Ongoing challenges to understanding multidrug- and rifampicin-resistant tuberculosis in children versus adults

Discussion

In most settings (45 out of 55 countries with high-quality data and reporting paediatric cases of MDR/RR-TB), and globally as a whole, there is no evidence that age is associated with odds of MDR/RR-TB. However, in some settings such as the former Soviet Union countries in general, and Georgia, Kazakhstan, Lithuania, Tajikistan and Uzbekistan in particular, as well as Peru, MDR/RR-TB is positively associated with age ≥15 years. Meanwhile, in the rest of Europe in general, and the UK, Poland, Finland and Luxembourg in particular, MDR/RR-TB is positively associated with age <15 years. In addition, there is weak evidence that MDR/RR-TB is positively associated with age <15 years in the Western Pacific and African regions, which warrants further investigation.

16 countries, primarily located in the WHO European Region, had sufficient data to compare the change over time between 2000–2011 and 2012–2018. We found strong evidence for decreases in the odds ratio of MDR/RR-TB in children compared to adults in Germany, Kazakhstan and the USA, and very weak evidence for a decline in Belarus, Namibia and Uzbekistan. At the same time, total TB incidence was decreasing, suggesting that transmission of drug-susceptible TB was decreasing (scenario 3 in table 1; supplementary material). This may mean that MDR/RR-TB transmission may have been decreasing over time in those settings (further details in the supplementary material), although we note that the low number of children with MDR/RR-TB in particular means that it is difficult to draw broad conclusions about changes in transmission. Unfortunately, weak evidence for an increasing odds ratio in Belgium is difficult to interpret and could reflect either an increase or decrease in MDR/RR-TB transmission (scenarios 4 or 6 in table 1). As a caveat, we note that in countries where a large fraction (often the majority) of TB occurs among foreign-born individuals, the interpretation of the odds ratio as a measure of the relative risk of local transmission of MDR/RR-M. tuberculosis versus drug-susceptible M. tuberculosis is probably not valid. In Germany, the USA and Belgium in particular, low rates of local transmission [10] mean that changes in the odds ratio reflect changes that are happening outside those countries.

In general agreement with previous research [3, 4], we find that in the majority of settings, there is no evidence that the odds of MDR/RR-TB for children are likely to be different to adults. The inclusion of data from an additional 20 countries, including seven high MDR/RR-TB burden countries not previously considered, totalling an additional 3852 (63%) children and 288 113 (91%) adults, strengthens these findings. In addition, we find some very weak evidence to support previous concerns over the odds for children in southern African countries with a high HIV burden, such as Namibia, Lesotho and Eswatini, although data for these countries remain limited and it is difficult to draw broad conclusions. Indeed, only in Western Europe, a setting with very low numbers of MDR/RR-TB cases [1], is there evidence of worse odds for children than adults, in line with previous findings from >5 years ago [4]. We do find that the odds for children compared to adults may be setting-specific, with evidence that children have much lower odds of MDR/RR-TB in countries of the former Soviet Union (where higher-quality data are more widely available), an aspect that had not previously been identified. As such, previous calculations [3, 6, 11] of the number of children with MDR/RR-TB in these high MDR/RR-TB burden settings may have been overestimated. In addition, several settings, particularly Western Europe, but also the Western Pacific and Africa Regions, require further investigation to identify whether children do indeed have higher odds of MDR/RR-TB in these settings, and if so, why.

However, we note that interpretation of our results is based on the implicit assumption that the odds ratio calculated reflects the ratio of actual MDR/RR-TB burden in children compared to adults. In reality, our results are only for the subset of cases for whom DST results are available, which is particularly challenging in children [2]. If the case-detection ratio for MDR/RR-TB compared to DS-TB is different for adults than children, then the odds we calculate could be biased upward or downward. Examples of such biases include rigorousness of DST testing for children (who are less likely to obtain bacteriological confirmation than adults), particularly if this increases for household contacts of MDR/RR-TB cases, and systematic screening in adult populations with a high MDR/RR-TB prevalence, such as prison populations in the former Soviet Union. The latter could explain the high odds of MDR/RR-TB in adults in the former Soviet Union. The available data do not allow us to determine the magnitude of these detection biases in our analysis.

Beyond these biases, in some settings such as the former Soviet Union clustering of MDR/RR-TB cases in certain settings composed of adults, notably prisons [12], could explain why adults have higher odds of MDR/RR-TB. Meanwhile, high odds of MDR/RR-TB for children in Western Europe, where DST rates are high [1], could represent an association that data elsewhere is not representative enough to identify. Potentially high odds of MDR/RR-TB for children in the Western Pacific and African regions are worrying, where the latter and its potential interaction with HIV has been previously identified as a concern [4]. However, the evidence from our results here is weak, and requires further investigation.

Where there are data to compare any change over time, in many cases the odds for children compared to adults are either unchanged or improving. Given the potential importance of children as sentinels for TB transmission [2], this is in line with a comparatively stable MDR/RR-TB incidence globally [1], although more evidence is required before conclusions can be drawn. Indeed, we note that this lack of statistical significance for country-specific odds is not necessarily an indication of a similar force of infection for children and adults, but may reflect limitations in available data, particularly the low number of recorded children with MDR/RR-TB.

As mentioned earlier, differences in case detection remain a further limitation of our study; namely, changes in the TB diagnostic algorithm over time may have been implemented differently among children compared to adults. In particular, the adoption of Xpert MTB/RIF as the initial diagnostic test in place of smear microscopy may have been more common in children, due to resource limitations in some settings preventing testing of all patient groups. The available data do not allow an assessment of how the proportion of bacteriologically confirmed cases for which DST was performed has changed over time for children compared to adults. At the same time, as in work by Zignol et al. [4], we were not able to separate treatment-naïve from previously treated cases in our data, where, as previously noted, the latter are more likely to be adults. In comparison, Jenkins et al. [3] compare children to treatment-naïve adults only, finding no difference. In our results, in addition to both previous instances, there is no evidence for a difference in odds by age, suggesting that either the importance of resistance acquisition in adults due to previous treatment is limited, or, more likely, that additional evidence is required to better understand the odds.

Finally, our analysis included data from only 13 of the 30 high MDR/RR-TB burden countries defined by WHO for the period of 2016–2020, and only four had data available for both time periods examined, namely, Belarus, Kazakhstan, Republic of Moldova and Uzbekistan. Half of the world's estimated incident RR-TB cases in 2018 were found in India, China and the Russian Federation, yet only limited high-quality data were available; indeed, in each country there was only 1 year where any paediatric MDR/RR-TB cases were reported. These gaps highlight the urgent need to strengthen diagnostic capacity through expanded sample referral systems and laboratory networks. Countries should strive towards achieving universal DST for all people with TB, as called for in WHO's End TB Strategy [13]. This should be coupled with the establishment of electronic case-based surveillance systems which would allow for finer age disaggregation than the cut-off of 15 years of age that we use here, allowing for comparisons in risk between groups such as younger children, adolescents and older adults. Without these advances in diagnosis, recording and reporting of cases in children, we cannot fully understand the burden and transmission risks of MDR/RR-TB in children, or trends in these over time.