Review
Paediatric tuberculosis

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Summary

Tuberculosis continues to cause an unacceptably high toll of disease and death among children worldwide, particularly in the wake of the HIV epidemic. Increased international travel and immigration have led to a rise in childhood tuberculosis rates even in traditionally low burden, industrialised settings, and threaten to promote the emergence and spread of multidrug-resistant strains. Whereas intense scientific and clinical research efforts into novel diagnostic, therapeutic, and preventive interventions have focused on tuberculosis in adults, childhood tuberculosis has been relatively neglected. However, children are particularly vulnerable to severe disease and death following infection, and those with latent infection become the reservoir for future transmission following disease reactivation in adulthood, fuelling future epidemics. Further research into the epidemiology, immune mechanisms, diagnosis, treatment, and prevention of childhood tuberculosis is urgently needed. Advances in our understanding of tuberculosis in children would provide insights and opportunities to enhance efforts to control this disease.

Introduction

Since the declaration by WHO of a “global tuberculosis emergency” in 1993,1 a wealth of publications has addressed important aspects of the burden, management, and control of tuberculosis. In general, however, the emphasis has been on adult disease. By contrast, paediatric tuberculosis has been relatively neglected, mainly because of greater challenges in diagnosis and the lower priority traditionally afforded to children by tuberculosis control programmes. As a result, both research and surveillance data in the field of childhood tuberculosis have been limited. Nevertheless, with roughly 1 million cases estimated globally each year,2, 3, 4, 5 and a much higher risk of severe disease and death in young children than in adults, paediatric tuberculosis remains a public-health emergency, particularly in developing countries with poor public-health infrastructure. Priorities for future research should therefore enhance collaborations between developing and developed nations. Furthermore, by providing insights into current rates of transmission and circulating strains, tuberculosis in children remains a sentinel indicator of the effectiveness of tuberculosis control programmes. This Review addresses some of the unique features of tuberculosis in children, summarises existing and novel diagnostic, therapeutic, and preventive measures, and outlines important areas of future research.

Section snippets

Transmission, exposure, and infection

A child's risk of infection by Mycobacterium tuberculosis is dependent on the probability, duration, and proximity of exposure to an infectious case, and on the infectiousness of the source.6, 7, 8, 9, 10, 11 The source is usually an adult with cavitatory pulmonary disease, although older children can also contribute to transmission.8, 12 Social factors, community tuberculosis prevalence, and age determine where exposure is most likely to occur3, 11, 13—eg, a household source is most commonly

Pathophysiology of tuberculosis in children

Following infection, children have a higher risk not only of progression to disease,36 but also of extrapulmonary dissemination and death.59 Infants have a particularly high morbidity and mortality from tuberculosis.60 Although many factors including host genetics, microbial virulence, and underlying conditions that impair immune competence (eg, malnutrition and HIV infection) determine the outcome of infection, it is likely that the high rate of progressive tuberculosis seen in young children

Host–pathogen interactions

Mycobacterial genetic variability, including large sequence polymorphism (LSP) and single nucleotide polymorphism (SNP),95, 96, 97 allows survival adaptation to environmental challenges. Six phylogeographical lineages of M tuberculosis have been defined by LSPs.98 Each lineage seems to have evolved to adapt to specific ethnic and geographical host populations, as a result of host–pathogen compatibility,98, 99, 100 which could have implications for tuberculosis control and the development and

Clinical spectrum of disease

The clinical spectrum of childhood tuberculosis reflects differences in the balance between the pathogen and the host immune response, with more severe disease resulting from either poor or over-exuberant attempts by the immune system to contain the disease. Many cases of primary tuberculosis infection in children are asymptomatic, self-healing, and remain completely unnoticed or accidentally discovered at a later stage.11 In previously healthy children it remains largely unknown what

Diagnosis of tuberculosis in children

Diagnostic difficulties pose the greatest challenge to childhood tuberculosis management.115 Tuberculosis is often not considered in the differential diagnosis in children, especially in low-endemicity settings. Tuberculosis can mimic many common childhood diseases, including pneumonia, generalised bacterial and viral infections, malnutrition, and HIV. However, the main impediment to the accurate diagnosis of active tuberculosis is the paucibacillary nature of the disease in children. Younger

Diagnosis of latent infection in children

Latent tuberculosis infection, in both children and adults, lacks a diagnostic gold standard. The diagnosis is usually pursued after a documented household exposure, or to assess whether chemoprophylactic therapy is indicated in the context of immunosuppression. In these assays, pre-existing M tuberculosis-specific host immune responses are measured to confirm previous infection. Data in adults have confirmed that IGRAs are more sensitive and specific than the TST28, 126 in this context.

Treatment of tuberculosis in children

For the first time in three decades there is a promising pipeline of new antituberculosis agents at various stages of development, and several have already entered clinical trials.135 Clinical trials are usually done in adults with microbiologically proven pulmonary tuberculosis, allowing objective microbiological case definitions and treatment outcomes. The difficulty achieving a clear microbiological diagnosis in most paediatric cases severely hampers trials in children, since microbiological

Drug-resistant tuberculosis

The emergence and spread of resistant tuberculosis poses a serious threat to disease control. Rates of MDR strains (resistant to both isoniazid and rifampicin) including XDR strains (also resistant to fluoroquinolones and at least one second-line injectable agent such as amikacin, kanamycin, and/or capreomycin) are rising in many parts of the world, particularly in southern Africa147 and the former Soviet Union (eg, 28% of isolates in Kazakhstan are MDR).148 Mass immigration from these

BCG vaccination

Several large-scale randomised clinical trials from different settings worldwide have suggested a protective efficacy of BCG vaccination against pulmonary tuberculosis that ranges from 0 to 80%.32 The variability in vaccine efficacy has been attributed to several factors,155 including strain-specific immunogenicity, technique of vaccine administration,156 age at vaccination, genetic differences between populations,157 host nutritional factors, host co-infection by parasites,158 exposure to

Conclusions

Tuberculosis in children presents particularly difficult challenges, but research priorities and advances in paediatric tuberculosis research60 could provide wider insights and opportunities for tuberculosis control. Some important research priorities are summarised in the panel. Although a new vaccine to prevent tuberculosis is the ultimate goal, better diagnostics probably represent the next most important step forward, and as such require urgent prioritisation. A reliable diagnostic tool

Search strategy and selection criteria

Data for this Review were identified by searches of PubMed and Embase. Publications from organisations such as WHO were also included. The search criteria focused predominantly on paediatrics; however, some literature on adults was included where this was relevant or illustrated important differences between paediatric and adult tuberculosis. Search terms included the following in various combinations: “paediatrics”, “children”, “tuberculosis”, “mycobacteria”, “Mycobacterium tuberculosis

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