Articles
Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis

https://doi.org/10.1016/S1473-3099(12)70033-6Get rights and content

Summary

Background

Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children.

Methods

We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion.

Results

We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54–90·80). Across all studies, 5·9% (95% CI 1·3–10·5) died, 6·2% (2·3–10·2) defaulted, and 39·1% (28·7–49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism.

Interpretation

The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available.

Funding

None.

Introduction

An estimated 12 million people worldwide have tuberculosis, of whom about 650 000 have multidrug-resistant (MDR) disease.1 Childhood tuberculosis is estimated to account for 10–15% of the global tuberculosis burden,2 and probably accounts for a similar proportion when considering only drug-resistant disease. The highest rates of paediatric MDR tuberculosis are reported in low-income countries,2 and in some regions the incidence of MDR tuberculosis has risen sharply in the past two decades—eg, in the Western Cape, South Africa, the proportion of culture-confirmed cases of tuberculosis with multidrug-resistance has tripled in the past 15 years from 2·3% to 7·3%.3

MDR tuberculosis is underdetected in children. Diagnosis of drug resistance needs mycobacterial culture and drug susceptibility testing (DST),4 but the difficulty in obtaining respiratory secretions, such as sputum or gastric aspirates, or specimens of extrapulmonary tuberculosis from young children,5 along with the fact that up to half of all children with a clinical diagnosis of tuberculosis disease are smear-negative and culture-negative, makes microbiological confirmation challenging.6 Strict programmatic requirements for microbiological confirmation of drug resistance combined with insufficient recognition of the importance of taking into account DST patterns from adult source cases can lead to substantial delays in diagnosis and initiation of appropriate treatment.7 These delays could lead to progression of disease, increased risk of infectiousness of children, greater risk of disease complications such as tuberculous meningitis, and higher rates of morbidity and mortality.8, 9

Paediatric drug-resistant tuberculosis is a neglected concern, with few children being treated relative to the estimated disease burden.10 WHO guidelines for the treatment of drug-resistant tuberculosis in adults are based on evidence from meta-analyses of individual patients' data.11 However, recommendations for children are based on expert opinion, drawing on data from case series and cohort studies,12, 13 often with small sample sizes. Consequently, variation exists in programmatic choices of treatment regimens, with the choice of drugs informed by previous drug exposure and DST results.14 Because of uncertainties about diagnosis and the best treatment regimens, and concerns about the toxic effects associated with MDR tuberculosis treatment, health-care providers are cautious about treating paediatric MDR tuberculosis.

We did a systematic review and meta-analysis of the available evidence for treatment outcomes in children with MDR tuberculosis, and assessed the characteristics of patients and studies that could have affected treatment success.

Section snippets

Search strategy and selection criteria

We searched for publications in PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. We developed a highly sensitive search strategy, using a combination of the search terms “tuberculosis”, “multidrug resistance”, “multidrug-resistant”, “treatment outcomes”, and “children”, both as exploded MESH headings and free-text terms. We reviewed the bibliographies of all retrieved articles. We also searched all electronically available conference abstracts

Results

The eight studies included in our analysis (figure 1) came from individual treatment programmes from five countries (Peru,20 Spain,21 the USA,22, 23 South Africa,7, 24, 25 and Latvia26) and reported on treatment outcomes for a range of eight patients21 to 111 patients.24 One study was a conference abstract;26 the rest were published as full text articles.

Studies were done in a range of settings, including countries with high7, 21, 24, 25 and low17, 22, 23, 26 MDR tuberculosis burdens. The

Discussion

Our systematic review suggests that MDR tuberculosis can be successfully treated in children, with the overall proportion of children achieving treatment success as good as, if not better than, that reported for adults receiving individualised treatment regimens (64%).15 Mortality and defaulting seemed to be lower for children than for adults, but these differences were not statistically significant.

Detailed data for adverse events were absent from some studies, and adverse events were not

References (42)

  • KA Houwert et al.

    Prospective evaluation of World Health Organization criteria to assist diagnosis of tuberculosis in children

    Eur Respir J

    (1998)
  • AC Hesseling et al.

    A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis

    Int J Tuberc Lung Dis

    (2002)
  • HS Schaaf et al.

    Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome

    Arch Dis Child

    (2003)
  • HS Schaaf et al.

    Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis

    Pediatr Infect Dis J

    (2009)
  • N Padayatchi et al.

    Multidrug-resistant tuberculous meningitis in children in Durban, South Africa

    Pediatr Infect Dis J

    (2006)
  • Sandgren A, Cuevas LE, Dara M, et al. Childhood tuberculosis: progress requires advocacy strategy now. Eur Respir J (in...
  • D Falzon et al.

    WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update

    Eur Respir J

    (2011)
  • CD Mitnick et al.

    Randomized trials to optimize treatment of multidrug-resistant tuberculosis

    PLoS Med

    (2007)
  • J Furin

    The clinical management of drug-resistant tuberculosis

    Curr Opin Pulm Med

    (2007)
  • RG Newcombe

    Interval estimation for the difference between independent proportions: comparison of eleven methods

    Stat Med

    (1998)
  • M Borenstien et al.
  • Cited by (153)

    • Updates in Pediatric Tuberculosis in International Settings

      2022, Pediatric Clinics of North America
    • Situational analysis of 10 countries with a high burden of drug-resistant tuberculosis 2 years post-UNHLM declaration: progress and setbacks in a changing landscape

      2021, International Journal of Infectious Diseases
      Citation Excerpt :

      The 1051 DR-TB children notified (mainly from South Africa and the Philippines) represent <1% of the 115,000 target established by the UNHLM for 2018–2022. DR-TB in children tends to have a good outcome when appropriate care is provided (Ettehad et al., 2012; Tola et al., 2020). However, programmatic advances appear to be minimal in the top 10 HBCs and globally (Dodd et al., 2016).

    • Multidrug resistant tuberculosis treatment outcome in children in developing and developed countries: A systematic review and meta-analysis

      2020, International Journal of Infectious Diseases
      Citation Excerpt :

      The pooled treatment success (cured plus completed) is 81.7% (Ettehad et al. 2012). A systematic review and meta-analysis reported by Isaakidis et.al (Isaakidis et al. 2015) is also indicated high treatment success (83.4%) and death (11.4%) but, lower lost to follow up (3.9%) proportions in comparison with the findings of previous review (Ettehad et al. 2012). Moreover, a recently published review study that pooled data on 975 children is indicated 78% of children treated successfully (Harausz et al. 2018).

    View all citing articles on Scopus

    These authors share last authorship

    View full text