**2.6. Clinical spectrum of paediatric TB disease**

The clinical spectrum of childhood TB also 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 to contain the disease. Many cases of primary TB infection in children are asymptomatic, self-healing and remain completely unnoticed or accidentally discovered at a later stage (Marais et al., 2004). In previously healthy children, what determines the differences in the host/pathogen interactions that lead to successful containment as opposed to progressive disease remains largely unknown. However, age and immunodefi‐ ciency are important factors. Thus, while an exuberant immune response, in immunocompe‐ tent adolescents, tends to result in adult-type, cavitating disease, (Marais et al., 2005) in young children and/or HIV co-infection, poor CMI is thought to allow unrestrained proliferation of bacilli with progressive parenchymal lung damage (with or without cavity formation) dissemination (Marais et al., 2005)

immature at birth relative to adult DCs and continue to express a less differentiated phenotype throughout early childhood (Upham et al., 2006). Some studies also suggest that neonatal APCs lack the capacity to deliver important Th1 polarising signals to T-cells. Their capacity to synthesise interleukin (IL)-12, a key APC-derived cytokine, matures slowly during childhood (Upham et al., 2002) and neonatal, monocyte-derived DCs have a specific defect in IL-12p35 expression (Goriely et al., 2001). IL-12 is critical for the initial phases of Th1 polarisation and also for maintaining the efficiency of the interferon (IFN)-γ transcription machinery in Th1

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Transmission within a community is measured by the Annual Risk of Infection (ARI) (Rieder, 2005). Infection rates rise with increased exposure in toddlers, around the ages of school entry and with increased social mobility in late teens and early adulthood (Marais et al., 2004). ARI is traditionally estimated using childhood tuberculin surveys, although this has limitations due to the poor specificity of the tuberculin skin test (TST), particularly where Bacille Calmette Guerin (BCG) vaccine is given at birth and non-tuberculous mycobacteria (NTM) are endemic. T-cell based interferon gamma release assays (IGRAs) may offer a more specific alternative (Dinnes et al., 2007), but have not yet found a use in this context due to their cost, ethical concerns about venepuncture in healthy children (Rieder, 2005), and uncertainty about the significance of a positive result for later development of active disease. Threfore, differences in the pathophysiology and clinical presentation of TB in children make diagnosis more challenging than in adults (Shingadia and Novelli, 2003) and the definitions of latent infection

Following infection, several factors appear to influence the balance of risk between latent TB infection (LTBI) or progression to active disease, including age (Marais et al., 2004) and nutritional (Cegielski and McMurray, 2004), vaccination and immune status (Chen, 2004). Children are at much higher risk of progression to active disease than adults. This risk is greatest for infants and children under 2 years of age (Marais et al., 2004). Active surveillance data from the pre-chemotherapy era suggest that the majority of children develop radiological abnormalities following infection, including 60-80% of children less than two years. However, less than 10% of those are notified, suggesting the disease is controlled by the host immune response in most cases (Marais et al., 2004). This has implications for case definitions based on radiological findings. Overall the risk of disease is highest among infants and in late teens, with the lowest risk between 5 and 10 years - the so-called "safe school years" (Marais et al., 2004). Most disease occurred in the first year following infection (Marais et al., 2004). Thus because disease in young children reflects recent infection, rather than secondary reactivation, the paediatric disease burden potentially provides a useful measure of current transmission

effector cells (Goriely et al., 2001).

**2.8. Latent tuberculosis in children**

and disease, are less clear cut (Marais et al., 2004).

*2.8.2. Activation from infection to disease*

*2.8.1. Detection of the infection*

While dissemination can occur to almost any site, TB meningitis (TBM) is one of the commonest consequences of extra-pulmonary TB and develops three to six months after primary infection (Donald and Schoeman, 2004). It is also the most severe and potentially devastating form of childhood TB with mortality or significant long term neurological sequelae occurring in almost 50% of cases (Thwaites and Tran, 2005). Anatomical differences in children, compared with adults, also modify the presentation of TB. Complications arising from enlarging lymph nodes and small airways are common in children less than five years of age (Marais, et al., 2004; Marais et al., 2005). Post-primary TB can result in upper-lobe pulmonary consolidation and cavitation with highly infectious patients, more likely to be seen in older children.

HIV infection often mimics TB associated signs and symptoms, such as weight loss, failure to thrive and chronic pulmonary symptoms, corroborating the diagnostic difficulties (reviewed in references (Marais et al., 2007). In turn, the treatment of HIV with ART can result in unmasking signs and symptoms of underlying LTBI or active TB in the form of immune reconstitution disease (IRD) (Walters et al., 2006) in young children is largely a reflection on the immaturity of the immune response.

#### **2.7. Differences in childhood immune responses to TB**

The alveolar macrophage is the first line of defense in the innate immune response to TB and plays a critical role in amplifying the response to infection. Studies in the animal and human host have consistently demonstrated reduced microbial killing and diminish‐ ed monocyte recruitment to the site of infection in infants compared to adults. Thus im‐ pairment of innate pulmonary defenses in the neonate and infant may allow mycobacteria to overwhelm the effects of the innate immune system prior to the initia‐ tion of an antigen-specific immune response.

Antigen presentation by dendritic cells (DC), the major antigen-presenting cell (APC) in the lung, and the efficiency with which naïve T cells respond to antigen, also appears less effective in infants and may contribute to the delay in initiating an appropriate antigen-specific response, resulting in development of active disease. Blood derived DCs are functionally immature at birth relative to adult DCs and continue to express a less differentiated phenotype throughout early childhood (Upham et al., 2006). Some studies also suggest that neonatal APCs lack the capacity to deliver important Th1 polarising signals to T-cells. Their capacity to synthesise interleukin (IL)-12, a key APC-derived cytokine, matures slowly during childhood (Upham et al., 2002) and neonatal, monocyte-derived DCs have a specific defect in IL-12p35 expression (Goriely et al., 2001). IL-12 is critical for the initial phases of Th1 polarisation and also for maintaining the efficiency of the interferon (IFN)-γ transcription machinery in Th1 effector cells (Goriely et al., 2001).

#### **2.8. Latent tuberculosis in children**

#### *2.8.1. Detection of the infection*

**2.6. Clinical spectrum of paediatric TB disease**

378 Tuberculosis - Current Issues in Diagnosis and Management

dissemination (Marais et al., 2005)

the immaturity of the immune response.

tion of an antigen-specific immune response.

**2.7. Differences in childhood immune responses to TB**

The clinical spectrum of childhood TB also 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 to contain the disease. Many cases of primary TB infection in children are asymptomatic, self-healing and remain completely unnoticed or accidentally discovered at a later stage (Marais et al., 2004). In previously healthy children, what determines the differences in the host/pathogen interactions that lead to successful containment as opposed to progressive disease remains largely unknown. However, age and immunodefi‐ ciency are important factors. Thus, while an exuberant immune response, in immunocompe‐ tent adolescents, tends to result in adult-type, cavitating disease, (Marais et al., 2005) in young children and/or HIV co-infection, poor CMI is thought to allow unrestrained proliferation of bacilli with progressive parenchymal lung damage (with or without cavity formation)

While dissemination can occur to almost any site, TB meningitis (TBM) is one of the commonest consequences of extra-pulmonary TB and develops three to six months after primary infection (Donald and Schoeman, 2004). It is also the most severe and potentially devastating form of childhood TB with mortality or significant long term neurological sequelae occurring in almost 50% of cases (Thwaites and Tran, 2005). Anatomical differences in children, compared with adults, also modify the presentation of TB. Complications arising from enlarging lymph nodes and small airways are common in children less than five years of age (Marais, et al., 2004; Marais et al., 2005). Post-primary TB can result in upper-lobe pulmonary consolidation and

HIV infection often mimics TB associated signs and symptoms, such as weight loss, failure to thrive and chronic pulmonary symptoms, corroborating the diagnostic difficulties (reviewed in references (Marais et al., 2007). In turn, the treatment of HIV with ART can result in unmasking signs and symptoms of underlying LTBI or active TB in the form of immune reconstitution disease (IRD) (Walters et al., 2006) in young children is largely a reflection on

The alveolar macrophage is the first line of defense in the innate immune response to TB and plays a critical role in amplifying the response to infection. Studies in the animal and human host have consistently demonstrated reduced microbial killing and diminish‐ ed monocyte recruitment to the site of infection in infants compared to adults. Thus im‐ pairment of innate pulmonary defenses in the neonate and infant may allow mycobacteria to overwhelm the effects of the innate immune system prior to the initia‐

Antigen presentation by dendritic cells (DC), the major antigen-presenting cell (APC) in the lung, and the efficiency with which naïve T cells respond to antigen, also appears less effective in infants and may contribute to the delay in initiating an appropriate antigen-specific response, resulting in development of active disease. Blood derived DCs are functionally

cavitation with highly infectious patients, more likely to be seen in older children.

Transmission within a community is measured by the Annual Risk of Infection (ARI) (Rieder, 2005). Infection rates rise with increased exposure in toddlers, around the ages of school entry and with increased social mobility in late teens and early adulthood (Marais et al., 2004). ARI is traditionally estimated using childhood tuberculin surveys, although this has limitations due to the poor specificity of the tuberculin skin test (TST), particularly where Bacille Calmette Guerin (BCG) vaccine is given at birth and non-tuberculous mycobacteria (NTM) are endemic. T-cell based interferon gamma release assays (IGRAs) may offer a more specific alternative (Dinnes et al., 2007), but have not yet found a use in this context due to their cost, ethical concerns about venepuncture in healthy children (Rieder, 2005), and uncertainty about the significance of a positive result for later development of active disease. Threfore, differences in the pathophysiology and clinical presentation of TB in children make diagnosis more challenging than in adults (Shingadia and Novelli, 2003) and the definitions of latent infection and disease, are less clear cut (Marais et al., 2004).

#### *2.8.2. Activation from infection to disease*

Following infection, several factors appear to influence the balance of risk between latent TB infection (LTBI) or progression to active disease, including age (Marais et al., 2004) and nutritional (Cegielski and McMurray, 2004), vaccination and immune status (Chen, 2004). Children are at much higher risk of progression to active disease than adults. This risk is greatest for infants and children under 2 years of age (Marais et al., 2004). Active surveillance data from the pre-chemotherapy era suggest that the majority of children develop radiological abnormalities following infection, including 60-80% of children less than two years. However, less than 10% of those are notified, suggesting the disease is controlled by the host immune response in most cases (Marais et al., 2004). This has implications for case definitions based on radiological findings. Overall the risk of disease is highest among infants and in late teens, with the lowest risk between 5 and 10 years - the so-called "safe school years" (Marais et al., 2004). Most disease occurred in the first year following infection (Marais et al., 2004). Thus because disease in young children reflects recent infection, rather than secondary reactivation, the paediatric disease burden potentially provides a useful measure of current transmission within a community, Marais et al., 2005) including multi-drug resistant (MDR) (Schaaf et al., 2006) and extensively drug resistant (XDR) strains.

case definitions of disease that rely exclusively on bacteriology. It is important to consider this overlap when case definitions are formulated for research purposes, particularly within the contact setting, although it is less relevant in everyday practice where there is no reason to

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Uncomplicated hilar adenopathy remains the most common disease manifestation in children and is usually regarded as the hallmark of primary tuberculosis. However, the prechemother‐ apy literature documented transient hilar adenopathy in the majority (50–60%) of children after recent primary pulmonary infection, of whom only a few progressed to disease (Marais et al., 2004). The natural history of disease illustrates that progression to disease is indicated by the onset of persistent, nonremitting symptoms, referred to as the breakpoint of clinical significance whereas the complete absence of symptoms usually indicates good organism containment (Marais et al., 2004). By convention, asymptomatic hilar adenopathy is currently treated as active disease, although early experience with isoniazid alone demonstrated that one-drug therapy was sufficient in these cases. In terms of pathophysiology, microbiology, and natural history, asymptomatic hilar adenopathy is more indicative of recent primary

This indicates that radiologic signs should be interpreted with caution in the absence of clinical data. The entity of so-called asymptomatic tuberculosis, where the case definition rests exclusively on radiographic criteria, is a case in point. High-resolution computed tomography is the most sensitive tool available to detect hilar adenopathy (Andronikou et al., 2004), as demonstrated by the fact that in children with recent M. tuberculosis infection and a normal chest radiograph, prominent intrathoracic nodes are frequently demonstrated by highresolution computed tomography. Particular caution is required when interpreting the relevance of these radiologic signs in the absence of clinical data. It is important to point out that there is no role for high-resolution computed tomography in the evaluation of asympto‐

In reality, differences in patient selection may result in the use of different functional case definitions even though the definitions appear similar on paper. In non-endemic areas where active contact tracing is diligently enforced, more children with transient radiologic signs indicative of recent primary infection will be identified, and those with active disease will be diagnosed at an earlier, less advanced stage. Active contact tracing is rarely enforced in endemic areas and children usually present to health care facilities with suspicious symptoms and more advanced disease (Marais et al., 2006). Unlike asymptomatic contacts in which visible radiologic signs probably indicate recent primary infection only, radiologic signs in sympto‐ matic children indicate active disease. From a research perspective it is important to be aware of these differences, as inconsistent case definitions may confound the scientific interpretation of results. In everyday practice, distinguishing between the signs and symptoms of recent primary infection and active disease is less relevant in high-risk children (less than 3 years of age and/or immune compromised) in whom infection frequently progresses to disease,

obtain cultures from completely asymptomatic children.

infection than active disease (Marais et al., 2004).

sometimes with rapid disease progression.

matic, immune-competent children exposed to M. tuberculosis.
