Advances in Pediatric Tuberculosis

Worldwide, tuberculosis (TB) continues to rank high in pediatric infections and deaths, especially with reductions in human immunodeficiency virus (HIV) perinatal transmission with antiretroviral therapy. In 2016, worldwide TB incident cases were estimated to be approximately 10.4 million with 1 million cases in children.[1] Cases in children may be underestimated due to the paucibacillary nature of the disease making culture diagnosis less frequent in high burden countries.[2] The World Health Organization (WHO) has made a goal of 90% reduction of TB deaths and 80% in TB incidence rate by 2030.[1] To achieve this lofty goal in all individuals, continued work must occur in pediatric TB. In this special issue of the Journal of Pediatric Infectious Diseases, advances in pediatric TB are discussed.

The first article presents the worldwide burden of disease in children including the problem of drug resistance. The authors delve into great detail about the difficulties in knowing rates of TB disease in children from various areas of the world. They lay out various modeling estimates of TB incidence rates in children. Risks for TB acquisition such as poverty, young age, and HIV infection are discussed. Community efforts to prevent pediatric TB such as use of Bacillus Calmette–Guérin (BCG) vaccination and contact tracing are discussed. The authors conclude that TB deaths are masked by other illnesses, and therefore the mortality rate may be underestimated.

The second article is an extensive pharmacology review of TB medication in children. Pharmacokinetic problems are unique to children due to differences in effects of ontogeny and frequent need for liquid formulations. Newer drugs such as bedaquiline and delamanid are reviewed including the limited pediatric information available.

In the third article, the authors discuss immunologic determinants of TB in children. The important components of the immune system important for mounting a response to mycobacterial TB in children are fully discussed. Vaccination, including vaccines in development, is reviewed at the end.

The fourth article covers diagnosis of TB infection and disease. Specificity of the Mantoux test for diagnosis of TB is limited by cross reactions with BCG and nontuberculous mycobacteria (NTM). The in vitro interferon (IFN)-γ release assays (IGRAs) are typically more specific. Literature on use of IGRAs to diagnosis infection in low burden countries is scarce and therefore the tuberculin skin test is preferred under age 5.[3] Newer diagnostic techniques are available to diagnose pulmonary disease. Most of these newer techniques are limited in use due to the lack of resources and available specimens from pediatric patients.[4]

The fifth and sixth articles deal with treatment of infection and central nervous system (CNS) disease, respectively. Daily isoniazid for 9 months has been recommended for drug-susceptible infection for decades due to known efficacy in preventing disease. Newer regimens involving shorter courses, with or without need for direct observed therapy, are available that make completion of therapy more likely. CNS disease, manifesting as either meningitis, intracranial tuberculoma, or spinal cord tuberculous arachnoiditis, results in the highest morbidity and mortality. TB meningitis must be treated early to prevent a poor outcome. Diagnosis, however, can be difficult with symptoms often nonspecific. The sixth article discusses principles of treatment including use of antituberculous medication with high CNS penetration. Use of corticosteroids and other adjunctive therapy as well as surgical intervention for hydrocephalus is discussed in detail. Finally, treatment of CNS TB in special situations such as HIV infection and multidrug (MDR) TB is covered.

The last article tackles treatment of MDR and extra drug-resistant TB. The prevalence of drug resistance in children mirrors what is seen in adults. With an estimated 30,000 cases of MDR TB in children worldwide, treatment regimens are desperately needed.[5] The authors highlight the problem of increased intolerance and adverse events seen with use of drugs needed to treat these resistant infections, made even more difficult by the limited pediatric formulations and minimal pharmacokinetic data for many of the drugs.

Due to difficulty in diagnosis and the low infectiousness of disease in children, TB in pediatrics has been a low priority for national TB programs. Newer estimates of TB incidence rates dictate that the disease cannot be ignored. Newer diagnostic tools over the last several decades to diagnose infection and disease have been developed but still do not replace clinical diagnosis. Many of these new tests are either not available in low-income countries or cannot be used due to lack of sputum. Treatment of pediatric TB requires knowledge of the unique pharmacokinetic and pharmacodynamic differences seen in this population. More pediatric-specific research is needed with any new TB medication. Treatment for TB also requires knowledge in treating the most difficult cases—CNS TB and drug-resistant TB. Finally, more research is needed in understanding the immunologic response to mycobacterial TB in pediatric patients so that effective vaccines can be developed. The future for the world's children requires innovation in the fight against TB.

• References

• 1 WHO. Global tuberculosis report 2016. Available at: http://apps.who.int/iris/bitstream/10665/250441/1/978241565394_eng.pdf . Accessed March 8, 2017
• 2 Starke JR. Improving tuberculosis care for children in high-burden settings. Pediatrics 2014; 134 (04) 655-657
• 3 Faddoul D. Childhood tuberculosis. Adv Pediatr 2015; 62 (01) 59-90
• 4 Kumar MK, Kumar P, Singh A. Recent advances in the diagnosis and treatment of childhood tuberculosis. J Nat Sci Biol Med 2015; 6 (02) 314-320
• 5 Jenkins HE, Tolman AW, Yuen CM. , et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet 2014; 383 (9928): 1572-1579