Pediatric Tuberculosis: A Review of Evidence-Based Best Practices PDF

pathogens Review Pediatric Tuberculosis: A Review of Evidence-Based Best Practices for Clinicians and Health Care Providers Brittany K. Moore 1, *, Stephen M. Graham 2,3,4 , Subhadra Nandakumar 1 , Joshua Doyle 1 and Susan A. Maloney 1 1 Divis...

pathogens Review Pediatric Tuberculosis: A Review of Evidence-Based Best Practices for Clinicians and Health Care Providers Brittany K. Moore 1, *, Stephen M. Graham 2,3,4 , Subhadra Nandakumar 1 , Joshua Doyle 1 and Susan A. Maloney 1 1 Division of Global HIV and Tuberculosis, U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329, USA; [email protected] (S.N.); [email protected] (J.D.); [email protected] (S.A.M.) 2 Centre for International Child Health, Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia; [email protected] 3 Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne 3052, Australia 4 International Union Against Tuberculosis and Lung Disease, 75001 Paris, France * Correspondence: [email protected] Abstract: Advances in pediatric TB care are promising, the result of decades of advocacy, operational and clinical trials research, and political will by national and local TB programs in high-burden countries. However, implementation challenges remain in linking policy to practice and scaling up innovations for prevention, diagnosis, and treatment of TB in children, especially in resource- limited settings. There is both need and opportunity to strengthen clinician confidence in making a TB diagnosis and managing the various manifestations of TB in children, which can facilitate the translation of evidence to action and expand access to new tools and strategies to address TB in this population. This review aims to summarize existing guidance and best practices for clinicians and health care providers in low-resource, TB-endemic settings and identify resources with more detailed and actionable information for decision-making along the clinical cascade to prevent, find, and cure TB in children. Keywords: pediatric; tuberculosis; infectious disease Citation: Moore, B.K.; Graham, S.M.; 1. Introduction Nandakumar, S.; Doyle, J.; Maloney, S.A. Pediatric Tuberculosis: A Review One quarter of the world’s population—1.7 billion people—is infected with tuberculo- of Evidence-Based Best Practices for sis (TB), including 67 million children (defined throughout as persons under 15 years of Clinicians and Health Care Providers. age) [1–3]. In 2022, 1.25 million children developed TB, and 214,000 children died from Pathogens 2024, 13, 467. https:// this preventable, curable disease, representing 12% of the global burden of TB disease and doi.org/10.3390/pathogens13060467 17% of all deaths from TB. An estimated 80% of these deaths are in children under five years of age, and 96% are in children who never received TB treatment. Children, Academic Editor: Steven L. Zeichner especially those under five years of age and those with HIV infection, severe acute mal- Received: 15 April 2024 nutrition (SAM), or other immunocompromising conditions, are more likely to progress Revised: 24 May 2024 rapidly from infection to severe disease and are more likely than adults to die from TB. Accepted: 28 May 2024 Such rapid progression provides a narrow window for intervention to prevent disease and Published: 1 June 2024 death [5–12]. The disproportionate TB burden in this age group is due to unique vulnerabilities, varying clinical presentations, and challenges in screening for, diagnosing, treating, and preventing TB in children. A schematic of the pathway through TB exposure, infection, and Copyright: © 2024 by the authors. disease in children and potential areas of challenge where children are lost along the clinical Licensee MDPI, Basel, Switzerland. care cascade is included in the World Health Organization’s (WHO’s) Roadmap to ending This article is an open access article distributed under the terms and TB in children and adolescents. For instance, children with TB often present with conditions of the Creative Commons non-specific clinical signs and symptoms resembling common childhood illnesses, seek Attribution (CC BY) license (https:// care at health clinics or departments that do not routinely screen to identify presumptive creativecommons.org/licenses/by/ TB, and/or do not have access to recommended diagnostic tests and radiography services 4.0/). to evaluate those identified with presumptive TB. Additionally, young children are more Pathogens 2024, 13, 467. https://doi.org/10.3390/pathogens13060467 https://www.mdpi.com/journal/pathogens Pathogens 2024, 13, 467 2 of 38 likely to have extrapulmonary TB (EPTB), which further increases variability in their clinical presentation. These challenges may hinder the appropriate evaluation of children for TB disease [6,14–16]. Children have difficulty providing high-quality, spontaneously expec- torated sputum for diagnostic testing, especially young children, and often require more invasive sampling procedures such as sputum induction or gastric aspiration [6,14,17,18]. Consequently, increased use of less invasive specimens (e.g., stool, urine, nasopharyngeal aspirates (NPA)) is now recommended. However, these specimen types often have fewer mycobacteria, resulting in decreased test sensitivities for young children [19,20]. Clinical diagnosis based on signs, symptoms, patient history, and radiography therefore remains critically important for identifying TB in children [18,21]. Furthermore, clinicians often need to use every piece of information available to guide a clinical decision on TB treatment for pediatric patients with presumed TB but with negative diagnostic test results (see Treatment Decision Algorithms below). Once initiated on treatment, children respond well to preventive and curative treat- ment regimens for drug-susceptible (DS) and drug-resistant (DR) TB, generally experienc- ing fewer and less severe side effects and better treatment outcomes than adults if treatment completion can be assured [6,18,22]. This better response to treatment underscores the opportunities lost due to challenges in TB case-finding for children. Fortunately, a greater focus on TB in children and adolescents, increasing confidence and familiarity with clinical diagnosis of TB in children, and recent advances in TB diagnostic testing, including the use of child-friendly specimens, have contributed to a four-fold increase in pediatric TB case detection during the last decade [4,13]. Moreover, there has been a growing recognition of the need to prioritize and strengthen pediatric TB prevention and treatment programs to decrease morbidity and mortality in children. Routine, systematic TB screening in settings where children seek care and child-focused case-finding efforts, like household contact investigations, can prevent disease and death by facilitating the provision of TB preventive treatment (TPT) or early diagnosis and appropriate treatment of TB disease [14,16,20,23–27]. There have also been advances in the development and accessibility of pediatric formula- tions for both TB preventive and disease treatment regimens, which have been procured by many programs in high-burden countries [28–30]. Finally, WHO recently released updated global guidelines on the management of TB in children and adolescents, recommending several shorter treatment regimens for children and young adolescents with non-severe drug-susceptible TB, TB meningitis (TBM), and DR TB [31–33]. But challenges remain, and in 2022 globally, only 42% of children under five years of age and 55% of children ages 5–14 years with TB disease were diagnosed, compared with 70% of adults. Among the estimated 25,000 to 32,000 children who develop DR TB every year, only 14% were diagnosed. These challenges have only grown in the wake of the COVID-19 pandemic, which led to limited access to TB services, fewer new TB diagnoses (which were more pronounced among children), a decrease in bacille Calmette–Guérin (BCG) vaccine availability and coverage, and an overall increase in mortality [1,34–36]. Global TB cases and deaths now resemble the burden of disease in 2016, erasing enormous progress realized in the years leading up to the COVID-19 pandemic. Advances in pediatric TB care are promising overall, the result of decades of advo- cacy, operational and clinical trial research, and political will among national and local TB programs in high-burden countries. However, implementation challenges remain in translating policy to practice and scaling up innovations for prevention, diagnosis, and treatment of TB in children, especially in low-resource settings. There is also both need and opportunity to strengthen clinician confidence in making a TB diagnosis and managing the various manifestations of TB in children, which can facilitate the translation of evidence to action and expand access to new tools and strategies to address TB in this population. This review aims to summarize existing guidance and best practices for clinicians and health care providers in low-resource, TB-endemic settings and identify resources (Table 1) with more detailed and actionable information for decision-making along the clinical cascade to prevent, find, and cure TB in children. Pathogens 2024, 13, 467 3 of 38 Table 1. Selected resources, guidelines, and training materials for management of TB in children and adolescents, adapted and informed by the Roadmap to end TB in children and adolescents. Resource Description Link (Accessed on 26 October 2023) Comprehensive Resources and Guidance WHO Consolidated Guidelines on Consolidated guidelines of new and existing Tuberculosis: Module 5: Management of recommendations (>130 recommendations) on https://www.who.int/publications/i/ Tuberculosis in Children and TB screening, prevention, diagnosis, treatment, item/9789240046764 Adolescents (2022) and models of care for children and adolescents Detailed practical considerations for implementing recommendations in the WHO guidelines; WHO Operational Handbook on Tuberculosis: provides treatment regimen composition and https://www.who.int/publications/i/ Module 5: Management of Tuberculosis in dosing charts, adverse events mapping, costing item/9789240046832 Children and Adolescents (2022) information and monitoring and evaluation templates for specific activities along with other tools and resources A decision-making aid intended for use by primary Diagnosis and Management of Tuberculosis in https://theunion.org/technical- health care workers; the fourth edition includes Children and Adolescents: A Desk Guide for publications/diagnosis-and- revisions to diagnostic approaches and options for Primary Health Care Workers (4th Edition), management-of-tuberculosis-in-children- treatment of both TB infection and disease and is International Union Against Tuberculosis and and-adolescents-a-desk-guide-for- available in African and Asian editions, which Lung Disease (2023) primary-health-care-workers incorporate more region-specific examples Provides a comprehensive and up-to-date WHO Global TB Report (2023) assessment of the TB epidemic and of progress in https://www.who.int/publications/i/ (updated annually) prevention, diagnosis, and treatment of the disease item/9789240083851 at global, regional, and country levels WHO Information Sheet: Management of Provides a high-level overview of key concepts, https://www.who.int/publications/m/ Tuberculosis in Children and burden of disease, and program and item/information-sheet-management-of- Adolescents (2022) policy priorities tuberculosis-in-children-and-adolescents Trainings Online, self-paced e-course containing teaching WHO e-course for health care workers on the modules on epidemiology, diagnosis, treatment management of tuberculosis in children and and prevention of TB and drug-resistant TB with a https://openwho.org/channels/end-tb adolescents (2023) focus on latest guidelines; developed by WHO and The Union with support from CDC Online, self-paced e-course containing teaching WHO e-course on tuberculosis in children and modules with programmatic considerations for adolescents: programmatic https://openwho.org/channels/end-tb managing TB in children and adolescents; considerations (2023) developed by WHO with support from CDC Online, self-paced e-course with comprehensive learning modules on epidemiology, detection, The Union e-course on child treatment and prevention of TB and drug-resistant https://theunion.org/our-work/union- and adolescent TB for health care workers TB; updated to align with 2022 WHO guidelines on courses (Updated 2022) management of TB in children and adolescents; developed by The Union in collaboration with the Elizabeth Glaser Pediatric AIDS Foundation Online e-course companion to the Union Atlas reviewing the Atlas’ algorithmic approach to CXR https://coursesonline.theunion.org/ The Union e-course on CXR interpretation in interpretation; includes learning modules with theunion/2023/interpretation-of-chest-x- children with presumptive TB (2023) reviews of various findings on CXR among rays-in-children-with-tb/393947/ children with presumptive TB TB-Speed is a Unitaid funded project aimed at reducing childhood TB mortality by developing decentralized, cost-effective, and feasible https://www.tb-speed.com/wp-content/ TB-SPEED CXR training to diagnose diagnostic strategies to increase case-finding in uploads/2020/09/TB-Speed_Interpret- childhood TB children; presentation-based training covers Child-CHR.pdf common features and findings on CXR in children with pulmonary TB Pathogens 2024, 13, 467 4 of 38 Table 1. Cont. Resource Description Link (Accessed on 26 October 2023) Diagnosis and Treatment An information note describing the complementary diagnostic approaches of Making the best out of available tools and microbiological testing and clinical evaluation and approaches: Summary guidance for https: assessment; developed by the Pediatric TB microbiological and clinical diagnosis of //www.stoptb.org/file/16091/download Operational and Sustainability Expertise Exchange pulmonary TB among children Taskforce of the Child and Adolescent TB Technical Working Group Outlines practical guidance for collecting and WHO Global Laboratory Initiative: Practical processing stool samples for use with Xpert and https://www.who.int/publications/i/ manual for processing stool samples for Xpert Ultra; developed by the Global item/9789240042650 diagnosis of childhood TB Laboratory Initiative A guide and toolkit outlining how to implement The KNCV Simple-One-Step Method Stoolbox: the simple-one-step stool processing method for https: An implementation package for the SOS Stool Xpert and Xpert Ultra; developed by the KNCV //www.kncvtbc.org/en/sos-stoolbox/ method to detect TB and rifampicin resistance Tuberculosis Foundation Diagnostic CXR Atlas for Tuberculosis in Outlines an algorithmic approach to evaluating Children: A Guide to Chest X-Ray CXRs in children and integrating these findings https://theunion.org/technical- Interpretation, International Union into treatment decisions based on classification of publications/diagnostic-cxr-atlas-for- Against Tuberculosis CXR features by radiological severity; presents tuberculosis-in-children and Lung Disease (2nd Edition, 2022) numerous CXR images with detailed annotations A companion to the Union Atlas containing a collection of CXR images from children under 15 years of age who present with symptoms and signs Diagnostic CXR Atlas for Tuberculosis in of TB; CXRs in this library provide examples of https://theunion.org/technical- Children: Image Library, International Union features highlighted in the Union Atlas arranged publications/diagnostic-cxr-atlas-for- Against Tuberculosis and Lung Disease (2022) into seven categories: uncomplicated lymph node tuberculosis-in-children disease, cavitary disease, complicated lymph node disease, consolidations, miliary TB, pleural effusions and other Consensus clinical standards designed to provide Clinical standards for Drug-Susceptible TB in guidance on ‘best practice’ for diagnosis, treatment https: Children and Adolescents. (2023) and management of drug-susceptible //pubmed.ncbi.nlm.nih.gov/35768923/ pulmonary TB Provides information on clinical and Management of Multidrug-Resistant programmatic practice for managing MDR-TB in https://sentinel-project.org/wp-content/ Tuberculosis in Children: A Field Guide, childrenes; includes case examples to demonstrate uploads/2022/03/DRTB-Field-Guide-20 Sentinel Project for Pediatric Drug-Resistant how recommendations can be put into practice; 21_v5.pdf TB (5th Edition, 2022) complements existing recommendations Prevention WHO operational handbook on tuberculosis: Companion implementation guide to https://www.who.int/publications/i/ module 1: prevention: tuberculosis the 2020 WHO guidelines on TPT, providing item/9789240002906 preventive treatment practical guidance on implementing TPT Guidance from the American Academy of Tuberculosis Infection in Children and Pediatrics and its Committee on Infectious http://publications.aap.org/pediatrics/ Adolescents: Testing and Treatment: Clinical Diseases; includes effective approaches to the article-pdf/148/6/e2021054663/1354238/ Report and Guidance from the American testing and treatment of TBI in children peds_2021054663.pdf Academy of Pediatrics (2021) and adolescents Provides guidance and tools for ministries of health to develop comprehensive TPT programs https: PEPFAR TPT Implementation Guide for PLHIV, including children; includes //www.state.gov/pepfar-solutions/ and Toolkit considerations for incorporating TPT into resources-and-tools/tb-preventive- differentiated service delivery models for adults treatment-tpt-implementation-tools/ and children Pathogens 2024, 13, 467 5 of 38 Table 1. Cont. Resource Description Link (Accessed on 26 October 2023) Special Issues and Key Publications Peer-reviewed “state-of-the-art” articles by recognized leaders in child TB research and Pathogens Special Issue: Recent Advances and clinical management, as well as perspectives on https://www.mdpi.com/journal/ Ongoing Challenges in the Management of challenges for programmatic implementation in pathogens/special_issues/Tuberculosis_ Tuberculosis in Children and “real life” settings; addresses topics such as Children_Adolescents Adolescents (2022) epidemiology, clinical care, prevention, and health systems strengthening for DS and DR TB in children and adolescents Experts in childhood TB address several aspects of the TB epidemic in children, including TB/HIV, Journal of the Pediatric Infectious Diseases COVID-19, medication interactions and adherence, https://academic.oup.com/jpids/issue/ Society, Special Supplement: What’s New in diagnostics, new treatment regimens, vaccine 11/Supplement_3 Childhood Tuberculosis? (2022) development, and programmatic approaches to TB care and services Advocacy and Program Presents important data and tools which can be used to consolidate and advance advocacy, WHO Roadmap for ending TB in children and commitment, resource mobilization and joint https://www.who.int/publications/i/ adolescents (3rd Ed, 2023) efforts by all stakeholders to provide health care item/9789240084254 and address the burden of TB among children A virtual network of public health experts in child and adolescent TB in the sub-Sahara Africa region, The Union/CDC Sub-Saharan Africa Regional providing a community of learning and practice https://theunion.us9.list-manage.com/ Child and Adolescent TB Virtual Centre for child and adolescent TB; resources, training track/click?u=6bdc29f3fb65cf617f7e060 of Excellence materials, webinars, and case discussions available fa&id=07d0b79a2f&e=f06cc95456 on the website Key activities and interventions related to the Checklist of and budgeting tools for including prevention and management of tuberculosis in https://www.stoptb.org/checklist-tb- child and adolescent interventions in Global children and adolescents that should be considered interventions-gf-proposals Fund Against AIDS, TB, and for inclusion in country proposals to strengthen Malaria applications programming and help closing the persistent https://stoptb.org/wg/dots_expansion/ for TB programs policy-practice gap for child and adolescent TB childhoodtb/posee.asp 2. Prevention of TB in Children The risk of developing disease after TB infection (TBI) in children is associated with numerous factors, including age at exposure, immune and nutritional status, genetics, and pathogen virulence. A recent modeling study estimated that HIV infection, undernutrition, and a lack of bacille Calmette–Guérin (BCG) vaccination in TB-endemic settings may account for 25% of new TB cases in children. Young age and HIV infection are the most important risk factors for severe or disseminated disease, such as TBM and miliary TB, which are the most common causes of death from TB in children. Children who develop TB disease usually do so within one year following infection; therefore, TB in children is also an indicator of ongoing transmission within a household or the community. The risk of progression from untreated TBI to TB disease varies by age. In a recent meta-analysis of children with close TB exposure, the two-year risk of developing TB in children with positive TBI tests who had not received TPT was 19% for children under five years of age, 9% for children 5–14 years of age, and 11% in adolescents 15–18 years of age. The risk of developing TB was highest during the first 90 days after exposure or evaluation and in the youngest children; 83% of children under five who developed TB did so within 90 days of their initial visit, underlining the importance of prompt contact investigations and initiation of TPT. The main interventions currently available to reduce the risk of TBI and/or progres- sion to active TB disease in children are: (1) community-based active case detection and treatment of people with TB (and TBI), (2) vaccination with BCG, (3) TPT, and (4) TB infec- tion prevention and control [14,39]. There are also numerous new TB candidate vaccines in development—some of which are in advanced clinical trials—offering the prospect of new interventions on the horizon, which will be discussed later in the manuscript. Pathogens 2024, 13, 467 6 of 38 2.1. Community-Based Active TB Case Detection and Treatment for TB and TBI One important population-based intervention that can reduce the risk of TB exposure and infection (and thereby TB disease) in children is a reduction in the overall number of TB cases in a population through community-wide screening, active case finding, and treat- ment for TB disease and TBI. The successful impact of these population-based interventions in reducing TB transmission and prevalence was demonstrated in Alaska, USA, more than 50 years ago. A recent cluster-randomized controlled study (called ACT3) evaluated the effectiveness of active, community-wide TB disease screening and treatment for adults in reducing TB and TBI prevalence in a high-TB burden province in Vietnam. At the end of the ACT3 study period, researchers found a statistically significant reduction (44%) in TB prevalence in the intervention clusters receiving community-based active screening and treatment for TB disease when compared to standard passive TB case detection alone. Furthermore, although this study did not find a statistical difference in TBI among young children born immediately before the interventions began, post ad-hoc analyses among older children (3–10 years of age at the start of the intervention) demonstrated a 50% reduction in the prevalence of TBI in these children when compared to children in control clusters. This study suggests that older children, who perhaps had more interactions in the community, benefited most from decreased TB transmission. Other modeling studies and randomized clinical trials, either underway or completed, have taken a holistic case-finding approach, finding and treating both active TB disease and TBI, to rapidly reduce TB in a durable way [42,43]. 2.2. BCG Vaccine BCG vaccine, the only vaccine currently licensed for the prevention of TB, is a live, attenuated vaccine using Mycobacterium bovis (a mycobacterium species that causes TB in cattle) launched over 100 years ago. In 2020, WHO reported that BCG vaccine was part of the national childhood vaccine schedule in 154 countries, with most countries reporting coverage of at least 90%. With millions of doses administered to infants globally every year, BCG is one of the most widely used vaccines in the world and is considered highly cost-effective in low-resource countries with high-TB burdens [45–48]. There have been numerous efficacy trials and epidemiological studies of BCG over the past several decades [47–56]. The greatest benefit of BCG vaccination, which drives its cost-effectiveness , is its efficacy in prevention of severe forms of TB (e.g., TBM and miliary TB), especially in young children. Randomized clinical trials (RCTs) indicate that BCG has 85% protective efficacy against severe forms of TB, with the highest protection found in infants immunized during the neonatal period (90% reduction in severe forms of TB). Worldwide, several BCG vaccines, based on different BCG strains, are available and administered by intradermal injection. BCG vaccination typically causes a scar at the site of injection; however, scar formation is not a marker for protection, and there may be differences in protective efficacy between vaccine strains. BCG vaccine can cause more severe, localized reactions, including hypersensitivity, ulceration, abscess formation, and regional lymphadenitis, but this is uncommon. Most of these adverse events are self- limited and do not require medical or surgical intervention. Disseminated BCG disease, which is associated with an overall case-fatality rate of up to 70% and was rare in the pre-HIV era (one case per 1 million BCG-vaccinated children), currently occurs mainly in children living with HIV (CLHIV) and in those with primary immunodeficiencies. Rates of disseminated BCG in children increased following the advent of the HIV epidemic and prior to early antiretroviral therapy (ART), with one South African study reporting a rate of 992 per 100,000 BCG-vaccinated CLHIV [57,58]. Fortunately, these rates have fallen following implementation of early ART for HIV-infected infants and are again a rare phenomenon. Disseminated BCG disease presents a clinical picture similar to TB, with findings including failure to thrive, anemia, hepatosplenomegaly, lymphadenitis, osteomyelitis, and pneumonia. BCG-derived M. bovis yields a positive result on initial Pathogens 2024, 13, 467 7 of 38 molecular tests, such as Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Xpert Ultra), so culture may be necessary to distinguish it from TB. Management of disseminated BCG disease usually includes treatment with isoniazid, rifampicin, and ethambutol (with or without a fluoroquinolone such as levofloxacin), as BCG is resistant to pyrazinamide and some strains are partially resistant to isoniazid [39,60]. WHO currently recommends that a single dose of BCG vaccine be given to all healthy neonates at birth (or at the earliest opportunity thereafter) for prevention of TB in countries and settings with a high incidence of TB, defined by WHO as more than 100 cases of TB per 100,000 population. Countries with a low incidence of TB may choose to selectively vaccinate high-risk neonates or other high-risk populations, such as immigrants from high-TB-incidence countries and health care workers, which has been found to be more cost-effective than universal BCG vaccination in these settings [50,59,62–65]. While CLHIV, when vaccinated with BCG at birth, are at increased risk of developing disseminated BCG disease , after a risk-benefit analysis, WHO guidelines now recommend that neonates and CLHIV in high TB incidence settings receive BCG vaccination if they are stable on ART (CD4% > 25% for children aged 5 years) or clinically stable if CD4 testing is unavailable. The timing of BCG vaccine administration is important to consider in infants exposed to HIV, infants living with HIV, and neonates exposed to mothers with infectious TB [14,39,47]. While BCG vaccine is known to be effective in protecting infants and children from severe TB disease, demonstrated protection has not been consistent against all forms of TB and in all age groups. Protection also varies by geographic latitude (which may be a marker for atypical mycobacterial prevalence). BCG vaccine efficacy against pulmonary TB (PTB) has varied widely across studies, with lower efficacy in adults, although some recent evaluations have found higher efficacy in certain groups. Evidence also indicates that BCG vaccine protects against TBI as well as TB disease; it has been estimated that BCG vaccine may prevent approximately 20% of vaccinated children from developing TBI following exposure to TB [47,52]. However, there is no evidence of effectiveness when BCG vaccine is used as a post-exposure prophylaxis after TBI [51,54,56]. BCG vaccine also demonstrates some effectiveness against leprosy, Buruli ulcer, and non-tuberculous mycobacteria (NTM) lymphadenitis in children as well as non-specific (likely immunologi- cally mediated) effects associated with decreased all-cause mortality rates, especially in children [39,47,66]. Protection after primary BCG vaccination could last for up to 15 years; however, overall vaccine efficacy declines over time [47,52]. 2.3. TB Preventive Treatment TBI is defined by WHO as “a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifested active TB disease”. An estimated 7.5 million children are infected with TB each year [67,68]. There are more than 67 million children infected with TB worldwide, including 2 million children infected with multidrug-resistant TB (MDR-TB) and 100,000 children with extensively drug-resistant TB (XDR-TB). After being exposed to a person with TB disease at home, it is estimated that up to 35% of children under five years of age will develop TBI and up to 10% will develop TB disease. Such findings underscore the importance of contact investigations in identifying and screening children who have been exposed to TB, which can greatly enhance TB and TBI case-finding, evaluation, and treatment [27,69]. In addition, CLHIV are 8–20 times more likely to develop TB disease than those without HIV infection, and this risk remains elevated, although blunted, in CLHIV on ART. Providing treatment for TBI to prevent progression to TB disease (TPT) is an effective and critical component of efforts to end TB locally and globally. Despite the importance of TPT, from 2018 to 2022, only 15.5 million people were treated with TPT globally. Most (11.3 million) were people living with HIV (PLHIV) treated through the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR)-supported programs , including nearly 600,000 CLHIV. However, far fewer eligible household Pathogens 2024, 13, 467 8 of 38 contacts receive TPT; in 2022, only 37% of eligible household contacts under five years of age and only 11% of contacts above five years of age were provided TPT. Most children who would benefit do not receive TPT either because they are not appropriately identified or because TPT is out of stock. Implementing an effective TB prevention program requires a comprehensive package of interventions: (1) identification, screening, and testing in populations with high TB risk; and (2) delivering and monitoring effective and safe preventive treatment. WHO has developed an application for monitoring this cascade of care called the PREVENT-TB tool , which is also included in the Resources Table (Table 1). 2.3.1. Identification, Screening, and Evaluation of Children at High Risk of TB WHO recommends TB contact investigations as well as systematic screening for children at high risk for TB disease and TBI in all clinical settings where children seek care. Systematic screening includes identifying people at risk for TB disease in a predetermined target group by assessing signs and symptoms and using tests, examinations, or other procedures that can provide rapid results to determine if further evaluation is needed. In children who screen positive, one or more diagnostic tests and clinical assessments are usually required to establish a TB diagnosis (see Section 3). Screening can also identify children who are eligible for and could benefit from TPT if the child does not have TB disease [14,39]. For all children, it is important to determine that a child does not have TB disease before initiating TPT. Screening approaches differ slightly for the two primary groups of children at high risk of TB: (1) those in close contact with a person with TB, and (2) those with elevated risk of progression from TBI to TB disease, including young children, CLHIV, children with SAM, and other risk groups [14,39,72]. Pathogens 2024, 13, 467 The WHO-recommended TBI and TPT eligibility algorithm (Figure 1) outlines 10 of 40 the steps involved in making a decision to initiate TPT. Figure 1. The WHO algorithm for screening for and evaluation of TBI and TPT eligibility in children 1. The Figurefrom the WHO algorithmhandbook WHO operational for screening for and Module on tuberculosis. evaluation of TBI and 5: management of TPT eligibility tuberculosis in in children children and adolescents. from the WHO operational handbook on tuberculosis. Module 5: management of tuberculosis in children and adolescents. 2.3.2. TPT Guidance and Implementation Considerations for Children TPT is a mainstay of TB prevention in children, as TPT can prevent TB disease in 91% of children and adolescents with TBI [38,39]. Further, a recent study modeled the com- bined intervention of contact investigations and TPT in 29 high-incidence countries and found it was cost-effective for household contacts of all ages, saving an estimated 850,000 lives (700,000 among household contacts under 15 years) by 2035 if short-course TPT was provided to all contacts who screened negative for TB. There are several short and effective TPT regimens recommended by WHO, follow- ing clinical trials that included children and adolescents (Table 2) [38,39,76]. WHO cur- Pathogens 2024, 13, 467 9 of 38 WHO currently recommends that child and adolescent household contacts of people with bacteriologically confirmed TB disease should be systematically screened for TB disease during contact investigations. Recommended screening includes symptom screening (with symptoms including cough for more than two weeks, fever for more than two weeks, poor weight gain [or weight loss] in the past three months, or reduced playfulness or lethargy in young children) and/or a chest X-ray (CXR) (both posteroanterior and lateral views). For those children under five years of age who are screened and found not to have TB disease, WHO recommends a course of TPT. For older children and adolescents who have been found not to have TB disease, WHO recommends consideration for TPT as well, if resources allow. WHO also recommends that CLHIV be systemically screened for TB disease at each visit to a health facility and evaluated for TPT in all settings [14,39]. For CLHIV, screening (with symptoms including current cough, fever of any duration, and poor weight gain in the past three months) is recommended during every encounter with a health care worker. There are additional situations in which CLHIV are prioritized for immediate evaluation, regardless of symptoms. Triggers for Diagnostic Evaluation for CLHIV (See also Section 3) : If CLHIV screen positive on a TB symptom screen, they should be immediately flagged for further diagnostic evaluation for TB disease. If CLHIV have a documented contact with someone with TB disease, they are priori- tized for immediate diagnostic evaluation, regardless of symptoms. For CLHIV with advanced HIV disease (AHD) or who are seriously ill, lateral flow urine lipoarabinomannan assays (LF-LAM) can be used as an initial TB test, regardless of the presence of symptoms. Provision of TPT when the TB screen is negative in CLHIV : CLHIV over 12 months of age who have a negative TB screening evaluation and live in a high TB burden setting should be offered TPT as part of a comprehensive package of HIV care, regardless of history of contact with a person with TB. For infants under 12 months of age living with HIV, TPT is recommended if there is a history of close contact with a person with TB and the infant has had a negative screen for TB disease. It should be noted that tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) have only limited utility as screening tools for TB disease in children (or adults), as both tests are unable to distinguish between TBI and TB disease. Both tests can serve as markers for TBI; however, they can each give false-positive and false-negative results [73,74]. TBI testing by TST or IGRA is not required before initiating TPT for household contacts under five years of age or CLHIV. These tests play a role in decision-making for TPT initiation (Figure 1) and in an extended diagnostic evaluation of children with presumed TB(discussed further in the Section 3). 2.3.2. TPT Guidance and Implementation Considerations for Children TPT is a mainstay of TB prevention in children, as TPT can prevent TB disease in 91% of children and adolescents with TBI [38,39]. Further, a recent study modeled the combined intervention of contact investigations and TPT in 29 high-incidence countries and found it was cost-effective for household contacts of all ages, saving an estimated 850,000 lives (700,000 among household contacts under 15 years) by 2035 if short-course TPT was provided to all contacts who screened negative for TB. Pathogens 2024, 13, 467 10 of 38 Table 2. Regimens for treating pediatric TB infection and drug-susceptible TB (non-severe, severe, and meningitis and osteoarticular). Interval of Monitoring Regimen Drugs * Duration (Months) Preferred Regimen Considerations for Use Administration Considerations ** TB Infection Children of all ages; child-friendly FDC (HR If fixed-dose combination (FDC) 50 mg/75 mg) is available; If FDC not Isoniazid (H) available, preferred for available, for HIV-negative children 3HR ‡ Daily 3 Rifampicin (R) HIV-negative 15 years), Isoniazid (H) in CLHIV 3HP ‡ Weekly (12 doses) 3 on TDF, EFV, DTG or Rifapentine (P) on ART (lopinavir/ritonavir (LPV/r), DTG, RAL-based ART NVP) are ongoing; WHO does not recommend 3HP for CLHIV. Take with food containing fat if possible. Pyridoxine for select patients. † Children of all ages; No pediatric Evaluate monthly formulation available: For CLHIV: TPT monitoring rifampin tablet (300 mg) can be used in 4R Rifampicin (R) Daily 4 can be aligned with ART; older children and Consider drug–drug adolescents; for younger children, interactions for CLHIV on pill crushing ART and TPT *** or compounding may be necessary. Children of all ages; Preferably use dispersible tablets in children; 3HR may be considered as an Preferred for CLHIV 6H or 9H Isoniazid (H) Daily 6 or 9 alternative regimen for children on on ART EFV-based ART; Monitor for signs of H-induced hepatotoxicity. Pyridoxine for select patients. † 1HP is recommended by WHO as an alternative TPT regimen for HIV-negative children aged ≥13 years and > 25 kg Isoniazid (H) Daily and CLHIV 1HP 1 Rifapentine (P) (28 doses) ≥13 years if on TDF, EFV, DTG or RAL-based ART. Take with food containing fat if possible. Pyridoxine for select patients. † Pathogens 2024, 13, 467 11 of 38 Table 2. Cont. Interval of Monitoring Regimen Drugs * Duration (Months) Preferred Regimen Considerations for Use Administration Considerations ** Non-Severe Drug-Susceptible TB Disease Follow definitions for non-severe disease Isoniazid (H) Children (3 months to determine Evaluate bi-weekly during 2 months HRZ(E), Rifampicin (R) < 16 years) with non-severe eligibility. For young children, Daily 4 intensive phase and 2 months HR Pyrazinamide (Z) pulmonary or peripheral lymph child-friendly, dispersible, and appropriate monthly thereafter ±Ethambutol (E) node disease FDC available (R75/H50/Z150; R75/H50; E100) Drug-Susceptible TB Disease Isoniazid(H) Children with severe disease Evaluate bi-weekly during 2 months HRZ(E), Rifampicin (R) and no presumptive drug Child-friendly formulations available Daily 6 intensive phase; monthly 4 months HR Pyrazinamide (Z) resistance; children not (see above) thereafter ±Ethambutol (E) responding to shorter regimen Child friendly formulations available for Isoniazid (H) 2 months HPZM, Evaluate bi-weekly during Children ≥ 12 years weighing ≥ all medications Rifapentine (P) 2 months Daily 4 intensive phase and 40 kg with drug-susceptible (see above) including moxifloxacin (100 Pyrazinamide (Z) (9 weeks) HPM monthly thereafter pulmonary TB mg). No FDC for full regimen. Cost may be Moxifloxacin (M) prohibitive in some settings. Drug-Susceptible TB Meningitis or Osteoarticular TB The optimal rifampicin dosages are still being evaluated Isoniazid (H) but higher CSF penetration can be achieved 2 months HRZE Rifampicin (R) Evaluate bi-weekly or at Children with TBM or Daily 12 with higher 10 months HR Pyrazinamide (Z) clinician discretion osteoarticular TB dosages (20–30 mg/kg). Ethambutol (E) Child-friendly formulations available (see above) Isoniazid (H) See above regarding optimal rifampicin 6 months Rifampin (R) Evaluate bi-weekly or at dosages. Child-friendly formulations Daily 6 Children with TBM HRZEto Pyrazinamide (Z) clinician discretion available for RHZE (see above), plus Eto Ethionomide (Eto) 125 mg Table adapted from: Nolt D, et al. ; and Yuen CM, et al. , and informed by the WHO operational handbook ; * For more detailed dosing information, including dosing based on weight bands please see WHO operational handbook. ** Monitoring should focus on the following: (1) weight checks; (2) presence of TB symptoms; (3) presence of adverse events related to TBI and TB drug regimen; and (4) adherence to treatment. Routine laboratory monitoring is not necessary for healthy children and adolescents, but should be considered for those with immunocompromise, existing hepatic disease, or on other hepatotoxic medications. *** For more detailed information on TPT regimens to use with ART, please see WHO operational handbook on tuberculosis. † Select patients include exclusively breastfed infants, children and adolescents on meat or milk-deficient diets, symptomatic CLHIV, children with nutritional deficiencies, and pregnant females. ‡ WHO Guidelines are expected out in July 2024 that will directly impact age limitations for 3HR and 3HP. Pathogens 2024, 13, 467 12 of 38 There are several short and effective TPT regimens recommended by WHO, following clinical trials that included children and adolescents (Table 2) [38,39,76]. WHO currently recommends the following TPT options for use in children, although there are special considerations for CLHIV (see below); Six or nine months of isoniazid daily (6H or 9H) (all ages); Three months of weekly isoniazid plus rifapentine (3HP); Three months of isoniazid plus rifampicin daily (3HR) (all ages); One month of daily isoniazid plus rifapentine (1HP); or; Four months of daily rifampicin (4R) (all ages). The age of the child, HIV status, ART regimen, and availability and affordability of child-friendly formulations have bearing on the choice of TPT regimen. Compared to 6H, the newer rifamycin-based regimens demonstrate equal efficacy with better adherence, less drug-related toxicity, and potentially lower costs due to decreased utilization of the health system. Rifampicin- and rifapentine-containing regimens should be prescribed with caution in CLHIV on ART because of potential drug–drug interactions with the most common ART regimens. Although pharmacokinetic and safety studies are underway to inform use of these regimens in this population, 6H is currently the preferred regimen for CLHIV under 13 years [14,39]. WHO guidelines are expected in July 2024 regarding use of rifapentine and dolutegravir. Globally, 3HR is the preferred TPT option among HIV-negative children because child-friendly dispersible fixed-dose combinations (FDCs) for rifampicin (75 mg) and isoniazid (50 mg) are widely available, used for TB treatment, and are less prone to dosing errors than single formulations. Pediatric formulations are unavailable in some countries, especially those with low TB incidence, so crushing of pills, opening capsules, or compounding are utilized to ensure correct dosing. Monitoring and evaluating children on TPT can take place at a health care facility, in the community (by treatment supporters), or by using digital tools such as video-supported treatment [23,39,78] at recommended monitoring intervals noted in Table 2. In high-risk household contacts of people with MDR-TB, WHO notes that TPT “may be considered based on individualized risk assessment and sound clinical justification”. WHO is currently updating guidelines regarding specific TPT regimens for children who are contacts of persons with MDR-TB; they are expected by July 2024. In the interim, a recent Rapid Communication from WHO stated that a regimen of six months of levofloxacin should now be used as TPT for contacts of MDR or rifampicin-resistant (RR) TB patients based on evidence from two well-conducted randomized clinical trials in South Africa and Vietnam [14,39,61,77]. 2.4. TB Infection Prevention and Control Infection prevention and control (IPC) in health care services and other settings at high risk for transmission is a pillar of global TB prevention efforts. Children with TB are often considered unlikely to transmit TB (due to paucibacillary disease and a relative lack of cough) [6,79], but children can and do transmit TB. Further, both children and adults are at risk for TB transmission in health care facilities and households without adequate infection control measures in place. Therefore, the same IPC principles apply for both children and adults in health care facilities and other high-risk transmission settings, including in areas dedicated solely to children. IPC recommendations to reduce TB transmission in these settings include: 1. administrative controls (e.g., fast-tracking people with TB symptoms for evaluation, isolating those with presumptive or diagnosed TB disease, initiating TB treatment immediately for those with TB, and encouraging cough etiquette and providing masks for anyone with an active cough or presumed TB); 2. environmental controls (e.g., natural and mechanical ventilation systems, and upper- room germicidal ultraviolet systems); and 3. respiratory protection for health care workers (HCWs) (e.g., N95 masks/particulate respirators). Pathogens 2024, 13, 467 13 of 38 The greatest risk of transmission to children in health facilities occurs when young children mix with adults and adolescents with untreated TB. Therefore, people with cough and/or presumptive TB should not mix with infants and children in child health settings (e.g., immunization clinics or well-baby checks) or children and adolescents at HIV clinics. In high-burden settings, there is a particularly high risk that adults accompanying or visiting children may have untreated TB disease. 3. Evaluating Children with Presumptive TB Diagnostic evaluation is the next step in the care cascade after a child has screened positive for TB. In practice, diagnosing TB in children necessitates using all available findings from clinical assessments, radiography, and laboratory investigations to inform a treatment decision. Since current diagnostic tests have lower sensitivity in children, especially young children and CLHIV (see Table 3), most of these children are diagnosed based on a careful medical history and clinical examination, along with CXR and TBI testing when available. Bacteriologic confirmation of TB disease in these children is important and utilizing the highest number and combination of traditional and alternative laboratory specimen types, including those that are more child-friendly and less invasive, can improve the likelihood of obtaining confirmation. Such efforts are important to guard against overdiagnosis and ensure pediatric patients have access to drug resistance testing. Older adolescents who present with TB symptoms similar to those in adults and can produce sputum and other specimen types recommended for adult patients can be evaluated using approaches designed for adults. In general, evaluating a child for TB relies on a combination of the following: Clinical assessment, Careful medical history, including contact with someone who had TB, previous TB treatment, BCG vaccination, and signs and symptoms consistent with TB; Clinical examination, including growth assessment; and HIV testing if the status is unknown. TBI testing (TST or IGRA), Radiological investigations, and Bacteriological investigations, including those relevant to presumed EPTB. We describe below WHO-recommended clinical assessment approaches as well as radiologic and bacteriological investigations and their applications. Also highlighted and discussed is the importance of integrated clinical decision algorithms designed to standardize and score the findings from these investigations to inform a treatment decision. Pathogens 2024, 13, 467 14 of 38 Table 3. Considerations for WHO-Recommended Rapid Diagnostic (WRD) Tests for Pediatric TB Detection *. Recommended Detects Drug Recommended Test Test Setting Turnaround Time Sensitivity † Specificity † Population Resistance Specimen Type # Sputum 64.6% (55.3 to 72.9) 99.0% (98.1 to 99.5) Gastric fluid 73.0% (52.9 to 86.7) 98.1% (95.5 to 99.2) Near point-of-care NPA 45.7% (27.6 to 65.1) 99.6% (98.9 to 99.8) (POC) Stool 61.5% (44.1 to 76.4) 98.5% (97.0 to 99.2) Xpert MTB/RIF All pediatric subgroups Requires Yes