The Wonder Years: What Can Primary School Children Teach Us About Immunity to Mycobacterium tuberculosis?

Abstract

In high burden settings, the risk of infection with Mycobacterium tuberculosis increases throughout childhood due to cumulative exposure. However, the risk of progressing from tuberculosis (TB) infection to disease varies by age. Young children (<5 years) have high risk of disease progression following infection. The risk falls in primary school children (5 to <10 years), but rises again during puberty. TB disease phenotype also varies by age: generally, young children have intrathoracic lymph node disease or disseminated disease, while adolescents (10 to <20 years) have adult-type pulmonary disease. TB risk also exhibits a gender difference: compared to adolescent boys, adolescent girls have an earlier rise in disease progression risk and higher TB incidence until early adulthood. Understanding why primary school children, during what we term the “Wonder Years,” have low TB risk has implications for vaccine development, therapeutic interventions, and diagnostics. To understand why this group is at low risk, we need a better comprehension of why younger children and adolescents have higher risks, and why risk varies by gender. Immunological response to M. tuberculosis is central to these issues. Host response at key stages in the immunopathological interaction with M. tuberculosis influences risk and disease phenotype. Cell numbers and function change dramatically with age and sexual maturation. Young children have poorly functioning innate cells and a Th2 skew. During the “Wonder Years,” there is a lymphocyte predominance and a Th1 skew. During puberty, neutrophils become more central to host response, and CD4+ T cells increase in number. Sex hormones (dehydroepiandrosterone, adiponectin, leptin, oestradiol, progesterone, and testosterone) profoundly affect immunity. Compared to girls, boys have a stronger Th1 profile and increased numbers of CD8+ T cells and NK cells. Girls are more Th2-skewed and elicit more enhanced inflammatory responses. Non-immunological factors (including exposure intensity, behavior, and co-infections) may impact disease. However, given the consistent patterns seen across time and geography, these factors likely are less central. Strategies to protect children and adolescents from TB may need to differ by age and sex. Further work is required to better understand the contribution of age and sex to M. tuberculosis immunity.

Prevalence and Clinico- Laboratory Profile of Tuberculosis in Children in Nobel Medical College, Biratnagar

“…Gastric lavage or sputum for AFB 1 (6.6%) * Each patient may have more than one positive investigation [4] In a study done by Gyawali N et al, prevalence of tuberculosis among household contacts was found to be 1.6% and Shrestha S et al found prevalence of tuberculosis to be 1.5% which was lower than our study.…”

Adolescent tuberculosis

“…Following the "golden years" of mid-childhood where tuberculosis cases drop significantly compared to early childhood, adolescence represents a period of increased susceptibility to tuberculosis, when both the prevalence of Mycobacterium tuberculosis (M.tb) infection and the incidence of tuberculosis disease rise considerably. [1][2][3][4] The reasons for this are not completely understood, although it is thought that sex hormones, changing social contact patterns and immunological changes may each have a role. 1 An estimated 1.8 million adolescents and young adults around the world develop tuberculosis disease each year, a burden which has been elucidated only recently due to a historical focus within tuberculosis surveillance on "children" (aged 0-14 years) and "adults" (aged ≥15 years), neglecting adolescents entirely.…”

“…[1][2][3][4] The reasons for this are not completely understood, although it is thought that sex hormones, changing social contact patterns and immunological changes may each have a role. 1 An estimated 1.8 million adolescents and young adults around the world develop tuberculosis disease each year, a burden which has been elucidated only recently due to a historical focus within tuberculosis surveillance on "children" (aged 0-14 years) and "adults" (aged ≥15 years), neglecting adolescents entirely. 5 In high-burden settings, adolescents make up both a substantial proportion of the general population, and a substantial proportion of patients with tuberculosis.…”

Clinical manifestations and epidemiology of adolescent tuberculosis in Ukraine

“…Because age may modify the effect of sex and HIV infection on immune response to Mtb, we assessed interactions between age group and sex and HIV for all outcomes [27]. As different risk factors have been reported for transmitted versus acquired RR-TB [26,28], we assessed interactions between DST result and new versus recurrent TB for the first three outcomes and between new versus recurrent TB and all other covariates for the fourth outcome.…”