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Wednesday, 10th of April 2013

PROGRESS AND CHALLENGES IN CHILDHOOD TUBERCULOSIS

The Lancet Infectious Diseases, Volume 13, Issue 4, Pages 287 - 289, April 2013

Published Online: 24 March 2013

Best viewed at http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2813%2970031-8/fulltext

Ben J Marais a , Stephen M Graham b, Markus Maeurer c, Alimuddin Zumla d e

The plight of children with tuberculosis is widely recognised and is increasingly becoming a priority for national tuberculosis control programmes. In 2012, WHO attempted for the first time to quantify the tuberculosis disease burden in children, estimating there to be 490 000 cases and 65 000 deaths in 2011.1Some limitations of this estimation were recognised within the WHO report1 (table), such as the assumption that the ratio of notified to incident cases is the same for children and adults, even though under-reporting of child tuberculosis cases is very common. The estimated number of children with tuberculosis equates to less than 6% of all incident cases (8·7 million), whereas estimates from tuberculosis endemic areas suggest proportions of 10—15%.2 Furthermore, tuberculosis-related deaths in children infected with HIV were classified as deaths due to HIV (not tuberculosis). Additionally, many children who die of common disorders such as severe pneumonia and malnutrition might have unrecognised tuberculosis.3

Table 1Table image

Recent progress and key challenges in childhood tuberculosis

Unfortunately, child tuberculosis data reported by national tuberculosis control programmes are often incomplete and hampered by restricted diagnostic access in most tuberculosis endemic areas.2 Children are frequently diagnosed in settings where the accuracy and quality of non-microbiological diagnoses is weak and linkage with existing tuberculosis reporting systems is poor. Massive roll-out of the Xpert MTB/RIF assay might increase diagnostic yield4 compared with sputum microscopy, but overall diagnostic yields remain low5and children are unlikely to be prioritised in settings where the early detection of drug-resistant tuberculosis is the key concern. Studies in a range of settings are needed to calculate the burden of tuberculosis and drug-resistant tuberculosis in children. The importance of linking tuberculosis prevention and care to maternal and child health programmes has been recognised, and more integrated approaches will be promoted in the future.6

Recent revision of recommended drug doses in children ended a period of prolonged uncertainty following recommendations that were not aligned with available quality assured paediatric formulations.7 Expansion of the recommended isoniazid dose range from 10—15 mg/kg to 7—15 mg/kg will allow existing formulations with a 1:2 isoniazid-to-rifampicin ratio to be used without dose changes, greatly simplifying treatment before a more ideal formulation with a 2:3 isoniazid-to-rifampicin ratio becomes available. Despite pragmatic strategies and existing policies to provide preventive therapy to young children exposed to an infectious source case,8 implementation is poor.7, 9 This problem is unlikely to improve unless the provision of preventive therapy, at least to the most susceptible children, is included in formal monitoring and assessment programmes.

Vaccination provides a highly effective strategy to control vaccine-preventable diseases; however, the fact that only a few people develop tuberculosis after Mycobacterium tuberculosis infection differentiates tuberculosis from classic vaccine-preventable diseases. More than 90% of immune-competent individuals seem to be inherently resistant to tuberculosis, which provides high levels of herd immunity at the community level (so-called natural herd immunity). The combined effect of known risk factors for tuberculosis, such as malnutrition, HIV infection, diabetes mellitus, cigarette and biofuel smoke exposure, chronic lung disease, and immunosuppressive drugs, reduces the protective effects of natural herd immunity to levels at which disease transmission can be sustained, particularly within susceptible subpopulations in the community.10 Combined strategies that reduce the social determinants of disease and explore the protective value of vaccination strategies are needed to achieve ultimate tuberculosis control.

The BCG vaccine offers some protection against disseminated forms of tuberculosis in young children (and against leprosy), but does not consistently protect against adult-type tuberculosis.11 Concerns about the safety of the BCG vaccine in HIV-infected children—especially the potential to increase HIV replication due to strong T-cell stimulation12—and disseminated BCG disease need careful consideration during genetically modified BCG vaccine development. Additionally, prominent T-cell epitopes are genetically highly conserved, similar to essential housekeeping genes, suggesting that M tuberculosis subverts some T-cell-mediated immune response to benefit its own survival and spread.13 An accurate correlate or biomarker of protection has not yet been identified.14 The important roles played by innate immune responses and localised (non-circulating) T-cell populations have only recently been described,15, 16 and these might lead to new discoveries. The diverse range of pathological abnormalities related to the ontogeny of the immune response in children17 presents opportunities to characterise important immunological mechanisms. Immunohistological studies could also advance understanding of protective immune responses in children with latent M tuberculosis infection18 and provide answers to many unresolved beliefs about latent tuberculosis infection.19

Improvements in the mechanistic understanding of tuberculosis disease and protection are greatly needed, as is a reduction in major policy—practice gaps, since most children in tuberculosis endemic areas are unable to access effective tuberculosis care.

We declare that we have no conflicts of interest.

References

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19 Zumla A, Atun R, Maeurer M, et al. Scientific dogmas, paradoxes and mysteries of latent Mycobacterium tuberculosis infection. Trop Med Int Health 2011; 16: 79-83. CrossRef | PubMed

a Sydney Emerging Infections and Biosecurity Institute, and The Children's Hospital at Westmead, University of Sydney, Locked Bag 4001, Sydney, NSW 2145, Australia

b Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia

c Division of Therapeutic Immunology, LabMed, and Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden

d Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK

e University of Zambia-University College London Medical School (UNZA-UCLMS) Research and Training Project, University Teaching Hospital, Lusaka, Zambia