Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates

Abstract

Background: Multidrug-resistant tuberculosis threatens to reverse recent reductions in global tuberculosis incidence. Although children younger than 15 years constitute more than 25% of the worldwide population, the global incidence of multidrug-resistant tuberculosis disease in children has never been quantified. We aimed to estimate the regional and global annual incidence of multidrug-resistant tuberculosis in children.

Methods: We developed two models: one to estimate the setting-specific risk of multidrug-resistant tuberculosis among child cases of tuberculosis, and a second to estimate the setting-specific incidence of tuberculosis disease in children. The model for risk of multidrug-resistant tuberculosis among children with tuberculosis needed a systematic literature review. We multiplied the setting-specific estimates of multidrug-resistant tuberculosis risk and tuberculosis incidence to estimate regional and global incidence of multidrug-resistant tuberculosis disease in children in 2010.

Findings: We identified 3403 papers, of which 97 studies met inclusion criteria for the systematic review of risk of multidrug-resistant tuberculosis. 31 studies reported the risk of multidrug-resistant tuberculosis in both children and treatment-naive adults with tuberculosis and were used for evaluation of the linear association between multidrug-resistant disease risk in these two patient groups. We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999,792 (95% CI 937,877-1,055,414) children developed tuberculosis disease in 2010, of whom 31,948 (25,594-38,663) had multidrug-resistant disease.

Interpretation: Our estimates underscore that many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children. Future estimates can be refined as more and better tuberculosis data and new diagnostic instruments become available.

Funding: US National Institutes of Health, the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Women's Hospital.

Figure 1

Search strategy

Figure 2. The linear relationship between the proportion of incident treatment-naïve adult TB cases with MDR-TB and the proportion of incident child TB cases with MDR-TB from extracted studies

LEGEND. Each black circle represents a study which provided data on the proportions among both adults and children. The size of the circle is proportional to the number of children in the study who had DST sufficient to diagnose MDR-TB. The red line shows the fitted linear relationship as predicted by our linear regression (which was weighted by the number of children in each study who had DST sufficient to diagnose MDR-TB). The equation shown represents the fitted linear regression with y equal to the proportion of child TB cases with MDR-TB and x equal to the proportion of adult TB cases with MDR-TB. Note that one study is excluded from the graph for visualization purposes (this study included only one child with DST and that child had MDR-TB resulting in a proportion of 1, currently off the scale of our graph). The inset shows the portion of the main plot that lies nearest to the X-Y intercept to show those data points more clearly. Note that, while they sizes of the data points in the inset remain proportional to the number of children that received DST in those studies, they are proportional relative to the other data points in the inset only and are not on the same scale as those in the main plot.

Figure 3. The relationship between the estimated percentage of TB cases that are amongst children (aged 0–14 years) and the log (base 10) estimated TB incidence per 100,000 by country/territory

Each point represents country/territory-specific data. The log (base 10) estimated TB incidence per 100,000 was as reported to the WHO for 2010. The percentage of TB cases that are amongst children was estimated as described in the methods using smear-positive reported incidence by age reported to the WHO for 2010. These were scaled up using data from previous studies to estimate the total TB incidence (smear-positive and negative) in each age group and thus the percentage of cases that were amongst children. When fitting a regression line to these data, we used simulation methods that incorporated the errors in the estimated percentage of TB cases amongst children and the TB incidence. Therefore, we generated 1000 regression lines to capture the errors in these input data (see methods for further details) The middle grey shaded area shows the region covered by the median values of the predictions from the 1000 fitted regression lines of the relationship between the percentage of TB cases that were amongst children and the log (base 10) estimated TB incidence per 100,000. The upper and lower grey shaded areas show the equivalent areas covered by the upper and lower 95% confidence limits (respectively) for the predicted values of the percentage of TB cases that were amongst children.