*2.2.4. Host genetic susceptibility to paediatric TB*

The immunological responses to MTB are due to the interaction between the immature immune system in children, the host, bacterial and environmental factors (Meya and McAdam, 2007). Genetic as well as acquired defects in host immune response pathways greatly increase the risk of progressive disease (Kampmann et al., 2005). Results from genome wide linkage studies suggest that TB disease susceptibility is highly likely to be polygenic, with contribu‐ tions from many minor loci (Hill, 2006) and a large number of TB susceptibility markers have been identified from candidate gene studies as 'disease-causing' genes which include TIRAP, HLA DQB1, VDR, IL-12β, IL12Rβ1, IFN-γ, SLC11A1 and MCP-1. However, to date the greatest evidence to support an underlying genetic basis for TB has come from the discovery of single gene defects predisposing to disseminated and often lethal mycobacterial disease. Most observations were initially made in children with reduced ability to activate macrophage antimycobacterial mechanisms through defects in the IFN-γ (Kampmann et al., 2005) /IL-12 pathway resulting in severe mycobacterial infection. However, subsequent studies have led to description of mutations in five susceptibility genes (Ottenhoff et al., 2005) confirming that up-regulation of the macrophage through the IL-12/23-IFN-γ pathway is a fundamental step in the containment of infection with mycobacteria. However, despite a growing adult literature on the role of candidate genes from this pathway, data from children is scarce. This is surprising given the marked differences in TB pathophysiology in children, which may also reflect differences in genetic factors. Further studies of TB genetics in well-defined paediatric populations are therefore needed.

increased TB incidence and poorer outcome have been observed among HIV infected children in a variety of settings (Palme et al., 2002) including an estimated 20-fold increased TB incidence associated with HIV infection in a study from South Africa. Methodological constraints in some

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Several observational studies from adults and children show an association between mal‐ nutrition and TB, (Cegielski and McMurray, 2004) although proving the direction of a causal link is challenging, as TB in itself causes wasting. Diagnosis is further complicated by frequently false negative TST in malnutrition, reverting to positivity only once nutri‐ tion has improved. Nevertheless these observational data, coupled with experimental ani‐ mal data and impaired CMI observed in malnutrition, support its role as a risk factor for childhood TB (Cegielski and McMurray, 2004). However the effect of differing types and degrees of malnutrition, and the population at risk due to malnutrition in communities

Among micronutrients, vitamin D deficiency has been most extensively studied, and shown to be associated with TB in UK immigrants. Its active metabolite 1-alpha, 25-dihydroxyvitamin D modulates the host response to TB infection in numerous ways, including the induction of antimicrobial peptides such as Cathelicidin LL-37 (Martineau et al., 2007).

The relationship between MTB strain genotype and clinical manifestation of disease is poorly documented in children. A study in the Western Cape Province of South Africa demonstrated that the Beijing and Haarlem genotype families are significantly associated with drug resistant TB in children (Marais et al., 2006). The high prevalence of Beijing and Latin American Mediterranean (LAM) strains in children reflects considerable transmission of these genotype

Genetic markers of virulence and transmissibility, (Lopez et al., 2003) and the ability to modulate host cellular immunity have been described for the Beijing strain, HN878 (Reed, et al., 2004). Similarly the East African-Indian lineage is characterized by an LSP (Large Sequence Polymorphism) conferring an immune subverting phenotype that contributes to its persistence and outbreak potential of this lineage (Newton et al., 2006). Strain differences in immunoge‐ nicity may result in reduced detection by TST (Anderson et al., 2006) as documented in a London school contact tracing investigation - an extremely worrying phenomenon which may lead to underestimates of the true global burden of TB and underscores the need for new diagnostics. Most studies of strain-specific responses are derived from adult TB cases, and it remains to be established whether results are equally applicable to children. Further research to characterize strain differences in pathogenicity and induction of immune responses should

studies may explain why this has not been a universal finding (Marais et al., 2007).

**2.4. Nutrition and paediatric TB**

where both are endemic, are yet to be defined.

**2.5. Host-pathogen interactions in paediatric TB**

families in this setting (Marais et al., 2006).

include children as well as adults.

#### **2.3. Impact of HIV epidemic paeditric TB**

Studies demonstrating a higher risk of TB among HIV- children (Jeena et al., 2002) highlight the essential role of cell mediated immunity (CMI) in preventing mycobacterial dissemination (Tena et al., 2003). Poor CMI in HIV co-infection often results in disseminated disease, especially in advanced stages of HIV-infection, resulting in poorer survival compared to HIVnegative children (Palme et al., 2002). Risk of active TB in HIV co-infected children is related to both CD4 count and more indirectly also to viral load (Elenga et al., 2005).Conversely, restoration of cellular immunity with anti-retroviral therapy partially reverses TB susceptibil‐ ity (Kampmann et al., 2006).

The impact of the Human Immunodeficiency Virus (HIV) epidemic on the burden of childhood TB has been less well characterized than for adults (Corbett et al., 2003). However, the observed shift in disease burden to younger adults it has caused, suggests that children are at particularly high risk of exposure as well as disease (Graham et al, 2001). Reported prevalence of HIV coinfection among children with TB range from below 5%, in industrialized settings, to over 50% in some high burden African settings (Nelson and Wells, 2004). However, it is often difficult to draw reliable inferences about the effect of HIV on TB incidence or risk from these obser‐ vational data due to ascertainment bias or diagnostic bias; incomplete ascertainment of HIV status and because denominator population data on the proportion of all children infected with HIV are usually lacking. (For example, children with HIV are more likely to be investi‐ gated for TB and diagnosis is unreliable because it is affected by HIV status). Nevertheless an increased TB incidence and poorer outcome have been observed among HIV infected children in a variety of settings (Palme et al., 2002) including an estimated 20-fold increased TB incidence associated with HIV infection in a study from South Africa. Methodological constraints in some studies may explain why this has not been a universal finding (Marais et al., 2007).
