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Keywords:

  • childhood;
  • paediatric;
  • roadmap;
  • tuberculosis

Abstract

  1. Top of page
  2. Abstract
  3. Key Points
  4. References
  5. MCQ Questions (Provide the Single Best Answer)

‘Every day, more than 200 children under the age of 15 die needlessly from tuberculosis (TB) – a disease that is preventable and curable. The World Health Organization estimates that as many as 1 in 10 TB cases globally (6–10% of all TB cases) are among this age group, but the number could be even higher because many children are simply undiagnosed.’ Childhood TB is emerging from the shadows. This quote comes from the recently launched international roadmap towards zero TB deaths in children. We provide a brief update of new developments and remaining challenges related to childhood TB, with particular emphasis on the new roadmap.


Key Points

  1. Top of page
  2. Abstract
  3. Key Points
  4. References
  5. MCQ Questions (Provide the Single Best Answer)
  • Around 1 million children develop tuberculosis (TB) each year. Children at greatest risk for disease and death due to TB are young, malnourished or immune compromised; the very same groups in whom the diagnostic challenges are most pronounced.
  • Treatment outcomes are usually excellent, including for drug-resistant disease, if TB is diagnosed in a timely fashion.
  • The Roadmap is a collaborative response to improve the care of children with TB; support of the paediatric and child health communities will be critical.

Tuberculosis (TB) was declared a global emergency in 1993. For many years, the global public health response focused almost exclusively on efforts to reduce the transmission of Mycobacterium tuberculosis through passive case finding and treatment of the most infectious cases (i.e. adults with sputum smear-positive disease). Young children were effectively excluded from global TB control efforts despite the fact that they are particularly vulnerable to severe, life-threatening forms of disease. This article provides a brief overview of recent progress and remaining challenges related to childhood TB (Table 1).

Table 1. Recent progress and remaining challenges in childhood tuberculosis
CategoryRecent progressRemaining challenges
  1. Adjusted from Marais BJ, Graham SM et al.[1] MDR-TB, multi-drug-resistant tuberculosis; TB, tuberculosis; WHO, World Health Organization.

Disease burdenWHO Child TB factsheet released on World TB day 2012, dedicated to childrenImprove quality of routinely reported dataBetter disease spectrum description
Formal estimates included in the 2012 and 2013 Global ReportsInclusion of children in prevalence surveys
Diagnosis

Wide-scale roll-out of Xpert MTB/RIF

Induced sputum, nasopharyngeal and gastric aspirates provide alternative respiratory samples in children who cannot expectorate

Fine needle aspiration biopsy proven to be an excellent option in children with peripheral lymphadenitis

Xpert MTB/RIF cartridge cost, suboptimal sensitivity in children

Enhanced methods to optimise bacterial yield in pauci-bacillary disease

Alternative specimen collection methods; use of more readily available specimens for testing

Improved immune-based diagnosis; ability to differentiate latent infection from active disease

TreatmentOptimised dosing guidance in children, recent revision allows use of existing quality-assured paediatric formulationsRole of ethambutol not well defined
Global Drug Facility supports provision of child-friendly TB drugs to resource-limited settingsAwait quality-assured fixed-dose combination preparations that meet new WHO dosing criteria
Pragmatic guidance for MDR management; excellent outcomes possible in children with MDR-TBFew children treated in existing MDR treatment programmes; significant side effects, especially ototoxicity with injectables
Regulatory authorities now encourage paediatric development plans for all new TB drugsNeed to establish safety, tolerability and pharmacokinetics of new TB drugs in children
PreventionGreater risk awareness and focus on simple infection control measuresMixing of vulnerable young children and coughing adults in waiting rooms
Pragmatic guidance using simple symptom-based screeningMassive policy practice gap; not currently included in monitoring and evaluation activities
New short course preventive therapy optionsSafety and tolerability of new short course options to be explored
First large trial to investigate a new TB vaccine in infantsNo protective effect demonstrated; ongoing search for immune correlates of protection

Over the last decade, there has been increasing awareness of the TB disease burden suffered by children in TB-endemic areas and a growing momentum to include them in global control efforts.[1] In 2006, the World Health Organization (WHO) TB control strategy expanded beyond the limited focus on smear-positive disease to include other vulnerable populations such as children. The first WHO guidance document for the management of childhood TB was published the same year, aimed at National TB Programmes (NTPs).[2] Despite important gains to reverse the epidemic in the past decade,[3] TB transmission remains uncontrolled in many areas where children are regularly exposed to infection. Reductions in morbidity and mortality due to vaccine-preventable infections such as measles, Haemophilus influenzae type b and pneumococcus, are increasing the relative importance of TB as a preventable and treatable cause of disease and death in young children.[4] There is a strong commitment from WHO to explicitly include children by linking with maternal and child health efforts that extend beyond the traditional vertical disease control approach when framing a new global TB control strategy.[5]

The increased attention on childhood TB has highlighted substantial challenges, particularly in TB-endemic areas with limited resources. In Australia, paediatric TB cases are readily identifiable in most instances as nearly all cases occur among immigrants from TB-endemic countries, and clinicians have access to a range of diagnostic capabilities.[6] However, in TB-endemic countries, TB occurs mostly in poor and vulnerable populations, the same groups that suffer the highest burden from multiple other causes of disease.[5] This poses major challenges for case finding and diagnosis, requiring a collaborative response that includes the child health sector and the NTP.

Key actions to address the challenges are outlined in the ‘Roadmap for childhood tuberculosis: towards zero TB deaths’ that was launched on 1 October 2013 in Washington (Fig. 1).[7] The Roadmap represents a collaborative effort to provide consensus guidance on the way forward. It emphasises important steps to do better with the policy frameworks and tools already available, estimating that it would require only a modest investment of $80 million per year globally. It focuses on issues particular to childhood TB, such as the need for the following: (i) local expertise to guide NTPs and support care delivery at all relevant levels; (ii) pragmatic implementation and operational research to address persistent policy practice gaps;[8, 9] and (iii) advocacy for a vulnerable population without a voice.[10]

figure

Figure 1. Roadmap and key actions to address childhood tuberculosis.

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A logical first step is to ‘know your epidemic’, which is critical for a range of purposes from identifying critical service delivery gaps to drug procurement estimates. Data of actual disease burden are difficult to obtain in TB-endemic areas due to inadequate case finding and the lack of accurate tools to microbiologically confirm diagnosis, especially in young children. However, the mandatory registration of all children treated for TB of all types together with improved recording and reporting practices can provide informative baseline data. Yet even these data are frequently unavailable. A recent study reported that only 1.6% of 4821 children treated for TB in Java were registered with the Indonesian NTP.[11]

The critical need is for a test that can provide accurate and prompt diagnosis. Global roll-out of the Xpert MTB/RIF® assay test (Cepheid Inc., Sunnyvale, CA, USA) has the potential to improve access to microbiological confirmation, but low diagnostic yields in child TB suspects and the prioritisation of its use for the detection of drug-resistant TB suggests that it will not be a game changer for children.[1] Current research is striving to develop more accurate, point-of-care test, such as exists for malaria and HIV, but this is still a distant goal. In the meantime, pragmatic screening and diagnostic approaches are required for health workers at the secondary and primary care settings, which is where the majority of child TB contacts and children with symptoms or signs suspicious of TB will present in TB-endemic countries.[2, 12]

Treatment outcomes are excellent for most forms of TB in children, and serious toxicity to first-line treatment is rare. Unfortunately, there are limited appropriate formulations available for young children, and until recently, dosage recommendations were extrapolated from those for adults. Recent assessments demonstrated the need to increase recommended dosages of first-line TB drugs in young children.[13, 14] It also provided the impetus to include children at an early stage in the development of new drugs and to develop more appropriate and child-friendly formulations to facilitate implementation by NTPs.[15]

Globally, the rise of multi-drug-resistant (MDR) TB poses a major threat, although MDR-TB rates are highly variable between regions. Molecular epidemiology from TB-endemic areas and household contact studies from Australia confirms that MDR-TB is efficiently transmitted, which puts children at risk.[16, 17] In neighbouring countries such as Papua New Guinea, high rates of MDR-TB have been reported with proof of primary transmitted disease.[18] Available data suggest that the proportion of MDR-TB in children is similar to that in treatment naïve adults.[16] Rigorous attempts to quantify the global TB disease burden in children estimate that 999 792 (95% confidence interval 937 877–1 055 414) children developed TB in 2010, among whom 31 948 (25 594–38 663) had MDR-TB.[19] This is nearly double the 530 000 (range 510 000–550 000) paediatric cases estimated by WHO to have occurred in 2012.[3] As for drug-sensitive disease, outcomes and tolerance of medication among children treated for MDR-TB are better than for adults, but case finding and prompt diagnosis are major challenges.[20] All the paediatric MDR-TB cases ever reported in the literature represent only 2% of new MDR-TB cases estimated to occur each year.[19]

Screening of children in close contact with an infectious TB case along with the provision of preventive therapy for those that are eligible has been supported by a strong evidence base for decades and is almost universally recommended. However, except in low-TB incidence countries such as Australia, it is rarely (if ever) implemented.[9] This represents a clear opportunity to reduce TB-related disease and death in endemic areas, but it requires co-ordination and close collaboration between child health and TB control services, a central theme throughout the Roadmap. Contact screening has the potential to provide a substantial benefit without requiring a large investment in additional resources, if initiated at a community care level.

The recent launch of the ‘Roadmap towards zero TB deaths in children’ represents a major step forward. Strong support from a range of stakeholders, including WHO, UNICEF, The Union, USAID, the Treatment Action Group and the Stop TB partnership, signifies a joint commitment to identify integrated care solutions that will improve service delivery to children that have been poorly served by traditional vertical TB control programmes. Australia can provide much needed collaborative regional leadership,[21] but the engagement and commitment of national and regional child health communities to support NTPs are critical to address wide policy practice gaps and to build on the recent global attention.

As Edith Lincoln, one of the pioneers of childhood TB observed, ‘There are many contributions which the pediatrician can make to a TB control program.’[22]

References

  1. Top of page
  2. Abstract
  3. Key Points
  4. References
  5. MCQ Questions (Provide the Single Best Answer)
  • 1
    Marais BJ, Graham SM, Mauerer MM, Zumla A. Progress and challenges in childhood tuberculosis. Lancet Infect. Dis. 2013; 13: 287289.
  • 2
    World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva, Switzerland: WHO press, 2006. WHO/HTM/TB/2006.371.
  • 3
    World Health Organization. Global Tuberculosis Report 2013. World Health Organisation, Geneva, Switzerland 2013. Available from: http://www.who.int/tb/publications/global_report/en/index.html [accessed March 2014].
  • 4
    Graham SM, Sismanidis C, Menzies HJ, Marais BJ, Detjen AK, Black RE. Tuberculosis is important in addressing child survival. Lancet 2014; 383: 16051607.
  • 5
    Getahun H, Sculier D, Sismanidis C, Grzemska M, Raviglione M. Prevention, diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. J. Infect. Dis. 2012; 205: S216227.
  • 6
    Britton PN, Yeung V, Lowbridge C, Isaacs D, Marais BJ. Spectrum of disease in children treated for tuberculosis at a tertiary children's hospital in Australia. J. Ped. Infect. Dis. Soc. 2013; 2: 224231.
  • 7
    World Health Organization. Roadmap for Childhood Tuberculosis: Towards Zero Deaths. Geneva, Switzerland: WHO Document Production Services, 2013. Available from:%20http://apps.who.int/iris/bitstream/10665/89506/1/9789241506137_eng.pdf [accessed May 2014]. WHO/HTM/TB/2013.12 2013.
  • 8
    Hill PC, Rutherford ME, Audas R, van Crevel R, Graham SM. Closing the policy-practice gap in the management of child contacts of tuberculosis in developing countries. PLoS Med. 2011; 8: e10001105.
  • 9
    Graham SM, Triasih R. Editorial commentary: more evidence to support screening of child contacts of tuberculosis cases: if not now, then when? Clin. Infect. Dis. 2013; 57: 16931694.
  • 10
    Sandgren A, Cuevas LE, Dara M. et.al. Childhood tuberculosis: progress requires an advocacy strategy now. Eur. Respir. J. 2012; 40: 294297.
  • 11
    Lestari T, Probandari A, Hurtig A-K, Utarini A. High caseload of childhood tuberculosis in hospitals on Java Island, Indonesia: a cross sectional study. BMC Pub. Health 2011; 11: 784.
  • 12
    Graham SM, The Union Child TB Working Group. Desk-guide for the Diagnosis and Management of TB in Children. IUATLD, 2010. Available from: http://www.theunion.org/index.php/en/resources/scientific-publications/tuberculosis/item/193-desk-guide-for-diagnosis-and-management-of-tb-in-children [accessed May 2014].
  • 13
    Donald PR, Ahmed A, Burman WJ et al. Requirements for the clinical evaluation of new antituberculosis agents in children. Int. J. Tuber. Lung Dis. 2013; 17: 794799.
  • 14
    Detjen AK, Macé C, Perrin C, Graham SM, Grzemska M. Adoption of revised dosage recommendations for childhood tuberculosis in countries with different childhood tuberculosis burdens. Pub. Health Action 2012; 2: 126132.
  • 15
    McNeely D, Lin J, Raouf A et al. The regulatory environment for the evaluation of new tuberculosis drugs in children. Progress Resp. Res. 2011; 40: 235242.
  • 16
    Marais BJ, Mlambo CK, Rastogi N et al. Epidemic spread of multidrug-resistant (MDR) tuberculosis in Johannesburg, South Africa. J. Clin. Microbiol. 2013; 51: 18181825.
  • 17
    Denholm JT, Leslie DE, Jenkin GA et al. Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in Victoria, Australia, 1995–2010. Int. J. Tuberc. Lung Dis. 2012; 16: 13201325.
  • 18
    Gilpin CM, Simpson G, Vincent S et al. Evidence of primary transmission of multidrug-resistant tuberculosis in the Western Province of Papua New Guinea. Med. J. Aust. 2008; 188: 148152.
  • 19
    Jenkins HE, Tolman AW, Yuen CM et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet 2014; 383: 15721579.
  • 20
    Seddon JA, Furin JJ, Gale M et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am. J. Respir. Crit. Care Med. 2012; 186: 953964.
  • 21
    Majumdar SS, Marais BJ, Denholm J, Britton W. Drug-resistant tuberculosis: collaborative regional leadership required. Med. J. Austr. 2014; 200: 241242.
  • 22
    Donald PR. Edith Lincoln, an American pioneer of childhood tuberculosis. Pediatr. Infect. Dis. J. 2013; 32: 241245.

MCQ Questions (Provide the Single Best Answer)

  1. Top of page
  2. Abstract
  3. Key Points
  4. References
  5. MCQ Questions (Provide the Single Best Answer)
  1. The Roadmap for Childhood Tuberculosis calls for the following (select the incorrect statement):

    1. Meet funding needs for childhood TB
    2. Foster local expertise and leadership
    3. Develop training and reference materials for health-care workers
    4. Children diagnosed with TB should be hospitalised to monitor treatment
    5. Do not miss critical opportunities for intervention

    Correct answer (incorrect statement): d.

  2. Select the correct statement

    • a) 
      TB is a rare cause of death in young children who live in TB-endemic areas
    • b) 
      TB is difficult to prevent and treat in children
    • c) 
      Every day, more than 200 children under the age of 15 die needlessly from TB
    • d) 
      Microbiological confirmation is easily attained in children with TB
    • e) 
      National TB control strategies should focus on sputum smear-positive cases only

    Correct answer: c.

  3. Regarding multi-drug-resistant (MDR)-TB (select the correct statement)

    • a) 
      Children do not develop MDR-TB
    • b) 
      Smear microscopy is sufficient to diagnose MDR-TB
    • c) 
      MDR-TB treatment outcomes are particularly poor in children
    • d) 
      MDR-TB is rarely transmitted
    • e) 
      Good MDR-TB treatment outcomes have been reported in children

    Correct answer: e.