**1. Introduction**

Until recently, tuberculosis (TB) had become a neglected disease, particularly in children. It was after the emergence of multi drug resistant TB, and the complications brought about by the HIV/AIDS coinfection, that TB took centre stage again. The common perception has been that children rarely develop severe forms of TB and that they do not contribute much to the spread of the epidemic. Although this could be the case in non-endemic areas, where diligent contact tracing is enforced, in children from endemic areas it is a different story as revealed by an autopsy study conducted in Zambia which demonstrated that tuberculosis was a major cause of death from respiratory disease (Chintu et al., 2002).

Children are particularly vulnerable to more rapid development of severe disease and death after infection, and those with latent infection become the reservoir of disease reactivation in adulthood, fueling the future epidemic (Nicol et al., 2011). Since focus has been on reducing transmission, previous TB control strategies have not prioritized childhood TB (Zar and Pai, 2011). Due to the difficulty in establishing an accurate diagnosis of childhood tuberculosis, the true extent of the tuberculosis-related morbidity and mortality suffered by children in endemic areas is rarely appreciated (Chintu et al., 2002). For example, Regional Data from the WHO in 2007 showed that smear-positive TB in children aged under 14 years accounted for 0.6–3.6% of reported cases but since about 95% of cases in children under 12 years of age are smear negative, these data underestimate the true burden of TB. Furthermore, in countries with a high prevalence of HIV infection, there has been a marked increase in the incidence and a decrease in the peak age prevalence of infectious TB; thus, most cases now occur in young adults, who are often parents of young children (WHO Report, 2009). This finding suggests that children in developing countries will emerge as a group at high risk. In industrialized countries, most childhood TB cases are detected through contact tracing and have good outcomes. This is in contrast to the situation in low- and middle-income countries, where

© 2013 Kirimuhuzya; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

childhood TB is closely associated with poverty, overcrowding, and malnutrition, with consequently higher death and lower treatment success rates (Nelson and Wells, 2010).

This chapter addresses some of the unique features of TB in children; presents existing and novel diagnostic, therapeutic and preventative measures; and outlines important areas of future research. The main challenges for future research are highlighted and in conclusion it is emphasized that well-targeted interventions, improved resources, and improved political commitment, may lead to a dramatic reduction in tuberculosis-related morbidity and mortality

Peadiatric Tuberculosis: Is the World Doing Enough?

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Poor case ascertainment, lack of resources for active case finding in most settings, and limited paediatric surveillance data from TB control programs all hamper efforts to define accurately the global burden of childhood TB (Nelson and Wells, 2004). Until recently, under the WHO Directly Observed Treatment Short Course (DOTS) strategy, only smear positive cases were being reported for children, yet smears are seldom performed in many high burden settings

Although limited surveillance data prevent reliable estimates of the contribution of TB to childhood mortality, available data indicate that pneumonia is the commonest cause of childhood death globally (Nelson et al., 2004) an implication that TB, being an important cause of pneumonia in many settings (Scott et al., 2008), may contribute significantly to these global childhood deaths. A necropsy study in Zambia found evidence of TB in 18% of HIV-positive and 26% of HIV-negative children dying of pneumonia (Chintu et al., 2002) although more robust regional data on the epidemiology of childhood TB are urgently needed to define the true burden of disease, and to characterize current transmission rates and circulating strains.

The natural history of TB in children and pediatric patients follows a series of steps in which phase 1 occurs after an incubation period of 3–8 weeks after primary infection. This is followed by appearance of well-defined signs that include fever, erythema nodosum, a positive tuberculin skin test response, and formation of the primary complex visible on chest radiog‐ raphy. Phase 2 occurs 1–3 months after the phase 1 in which period, the bacillus can migrate to other parts of the body via the blood and this represents the period of the highest risk for the development of tuberculous meningitis and miliary tuberculosis in young children. This is the phase where dissemination of the bacillus most frequently occurs. Phase 3 occurs 3–7 months after primary infection and is the period of pleural effusions in children greater than 5 years old and bronchial disease in children less than 5 years. Phase 4 presents after 1–3 years after phase 1 and is during which the osteoarticular tuberculosis in children 5 years and below, appears. Phase 5 occurs up to 3 years after phase 1 and it is presented after calcification has

among children.

**2. Epidemiology of paediatric TB**

**2.1. Global disease burden of paediatric TB**

and most disease in children is smear negative.

**2.2. Pathophysiology of TB in children**

*2.2.1. Natural history of TB in children*

Studies have revealed that children contribute a significant proportion to the disease burden and suffer severe tuberculosis-related morbidity and mortality, particularly in endemic areas. TB is now among the 10 major causes of mortality among children, with a global estimate of 130,000 deaths per year (WHO Report, 2009). Mortality has a strong correlation with socioe‐ conomic status, underlying nutritional status and immunocompetence (Palme, 2002). TB has also been reported to be the third most common cause of death in HIV-infected children with a clinical diagnosis of acute severe pneumonia (Palme, 2002). With roughly a million cases estimated globally each year (Walls and, Shingadia, 2004) and a much higher risk of severe disease and death among young children than adults, paediatric TB remains a public health emergency and this is particularly evident in developing countries with poor public health infrastructure.

As in adults, the majority of cases occur in the 22 high burden countries, where a combination of high transmission rates and a large proportion of the population under the age of 15 years mean children account for up to 25-40% of cases, with incidence rates for paediatric TB ranging from 60-600 per 100,000 per year (Nelson and Wells, 2004). Increasing rates of childhood TB have also been reported in Eastern Europe in the wake of the explosive TB epidemic which followed the break up of the Soviet Union (Walls and Shingadia, 2007). Even traditionally lowburden countries have seen a rise in cases, mainly due to immigration from TB endemic areas. In most countries of Western Europe and North America, where children account for 4-7% cases, paediatric incidence rates vary from about 1 to 15 per 100,000 per year, although much higher rates are observed in some cities, such as London (Newton et al., 2008).

Despite this huge disease burden, children's access to anti-tuberculosis treatment in most endemic areas remains poor, as tuberculosis control programs focus predominantly on the treatment of sputum smear–positive adults (Starke, 2002). Recent technological advancements in diagnosis of TB in adults have not been validated in children and, similarly, trials of new drugs and development of pediatric formulations of standard first- and second-line drugs are lagging behind. As a result both research and surveillance data in the field of childhood TB have been greatly limited. Further research into the epidemiology, immune mechanisms, diagnosis, treatment and prevention of childhood TB is urgently needed to enhance our understanding of TB in children which may provide wider insights and opportunities to facilitate efforts to control TB in the population.

Another problem is that most programs for TB control are limited because they target and treat only active cases (Graham, et al., 2004) when most TB cases in children present as latent tuberculosis infection (LTBI) with active disease occurring mainly in developing countries (Dogra, et al., 2007). Without treatment, the majority of infants aged under 1 year die due to TB. Even with effective antimicrobial therapy, severe TB continues to occur in young children (Ávalos and Montes de Oca, 2012). Priorities for future research should, therefore, enhance collaborations between developing and developed nations.

This chapter addresses some of the unique features of TB in children; presents existing and novel diagnostic, therapeutic and preventative measures; and outlines important areas of future research. The main challenges for future research are highlighted and in conclusion it is emphasized that well-targeted interventions, improved resources, and improved political commitment, may lead to a dramatic reduction in tuberculosis-related morbidity and mortality among children.
