR-TB for children aged 3 years or more on
longer regimens (conditional recommendation, moderate certainty in the estimates of effect); and
in the priority grouping of medicines for use in longer regimens it was classified as a group C drug
(83). The 2019 GDG nonetheless had concerns about the feasibility of administering the correct
dose to children aged 3–5 years, given that the only tablet available at the time was the one used
for adults (i.e. 50 mg), which presents challenges in manipulating its contents without compromising
its effectiveness. Subsequent reviews of the WHO guidelines in 2020 did not prompt any change in
the 2019 recommendation, which was the one in place at the time of the GDG meeting on child and
adolescent TB during May-June 2021.
Gap: The recommendations that apply to children were based on extrapolation of efficacy data
in adults, in combination with PK and safety data from phase II trials for children aged 3–17 years.
However, a recommendation on the use of delamanid in children aged less than 3 years has not been
possible in the past, due to a lack of evidence, particularly on PK, safety and tolerability. This has made
it challenging for clinicians to design all-oral regimens for children under the age of 3 years, especially
for children with (or a source case with) fluoroquinolone resistance, where choices are limited among
group A and B drugs. The use of delamanid in children below 3 years of age was therefore identified
as a gap to be addressed as part of the 2021 update of the child and adolescent TB guidelines.
Evidence: To answer the PICO question on the use of delamanid in children under the age of 3
years, data were reviewed by the GDG from a phase I, open-label, age de-escalation trial designed
to assess the PK, safety and tolerability of delamanid administered twice daily for 10 days in children
with MDR/RR-TB on treatment with an optimized background regimen (protocol 242–12–232)34 and
from the corresponding open-label extension study (protocol 242–12–233).35 Data from cohorts 1
(age 12–17 years), 2 (age 6–11 years), 3 (age 3–5 years) and 4 (age 0–2 years) for both protocols
were reviewed. Exposures in the 0–2 year age group were lower than those of children aged 3 years
and older, necessitating a modelling/simulation approach to dosing. No cardiac safety signals distinct
from those reported in adults were observed in children 0–2 years of age. However, these findings
should be considered knowing that children had lower drug exposures compared to adults. However,
pharmacodynamic simulations suggested that clinically meaningful changes in QT (i.e. prolongation)
would be unlikely in children under 3 years of age, even if higher doses were used to reach drug
exposures comparable to those achieved in adults.
Central nervous system effects were included in the delamanid label for both adults and children
(paraesthesia, tremors, anxiety, depression and insomnia) as important potential safety concerns for
the drug. In March 2021, the study sponsor released a statement of intent to modify the labelling to
include hallucinations as an adverse reaction. This new safety signal has been more prevalent among
children (versus adults) with 15 reports in 14 children 2–16 years of age in India, Philippines, South
Africa, Tajikistan and Ukraine. Children experiencing this safety signal included some with extensively
resistant forms of TB (MDR/XDR-TB) treated with delamanid under programmatic conditions (12
reports) as well as children enrolled in a clinical trial studying delamanid for TB prevention (three
reports). Seven of the 15 reports were for children also receiving cycloserine (under programmatic
conditions). The GDG noted the importance of side-effects involving the central nervous system in
young children, considering their dynamic brain development.
In addition to data from the trials, data from a paediatric DR-TB IPD were analysed descriptively (24
231 records from all six WHO regions, the majority from India and South Africa). The search was
34
Pharmacokinetic and safety trial to determine the appropriate dose for pediatric patients with multidrug resistant tuberculosis (https://
clinicaltrials.gov/ct2/show/NCT01856634, accessed 21 January 2022).
35
A 6-month safety, efficacy, and pharmacokinetic (PK) trial of delamanid in pediatric participants with multidrug resistant tuberculosis
(MDR-TB) (https://clinicaltrials.gov/ct2/show/NCT01859923, accessed 21 January 2022).

conducted in April 2020. Just under 20 000 of these records were used for a matched analysis of
treatment outcomes in children being treated for DR-TB. The paediatric DR-TB IPD included only
seven children aged below 3 years treated with delamanid, 14 children aged 3–6 years, and 69
children aged 6–12 years. All 21 children aged below 6 years were successfully treated. The number
of children was insufficient for a matched analysis.
GDG considerations: The GDG noted that when the delamanid phase II trial was started, many of the
companion drugs in the optimized background regimen were not widely available (such as linezolid
and moxifloxacin). By the time the phase III trial started, linezolid and moxifloxacin became more
accessible, which meant that the optimized background regimens in the trial were likely more effective,
making it more difficult to prove the added effect of a drug (i.e. delamanid) in the intervention
regimen. The GDG concluded that the desirable effects are small. The GDG discussion around the
undesirable effects focused on adverse events, including those related to the central nervous system
and cardiac toxicities, as well as the newly reported adverse event of hallucinations which was of
some concern to GDG members given the period of dynamic brain development in children. The
GDG considered that the risks and benefits (and balance of both) are very different for treating a
child with resistant forms of TB (i.e. MDR/RR-TB and XDR-TB) and with limited treatment options,
compared to a healthy child at future risk of developing MDR-TB (i.e. where delamanid is used for
prevention). Therefore, the GDG concluded that the balance between desirable and undesirable effects
probably favours the intervention. The GDG further stated that with the 25 mg dispersible tablet, that
would be available in the future, the resource implications could vary. Delamanid containing longer
treatment regimens were thought to potentially increase equity and be acceptable to stakeholders. In
addition, the GDG judged that the use of delamanid in children of all ages would probably be feasible,
especially as the child-friendly formulation of delamanid was expected to become available later in
2021 (this formulation is now available). This judgement also considered that adult tablets cannot be
split, crushed or dissolved to ease administration in children without potentially altering bioavailability.
Subgroup considerations
Extrapulmonary TB: The use of delamanid in children with extrapulmonary MDR/RR-TB may be
considered (as part of longer regimens used for children with extrapulmonary MDR/RR-TB) by
extrapolating data from those with PTB; the delamanid trials, however, have studied PK and safety
among children with pulmonary MDR/RR-TB.
Children living with HIV: Children living with HIV were not enrolled in trials 242–12–232 and 233.
Although evaluated in healthy adult volunteers, reports from antiretroviral drug-drug interaction
studies suggest that the CYP3A4 inhibitor lopinavir/ritonavir increases delamanid total body
exposure up to 25% [GMR: 1.22 (90% CI 1.06,1.40)] (90). This increase is not clinically relevant and
does not necessitate any dose adjustments. No change in delamanid exposure was observed with
co-administration of either tenofovir [GMR: 0.96 (90% CI 0.84,1.10)], a CYP1A2 inhibitor, or efavirenz
[GMR: 0.94 (90% CI 0.72,1.23)], a weak CYP3A4 inducer. Delamanid does not affect plasma exposure
of the antiretroviral drugs tenofovir, lopinavir/ritonavir or efavirenz (94). No drug interaction studies
of delamanid together with integrase inhibitors have been performed, but based on knowledge
of metabolic pathways, the risk of metabolic drug interaction potential is expected to be low (95).
Therefore, based on available evidence, delamanid can be given to CLHIV with MDR/RR-TB on ART
regimen without dose adjustments.
Implementation considerations
Delamanid has been in use for adults and adolescents since 2014 and for children since 2016 (from
6 years of age) and 2019 (from 3 years) and therefore the implementation considerations related
to its use in children below 3 years of age are an extension of those currently in place. The main
implementation considerations specifically applicable to this age group are dosing based on the
availability of the 25 mg dispersible formulation and the neuropsychiatric side effects.
Delamanid formulations: In the trial, delamanid was dosed with the dispersible 25 mg tablet
tested in children aged 3–5 years. Bioavailability of delamanid may be altered when the 50 mg
adult tablet is split, crushed or dissolved. There are also concerns that the adult tablet may shatter if
attempts are made to split it, and its contents are exceedingly bitter and unpalatable. The tablets are
susceptible to oxidation and heat; thus, retaining pill fragments for use at any time other than the
time of administration is likely to result in the delivery of lower-than-expected active compound and
unspecified oxidation by-products. The child-friendly formulation of delamanid (25 mg dispersible
tablet, unscored) has been included in the 8th WHO Essential Medicine List for Children (EMLc),
released in October 2021 (88), was approved by the European Medicines Agency in September 2021
and has been available through the Stop TB Partnership GDF since October 2021. Children in the
0–2-year cohort in study 242–12–233 were administered a 5 mg paediatric dispersible formulation
that is not expected to be commercialized. There has been no direct bioequivalence comparison
for the 5 mg paediatric formulation and the 50 mg adult tablet. In a crossover bioequivalence study,
neither Cmax [90%CI GMR 0.701,0.809] nor AUC [90%CI GMR 0.775,0.909] satisfied the criteria for
bioequivalence as specified by regulatory agencies. As such, the 5 mg paediatric and the 50 mg adult
formulations are not interchangeable (96).
Dosing guidance for the use of delamanid in children below 3 years of age is provided in the
operational handbook, based on an expert consultation on dosing that was conducted after the
GDG meeting. The guidance takes into account the availability of the 25 mg dispersible delamanid
formulation.
Administration of delamanid: Bioavailability of delamanid was optimized in the trials by administering
delamanid with a high-fat meal; and therefore administration of delamanid with food is an important
aspect to consider for practical implementation. In neonates, there are higher feeding frequencies,
which aligns well with the goal of administering with higher-fat content.
Regimen building of longer regimens: Guidance on how to construct optimal treatment regimens
for children with MDR/RR-TB (with drugs based on WHO recommended drug classification as well
as optimal treatment duration) who are not eligible for shorter, all-oral regimens is provided in the
operational handbook.
Duration of treatment: Shortening the total treatment duration to less than 18 months may be
considered for children without extensive disease (61). Extensive (or advanced) TB disease refers to the
presence of bilateral cavitary disease or extensive parenchymal damage on CXR. Severe EPTB refers
to the presence of miliary TB or TBM in adolescents and adults over 15 years of age. In children aged
below 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or
isolated mediastinal mass without compression) are considered as severe (adapted from (86)).
Concurrent use of delamanid and bedaquiline, and use of delamanid beyond six months: With
regards to concurrent delamanid and bedaquiline use, evidence assessed by a GDG in November 2019
included new data on concurrent bedaquiline and delamanid use. The new evidence was insufficient
to allow the GDG to make a statement about the effectiveness of concurrent use of both medicines.
However, the group concluded that the safety data assessed in 2019 suggest no additional safety
concerns with regard to the concurrent use of bedaquiline and delamanid. Therefore, bedaquiline and
delamanid may be used in people with MDR/RR-TB who have limited options for other treatment,
such as those with few effective drugs that can be included in their regimen, for example due to an
extensive drug-resistance profile or intolerance to other second-line TB medications. Appropriate
schedules of safety monitoring (at baseline and throughout treatment) should be in place for these
patients, including ECG and electrolyte monitoring, and clinicians should be aware of other medicines
in the regimen that can either prolong the QT interval or cause other potential adverse events. The
available evidence of delamanid use is currently limited to the on-label 6-month duration alongside
other medicines in a longer regimen; prolongation beyond 6 months can be considered on a case-
by-case basis (9).

Monitoring and evaluation
In children, smear and culture monitoring of the response to treatment may be challenging, due to
difficulties in obtaining appropriate specimens for testing, for the same reasons it is difficult to obtain a
bacteriological confirmation of the diagnosis. In children with a bacteriologically confirmed diagnosis,
all reasonable efforts should be taken to demonstrate bacteriological conversion. Once cultures have
become negative or in children who never had a confirmed diagnosis, repeated respiratory sampling
may not be useful if the child is otherwise responding well clinically. Resolution of clinical symptoms
and weight gain can be used as indicators of improvement. All children should have regular clinical
follow-up, including weight and height monitoring. Drug dosages should be adjusted with weight
gain, as needed.
The risk of emergence of delamanid resistance should be a key consideration when the drug is
being used. Due to the difficulties in obtaining a suitable sample from children aged below 3 years,
performing DST may be challenging. However, if there are concerns about acquired drug resistance,
every effort should be made to obtain a suitable sample, such as through gastric aspirate, sputum
induction or NPA.
No cardiac safety signals distinct from those reported in adults were observed in children 0–2 years of
age; however, these are largely based on subtherapeutic concentrations. Given that a QTc evaluation
prior to delamanid administration may not always be feasible, it may be important to adapt risk
mitigation strategies when administering delamanid in combination with other agents that prolong
QTc (such as electrolytes which are stable).
Monitoring the emergence of neuropsychiatric effects (including hallucinations) in children treated
with delamanid – both who are admitted to hospitals and treated in households – will be very
important. Particular attention should be paid to children who are receiving other medications that
have known neuropsychiatric effects, such as cycloserine. Therefore, active TB drug safety monitoring
and management systems must be functional to detect, manage and report suspected or confirmed
drug toxicities in a timely manner.
Recording and reporting of details on the diagnosis, treatment regimens, clinical monitoring and
treatment outcomes of children and adolescents with MDR/RR-TB is important for monitoring the
programmatic implementation of newly recommended regimens as well as for efforts to improve case
finding of children with DR-TB. Data from national programmes on the use of delamanid in children
of all ages is important to expand the evidence base.
5.4. Consolidated recommendations on TB treatment
for children and adolescents
Table 6: WHO recommendations on TB treatment relevant to children and adolescents
Guidance for national tuberculosis programmes on the management of tuberculosis in

children. Second edition, 2014 (8)
Children with pulmonary TB or tuberculous peripheral lymphadenitis who live in settings with
low HIV prevalence and/or low prevalence of isoniazid resistance and children who are HIV-
negative, can be treated with a three-drug regimen (HRZ) for 2 months followed by a two-drug
(HR) regimen for 4 months at standard dosages.
(Strong recommendation, moderate quality of evidence)
Children and adolescents with severe pulmonary disease should be treated with a four-drug
regimen (HRZE) for 2 months followed by a two-drug regimen (HR) for 4 months at standard
dosages.
Infants aged 0–3 months with suspected or confirmed pulmonary TB or tuberculous peripheral
lymphadenitis should be promptly treated with the 6-month treatment regimen (2HRZ(E)/4HR).
Treatment may require dose adjustment to reconcile the effect of age and possible toxicity
in young infants. The decision to adjust doses should be taken by a clinician experienced in
managing paediatric TB.
(Strong recommendation, low certainty of evidence)
Children with suspected or confirmed osteoarticular TB should be treated with a four-drug
regimen (HRZE) for 2 months, followed by a two-drug regimen (HR) for 10 months, the total
duration of treatment being 12 months.
Streptomycin should not be used as part of first-line treatment regimens for children with
pulmonary TB or tuberculous peripheral lymphadenitis.
WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-susceptible
tuberculosis treatment, 2022 update (55)
New patients with pulmonary TB should receive a regimen containing 6 months of rifampicin:
2HRZE/4HR.36
(Strong recommendation, high certainty of evidence)
In all patients with drug-susceptible pulmonary TB, the use of thrice-weekly dosing is not
recommended in both the intensive and continuation phases of therapy, and daily dosing
remains the recommended dosing frequency.
(Conditional recommendation, very low certainty in the evidence)
The use of FDC tablets is recommended over separate drug formulations in treatment of
patients with drug-susceptible TB.
(Conditional recommendation, low certainty in the evidence)
36
This recommendation is applicable to adolescents from 15 years of age

In patients with tuberculous meningitis, an initial adjuvant corticosteroid therapy with
dexamethasone or prednisolone tapered over 6–8 weeks should be used.
(Strong recommendation, moderate certainty in the evidence)
Patients aged 12 years and older with drug-susceptible pulmonary TB, may receive a 4-month
regimen of isoniazid, rifapentine, moxifloxacin and pyrazinamide.
(NEW in DS-TB guidelines: Conditional recommendation, moderate certainty evidence)
WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant
tuberculosis treatment, 2020 update (9)
Regimen for rifampicin-susceptible and isoniazid-resistant tuberculosis
In patients with confirmed rifampicin-susceptible, isoniazid-resistant tuberculosis (Hr-TB),
treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a
duration of 6 months.
In patients with confirmed rifampicin-susceptible, isoniazid-resistant tuberculosis, it is not
recommended to add streptomycin or other injectable agents to the treatment regimen.
Shorter all-oral bedaquiline-containing regimen for multidrug- or rifampicin-resistant
tuberculosis (MDR/RR-TB)
A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended
in eligible patients with confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB)
who have not been exposed to treatment with second-line TB medicines used in this regimen
for more than 1 month, and in whom resistance to fluoroquinolones has been excluded.
(Conditional recommendation, very low certainty in the evidence in adults and adolescents)
Longer regimens for MDR- or RR-TB
In multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) patients on longer regimens,
all three Group A agents and at least one Group B agent should be included to ensure that
treatment starts with at least four TB agents likely to be effective, and that at least three agents
are included for the rest of treatment if bedaquiline is stopped. If only one or two Group A
agents are used, both Group B agents are to be included. If the regimen cannot be composed
with agents from Groups A and B alone, Group C agents are added to complete it.
Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on
longer regimens.
Levofloxacin or moxifloxacin should be included in the treatment of MDR/RR-TB patients on
longer regimens.
Linezolid should be included in the treatment of MDR/RR-TB patients on longer regimens.
Clofazimine and cycloserine or terizidone may be included in the treatment of MDR/RR-TB
patients on longer regimens.
Ethambutol may be included in the treatment of MDR/RR-TB patients on longer regimens.
Pyrazinamide may be included in the treatment of MDR/RR-TB patients on longer regimens.
Imipenem–cilastatin or meropenem may be included in the treatment of MDR/RR-TB patients
on longer regimens.37
Amikacin may be included in the treatment of MDR/RR-TB patients aged 18 years or more
on longer regimens when susceptibility has been demonstrated and adequate measures to
monitor for adverse reactions can be ensured. If amikacin is not available, streptomycin may
replace amikacin under the same conditions.
Ethionamide or prothionamide may be included in the treatment of MDR/RR-TB patients on
longer regimens only if bedaquiline, linezolid, clofazimine or delamanid are not used, or if
better options to compose a regimen are not possible.
(Conditional recommendation against use, very low certainty in the estimates of effect)
P-aminosalicylic acid may be included in the treatment of MDR/RR-TB patients on longer
regimens only if bedaquiline, linezolid, clofazimine or delamanid are not used, or if better
options to compose a regimen are not possible.
(Conditional recommendation against use, very low certainty in the estimates of effect)
Clavulanic acid should not be included in the treatment of MDR/RR-TB patients on
longer regimens.
(Strong recommendation against use, low certainty in the estimates of effect)
The bedaquiline, pretomanid and linezolid (BPaL) regimen for multidrug-resistant
tuberculosis with additional fluoroquinolone resistance
A treatment regimen lasting 6–9 months, composed of bedaquiline, pretomanid and linezolid
(BPaL), may be used under operational research conditions in multidrug-resistant tuberculosis
(MDR-TB) patients with TB that is resistant to fluoroquinolones, who have either had no
previous exposure to bedaquiline and linezolid or have been exposed for no more than 2
weeks.
Note: this recommendation concerns patients aged 14 years and above.
37
Imipenem-cilastatin and meropenem are administered with clavulanic acid, which is available only in formulations combined with
amoxicillin. Amoxicillin-clavulanic acid is not counted as an additional effective TB agent, and should not be used without imipenem-
cilastatin or meropenem.

Monitoring patient response to MDR-TB treatment using culture
In multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) patients on longer regimens, the
performance of sputum culture in addition to sputum smear microscopy is recommended to
monitor treatment response.
(Strong recommendation, moderate certainty in the estimates of test accuracy). It is desirable for
sputum culture to be repeated at monthly intervals.
Subgroup considerations: Patients <15 years of age with MDR/RR-TB comprised less than
2% of the IPD-MA analysed for PICO question 11 (MDR/RR-TB, 2018). Younger children usually
cannot produce sufficient sputum spontaneously to allow a bacteriological diagnosis (many are
typically sputum smear-microscopy negative). In these patients, culture may be a more sensitive
means to detect viable TB bacilli even if very few organisms are present in the sputum or other
samples, below the detection threshold of direct microscopy. However, in children who are unable
to expectorate, gastric aspirates or induced sputa may be possible but the repetition of such tests
at monthly frequency may not be acceptable.
6. Models of TB care for case
detection and provision of TPT
This chapter contains two new recommendations and other valid WHO recommendations that
apply to patient support and models of care (section 6.2). The two new recommendations, on the
implementation of decentralized models of care and integrated family-centred models of care to
improve both case detection and the provision of TPT, are described in full detail as this information
is being published for the first time. Other consolidated recommendations in this chapter are related
to patient support, health education and counselling, the provision of treatment support or video
supported treatment and decentralized models of care for MDR/RR-TB services.
The recommendations in this chapter have been consolidated from current WHO guidelines on TB
treatment and the context in which it should be provided, namely the Guidelines for treatment of
drug-susceptible tuberculosis and patient care, 2017 update (97) and the WHO consolidated guidelines
on tuberculosis. Module 4: treatment – drug-resistant tuberculosis treatment, 2020 update (9). For
more information on each recommendation including the remarks, source of evidence, justification,
subgroup-, implementation- and monitoring and evaluation considerations, the source guidelines
or WHO TB KSP should be consulted.
Capacity for paediatric TB is often highly centralized at secondary/tertiary level, where children
may present as seriously ill, after delays in accessing care. At higher levels of care, services are often
managed in a vertical, non-integrated way (10, 98). Health care workers at the PHC level may have
limited capacity and confidence in managing paediatric TB, although this is where most children with
TB or at risk of TB seek care (10). In addition, TB screening is often not systematically part of clinical
algorithms for child health, such as integrated management of childhood illness (IMCI) and integrated
community case management (iCCM). Private sector providers play an increasing role as first point
of care in many countries (99). There are many missed opportunities for contact tracing, as well as
TB prevention, detection and care due to weak integration of child and adolescent TB services with
other programmes and services.
Decentralization and provision of family-centred, integrated care are highlighted as one of 10 key
actions in the 2018 Roadmap (10). The Roadmap highlights that consistently and systematically
addressing gaps and bottlenecks along children’s and adolescents’ pathway through TB exposure,
TB infection and TB disease can lead to reduced transmission of TB, expansion of prevention of TB
infection and earlier TB diagnosis with better outcomes. Achieving this continuum of care requires
collaboration across service areas, practice disciplines and sectors, community engagement, as well
as decentralization and integration of service delivery at the PHC level (10).
The Roadmap suggests actions to integrate child and adolescent TB into family- and community-
centred care, including: (i) strengthening country-level collaboration and coordination across all
health-related programmes engaged in woman, adolescent and child health – especially reproductive
health, maternal, neonatal, child and adolescent health (MNCAH), nutrition, HIV, primary and
community health – with clearly defined roles, responsibilities and joint accountability; (ii) decentralizing
6. Models of TB care for case detection and provision of TPT in children and adolescents 57
and integrating successful models of care for TB screening, prevention and diagnosis with other
existing service delivery platforms for maternal and child health (such as antenatal care (ANC), iCCM,
IMCI) as well as other related services (such as HIV, nutrition, immunization); (iii) ensuring that children
and adolescents with other common comorbidities (such as meningitis, malnutrition, pneumonia,
chronic lung disease and HIV infection) are routinely evaluated for TB; (iv) ensuring community health
strategies integrate child and adolescent TB education, screening, prevention and case finding into
the training and service delivery activities; and (v) increasing awareness of and demand for child and
adolescent TB services in communities and among health workers (10).
This set of PICO questions examined the impact of: (i) decentralization and (ii) family-centred, integrated
approaches of child and adolescent TB services on case detection in children and adolescents who
present with signs and symptoms of TB. They also examine the impact of these approaches on
coverage of TPT among children and adolescents.
6.1. Decentralized and family-centred, integrated

models of care to deliver child and adolescent TB
services
Recommendations:
In TB high burden settings, decentralized models of care may be used to deliver TB services
to children and adolescents with signs and symptoms of TB and/or those exposed to TB
(conditional recommendation, very low certainty evidence).
Family-centred, integrated models of care to deliver TB services may be used in children
and adolescents with signs and symptoms of TB and/or those exposed to TB, in addition to
standard models of care (conditional recommendation, very low certainty evidence).
Remarks
• These recommendations are applicable to TB services along the full cascade of care with a
focus on case detection and provision of TPT.
• They are applicable to children and adolescents with signs and symptoms of TB in terms of the
impact on case detection. They also apply to children and adolescents who are exposed to TB
(TB contacts) who are eligible for TPT, in terms of the impact on provision of TPT. Children and
adolescents with signs and symptoms who need evaluation for TB disease may also have a
history of exposure to TB (TB contacts). Children and adolescents who are TB contacts who do
not have signs and symptoms need to be evaluated for TPT eligibility.
• The recommendation on decentralized services refers to enhancing child and adolescent TB
services at peripheral levels of the health system and closer to the community, not to replacing
specialized paediatric TB services at higher levels of the health system.
• Decentralization should be prioritized for settings and populations with poor access to existing
services and/or in high TB prevalence areas.
• Family-centred, integrated approaches are recommended as an additional option to standard
TB services, for example alongside specialized services that may have a limited level of
integration with other programmes or linkages to general health services.
• Family-centred care is a cross-cutting principle of child care at all levels of the health system.
PICO questions:
a. In children and adolescents with signs and symptoms of TB, should decentralization of child and
adolescent TB services versus centralized child and adolescent TB services (at referral or tertiary
hospital level) be used?
b. In children and adolescents exposed to TB, should decentralization of child and adolescent TB
prevention and care services versus centralized prevention and care services (at referral or tertiary
hospital level) be used to increase coverage of TPT in eligible children and adolescents?
c. In children and adolescents with signs and symptoms of TB, should family-centred, integrated
services versus standard, non-family-centred, non-integrated services be used?
d. In children and adolescents exposed to TB, should family-centred, integrated services versus
standard, non-family-centred, non-integrated services be used to increase TPT coverage in eligible
children and adolescents?
For definitions of decentralization and family-centred, integrated services, please refer to the section
with definitions from page xi.
Evidence: A systematic review of studies assessing the impact of decentralized, integrated or family-
centred care models on TB diagnosis, treatment or prevention outcomes in children and adolescents
with TB between 0 and 19 years old, comprising both children (0–9 years old) and adolescents (10–
19 years old), was conducted to answer this group of PICO questions. The PubMed, Embase, Web
of Science, Global Index Medicus, Global Health and Cochrane Central databases were searched in
February 2021, as well as the references of 17 related reviews. 3265 abstracts from databases and
129 additional references from related reviews were identified and assessed. 516 full-text articles were
assessed for eligibility, from which 25 comparative studies (7 randomized, 18 observational) were
identified; one unpublished observational study was added making a total of 26 studies. Four studies
(one randomized, three observational) were excluded after review because the care model described
was community-based treatment support, for which a WHO recommendation already exists (100). Of
the remaining included studies, 16 had elements of decentralization, five had elements of integration,
and three had elements of family-centred care; four studies had elements of more than one care
model of interest, but were only included based on their main model, such as either decentralization
or family-centred, integrated care. Most studies focused on the 0–14-year age group.
Studies where the primary intervention was decentralization mostly assessed diagnosis or case
notification outcomes (n=16) (48, 101–115), with fewer assessing TPT outcomes (n=3) (106, 116, 117).
In general, interventions that included both strengthening of diagnostic capacity in primary care
settings as well as strengthening linkages between communities and facilities consistently showed an
increase in case notifications and TPT initiations, while interventions that involved only community-
based activities did not.
Two studies of service integration were identified (118, 119), which showed limited impact on case
notifications of screening in IMCI clinics or co-location of TB and ART services. The two studies of
family-centred care that were identified (120, 121) showed that provision of socioeconomic support
packages to families affected by TB was associated with increased TPT initiation and completion.
The reviewers noted that, while substantial wider literature on integration and family-centred care
is available, evidence for the specific impact on child and adolescent TB outcomes is limited. Some
overlap was noted between integration of TB services into non-specialized settings, such as general
outpatient or primary care services, or decentralization. For the evidence review this was a slightly
artificial separation, while in practice decentralization and integration into PHC may happen together.
GDG considerations: Regarding the evidence reviewed on the impact of decentralization on TB case
detection, the GDG observed that two trials (109, 111) and one observational study of home-based
screening (without facility-based strengthening) (114) had fewer diagnoses or notifications among
children aged below 15 years in the intervention group compared to the control group, but that
none of these differences were statistically significant. The GDG discussed that while there may be a
reduction in case notifications at higher levels of care, TB detection may improve if children are seen
by a competent clinician at the first point of access (such as at PHC level). The evidence overall was
recognized as uncertain. The benefit of increased case finding and increased number of children with
TB who are initiated on TB treatment was considered to outweigh the concern for overtreatment.
Therefore, undesirable effects for case detection were considered trivial. The GDG discussed potential
risks of provision and management of TPT at the peripheral level, including undetected drug-related
adverse events such as hepatotoxicity and insufficient capacity to manage these. In addition, there
may be a risk of TB disease being treated with a course of TPT rather than with a complete treatment
regimen. All these undesirable events can potentially happen but were considered rare and not of
major concern. Therefore, undesirable effects for TPT provision were considered trivial as well. Overall,
the GDG agreed that the balance of desirable and undesirable effects probably favours decentralized
TB services for case detection and provision of TPT to children and adolescents. The panel noted that
differences in setting and availability of adequate resources are important considerations.
The GDG discussed that family-centred, integrated care includes interventions at the household level
to identify members of the household requiring evaluation for TB disease, TPT, treatment support,
etc. Some overlap between integration of TB services into non-specialized settings such as general
outpatient or primary care services, and decentralization was noted. For the evidence review, this
was a slightly artificial separation, while in practice decentralization and integration into PHC may
happen together. Overall, despite a lack of evidence on undesirable effects and low quality of the
data, the panel agreed that there is evidence of positive effects of family-centred integrated care. It
was suggested that family-centred, integrated care could be an addition to the standard of care as
well as to specialized services which do not have an integration component. Family-centred care in
the sense of family involvement was highlighted as a core principle of child health care.
The GDG discussed that setting specific factors related to TB burden or the organization of health
services may impact feasibility, acceptability and equity considerations. They also discussed that the
initial health system costs to establish decentralized and family-centred, integrated services may be
relatively high (such as infrastructure, human resources, training, equipment, community engagement),
but that costs are likely to decrease over time, assuming that people with TB are effectively managed
and TPT is provided at the peripheral level, leading to a reduction in TB incidence. Decentralized
and family-centred, integrated services may result in important savings for affected families. Equity
was considered an important cross-cutting issue impacting cost as well. The GDG highlighted that
TPT implementation can be very challenging with high levels of loss-to-follow-up in programmes
implemented at higher levels of the health system, considering that children who are eligible for
TPT are not sick. The panel agreed that decentralization and integration of services can potentially
increase equity and enhance the success of the programme and judged that cost-effectiveness
probably favours decentralized and family-centred, integrated approaches to both case finding and
provision of TPT.
While the GDG stressed the importance of taking into consideration the potential impact of stigma
when decentralizing TB services for children and adolescents to lower levels, the panel judged
that decentralized approaches are probably acceptable to key stakeholders. Overall decentralized
and family-centred, integrated approaches were judged feasible to implement, although feasibility
may vary depending on infrastructure, available funding and the structure of the NTP, among
others. However, adequate investment is critical to enable the acceptability, equity and feasibility of
decentralized approaches.
Adolescents have a disease presentation that is similar to adults, and therefore may need different
interventions than young children. Additional subgroup considerations for adolescents are included
in the operational handbook, taking into account their specific health-seeking behaviour and the
need for adolescent-friendly services.
TB contacts: Provision of TPT has focused mainly on children under 5 years of age for many years.
In 2018, target groups for the provision of TPT were expanded to include contacts of all ages (122).
Available data from the global TB database (78) show that coverage of TPT in household contacts is
poor, especially in those over 5 years of age.
In children with common illnesses with overlapping signs and symptoms of TB, approaches to integrate
TB services in their care can improve case detection and provision of TPT.
These subgroups include:
• Children with SAM
• Children with severe pneumonia
• Children living with HIV
• Children with other chronic diseases.

Health system requirements: Training of health care workers at peripheral levels of the health system
is a critical requirement to ensure adequate implementation of decentralized approaches. Similarly,
resources are needed at the peripheral level, especially initially to establish services. It is expected
that as services are established and effectively implemented, the long-term impact will result in a
decrease in TB incidence with an associated reduction in resource requirements. A phased approach
may be applied if this is most appropriate in the country or area, depending on the local burden of
TB, availability of domestic or donor funding and of technical and programmatic support.
Factors to consider in decentralizing child and adolescent TB services include: existing infrastructure (such
as baseline health infrastructure, needs for expansion or upgrading), applicable regulatory framework,
financing, choosing between an operational research setting or programmatic implementation, human
resource issues (including staffing requirements and human resources development, such as capacity
building/training and consultation skills), monitoring and evaluation, conducting qualitative research
into community needs, perceptions (including views on stigma) and suggestions. Decentralization of
services to the PHC level requires child and adolescent TB services to be integrated within general
PHC services, resulting in possible significant overlap between decentralization and family-centred,
integrated approaches.
Contact investigation: Active contact investigation at community and household level is a critical
intervention for enhancing both case finding and provision of TPT among children and adolescents.
Task shifting: Decentralization should not only concern the levels of the health system but should
ideally also take place within the same structure, by training all health care providers of all child and
adolescent care services in the recognition and management of TB. This so-called task shifting was
mentioned by the GDG as an important implementation factor.
Family-centred and integrated care: Although in child health, care evolves around the family, the
concept of family-centred care has not been well defined. Family-centred care is related to the more
common concept of patient-centred care. In the End TB Strategy (6): “Patient-centred care involves
systematically assessing and addressing the needs and expectations of patients. The objective is to
provide high-quality TB diagnosis and treatment to all patients – men, women and children – without
their having to incur catastrophic costs. Depending on patients’ needs, educational, emotional and
economic support should be provided to enable them to complete the diagnostic process and the
full course of prescribed treatment.” Multiple descriptions exist that include components of support
and education based on individual needs, building a patient-provider partnership and participatory
decision-making. Family-centred care also includes interventions at the level of the household to
identify members of the household requiring evaluation for TB disease, TPT, treatment support,
etc. As the concept of family-centred, integrated care may be setting specific, one of the first steps
in implementation includes clarifying which definition applies to the setting in which it is to be
implemented. Similarly, the implementation strategy varies by setting and needs to be country- or
region-specific, informed by social, cultural and societal values.
The package of TB services to be provided needs to be defined and developed by the NTP, in close
coordination with other relevant programmes, such as through an existing child and adolescent TB
technical working group. This package needs to be based on identifying and addressing capacity
needs for national programmes interested in the uptake of proposed interventions, and ideally based
on family and community perceptions on the ideal family-centred model of care. It could include
community-based models for active contact investigation, identifying children with TB signs and
symptoms or exposure as part of routine growth monitoring services, or an integrated model for
IMCI integration, starting with the sick child and identifying signs and symptoms pointing to a high
likelihood of TB.
Integration can start within the family, by equipping the family with the knowledge to recognize signs
and symptoms to understand the importance of a history of contact, to know when to seek help at
the health care facility and how to minimize stigma related to TB. High yield entry points provide a
good starting point within the health system. For example, child and adolescent TB services can be
integrated in malnutrition clinics, ANC, the expanded programme on immunization, inpatient sites,
adult TB and chest clinics, HIV and general paediatric clinics. Ideally TB care should be integrated into
general health services, rather than be limited to enhanced coordination between two programmes.
However, defining an optimal patient flow between services and creating strong linkages between child
health entry points and TB clinics remains essential, especially in facilities where services are physically
separated. This is critical to enhance the quality of services, including the follow-up of persons with
TB during the diagnostic evaluation, to also ensure accuracy of recording and reporting. In the early
phase, pilot programmes could be considered, which should be evaluated and adjusted as needed
and then scaled up.
Factors to consider in designing an integrated approach to child and adolescent TB care include
existing infrastructure (such as baseline health infrastructure, needs for expansion or upgrading), the
applicable regulatory framework, financing, choosing between an operational research setting or
programmatic implementation, human resource issues (including staffing requirements and human
resources development such as capacity building/training and consultation skills), monitoring and
evaluation, conducting qualitative research into community needs, perceptions (including views on
stigma) and suggestions.
Differentiated service delivery (DSD): DSD is a person-centred approach developed in the HIV
programme that simplifies and adapts HIV services across the cascade of care in ways that both serve
the needs of people living with and vulnerable to HIV and optimize the available resources in health
systems. The principles of DSD can be applied to prevention, testing, linkage to care, ART initiation
and follow-up, and integration of HIV care and coinfections and comorbidities (123). This approach
embraces the idea that when families are given the choice to interact with the health system, it could
provide a possible mechanism for integration of child and adolescent TB services within primary
health or other programmes. Examples of implementing DSD for children and adolescents with or at
risk of TB are provided in the operational handbook.
Moving to decentralized, family-centred, integrated services requires careful planning and regular
monitoring of implementation against the plan. The capacity needs of NTPs for implementing the
proposed interventions need to be identified and addressed.
Enhanced data collection around child and adolescent TB potentially takes a substantial amount of
additional time and detailed data collection may only be feasible in specific operational research
settings. Programmes generally have registers in place for contact investigation, treatment registration
and outcomes, as well as TPT registers. The use of these (preferably electronic) tools is important
as programmes move to a more decentralized and family-centred, integrated approach, to ensure
comprehensive management and treatment. The use of these tools needs to be evaluated and
enhanced, including through operational research.
It will be important to monitor the number of children diagnosed at different levels of the health
system, including the proportion of children that have bacteriological confirmation, the proportion
who were clinically diagnosed as well as the number of children initiated on and completing TPT.
Disaggregation of data by sex will be important to evaluate the impact on gender equity. Evaluating
the quality of services (covering the quality of all steps in the patient pathway, from screening, to
diagnosis and treatment) as well as client satisfaction are important components as well.
6.2. Consolidated recommendations on models of TB

care relevant to children and adolescents
Table 7: WHO recommendations on models of TB care relevant to children and
adolescents
WHO consolidated guidelines on tuberculosis. Module 4: treatment – care and support

during tuberculosis treatment (100)
Health education and counselling on the disease and treatment adherence should be provided
to patients on TB treatment.
(Strong recommendation, moderate certainty in the evidence)
A package of treatment adherence interventions38 may be offered for patients on TB treatment
in conjunction with the selection of a suitable treatment administration option.39
(Conditional recommendation, low certainty in the evidence)
38
Treatment adherence interventions include social support such as patient education and counselling, material support (e.g. food, financial
incentive, and transport fee); psychological support; tracers such as home visit or digital health communication (e.g. SMS, telephone
call); medication monitor; and staff education. The interventions should be selected on the basis of the assessment of individual patient’s
needs, provider’s resources and conditions for implementation.
39
Suitable treatment administration options include various forms of treatment support, such as video-supported treatment and regular
community of home-based treatment support.
One or more of the following treatment adherence interventions (complementary and not
mutually exclusive) may be offered to patients on TB treatment or to health care providers:
a. tracers40 or digital medication monitor41 (Conditional recommendation, very low certainty in
the evidence)
b. material support to the patient42 (Conditional recommendation, moderate certainty in
the evidence);
c. psychological support to the patient43 (Conditional recommendation, low certainty in
the evidence)
d. staff education44 (Conditional recommendation, low certainty in the evidence).
The following treatment administration options may be offered to patients on TB treatment:
a. Community- or home-based treatment support is recommended over health facility-based
treatment support or unsupported treatment (conditional recommendation, moderate
certainty in the evidence);
b. Treatment support administered by trained lay providers or health care workers is
recommended over treatment support administered by family members or unsupported
treatment (conditional recommendation, very low certainty in the evidence)
c. Video supported treatment (VST) can replace treatment support when the video
communication technology is available and can be appropriately organized and operated
by health-care providers and patients (conditional recommendation, very low certainty in
the evidence).
Patients with multidrug-resistant TB (MDR-TB) should be treated using mainly ambulatory care
rather than models of care based principally on hospitalization.
A decentralized model of care is recommended over a centralized model for patients on
MDR-TB treatment.
(Conditional recommendation, very low certainty in the evidence)
40
Tracers refer to communication with the patient including via SMS, telephone (voice) calls, or home visit.
41
A digital medication monitor is a device that can measure the time between openings of the pill box. The medication monitor may have
audio reminders or send an SMS to remind patient to take medications, along with recording when the pill box is opened.
42
Material support can be food or financial support such as: meals, food baskets, food supplements, food vouchers, transport subsidies,
living allowance, housing incentives, or financial bonus. This support addresses indirect costs incurred by patients or their attendants
in order to access health services, and possibly tries to mitigate consequences of income loss related to the disease.
43
Psychological support can be counselling sessions or peer-group support.
44
Staff education can be adherence education, chart or visual reminder, educational tools and desktop aids for decision-making
and reminder.
7. Special situations
This chapter includes valid WHO recommendations that apply to children and adolescents in
special situations such as for the management of TB in the context of HIV infection or malnutrition
and optimal feeding of infants of mothers infected with TB. The recommendations have been
consolidated from several current WHO guidelines on TB/HIV coinfection and nutrition, namely
the WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other
stakeholders (124), the Consolidated guidelines on HIV prevention, testing, treatment, service delivery
and monitoring: recommendations for a public health approach, July 2021 (125), the Guideline: updates
on the management of severe acute malnutrition in infants and children, 2013 (60), and the Guideline:
Nutritional care and support for patients with tuberculosis, 2013 (126). For more information on each
recommendation including the remarks, source of evidence, justification, subgroup-, implementation-
and monitoring and evaluation considerations, the source guidelines or WHO TB KSP should be
consulted.
Table 8: WHO recommendations on TB/HIV coinfection and nutrition relevant to

WHO policy on collaborative TB/HIV activities: guidelines for national programmes and
other stakeholders, 2012 (124)
Routine HIV testing should be offered to all patients with presumptive and diagnosed TB.
Consolidated guidelines on HIV prevention, testing, treatment, service delivery and
monitoring: recommendations for a public health approach, July 2021 (125)
Co-trimoxazole prophylaxis for infants, children and adolescents living with HIV
Co-trimoxazole prophylaxis is recommended for infants, children and adolescents with HIV,
regardless of clinical and immune conditions. Priority should be given to all children younger
than 5 years old regardless of CD4 cell count or clinical stage and children with severe or
advanced HIV clinical disease (WHO clinical stage 3 or 4) and/or those with CD4 cell count
≤350 cells/mm3.
(Strong recommendation, high certainty evidence)
In settings where malaria and/or severe bacterial infections are highly prevalent, co-trimoxazole
prophylaxis should be continued until adulthood, irrespective of whether ART is provided.
(Conditional recommendation, moderate certainty evidence)
In settings with low prevalence for both malaria and bacterial infections, cotrimoxazole
prophylaxis may be discontinued for children 5 years of age and older who are clinically stable
and/or virally suppressed on ART for at least six months and with a CD4 count >350 cells/mm3.
(Strong recommendation, very low certainty evidence).
Co-trimoxazole prophylaxis is recommended for HIV-exposed infants from 4 to 6 weeks of age
and should be continued until HIV infection has been excluded by an age-appropriate HIV test
to establish final diagnosis after complete cessation of breastfeeding.
(Strong recommendation, very low certainty evidence)
Routine co-trimoxazole prophylaxis should be given to all people living with HIV with TB disease
regardless of CD4 cell count.
(Strong recommendation, high certainty evidence)
General recommendations on eligibility for ART
ART should be initiated for all people living with HIV regardless of WHO clinical stage and at
any CD4 cell count.
• Pregnant and breastfeeding women (strong recommendation, moderate certainty evidence)
• Adolescents (conditional recommendation, low certainty evidence)
• Children living with HIV, one year old to less than 10 years old (conditional recommendation,
low certainty evidence)
• Infants diagnosed in the first year of life (strong recommendation, moderate certainty evidence)
Rapid ART initiation should be offered to all people living with HIV following a confirmed HIV
diagnosis and clinical assessment.
(Strong recommendation, high-certainty evidence for adults and adolescents; low certainty
evidence for children).
Rapid initiation is defined as within seven days from the day of HIV diagnosis; people with
advanced HIV disease should be given priority for assessment and initiation.
ART initiation should be offered on the same day to people who are ready to start.
(Strong recommendation, high certainty evidence for adults and adolescents; low certainty
evidence for children)
Timing of ART for children and adolescents with TB
ART should be started as soon as possible within 2 weeks of initiating TB treatment, regardless
of CD4 count, among adolescents and children living with HIV (except when signs and
symptoms of meningitis are present). (Adolescents: strong recommendation, low- to moderate-
certainty evidence; Children and infants: strong recommendation, very low certainty evidence)
ART should be delayed at least 4 weeks (and initiated within 8 weeks) after treatment for TB
meningitis is initiated.
First-line ART regimens
Dolutegravir (DTG) in combination with a nucleoside reverse-transcriptase inhibitor (NRTI)
backbone is recommended as the preferred first-line regimen for people living with HIV
initiating ART
• Adolescents (strong recommendation, moderate certainty evidence)
• Infants and children with approved DTG dosing (conditional recommendation, low
certainty evidence)
A raltegravir (RAL)-based regimen may be recommended as the preferred first-line regimen for
neonates
Second-line ART regimens
DTG in combination with an optimized NRTI backbone may be recommended as a preferred
second-line regimen for people living with HIV for whom non-DTG-based regimens are failing.
• Adolescents (conditional recommendation, moderate certainty evidence)
• Children with approved DTG dosing (conditional recommendation, low certainty evidence)
Boosted protease inhibitors in combination with an optimized NRTI backbone are
recommended as a preferred second-line regimen for people living with HIV for whom DTG-
based regimens are failing.
(Strong recommendation, moderate certainty evidence)
Guidelines: updates on the management of severe acute malnutrition in infants and
children, 2013 (60)
Infants with severe acute malnutrition who are admitted for inpatient care should be given
parenteral antibiotics to treat possible sepsis and appropriate treatment for other medical
complications such as tuberculosis, HIV, surgical conditions or disability.
Guideline: nutritional care and support for patients with tuberculosis, 2013 (126)
Management of severe acute malnutrition
School-age children and adolescents (5 to 19 years), and adults, including pregnant and
lactating women, with TB disease and severe acute malnutrition (very low BMI-for-age)
should be treated in accordance with the WHO recommendations for management of severe
acute malnutrition.
Children who are less than 5 years of age with TB disease and severe acute malnutrition (mid-
upper arm circumference more than 115 mm or weight-for-height/length more than three
z-scores below the WHO child growth standards median, or with any degree of bilateral
pitting oedema) should be treated in accordance with the WHO recommendations for the
management of severe acute malnutrition in children who are less than 5 years of age.
Management of moderate undernutrition
School-age children and adolescents (5 to 19 years) and adults, including lactating women,
with TB disease and moderate undernutrition, who fail to regain normal body mass index after
2 months’ TB treatment, as well as those who are losing weight during TB treatment, should
be evaluated for adherence and comorbid conditions. They should also receive nutrition
assessment and counselling and if indicated be provided with locally available nutrient-rich or
fortified supplementary foods as necessary to restore normal nutritional status.
(Conditional recommendation, low certainty evidence)
Children who are less than 5 years of age with TB disease and moderate undernutrition should
be managed as any other children with moderate undernutrition. This includes provision of
locally available nutrient-rich or fortified supplementary foods, in order to restore appropriate
weight-for-height.
Patients with multidrug-resistant TB and moderate undernutrition should be provided with
locally available nutrient-rich or fortified supplementary foods, as necessary, to restore normal
nutritional status.
A daily multiple micronutrient supplement at 1× recommended nutrient intake should be
provided in situations where fortified or supplementary foods should have been provided in
accordance with standard management of moderate undernutrition,45 but are unavailable.
Nutrition screening as part of contact investigation
In settings where contact tracing is implemented, household contacts of people with TB
disease should have a nutrition screening and assessment as part of contact investigation. If
malnutrition is identified, it should be managed according to WHO recommendations.
Remarks:
• There is no evidence that nutritional management of acute malnutrition of patients with TB
disease should be different than for those without TB.
• Concerns about weight loss or failure to gain weight should trigger further clinical assessment
(e.g. resistance to TB drugs, poor adherence, comorbid conditions) and nutrition assessment, in
order to determine the most appropriate interventions.
• Closer nutritional monitoring and earlier initiation of nutrition support (before the first 2 months
of TB treatment are completed) should be considered if the nutritional indicator is approaching
the cut-off value for a diagnosis of severe undernutrition.
45
Pyridoxine supplementation is recommended along with isoniazid treatment for all pregnant (or breastfeeding) women, as well as for
people with conditions such as HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease or renal failure. Pyridoxine
provision together with isoniazid treatment was not analysed for the 2013 nutrition guideline.
8. Research priorities
This chapter includes research gaps or priorities that were identified by the GDG members while
considering the evidence related to each of the PICO questions. Addressing the identified research
gaps has the potential to inform the development of future research questions that can improve
TB prevention and care. This list of research priorities is not exhaustive; but it complements the
existing research agenda outlined in Research priorities for paediatric tuberculosis (127) and other
WHO guidelines.
TB screening (adapted from WHO consolidated guidelines on tuberculosis. Module 2:

screening – systematic screening for tuberculosis disease (11))
• Studies evaluating the use of molecular WHO recommended rapid diagnostics for screening
children and adolescents.
• More research and development on better screening tools and approaches for use in children and
adolescents (screening approaches that target specific and distinct age ranges including infants
younger than 12 months, children younger than 5 years, children up to the age of 10 years and
those aged 10–19 years).
• Data to determine the frequency with which screening should be conducted among the
subpopulations of children at highest risk of TB.
• Well-designed clinical trials to provide evidence on patient-important outcomes for TB screening
in children.
Diagnostic approaches
The use of integrated treatment decision algorithms in children with presumptive

pulmonary TB attending health care facilities
• External validation of the newly developed integrated treatment decision algorithms, including for
specific subpopulations and in various settings.
• Implementation/operational research on the use and impact of the newly developed integrated
treatment decision algorithms, including how to tailor them to local epidemiological settings (such
as settings with differing burdens of TB, different health care settings, including settings with limited
access to CXR).
• Modelling studies to determine the potential impact of treatment decision algorithms on case
detection and treatment initiation.
• Qualitative studies on the feasibility and acceptability of the newly developed integrated treatment
decision algorithms among relevant stakeholders in various settings.
• Diagnostic test accuracy studies and effectiveness studies of algorithms for the diagnosis of EPTB.
The use of Xpert Ultra in gastric aspirate or stool samples to diagnose pulmonary TB in
children (adapted from 2021 rapid diagnostics guidelines (16) and 2018 research priorities
for paediatric tuberculosis (127))
• Evaluation of the benefits and incremental yield of combining multiple specimen types. Limited
data suggest that the combination of non-invasive specimens performs comparably with traditional
gastric specimens or induced sputum specimens.
• Additional operational and qualitative research to determine the best approach to less invasive
specimen collection in children, including: implementation studies on a method of suction for
nasopharyngeal aspiration that is appropriate for low-skill or low-resource environments; research
on the use of stool as a diagnostic specimen as part of treatment decision algorithms; definition
of laboratory protocols that successfully balance the ease of implementation and diagnostic
performance; and the impact of stool testing on patient-important outcomes.
• Identification, evaluation and validation of host and pathogen associated biomarkers in paediatric
populations as potential novel tests for TB infection, TB disease, risk of disease progression and
response to treatment among children, ideally requiring non-invasive samples and for use at the
point of care.
• Optimization of the current microbiological reference standard by improving and harmonizing
specimen collection; supporting laboratory research to improve specimen processing to optimize
diagnostic yield using current assays; and improving phenotypic and genotypic drug-susceptibility
testing on paediatric clinical specimens, including on stool samples.
• Qualitative research on equity, acceptability and feasibility aspects of diagnostic approaches,
including specimen types and diagnostic tools.
A four-month treatment regimen for children and adolescents with non-severe

drug-susceptible TB
• Stronger evidence on the feasibility of making a diagnosis of non-severe drug-susceptible TB
among children and adolescents in settings with no access to diagnostic tools, in particular to CXR.
• Evaluation of societal costs, including direct and indirect costs to persons with TB, in the
implementation of shorter treatment regimens for drug-susceptible TB (including, but not limited
to transport costs and loss of family income).
• Automated software for CXR reading, including differentiating severe from non-severe forms of
intrathoracic TB disease among children.
MDR/RR-TB treatment regimens for children
Bedaquiline
• Treatment outcomes in children with MDR/RR-TB of all ages treated with shorter and longer all-
oral, bedaquiline containing regimens.
• Studies aimed at optimizing dosing of bedaquiline in children.
• Specific cost-effectiveness analyses on the use of bedaquiline in children.
• Studies exploring mechanisms of acquisition of resistance to bedaquiline and genetic markers to
identify resistance (this evidence is likely to come from studies on adults with MDR/RR-TB but will
have implications for children and adolescents).
• Studies exploring the optimization of the duration of bedaquiline use in children related to PK
and safety.
• Studies exploring the concomitant use of bedaquiline and delamanid in children related to PK
and safety.
• Qualitative research on acceptability, equity and feasibility issues.
Delamanid
• Data on long-term safety and side-effects of delamanid, especially related to neuropsychiatric
safety signals.
• Studies aimed at optimizing dosing of delamanid in children (some studies are already ongoing,
such as IMPAACT P2005, “A phase I/II open-label, single-arm study to evaluate the PK, safety,
and tolerability of delamanid in combination with optimized multidrug background regimen
for multidrug-resistant tuberculosis (MDR-TB) in HIV-infected and HIV-uninfected children with
MDR-TB)”.
• Specific cost-effectiveness studies on the use of delamanid in children.
• Studies exploring mechanisms of acquisition of resistance to delamanid and genetic markers to
identify resistance.
• Studies exploring the optimization of the duration of delamanid use in children related to PK
and safety.
Treatment of presumed or bacteriologically confirmed drug-susceptible TB meningitis

• Comparative efficacy and safety data on the short intensive and standard treatment regimens.
• Dosing for the shorter intensive regimen and for alternative regimens under research, including
regimens that include higher doses of medicines than are currently recommended.
• Considerations regarding equity including equitable access to medicines in the short
intensive regimen.
• Cost-effectiveness of shorter regimens versus the current standard of care.
• Feasibility and acceptability of regimens for the treatment of TBM.
• Research on the sequelae of TBM (including the type and severity of sequelae and the ability to
prevent or manage them) as well as objective measures of quality of life/functionality post-treatment.
• Co-administration of anti-inflammatory agents in the treatment of children and adolescents
with TBM.
• Optimal regimens to treat TBM among CALHIV.
Models of TB care for children and adolescents
Decentralization of TB services for children and adolescents with signs and symptoms
of TB and for children and adolescents exposed to TB
• Cost-effectiveness of decentralization/integration for case detection and provision of TPT.
• Impact of decentralization of services on health equity.
• Acceptability and feasibility of decentralized approaches to child and adolescent TB care for case
detection and for TPT provision.
Family-centred, integrated services for children and adolescents with signs and
symptoms of TB and for children and adolescents exposed to TB
• Detailed description of currently operating family-centred and integrated services; associated costs
and cost-effectiveness.
• Implementation research on the components of these interventions; assessment of real-world
implementation of these programmes.
• Feasibility and acceptability of family-centred, integrated and/or decentralized approaches to child
and adolescent TB care for case detection and TPT provision in different settings, from person with
TB, caregiver and provider perspectives.
• Costs and catastrophic costs.
• Cost-effectiveness evaluations of family-centred, integrated and/or decentralized approaches,
considering currently available resources (some models assume that these interventions are built
upon existing structures that may not be available).
• Outcomes of interest: initiation of TPT; number of additional children and adolescents diagnosed;
delay, retention in care, treatment completion, clinical outcomes (such as treatment success);
qualitative research related stigma, mental health outcome, school interruption, equity.
• Evaluation of outcomes of interest using randomized/non-randomized designs and qualitative design.
• Baseline needs assessment in the community, community perceptions regarding TB care and
prevention for children and adolescents.
• Research on the quality of TB diagnosis in children – addressing both under-diagnosis and
over-diagnosis.
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117. Zachariah R, Spielmann MP, Harries AD, Gomani P, Graham SM, Bakali E, et al. Passive versus active
tuberculosis case finding and isoniazid preventive therapy among household contacts in a rural district of
Malawi. Int J Tuberc Lung Dis. 2003;7(11):1033-9.
118. Ketema L, Dememew ZG, Assefa D, Gudina T, Kassa A, Letta T, et al. Evaluating the integration of tuberculosis
screening and contact investigation in tuberculosis clinics in Ethiopia: A mixed method study. PLoS ONE.
2020;15(11):e0241977 (https://doi.org/10.1371/journal.pone.0241977, accessed 23 February 2022).
9. References 79
119. Miyano S, Dube C, Kayama N, Ishikawa N, Nozaki I, Syakantu G. Association between tuberculosis
treatment outcomes and the mobile antiretroviral therapy programme in Zambia. Int J Tuberc Lung Dis.
2013;17(4):540-5.
120. Wingfield T, Tovar MA, Huff D, Boccia D, Montoya R, Ramos E, et al. A randomized controlled study of
socioeconomic support to enhance tuberculosis prevention and treatment, Peru. Bull World Health Organ.
2017;95(4):270-80.
121. Rocha C, Montoya R, Zevallos K, Curatola A, Ynga W, Franco J, et al. The Innovative Socio-economic
Interventions Against Tuberculosis (ISIAT) project: an operational assessment. Int J Tuberc Lung Dis. 2011;15
Suppl 2(Suppl 2):50-7.
122. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management.
February 2022).
123. Updated recommendations on service delivery for the treatment and care of people living with HIV. Geneva:
World Health Organization; 2021 (https://apps.who.int/iris/handle/10665/341052, accessed 23 February
2022).
124. WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders.
December 2021).
125. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring:
recommendations for a public health approach. Geneva: World Health Organization; 2021 (https://apps.
who.int/iris/handle/10665/342899, accessed 1 December 2021).
126. Guideline: nutritional care and support for patients with tuberculosis. Geneva: World Health Organization;
127. Research priorities for paediatric tuberculosis. New York: Treatment Action Group, Child and Adolescent
TB Working Group; 2018 (https://www.treatmentactiongroup.org/wp-content/uploads/2018/09/Paediatric_
TB_ResearchPriorities_10_8_18_Web.pdf, accessed 1 December 2021).
Annex 1. WHO
recommendations incorporated
in the guidelines on the
management of TB in children
and adolescents
In order of presentation:
WHO consolidated guidelines on tuberculosis. Module 2: screening – systematic screening for
tuberculosis disease. Geneva: World Health Organization; 2021.
Recommendations for investigating contacts of persons with infectious tuberculosis in low- and
middle-income countries. Geneva: World Health Organization; 2012.
WHO guidelines on tuberculosis infection prevention and control, 2019 update. Geneva: World Health
Organization; 2019.
BCG vaccines: WHO position paper – February 2018. Weekly Epidemiological Record. 2018;93(08):73–96.
WHO consolidated guidelines on tuberculosis. Module 1: prevention – tuberculosis preventive
WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics for tuberculosis
detection, 2021 update. Geneva: World Health Organization; 2021.
WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-susceptible tuberculosis
treatment, 2022 update.
WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant tuberculosis
WHO consolidated guidelines on tuberculosis. Module 4: treatment – care and support during
tuberculosis treatment. Geneva: World Health Organization; 2022.
Guidance for national tuberculosis programmes on the management of tuberculosis in children.
Second edition. Geneva: World Health Organization; 2014.
Updated recommendations on HIV prevention, infant diagnosis, antiretroviral initiation and monitoring:
March 2021. Geneva: World Health Organization; 2021.
Guideline: nutritional care and support for patients with tuberculosis. Geneva: World Health
Organization; 2013.
Guideline: updates on the management of severe acute malnutrition in infants and children. Geneva:
World Health Organization; 2013.
Essential nutrition actions: mainstreaming nutrition through the life-course. Geneva: World Health
Organization; 2019.
Annex 1. WHO recommendations incorporated in the guidelines on the management of TB in children and adolescents 81
Annex 2. Supplementary table
Summary of changes to recommendations as
included in the second edition of the Guidance
for national tuberculosis programmes on the
management of tuberculosis in children, 2014
Annex 2. Supplementary table 83

84
WHO consolidated guidelines on tuberculosis, Module 5: Management of tuberculosis in children and adolescents
Recommendation in Guidance for national

tuberculosis programmes on the management
No. Status46 Updated recommendation and source guideline
of tuberculosis in children (second edition) 2014,
and source guideline
1 Xpert MTB/RIF should be used rather than Updated In children with signs and symptoms of pulmonary TB, Xpert
2 conventional microscopy and culture as the initial MTB/RIF should be used as an initial diagnostic test for
diagnostic test in children suspected of having MDR TB and rifampicin-resistance detection in sputum, gastric
TB or HIV-associated TB aspirate, nasopharyngeal aspirate and stool rather than smear
(Strong recommendation, very low quality of evidence) microscopy/culture and phenotypic DST.
Source: Automated real-time nucleic acid amplification technology for rapid (Strong recommendation, moderate certainty for accuracy in
and simultaneous detection of tuberculosis and rifampicin resistance: Xpert sputum; low certainty of evidence for test accuracy in gastric
MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in aspirate, nasopharyngeal aspirate and stool)
adults and children. Policy Update. 2013. In children with signs and symptoms of pulmonary TB, Xpert
Xpert MTB/RIF may be used rather than conventional Ultra should be used as the initial diagnostic test for TB and
microscopy and culture as the initial test in all children detection of rifampicin resistance in sputum, nasopharyngeal
suspected of having TB aspirate, gastric aspirate or stool, rather than smear
microscopy/culture and phenotypic DST
(Conditional recommendation acknowledging resource
implications, very low quality of evidence) (NEW Strong recommendation, moderate certainty of evidence
Source: Automated real-time nucleic acid amplification technology for rapid
for test accuracy in stool and gastric aspirate; low certainty
and simultaneous detection of tuberculosis and rifampicin resistance: Xpert of evidence for test accuracy in sputum; very low certainty of
MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in evidence for test accuracy in nasopharyngeal aspirate).
adults and children. Policy Update. 2013. Sources:
WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics
for tuberculosis detection, 2021 update. 2021.
WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis
in children and adolescents, 2022.
46
Status: Removed (the recommendation has been superseded and is no longer relevant); Copied (the recommendation remains valid and is retained unchanged); Edited (There is no change in the evidence
or in the intention of the recommendation, but the precise wording has been edited); Updated (a new evidence synthesis was conducted with review by the GDG with a full evidence-to-decision procedure);
Developed de novo (a new topic, subgroup or intervention has been covered with a new evidence synthesis and a full evidence-to-decision procedure by the GDG)
3 Xpert MTB/RIF may be used as a replacement test Updated In adults and children with signs and symptoms of
for usual practice (including conventional microscopy, extrapulmonary TB, Xpert MTB/RIF may be used in lymph
culture, and/or histopathology) for testing of specific node aspirate, lymph node biopsy, pleural fluid, peritoneal
non-respiratory specimens (lymph nodes and fluid, pericardial fluid, synovial fluid or urine specimens as the
other tissues) from children suspected of having initial diagnostic test rather than smear microscopy/culture.
extrapulmonary TB (Conditional recommendation, moderate certainty of evidence
(Conditional recommendation, very low quality for test accuracy for pleural fluid; low certainty for lymph node
of evidence) aspirate, peritoneal fluid, synovial fluid, urine; very low certainty
Source: Automated real-time nucleic acid amplification technology for rapid for pericardial fluid, lymph nodes biopsy)
and simultaneous detection of tuberculosis and rifampicin resistance: Xpert In adults and children with signs and symptoms of
MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in extrapulmonary TB, Xpert Ultra may be used in lymph node
adults and children. Policy Update. 2013. aspirate and lymph node biopsy as the initial diagnostic test
rather than smear microscopy/culture.
In adults and children with signs and symptoms of
extrapulmonary TB, Xpert MTB/RIF or Xpert Ultra should be
used for rifampicin-resistance detection rather than culture and
phenotypic DST.
(Strong recommendation, high certainty of evidence for test
accuracy for Xpert MTB/RIF; low certainty of evidence for
Xpert Ultra)
In HIV-positive adults and children with signs and symptoms of
disseminated TB, Xpert MTB/RIF may be used in blood, as an
initial diagnostic test for disseminated TB.

(Conditional recommendation, very low certainty of evidence for
test accuracy)
Source: WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid
diagnostics for tuberculosis detection, 2021 update. 2021.
85
86

4 Xpert MTB/RIF should be used in preference Updated In adults and children with signs and symptoms of TB
to conventional microscopy and culture as the meningitis, Xpert MTB/RIF or Xpert Ultra should be used in
initial diagnostic test in testing cerebrospinal fluid cerebrospinal fluid (CSF) as an initial diagnostic test for TB
specimens from children suspected of having TB meningitis rather than smear microscopy/culture.
meningitis (Strong recommendation: moderate certainty of evidence for
(Strong recommendation given the urgency of rapid test accuracy for Xpert MTB/RIF; low certainty of evidence for
diagnosis, very low quality of evidence) test accuracy for Xpert Ultra)
Source: Automated real-time nucleic acid amplification technology for rapid Source: WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid
and simultaneous detection of tuberculosis and rifampicin resistance: Xpert diagnostics for tuberculosis detection, 2021 update. 2021.
MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in
adults and children. Policy Update. 2013.
5 Interferon-gamma release assays (IGRAs) should Updated Either a tuberculin skin test (TST) or interferon-gamma release
not replace the tuberculin skin test (TST) in low- and assay (IGRA) can be used to test for TB infection.
middle-income countries for the diagnosis of TB (Strong recommendation, very low certainty in the estimates
infection in children or for the diagnostic work-up of of effect)
children (irrespective of HIV status) suspected of TB
Source: WHO consolidated guidelines on tuberculosis. Module 1: prevention –
disease in these settings.
Tuberculosis preventive treatment. 2020.
(Strong recommendation, low quality of evidence)
Source: Use of tuberculosis interferon-gamma release assays (IGRAs) in low-
and middle-income countries: policy statement. 2011.
6 Commercial serodiagnostics should not be used Copied Commercial serodiagnostics should not be used in children
in children suspected of active pulmonary or suspected of active pulmonary or extrapulmonary TB,
extrapulmonary TB, irrespective of their HIV status irrespective of their HIV status
(Strong recommendation, very low quality of evidence (Strong recommendation, very low certainty of evidence for the
for the use of commercial serodiagnostics) use of commercial serodiagnostics)
Source: Commercial serodiagnostic tests for diagnosis of tuberculosis: policy Source: Commercial serodiagnostic tests for diagnosis of tuberculosis: policy statement.
statement. 2011. 2011.
7 Routine HIV testing should be offered to all patients, Copied Routine HIV testing should be offered to all patients, with
including children, with presumptive and diagnosed TB presumptive and diagnosed TB
(Strong recommendation, low quality of evidence) (Strong recommendation, low certainty of evidence)
Source: WHO policy on collaborative TB/HIV activities, guidelines for national Source: WHO policy on collaborative TB/HIV activities, guidelines for national programmes
programmes and other stakeholders. 2012. and other stakeholders. 2012.
8 The following dosages of TB medicines should be opied and moved

C Drug dosing is included in a dosing table in the operational
used daily for the treatment of TB in children: to the dosing table handbook on the management of TB in children
• Isoniazid (H) 10 mg/kg (range 7–15 mg/kg); in the operational and adolescents.
maximum dose 300 mg/day handbook
• Rifampicin (R) 15 mg/kg (range 10–20 mg/kg);
maximum dose 600 mg/day
• Pyrazinamide (Z) 35 mg/kg (range 30–40 mg/kg)
• Ethambutol (E) 20 mg/kg (range 15–25 mg/kg)
(Strong recommendation, moderate quality
of evidence)
Sources:
1. Rapid advice: treatment of tuberculosis in children. 2010.
2. Updated dosing range for isoniazid from Thee S, Seddon JA, Donald
PR, Seifart HI, Werely CJ, Hesseling AC, et al. Pharmacokinetics of
isoniazid, rifampin, and pyrazinamide in children younger than two years
of age with tuberculosis: evidence for implementation of revised World
Health Organization recommendations. Antimicrob Agents Chemother.

2011;55:5560–7.
87
88

9 Children with suspected or confirmed pulmonary Split into two In children and adolescents aged between 3 months and 16
TB or tuberculous peripheral lymphadenitis who recommendations years with non-severe TB (without suspicion or evidence of
live in settings with low HIV prevalence47 and/or low considering that the MDR/RR-TB), a 4-month treatment regimen (2HRZ(E)/2HR)
prevalence of isoniazid resistance48 and children who SHINE trial was a should be used.
are HIV-negative, can be treated with a three-drug non-inferiority trial. (NEW Strong recommendation, moderate certainty of evidence)
regimen (HRZ) for 2 months followed by a two-drug Therefore the
(HR) regimen for 4 months at the dosages specified The use of ethambutol in the first 2 months of treatment is
6-month regimen recommended in settings with a high prevalence of HIV,44 or of
in Recommendation 8 (above) remains an option isoniazid resistance.45
(Strong recommendation, moderate quality of evidence) that can be used.
Children with pulmonary TB or tuberculous peripheral
Source: Rapid advice: treatment of tuberculosis in children. 2010.
lymphadenitis who live in settings with low HIV prevalence44
10 Children with suspected or confirmed pulmonary Split into 2 and/or low prevalence of isoniazid resistance45 and children
TB or tuberculosis peripheral lymphadenitis and/ recommendations: who are HIV-negative, can be treated with a three-drug
or children with extensive pulmonary disease, living regimen (HRZ) for 2 months followed by a two-drug (HR)
Updated (as above) regimen for 4 months at standard dosages.
in settings where the prevalence of HIV is high and/
or the prevalence of isoniazid resistance is high,44,45 i. Copied and (Strong recommendation, moderate quality of evidence)
should be treated with a four-drug regimen (HRZE) edited for children
Source: WHO consolidated guidelines on tuberculosis. Module 5: management of
for 2 months followed by a two-drug regimen and adolescents
tuberculosis in children and adolescents, 2022.
(HR) for 4 months at the dosages specified in with extensive PTB
Recommendation 8. not eligible for the Children with severe pulmonary TB disease should be treated
new 4-month regi- with a four-drug regimen (HRZE) for 2 months followed by a
(Strong recommendation, moderate quality men (removal of the two-drug regimen (HR) for 4 months.
of evidence) reference to recom- (Strong recommendation, moderate quality of evidence)
Source: Rapid advice: treatment of tuberculosis in children. 2010. mendation 8 and
of wording around
the prevalence of
HIV infection or iso-
niazid resistance as
this applies to both
recommendations
now)
47
Defined as countries, subnational administrative units, or selected facilities, where the HIV prevalence among adult pregnant women is ≥1% or among TB patients is ≥5% in the 2014 Guidance for national
tuberculosis programmes on the management of tuberculosis in children (second edition) (8).
48
WHO does not intend to establish thresholds for low, moderate or high levels of prevalence of isoniazid resistance: NTPs will establish definitions for their own countries.
11 Infants aged 0–3 months with suspected or Copied and edited Infants aged 0–3 months with suspected or confirmed
confirmed pulmonary TB or tuberculous peripheral slightly (reference to pulmonary TB or tuberculous peripheral lymphadenitis should
lymphadenitis should be promptly treated with recommendations 9 be promptly treated with the 6-month treatment regimen
the standard treatment regimens, as described in and 10 is removed (2HRZ(E)/4HR). Treatment may require dose adjustment to
recommendation 9 or 10. Treatment may require and the standard reconcile the effect of age and possible toxicity in young
dose adjustment to reconcile the effect of age and treatment regimen infants. The decision to adjust doses should be taken by a
possible toxicity in young infants. The decision has been replaced clinician experienced in managing paediatric TB.
to adjust doses should be taken by a clinician with the 6-month (Strong recommendation, low certainty of evidence)
experienced in managing paediatric TB. treatment regimen)
(Strong recommendation, low quality of evidence)
12 During the continuation phase of treatment, thrice- Updated In all patients with drug-susceptible pulmonary TB, the use of
weekly regimens can be considered for children thrice-weekly dosing is not recommended in both the intensive
known not to be HIV-infected and living in settings and continuation phases of therapy, and daily dosing remains
with well-established directly-observed therapy the recommended dosing frequency.
(DOT). (Conditional recommendation, very low certainty in the
(Conditional recommendation, very low quality of evidence)49
evidence for use of intermittent treatment in children Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-
in specific settings) susceptible tuberculosis treatment, 2022 update.
13 Streptomycin should not be used as part of first-line Copied Streptomycin should not be used as part of first-line treatment
treatment regimens for children with pulmonary TB regimens for children with pulmonary TB or tuberculous
or tuberculous peripheral lymphadenitis. peripheral lymphadenitis.

(Strong recommendation, moderate quality (Strong recommendation, moderate certainty of evidence)
of evidence) Source: Rapid advice: treatment of tuberculosis in children. 2010.
49
Twice-weekly dosing is totally not recommended. See Guidelines for treatment of tuberculosis, fourth edition. Geneva: World Health Organization; 2010 (http://www.who.int/tb/publications/2010/9789241547833/
en/).
89
90

14 Children with suspected or confirmed tuberculous Updated and Children and adolescents with suspected or confirmed TB
meningitis and children with suspected or confirmed validated for the meningitis should be treated with a four-drug regimen (HRZE)
osteoarticular TB should be treated with a four- recommendation on for 2 months, followed by a two-drug regimen (HR) for 10
drug regimen (HRZE) for 2 months, followed by a treatment of TBM months; the total duration of treatment being 12 months.
two-drug regimen (HR) for 10 months; the total (a new regimen was (Strong recommendation, low certainty of evidence)
duration of treatment being 12 months. The doses recommended as
recommended for the treatment of tuberculous an alternative to the
meningitis are the same as those described for existing regimen) In children and adolescents with microbiologically confirmed
pulmonary TB. Copied and drug or in those who have clinically diagnosed and presumed
(Strong recommendation, low quality of evidence) edited for the drug-susceptible TB meningitis (without suspicion or evidence
Source: Rapid advice: treatment of tuberculosis in children. 2010. recommendation of MDR/RR-TB), a 6-month intensive regimen (6HRZEto) may
on the treatment of be used as an alternative option to the 12-month regimen
osteoarticular TB (2HRZE/10HR).
(NEW Conditional recommendation, very low certainty of
the evidence)
Children with suspected or confirmed osteoarticular TB should

be treated with a four-drug regimen (HRZE) for 2 months,
followed by a two-drug regimen (HR) for 10 months, the total
duration of treatment being 12 months.
15 In settings where TB is highly endemic or where there Updated in WHO In countries or settings with a high incidence of TB and/
is high risk of exposure to TB, a single dose of BCG position paper or leprosy, a single dose of BCG vaccine should be given
vaccine should be given to all infants. (based on advice to neonates at birth, or as soon as possible thereafter, for
(Recommendation strength and evidence quality have from the WHO prevention of TB and leprosy disease. If it cannot be given at
not been graded)50 Strategic Advisory birth, it should be given at the earliest opportunity thereafter
Group of Experts and should not be delayed. Any delay in vaccination may lead
Source: Revised BCG vaccination guidelines for infants at risk for HIV
on Immunization to opportunities for known or unknown exposure to TB- or
infection. Weekly Epidemiological Record. 2007;82:193–196.
(SAGE)) leprosy-infected contacts.
Co-administration of BCG with the hepatitis B birth dose is
safe and strongly recommended. In order to avoid missed
opportunities for neonatal vaccination, BCG multi-dose
vials should be opened and used despite any wastage of
unused vaccine.
If the birth dose was missed, catch-up vaccination of
unvaccinated older infants and children is recommended since
evidence shows it is beneficial. Catch-up vaccination should
be done at the earliest convenient encounter with the health
care system to minimize known or unknown exposure to TB or
leprosy infected contacts.
Countries with a low incidence of TB or leprosy may choose
to selectively vaccinate neonates in recognized risk groups
for developing disease. High-risk groups to be considered for
vaccination include the following:
• Neonates to parents (or other close contacts/relatives) with

previous TB or leprosy
• Neonates in households with contacts to countries with high
incidence of TB and/or leprosy
• Neonates in any other locally identified risk group for TB and/
or leprosy
50
The Global Advisory Committee on Vaccine Safety (GACVS) does not use the GRADE methodology for evaluating the quality of evidence; the BCG-related recommendations will therefore remain ungraded.
91
92

In a few countries with low TB incidence, BCG vaccination is
largely replaced by intensified case detection, contact tracing
and supervised early treatment.
Studies show minimal or no evidence of any additional benefit
of repeat BCG vaccination against TB or leprosy. Therefore,
revaccination is not recommended even if the TST reaction or
result of an IGRA is negative. The absence of a BCG scar after
vaccination is not indicative of a lack of protection and is not
an indication for revaccination.
Source: BCG vaccines: WHO position paper – February 2018. Weekly Epidemiological
Record. 2018;93(8):73–96.
16 In children who are known to be HIV-infected, BCG Updated in WHO Children who are HIV-infected when vaccinated with BCG at
vaccine should not be given. position paper birth are at increased risk of developing disseminated BCG
(Recommendation strength and evidence quality have (based on advice disease. However, if HIV-infected individuals including children,
not been graded)4 from the WHO SAGE) are receiving ART, are clinically well and immunologically stable
(CD4% >25% for children aged <5 years or CD4 count ≥200 if
Source: Revised BCG vaccination guidelines for infants at risk for HIV
aged >5 years) they should be vaccinated with BCG.
infection. Weekly Epidemiological Record. 2007;82:193–196.
• In general, populations with high prevalence of HIV infection
also have the greatest burden of TB; in such populations
the benefits of potentially preventing severe TB through
vaccination at birth are outweighed by the risks associated
with the use of BCG vaccine. Therefore, it is recommended
that in such populations:
• Neonates born to women of unknown HIV status should
be vaccinated as the benefits of BCG vaccination outweigh
the risks.
• Neonates of unknown HIV status born to HIV-infected
women should be vaccinated if they have no clinical evidence
suggestive of HIV infection, regardless of whether the mother
is receiving ART.
Although evidence is limited, for neonates with HIV infection
confirmed by early virological testing, BCG vaccination should
be delayed until ART has been started and the infant confirmed
to be clinically and immunologically stable (CD4% >25%).
Record. 2018;93(8):73–96.
17 In infants whose HIV status is unknown and who Updated in WHO Children who are HIV-infected when vaccinated with BCG at
are born to HIV-positive mothers and who lack position paper birth are at increased risk of developing disseminated BCG
symptoms suggestive of HIV, BCG vaccine should be (based on advice disease. However, if HIV-infected individuals, including children,
given after considering local factors from the WHO SAGE) are receiving ART, are clinically well and immunologically stable
(Recommendation strength and evidence quality have (CD4% >25% for children aged <5 years or CD4 count ≥200 if
not been graded) 4 aged >5 years) they should be vaccinated with BCG.
Source: Revised BCG vaccination guidelines for infants at risk for HIV • In general, populations with high prevalence of HIV infection
infection. Weekly Epidemiological Record. 2007;82:193–196. also have the greatest burden of TB; in such populations
the benefits of potentially preventing severe TB through
vaccination at birth are outweighed by the risks associated
with the use of BCG vaccine. Therefore, it is recommended
that in such populations:
– Neonates born to women of unknown HIV status should
be vaccinated as the benefits of BCG vaccination outweigh
the risks.
– Neonates of unknown HIV status born to HIV-infected
women should be vaccinated if they have no clinical
evidence suggestive of HIV infection, regardless of whether

the mother is receiving ART.
– Although evidence is limited, for neonates with HIV
infection confirmed by early virological testing, BCG
vaccination should be delayed until ART has been
started and the infant confirmed to be clinically and
immunologically stable (CD4% >25%).
Record. 2018;93(8):73–96.
93
94

18 Clinical evaluation of household and close contacts Removed
for TB disease should be done on the basis of their
risk for having or developing TB disease or for the
potential consequences of the disease if it develops.
Priority should be given to contacts who are:
• children with symptoms suggestive of TB;
• children <5 years of age;
• children with known or suspected
immunocompromising conditions (especially those
living with HIV); and
• child contacts of index cases with multidrug-
resistant or extensively drug-resistant TB (proven
or suspected).
(Strong recommendation, very low quality of evidence)
Source: Recommendations for investigating contacts of persons with
infectious tuberculosis in low- and middle-income countries. 2012.
19 It is recommended that contact investigation be Removed

conducted for household and close contacts when
the index case has any of the following characteristics:
• has sputum smear-positive pulmonary TB;
• has multidrug-resistant or extensively drug-resistant
TB (proven or suspected);
• is a person living with HIV; or
• is a child <5 years of age.
(Strong recommendation, very low quality of evidence)
20 Contact investigation may be conducted for Removed
household and close contacts of all other index cases
with pulmonary TB, in addition to the index cases
covered in Recommendation 19.
(Conditional recommendation, very low quality
of evidence)
21 Children <5 years of age who are household or Updated Children aged <5 years who are household contacts of people
close contacts of people with TB and who, after an with bacteriologically confirmed pulmonary TB and who
appropriate clinical evaluation, are found not to are found not to have TB disease on an appropriate clinical
have TB disease should be given 6 months of IPT evaluation or according to national guidelines should be
(10 mg/kg per day, range 7–15 mg/kg, maximum given TB preventive treatment even if TB infection testing is
dose 300 mg/day). unavailable.
(Strong recommendation, high quality of evidence) (Strong recommendation, high certainty in the estimates of effect)
Source: Recommendations for investigating contacts of persons with Children aged ≥5 years, adolescents and adults who are
infectious tuberculosis in low- and middle-income countries. 2012. household contacts of people with bacteriologically confirmed
pulmonary TB who are found not to have TB disease by
an appropriate clinical evaluation or according to national
guidelines may be given TB preventive treatment.
(Conditional recommendation, low certainty in the estimates of
effect)
The following options are recommended for the treatment

of TB infection regardless of HIV status: 6 or 9 months of
daily isoniazid, or a 3-month regimen of weekly rifapentine
plus isoniazid,51 or a 3-month regimen of daily isoniazid plus
rifampicin.
(Strong recommendation, moderate to high certainty in the
estimates of effect).
51
In ages two years and above.
95
96

A 1-month regimen of daily rifapentine plus isoniazid52 or
4 months of daily rifampicin alone may also be offered as
alternatives.
(Conditional recommendation, low-to-moderate certainty in the
estimates of effect)
In settings with high TB transmission, adults and adolescents
living with HIV who have an unknown or a positive TB infection
test and are unlikely to have TB disease should receive at least
36 months of daily isoniazid preventive therapy (IPT). Daily IPT
for 36 months should be given whether or not the person is
on ART, and irrespective of the degree of immunosuppression,
history of previous TB treatment and pregnancy in settings
considered to have a high TB transmission as defined by
national authorities.
(Conditional recommendation, low certainty in the estimates
of effect)
Source: WHO consolidated guidelines on tuberculosis: Module 1: prevention –
Tuberculosis preventive treatment. 2020.
22 In settings of high HIV prevalence, all household Copied In settings of high HIV prevalence, all household and close
and close contacts of people with TB should be contacts of people with TB should be counselled and tested
counselled and tested for HIV. for HIV.
(Strong recommendation, very low quality of evidence) (Strong recommendation, very low quality of evidence)
Source: Recommendations for investigating contacts of persons with Source: Recommendations for investigating contacts of persons with infectious
infectious tuberculosis in low- and middle-income countries. 2012. tuberculosis in low- and middle-income countries. 2012.
52
In ages 13 and above.
23 In settings of low HIV prevalence, all household Copied In settings of low HIV prevalence, all household members
members and close contacts of people with TB who and close contacts of people with TB who have symptoms
have symptoms compatible with TB disease may be compatible with TB disease may be offered counselling and
offered counselling and testing for HIV as part of their testing for HIV as part of their clinical evaluation.
clinical evaluation. (Conditional recommendation, very low quality of evidence)
(Conditional recommendation, very low quality Source: Recommendations for investigating contacts of persons with infectious
of evidence) tuberculosis in low- and middle-income countries. 2012.
24 All household contacts of an index case who is a Copied All household contacts of an index case who is a person living
person living with HIV should be counselled and with HIV should be counselled and tested for HIV.
tested for HIV. (Strong recommendation, very low quality of evidence)
(Strong recommendation, very low quality of evidence) Source: Recommendations for investigating contacts of persons with infectious
Source: Recommendations for investigating contacts of persons with tuberculosis in low- and middle-income countries. 2012.
97
98

25 Children living with HIV who are more than 12 Updated Adults and adolescents living with HIV who are unlikely to have
months of age and who are unlikely to have TB TB disease should receive TB preventive treatment as part of
disease on symptom-based screening and who have a comprehensive package of HIV care. Treatment should also
no contact with a TB case: be given to those on antiretroviral treatment, to pregnant
• should be offered 6 months of IPT (10 mg/kg per women and to those who have previously been treated for TB,
day, range 7–15 mg/kg, maximum dose 300 mg/ irrespective of the degree of immunosuppression and even if
day) as part of a comprehensive package of HIV TB infection testing is unavailable.
prevention and care services if living in settings with (Strong recommendation, high certainty in the estimates
a high TB prevalence of effect)
(Strong recommendation, low quality of evidence) Infants aged <12 months living with HIV who are in contact
• might be offered 6 months of IPT (10 mg/kg per with a person with TB and unlikely to have TB disease on
day, range 7–15 mg/kg, maximum dose 300 mg/ an appropriate clinical evaluation or according to national
day) as part of a comprehensive package of HIV guidelines should receive TB preventive treatment.
prevention and care services if living in settings with (Strong recommendation, moderate certainty in the estimates
a medium or low TB prevalence. of effect)
(Conditional recommendation, low quality
of evidence) Children aged ≥12 months living with HIV who are considered
unlikely to have TB disease on an appropriate clinical
Source: Guidelines for intensified case-finding for tuberculosis and isoniazid
evaluation or according to national guidelines should be
preventive therapy for people living with HIV in resource-constrained
settings. 2011.
offered TB preventive treatment as part of a comprehensive
package of HIV prevention and care if they live in a setting with
This recommendation had been updated from the 2011 Guidelines for high TB transmission, regardless of contact with TB.
intensified case-finding for tuberculosis and isoniazid preventive therapy
for people living with HIV in resource-constrained settings on the basis of (Strong recommendation, low certainty in the estimates
more recent evidence. of effect)
All children living with HIV who have successfully completed
treatment for TB disease may receive TB preventive treatment.
(Conditional recommendation, low certainty in the estimates
of effect)
Source: WHO consolidated guidelines on tuberculosis. Module 1: prevention – tuberculosis
preventive treatment. 2020.
26 Children with suspected or confirmed pulmonary Updated In all patients with drug-susceptible pulmonary TB, the use of
TB or tuberculous peripheral lymphadenitis living thrice-weekly dosing is not recommended in both the intensive
in settings with a high HIV prevalence (or with and continuation phases of therapy, and daily dosing remains
confirmed HIV infection) should not be treated with the recommended dosing frequency
intermittent regimens (that is, twice-weekly or thrice- (Conditional recommendation, very low certainty in
weekly doses). the evidence)
(Strong recommendation, low-to- moderate quality Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-
evidence against the use of intermittent treatment susceptible tuberculosis treatment, 2022 update.
in children)
27 Children with proven or suspected pulmonary TB Updated In children with MDR/RR-TB aged below 6 years, an all-oral
or tuberculous meningitis caused by multidrug- treatment regimen containing bedaquiline may be used.
resistant bacilli can be treated with a fluoroquinolone (NEW Conditional recommendation, very low certainty of
in the context of a well-functioning MDR-TB control the evidence).
programme and within an appropriate MDR-TB
regimen. The decision to treat should be taken by a This recommendation applies to and complements current
clinician experienced in managing paediatric TB. WHO recommendations on shorter and longer regimens that
contain bedaquiline:
(Strong recommendation, very low quality evidence)
• A shorter all-oral bedaquiline-containing regimen of
9–12 months duration is recommended in eligible patients
with confirmed multidrug- or rifampicin-resistant tuberculosis
(MDR/RR-TB) who have not been exposed to treatment with
second-line TB medicines used in this regimen for more than
1 month, and in whom resistance to fluoroquinolones has

been excluded.
(Conditional recommendation, very low certainty in
the evidence)
• Bedaquiline should be included in longer multidrug-resistant
TB (MDR-TB) regimens for patients aged 18 years or more.
(Strong recommendation, moderate certainty in the estimates
of effect)
99
100

• Bedaquiline may also be included in longer MDR-TB regimens
for patients aged 6–17 years.
(Conditional recommendation, very low certainty in the estimates
of effect)
In children with MDR/RR-TB aged below 3 years delamanid may
be used as part of longer regimens.
(NEW Conditional recommendation, very low certainty of
the evidence).
This recommendation complements the current WHO
recommendation on longer regimens that contain delamanid:
• Delamanid may be included in the treatment of MDR/RR-TB
patients aged 3 years or more on longer regimens. (Conditional
recommendation, moderate certainty in the estimates of effect)
In multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB)

patients on longer regimens, all three Group A agents and at
least one Group B agent should be included to ensure that
treatment starts with at least four TB agents likely to be effective,
and that at least three agents are included for the rest of
treatment if bedaquiline is stopped. If only one or two Group A
agents are used, both Group B agents are to be included. If the
regimen cannot be composed with agents from Groups A and B
alone, Group C agents are added to complete it.
(Conditional recommendation, very low certainty in the estimates
of effect)
For details on drug grouping and recommendations on
individual drugs to use in longer regimens, refer to the source
document below.
Source: WHO consolidated guidelines on tuberculosis. Module 4: treatment – drug-resistant
tuberculosis treatment. 2020.
28 All children treated for TB should be recorded and Copied and moved This is a good practice statement and will be incorporated
reported by the NTP in one of two age bands (0–4 to the operational into the operational handbook, with revised age bands for
years and 5–14 years) handbook reporting. The age bands for reporting TB in children and
(This recommendation is not graded: it is based on adolescents have been updated and are now: 0–4, 5–9, 10–14
good clinical practice) and 15–19 years.
Sources: Guidance for national tuberculosis programmes on the
management of tuberculosis in children. 2006.
Definitions and reporting framework for tuberculosis – 2013 revision. 2013.
- New interim recommendation Developed de novo In children with presumptive pulmonary TB attending health
care facilities, integrated treatment decision algorithms may be
used to diagnose pulmonary TB.
(NEW Interim conditional recommendation, very low
certainty evidence)
- New recommendation Developed de novo In TB high burden settings, decentralized TB services may be
used in children and adolescents with signs and symptoms of
TB and/or those exposed to TB.
(NEW Conditional recommendation, very low
certainty evidence)
Family-centred, integrated services in addition to standard TB
services may be used in children and adolescents with signs

and symptoms of TB and/or those exposed to TB.
(NEW Conditional recommendation, very low
certainty evidence)
101
For further information, please contact:
World Health Organization
20, Avenue Appia CH-1211 Geneva 27 Switzerland
Global TB Programme
Web site: www.who.int/tb

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ISBN 978–92–4-004676–4 (electronic version)

© World Health Organization 2022

Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.

Design by Inis Communication

2. TB screening and contact investigation 9

5. Treatment of TB disease in children and adolescents 31

Annex 2. Supplementary table  83

Guideline Development Group

External Review Group

WHO Steering Group

Executive summary xvii

Recommendations on the management of TB in

Table 1: New recommendations in the WHO consolidated guidelines on tuberculosis.

Table 2: Recommendations in the WHO consolidated guidelines on tuberculosis. Module 5:

Executive summary xix

Executive summary xxi

1.2. Rationale for the development of the 2022

1.3. Objectives of the 2022 consolidated guidelines

1.4. Target audience

1.5. WHO recommendations relevant to the

1.6. Scope of the guideline update

Models of Care TB case

Susceptible Accessed health care system

Inputs Activities Short-term Long-term

• Stakeholder • Contact investigation • Earlier and increased • Reduced TB incidence

1.6.1. PICO questions

PICO question 2: TB diagnostic approaches in children

1.6.2. Background questions

1.7. Publication, dissemination, evaluation and expiry

1.8. Document structure

Î Chapter 1 is the introduction and provides background information, an overview of the

Table 3: WHO recommendations on TB screening and contact investigation relevant to

WHO consolidated guidelines on tuberculosis. Module 2: screening – systematic

2. TB screening and contact investigation 9

Table 4: WHO recommendations on TB infection prevention and control, BCG

TB infection prevention and control: WHO guidelines on tuberculosis infection

4. Diagnostic approaches for TB in children and adolescents 17

4.1. The use of the Xpert MTB/RIF Ultra assay

4.1.1. Justification and evidence

4. Diagnostic approaches for TB in children and adolescents 19

4.1.2. Subgroup considerations

4.1.3. Implementation considerations

4.1.4. Monitoring and evaluation

4. Diagnostic approaches for TB in children and adolescents 21

4.2.1. Justification and evidence

4. Diagnostic approaches for TB in children and adolescents 23

4.2.2. Subgroup considerations

4.2.3. Implementation considerations

4.2.4. Monitoring and evaluation

4. Diagnostic approaches for TB in children and adolescents 25

WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics

4. Diagnostic approaches for TB in children and adolescents 27

4. Diagnostic approaches for TB in children and adolescents 29

5. Treatment of TB disease in children and adolescents 31

5.1.1. Justification and evidence

5. Treatment of TB disease in children and adolescents 33

5.1.2. Subgroup considerations

5.1.3. Implementation considerations

2. TB screening and contact investigation 9

5. Treatment of TB disease in children and adolescents 31

Annex 2. Supplementary table 83

8 The following dosages of TB medicines should be opied and moved