Abstract
Millions of children are exposed to tuberculosis (TB) each year, many of which become infected with Mycobacterium tuberculosis. Most children can immunologically contain or eradicate the organism without pathology developing. However, in a minority, the organism overcomes the immunological constraints, proliferates and causes TB disease. Each year a million children develop TB disease, with a quarter dying. While it is known that young children and those with immunodeficiencies are at increased risk of progression from TB infection to TB disease, our understanding of risk factors for this transition is limited. The most immunologically disruptive process that can happen during childhood is infection with another pathogen and yet the impact of co-infections on TB risk is poorly investigated. Many diseases have overlapping geographical distributions to TB and affect similar patient populations. It is therefore likely that infection with viruses, bacteria, fungi and protozoa may impact on the risk of developing TB disease following exposure and infection, although disentangling correlation and causation is challenging. As vaccinations also disrupt immunological pathways, these may also impact on TB risk. In this article we describe the pediatric immune response to M. tuberculosis and then review the existing evidence of the impact of co-infection with other pathogens, as well as vaccination, on the host response to M. tuberculosis. We focus on the impact of other organisms on the risk of TB disease in children, in particularly evaluating if co-infections drive host immune responses in an age-dependent way. We finally propose priorities for future research in this field. An improved understanding of the impact of co-infections on TB could assist in TB control strategies, vaccine development (for TB vaccines or vaccines for other organisms), TB treatment approaches and TB diagnostics.
Highlights
Each year millions of children are exposed to infectious cases of tuberculosis (TB) and estimates suggest that around 70 million children currently have TB infection globally [1]
Understanding which children are at high risk of disease progression, following infection, would be useful to better understand host-mycobacterial interactions which in turn could help with vaccine design, host directed therapies, as well as diagnostics that might assist in predicting which TBinfected children are at high risk of future disease
Chukwuanukwu et al recently showed that patients co-infected with malaria had an increase in the production of Th2-associated cytokine IL-4 and antiinflammatory IL-10 in tuberculin-stimulated cells of TB patients >12 years of age compared to malaria-free TB patients, suggesting that malaria co-infection diverts immune response toward a Th2/anti-inflammatory response [231]
Summary
Each year millions of children are exposed to infectious cases of tuberculosis (TB) and estimates suggest that around 70 million children currently have TB infection globally [1]. Each year about a million children develop TB disease [2] a clinical state characterized by symptoms, signs, radiological changes, and in some children, microbiological isolation of M. tuberculosis. Some societal and behavioral elements may influence these age-related changes in risk of disease progression and resulting disease phenotype, it is likely that to a large extent these result from age-related changes in the host immune system. These changes may be driven by a variety of environmental factors, including coinfection (Figure 1).
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