Review
Tuberculosis susceptibility and protection in children

https://doi.org/10.1016/S1473-3099(18)30157-9Get rights and content

Summary

Children represent both a clinically important population susceptible to tuberculosis and a key group in whom to study intrinsic and vaccine-induced mechanisms of protection. After exposure to Mycobacterium tuberculosis, children aged under 5 years are at high risk of progressing first to tuberculosis infection, then to tuberculosis disease and possibly disseminated forms of tuberculosis, with accompanying high risks of morbidity and mortality. Children aged 5–10 years are somewhat protected, until risk increases again in adolescence. Furthermore, neonatal BCG programmes show the clearest proven benefit of vaccination against tuberculosis. Case-control comparisons from key cohorts, which recruited more than 15 000 children and adolescents in total, have identified that the ratio of monocytes to lymphocytes, activated CD4 T cell count, and a blood RNA signature could be correlates of risk for developing tuberculosis. Further studies of protected and susceptible populations are necessary to guide development of novel tuberculosis vaccines that could facilitate the achievement of WHO's goal to eliminate deaths from tuberculosis in childhood.

Introduction

Traditionally, the field of paediatric tuberculosis has been neglected, although recent years have seen a welcome increase in policy focus including the goal of zero childhood tuberculosis deaths.1 To achieve this ambition, substantial progress now needs to occur, given that more than 1 million children developed active tuberculosis in 2016 with 250 000 children dying of the disease.2 This number represents 10% of the total global burden of incident tuberculosis and 15% of associated total mortality.2 Children can equally be affected by resistant strains of Mycobacterium tuberculosis, with an estimated 25 000 children developing multidrug-resistant (MDR) tuberculosis and 1200 developing extensively drug-resistant (XDR) tuberculosis in 2014 alone.3 There are numerous social, epidemiological, immunological, diagnostic, and therapeutic differences between childhood and adult tuberculosis,4 hence paediatric tuberculosis requires specific considerations in clinical, public health, and research aspects.

Children and adolescents represent clinically important populations with increased susceptibility to tuberculosis, and key groups in whom to study mechanisms of protection. The precise definition of paediatric tuberculosis is debated: WHO reports tuberculosis data for those younger than 15 years, the UN Convention on the Rights of the Child defines a child as someone younger than 18 years, and adolescence is increasingly considered to last until the age of 24 years.2, 5, 6 In this Review, we use the term paediatric to broadly refer to those younger than 18 years, while acknowledging that the burden of disease in adolescents is therefore underestimated.

Children aged under 5 years have the highest risk of progressing to disease after infection, with infection defined as mycobacterial sensitisation shown by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). They are also at the highest risk of disseminated forms of tuberculosis such as miliary tuberculosis and tuberculous meningitis.7 Young children are also the most likely to die, with tuberculosis mortality rates from the pre-treatment era of nearly 50% in those younger than 5 years, substantially higher than in older children.8

By contrast, young school-aged children (5–10 years old) seem to be protected against tuberculosis, before a second peak in incidence during adolescence and into adulthood (figure 1).12 In fact, many children control M tuberculosis without intervention. Studies from the pre-chemotherapy era show that most children survive tuberculosis disease without treatment,8 pathological appearances on pulmonary radiographs frequently clear spontaneously,9 and M tuberculosis can be cultured from recently infected children who are asymptomatic and do not proceed to become unwell.13 Contemporary data confirm that some children with culture-confirmed MDR tuberculosis remain well and symptom free in the absence of treatment.14 Therefore, the interactions between human host and the mycobacterial pathogen are increasingly recognised to develop along a spectrum rather than falling within clearly delineated categories.15, 16, 17, 18

This diversity in human responses to M tuberculosis exposure raises the question of whether a protective immune response can be promoted by a new vaccine. The development of a protective vaccine by 2025 is a cornerstone of the WHO End TB Strategy.19 Children are the only group for whom there is strong evidence of inducible protection though vaccination.20, 21, 22 BCG, a live, attenuated vaccine, was first given to humans in 1921 and has been administered to more people than any other vaccine in history. Infants (younger than 12 months) were the target population for the first phase 2 randomised placebo-controlled clinical trial23 of a new tuberculosis vaccine, the modified vaccinia virus Ankara expressing antigen 85A (MVA85A). Unfortunately, the MVA85A vaccine showed no additional efficacy against tuberculosis disease or infection beyond that of BCG in South African infants. These results, which did not confirm previous animal models and human immunogenicity data, prompted reappraisal of future strategies in the field of tuberculosis vaccine development.24, 25, 26

The investigation of human correlates of protection against M tuberculosis remains a major research priority.19, 24 To date, our understanding of protection in children has been derived from three main research approaches. One such approach has been the use of case-control studies, nested within paediatric and adolescent interventional trials or cohorts. Commonly, patients who developed tuberculosis disease, are compared with those who remained well. Such studies have enrolled more than 15 000 children and young people between them, almost entirely from South Africa, and have used various laboratory approaches in the search for correlates of risk and protection (table).16, 23, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 A second approach has been active contact tracing, assessment, and follow up of individuals exposed to M tuberculosis, for example, through household contact studies or outbreak investigations.10, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 A third approach has been identification of genetic defects in children with severe forms of mycobacterial disease. By examining the immunological pathways involved, critical aspects of the human immune response necessary to contain M tuberculosis can be identified.50, 51, 52 In this Review, we first summarise key components of the paediatric immune response to M tuberculosis (figure 2) before focusing on the understanding of risk and protective factors when children encounter M tuberculosis (figure 3). For clarity, we have structured our discussion around the concepts of exposure, infection, pulmonary disease, severe disease, and death, although we acknowledge that this structure represents a simplification of the clinical spectrum.

Section snippets

Key components of the paediatric immunological response to M tuberculosis

There are several possible outcomes when a child inhales M tuberculosis; there can be changes in status over time as well as heterogeneity of outcomes within an individual's lungs.18 These outcomes are: elimination of M tuberculosis by the innate immune system; asymptomatic control of the mycobacteria accompanied by a cell-mediated immune memory response (tuberculosis infection) with or without persistence of viable organisms; direct progression to pulmonary disease (previously known as primary

Risk of exposure to M tuberculosis

The relationship between paediatric tuberculosis and poverty is overwhelming (figure 4) and confounds other risk factors.70, 71 The influence of poverty extends across the whole spectrum of paediatric tuberculosis and is associated with increased risk of being exposed to tuberculosis, of becoming infected, of developing disease, and of poor outcomes.72

The risk of exposure to M tuberculosis is a combination of epidemiological, environmental, sociocultural, and behavioural factors that reflect

Risk of infection with M tuberculosis

After exposure, the risk that a child will develop M tuberculosis infection is influenced by the infectiousness of the source case, the duration and intensity of the interaction, the infectivity of the organism and the immune responses of the child.73 Source cases are more infectious if they have a high bacterial load, which is clinically reflected by sputum smear-positivity.42 Extensive pulmonary disease in the source case, defined as affecting multiple zones on a chest radiograph, is

Protection against infection by M tuberculosis

Understanding why some children who are exposed to M tuberculosis show no signs of infection is crucial in understanding an effective early human immune response to M tuberculosis. This knowledge could definitively inform the design of vaccines able to induce protection against infection.93, 94 In the absence of a gold standard, protection against infection is considered to be absence of a positive TST or IGRA despite documented exposure or living in high prevalence regions. A Colombian

Risk of pulmonary tuberculosis disease

Data from the pre-chemotherapy era showed clearly that age is one of the most important factors in predicting which children will progress to disease. In the absence of any preventive therapy, infected infants have a 50% risk of progression to disease; however, this risk reduces between 5 and 10 years of age, before rising again as children enter adolescence (figure 1).9, 101, 102, 103 The pattern of increased susceptibility with young age is supported by contemporary data, with progression

Protection against pulmonary tuberculosis disease

Existing, safe, and effective interventions to prevent children exposed to or infected with tuberculosis from progressing to disease already exist.129, 130 WHO makes a dual recommendation that household or close contacts of patients with tuberculosis are actively traced with particular focus on children,131 and that children younger than 5 years who are found not to have tuberculosis disease should be given isoniazid daily for 6 months.132 The decades of experience with isoniazid preventive

Risk of severe tuberculosis disease and death

Mycobacterial and host factors influence the risk of disease progression to disseminated disease or death.147, 148, 149 The Beijing strain of M tuberculosis has been shown in some studies to be associated with disseminated disease in adults.80 However, this pattern has not been shown convincingly in children.149, 150, 151 Young age, MDR-tuberculosis, HIV infection, malnutrition, extrapulmonary tuberculosis, and a TST result of less than 5 mm, have all been found to be associated with death from

Protection against severe tuberculosis disease

Evidence for the efficacy of BCG is strongest for prevention of severe disease. BCG protects young children from tuberculous meningitis and miliary tuberculosis, with an efficacy of 75–85%.20, 22 However, this value varies in different geographical regions, with a reported efficacy in the UK of up to 80%, versus 0–20% in low-income countries nearer the equator, where there is increased prevalence of helminth infections and exposure to environmental mycobacteria.22, 145 The immunogenicity of BCG

Future directions

Despite many years of substantial research, through combinations of hypothesis-based and hypothesis-generating methodologies, with the evaluation of unstimulated and mycobacteria-stimulated samples, and with more than 15 000 infants and adolescents enrolled into trials that enabled case-control comparisons, true correlates of protective paediatric immunity remain elusive (table). It is essentially unknown why BCG protects some children but not others. Differential responses to BCG vaccination

Search strategy and selection criteria

We searched PubMed for articles, using combinations of the search terms “tuberculosis”, “risk”, “susceptibility”, “immune correlate”, “epidemiology,” “infection”, “disease”, “correlate”, “preventive”, “prophylactic”, “protect*”, “genome-wide association study”, “genetics”, and “immunology”. Results were restricted to studies in people aged 0–18 years, without language restrictions, published any date before April 30, 2017. Articles resulting from these searches and relevant references cited in

References (162)

  • PC Hill et al.

    Tuberculosis case-contact research in endemic tropical settings: design, conduct, and relevance to other infectious diseases

    Lancet Infect Dis

    (2010)
  • BD Gessner et al.

    Risk factors for pediatric tuberculosis infection and disease after household exposure to adult index cases in Alaska

    J Pediatr

    (1998)
  • C Jones et al.

    Immunology and pathogenesis of childhood TB

    Paediatr Respir Rev

    (2011)
  • S Smith et al.

    Immunobiology of childhood tuberculosis: a window on the ontogeny of cellular immunity

    J Pediatr

    (1997)
  • H Qi et al.

    Toll-like receptor 1 (TLR1) gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children

    Tuberc

    (2015)
  • S-Y Eum et al.

    Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB

    Chest

    (2010)
  • D Di Liberto et al.

    Decreased serum granulysin levels in childhood tuberculosis which reverse after therapy

    Tuberculosis

    (2007)
  • SA Lule et al.

    Factors associated with tuberculosis infection, and with anti-mycobacterial immune responses, among five year olds BCG-immunised at birth in Entebbe, Uganda

    Vaccine

    (2015)
  • S Babu et al.

    Helminth-tuberculosis co-infection: an immunologic perspective

    Trends Immunol

    (2016)
  • LM Verhagen et al.

    Helminths and skewed cytokine profiles increase tuberculin skin test positivity in Warao Amerindians

    Tuberculosis

    (2012)
  • The roadmap for childhood TB: toward zero deaths

    (2013)
  • Global tuberculosis report 2017

    (2017)
  • CM Perez-Velez et al.

    Tuberculosis in children

    N Engl J Med

    (2012)
  • R Basu Roy et al.

    Why the Convention on the Rights of the Child must become a guiding framework for the realization of the rights of children affected by tuberculosis

    BMC Int Health Hum Rights

    (2016)
  • BJ Marais et al.

    The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era

    Int J Tuberc Lung Dis

    (2004)
  • C Lienhardt et al.

    Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in The Gambia, West Africa

    Pediatrics

    (2003)
  • R Wood et al.

    Changing prevalence of tuberculosis infection with increasing age in high-burden townships in South Africa

    Int J Tuberc Lung Dis

    (2010)
  • A Wallgren

    Primary pulmonary tuberculosis in childhood

    Am J Dis Child

    (1935)
  • M Loveday et al.

    Dilemma of managing asymptomatic children referred with ‘culture-confirmed’ drug-resistant tuberculosis

    Arch Dis Child

    (2016)
  • MPR Berry et al.

    An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

    Nature

    (2010)
  • H Esmail et al.

    Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography

    Nat Med

    (2016)
  • A Lenaerts et al.

    Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses

    Immunol Rev

    (2015)
  • C Lienhardt et al.

    Translational research for tuberculosis elimination: priorities, challenges, and actions

    PLoS Med

    (2016)
  • A Roy et al.

    Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis

    BMJ

    (2014)
  • P Mangtani et al.

    Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials

    Clin Infect Dis

    (2014)
  • CL Karp et al.

    Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool

    Immunol Rev

    (2015)
  • R Kashangura et al.

    Effects of MVA85A vaccine on tuberculosis challenge in animals: systematic review

    Int J Epidemiol

    (2015)
  • HA Fletcher et al.

    T-cell activation is an immune correlate of risk in BCG vaccinated infants

    Nat Commun

    (2016)
  • SA Harris et al.

    Process of assay selection and optimization for the study of case and control samples from a phase IIb efficacy trial of a candidate tuberculosis vaccine, MVA85A

    Clin Vaccine Immunol

    (2014)
  • S Madhi et al.

    Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children

    N Engl J Med

    (2011)
  • V Naranbhai et al.

    The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life

    BMC Med

    (2014)
  • H Mahomed et al.

    TB incidence in an adolescent cohort in South Africa

    PLoS One

    (2013)
  • S Machingaidze et al.

    Predictive value of recent QuantiFERON conversion for tuberculosis disease in adolescents

    Am J Respir Crit Care Med

    (2012)
  • H Mahomed et al.

    Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa

    Int J Tuberc Lung Dis

    (2011)
  • H Mahomed et al.

    The tuberculin skin test versus QuantiFERON TB Gold® in predicting tuberculosis disease in an adolescent cohort study in South Africa

    PLoS One

    (2011)
  • JR Andrews et al.

    The dynamics of QuantiFERON-TB Gold in-tube conversion and reversion in a cohort of South African adolescents

    Am J Respir Crit Care Med

    (2015)
  • A Hawkridge et al.

    Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trial

    BMJ

    (2008)
  • BMN Kagina et al.

    Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guérin vaccination of newborns

    Am J Respir Crit Care Med

    (2010)
  • HA Fletcher et al.

    Human newborn bacille Calmette-Guérin vaccination and risk of tuberculosis disease: a case-control study

    BMC Med

    (2016)
  • GJ Fox et al.

    Contact investigation for tuberculosis: a systematic review and meta-analysis

    Eur Respir J

    (2013)
  • Cited by (66)

    View all citing articles on Scopus
    View full text