*2.2.1. Natural history of TB in children*

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 been completed. It is after this stage that manifestations of classical adult tuberculosis appear (Marais et al., 2004).

immune responses in the neonate and young children raise the question of whether antigenspecific immune responses to mycobacteria are equally affected. Delayed type hypersensitivity (DTH) to purified protein derivative (PPD) may be absent in up to 40% of HIV negative children presenting with extrapulmonary TB, (van der Weert et al., 2006) compounding the difficulties of diagnosis in young children. However, studies measuring responses to neonatal vaccination with M. bovis BCG demonstrate potent Th1 responses, possibly related to the activating properties of BCG vaccine on the potent antigen-presenting cells (APC). Indeed while the long term efficacy of BCG vaccination may be limited, it does offer protection against disseminated disease in infants and young children. The risk of serious and potentially devastating disease is nevertheless still high in the first two years of life, underscoring the need for a better understanding of the determinants of host protection particularly in this vulnerable

Peadiatric Tuberculosis: Is the World Doing Enough?

http://dx.doi.org/10.5772/54953

375

In the natural history of childhood intrathoracic TB, primary infection before 2 years of age frequently progresses to disease within the first 12 months (Marais, et al., 2004). Young age and HIV infection are the most important risk factors for severe or disseminated disease; the risk of disease progression decreases during childhood, least at 5–10 years of age, and increases again during adolescence. Pulmonary parenchymal disease and intrathoracic adenopathy are the most common clinical manifestations of pediatric TB, accounting for 60%–80% of all cases (Jensen, 2002). Among extra-pulmonary manifestations, lymphadenopathy is the most common (67%), followed by central nervous system involvement (13%) and pleural (6%), disseminated (5%), and skeletal (4%) TB (Marais, 2006). Disseminated disease and TB menin‐ gitis are usually found in very young children (age, under 3 years) and/or HIV-infected children (Starke, 2003). More research is required to identify better strategies for case detection and contact tracing, especially in high-burden settings, and to study the role of genetic and

HIV-infected children are at risk of both atypical pulmonary presentation and extra-pul‐ monary disease, which comprises up to 60% of TB in this population (Starke, 2003). Symptom-based diagnostic approaches perform poorly, because other HIV-related condi‐ tions, such as lymphocytic interstitial pneumonitis, broncho-ectasis, and respiratory infec‐ tions (including viral pneumonitis), mimic the clinical and radiographic features of TB (Marais, 2007). Lymphocytic interstitial pneumonitis tends to occur in children aged less than two years, presents with recurrent respiratory symptoms, and is associated with clubbing and generalized lymphadenopathy and a miliary TB-like picture on chest radio‐ graph. Although these patients improve temporarily with antibiotic therapy, antiretrovi‐ ral treatment is required for sustained benefit and to avoid development of chronic lung disease. In the short term, there is little prospect of achieving a widely available gold standard diagnosis of TB in children either by means of culture, microscopy, PCR, or se‐ rological testing. Consequently, clinicians must rely on clinical criteria, chest radiography, and tuberculin testing, and attempts must be made to improve the predictive power of

nutritional factors that protect children from TB infection and disease.

available tools (Swaminathan and Rekha, 2010).

age group.

Extrapulmonary tuberculosis or miliary TB is a complication of primary TB in young children. It includes peripheral lymphadenopathy, TB meningitis, skeletal TB, and other organ involve‐ ment. Other unusual sites for TB include the middle ear, gastrointestinal (GI) tract, skin, kidneys, and ocular structures (Marais et al., 2006). Lymph node involvement typically occurs 6-9 months following initial infection by the tubercle bacilli. More superficial lymph nodes commonly are involved. Frequent sites of involvement include the anterior cervical, subman‐ dibular, and supraclavicular nodes. TB of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes. Typically, infected lymph nodes are firm and non- tender with non erythematous overlying skin. The nodes are initially non-fluctuant. Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the development of necrosis (Marais et al., 2006).

Bone or joint TB or skeletal TB may present acutely or sub-acutely. Vertebral disease may go unrecognized for months to years because of its indolent nature. Common sites involved include the large weight-bearing bones or joints, including the vertebrae (50%), hip (15%), and knee (15%). Destruction of the bones with deformity is a late sign of TB. Manifestations for skeletal TB may include angulation of the spine (gibbus deformity) and/or Pott disease (severe kyphosis with destruction of the vertebral bodies). Cervical spine involvement may result in allantoaxial subluxation, which may lead to paraplegia or quadriplegia.

#### *2.2.2. TB risk factors*

Following infection children have a higher risk not only of progression to disease, but also of extrapulmonary dissemination and death. Infants have a particularly high morbidity and mortality from TB (WHO, 2007). While many factors including host genetics, microbial virulence and underlying conditions that impair immune competence (as is the case with malnutrition and HIV infection) determine the outcome of infection, it is likely that the high rate of progressive TB seen in young children is largely a reflection of the immaturity of the immune response. Risk factors for the acquisition of tuberculosis (TB) are usually exogenous to the patient. Thus, the likelihood of being infected depends on the environment and the features of the index case. However, the development of TB disease depends on inherent immunologic status of the host. For example, tuberculosis has been reported in patients treated for arthritis, inflammatory bowel disease, and other conditions with tumor necrosis factor (TNF)-alpha blockers/antagonists.

#### *2.2.3. Factors for acquiring paediatric TB disease*

Neonatal CD4 cells appear intrinsically deficient in their capacity to express Th1 effector function, partially attributed to hypermethylation of the proximal promoter of the IFN-γ gene, (White et al., 2002) and this results in a highly restricted pattern of IFN-γ response to a variety of stimuli (Kampmann et al., 2006). CD154 (CD40 ligand) expression is also significantly reduced compared with adult cells. These findings of generally impaired cell-mediated immune responses in the neonate and young children raise the question of whether antigenspecific immune responses to mycobacteria are equally affected. Delayed type hypersensitivity (DTH) to purified protein derivative (PPD) may be absent in up to 40% of HIV negative children presenting with extrapulmonary TB, (van der Weert et al., 2006) compounding the difficulties of diagnosis in young children. However, studies measuring responses to neonatal vaccination with M. bovis BCG demonstrate potent Th1 responses, possibly related to the activating properties of BCG vaccine on the potent antigen-presenting cells (APC). Indeed while the long term efficacy of BCG vaccination may be limited, it does offer protection against disseminated disease in infants and young children. The risk of serious and potentially devastating disease is nevertheless still high in the first two years of life, underscoring the need for a better understanding of the determinants of host protection particularly in this vulnerable age group.

been completed. It is after this stage that manifestations of classical adult tuberculosis appear

Extrapulmonary tuberculosis or miliary TB is a complication of primary TB in young children. It includes peripheral lymphadenopathy, TB meningitis, skeletal TB, and other organ involve‐ ment. Other unusual sites for TB include the middle ear, gastrointestinal (GI) tract, skin, kidneys, and ocular structures (Marais et al., 2006). Lymph node involvement typically occurs 6-9 months following initial infection by the tubercle bacilli. More superficial lymph nodes commonly are involved. Frequent sites of involvement include the anterior cervical, subman‐ dibular, and supraclavicular nodes. TB of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes. Typically, infected lymph nodes are firm and non- tender with non erythematous overlying skin. The nodes are initially non-fluctuant. Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the

Bone or joint TB or skeletal TB may present acutely or sub-acutely. Vertebral disease may go unrecognized for months to years because of its indolent nature. Common sites involved include the large weight-bearing bones or joints, including the vertebrae (50%), hip (15%), and knee (15%). Destruction of the bones with deformity is a late sign of TB. Manifestations for skeletal TB may include angulation of the spine (gibbus deformity) and/or Pott disease (severe kyphosis with destruction of the vertebral bodies). Cervical spine involvement may result in

Following infection children have a higher risk not only of progression to disease, but also of extrapulmonary dissemination and death. Infants have a particularly high morbidity and mortality from TB (WHO, 2007). While many factors including host genetics, microbial virulence and underlying conditions that impair immune competence (as is the case with malnutrition and HIV infection) determine the outcome of infection, it is likely that the high rate of progressive TB seen in young children is largely a reflection of the immaturity of the immune response. Risk factors for the acquisition of tuberculosis (TB) are usually exogenous to the patient. Thus, the likelihood of being infected depends on the environment and the features of the index case. However, the development of TB disease depends on inherent immunologic status of the host. For example, tuberculosis has been reported in patients treated for arthritis, inflammatory bowel disease, and other conditions with tumor necrosis factor

Neonatal CD4 cells appear intrinsically deficient in their capacity to express Th1 effector function, partially attributed to hypermethylation of the proximal promoter of the IFN-γ gene, (White et al., 2002) and this results in a highly restricted pattern of IFN-γ response to a variety of stimuli (Kampmann et al., 2006). CD154 (CD40 ligand) expression is also significantly reduced compared with adult cells. These findings of generally impaired cell-mediated

allantoaxial subluxation, which may lead to paraplegia or quadriplegia.

(Marais et al., 2004).

*2.2.2. TB risk factors*

(TNF)-alpha blockers/antagonists.

*2.2.3. Factors for acquiring paediatric TB disease*

development of necrosis (Marais et al., 2006).

374 Tuberculosis - Current Issues in Diagnosis and Management

In the natural history of childhood intrathoracic TB, primary infection before 2 years of age frequently progresses to disease within the first 12 months (Marais, et al., 2004). Young age and HIV infection are the most important risk factors for severe or disseminated disease; the risk of disease progression decreases during childhood, least at 5–10 years of age, and increases again during adolescence. Pulmonary parenchymal disease and intrathoracic adenopathy are the most common clinical manifestations of pediatric TB, accounting for 60%–80% of all cases (Jensen, 2002). Among extra-pulmonary manifestations, lymphadenopathy is the most common (67%), followed by central nervous system involvement (13%) and pleural (6%), disseminated (5%), and skeletal (4%) TB (Marais, 2006). Disseminated disease and TB menin‐ gitis are usually found in very young children (age, under 3 years) and/or HIV-infected children (Starke, 2003). More research is required to identify better strategies for case detection and contact tracing, especially in high-burden settings, and to study the role of genetic and nutritional factors that protect children from TB infection and disease.

HIV-infected children are at risk of both atypical pulmonary presentation and extra-pul‐ monary disease, which comprises up to 60% of TB in this population (Starke, 2003). Symptom-based diagnostic approaches perform poorly, because other HIV-related condi‐ tions, such as lymphocytic interstitial pneumonitis, broncho-ectasis, and respiratory infec‐ tions (including viral pneumonitis), mimic the clinical and radiographic features of TB (Marais, 2007). Lymphocytic interstitial pneumonitis tends to occur in children aged less than two years, presents with recurrent respiratory symptoms, and is associated with clubbing and generalized lymphadenopathy and a miliary TB-like picture on chest radio‐ graph. Although these patients improve temporarily with antibiotic therapy, antiretrovi‐ ral treatment is required for sustained benefit and to avoid development of chronic lung disease. In the short term, there is little prospect of achieving a widely available gold standard diagnosis of TB in children either by means of culture, microscopy, PCR, or se‐ rological testing. Consequently, clinicians must rely on clinical criteria, chest radiography, and tuberculin testing, and attempts must be made to improve the predictive power of available tools (Swaminathan and Rekha, 2010).
