Consolidated Guidelines

Around 25 000-32 000 children are estimated to develop MDR/RR-TB every year (75-77). In 2018, 3398 children (aged below 15 years) were started on second-line treatment for MDR/RR-TB. After increasing to 5586 in 2019, due to the impact of the COVID-19 pandemic, this number dropped back to 3234 in 2020, representing only 2.5% of the total number of persons with MDR/RR-TB initiated on treatment and only 10.1%-12.9% of the estimated number of children with incident MDR/RR-TB (78).

Implementation of this recommendation should be subject to ongoing monitoring and evaluation to ensure high quality implementation adapted to the local context. Uptake of the regimen and monitoring of treatment outcomes among patients who receive this regimen are also of interest. The overall incidence of TBM as a form of EPTB in children and adolescents reflects the ongoing transmission of TB to children, as well as delays in the diagnosis of TB and is therefore important information to monitor as well.

One key implementation consideration is the administration of the intervention regimen with the correct dosages of the included medicines, using currently available child-friendly formulations, including FDC formulations when possible. The regimen includes isoniazid, rifampicin, pyrazinamide and ethionamide, and is dosed as follows:

Children living with HIV infection: Most studies in the review were restricted to HIV-negative children. HIV-positive children represented a small proportion of children with TBM overall, and all received the intervention regimen. In the three studies using the intervention regimen included in the evidence review, 11 children were identified as having HIV infection (of a total of 724 children). Therefore, it was not possible to undertake analyses stratified by HIV infection.

Following M. tuberculosis infection, young children are at high risk of developing the most severe forms of the disease, of which the most devastating form is TBM. This predominantly affects young children with a peak age of onset of 2-4 years (2). Up to 15% of childhood TB may present as TBM (62); with a decreasing incidence of bacterial meningitis attributed to other causes, TB is the leading cause of bacterial meningitis in many settings (63).

Recommendation

In children and adolescents with bacteriologically confirmed or clinically diagnosed TB meningitis (without suspicion or evidence of MDR/RR-TB), a 6-month intensive regimen (6HRZEto) may be used as an alternative option to the 12-month regimen (2HRZE/10HR) (Conditional recommendation, very low certainty of the evidence).

Remarks

The clinical monitoring requirements for the shorter regimen remain the same as for the 6-month regimen and treatment outcomes are determined at the end of the 4-month regimen.

Should there be insufficient clinical improvement after completion of the 4-month regimen, the clinician may decide to extend treatment to 6 months while considering alternative diagnoses, including DR-TB.

Assessing severity of disease:The feasibility of assessing the severity of TB disease, particularly in settings without access to CXR or capacity for CXR interpretation and WHO-recommended diagnostic tests was identified as a major implementation consideration. Chest radiography was identified by the GDG as a critical tool to evaluate the severity of intrathoracic disease.

Children with peripheral lymph node TB: Although the number of children with peripheral lymph node TB in the SHINE trial were small (N=19 in the 16-week arm and N=21 in the 24-week arm), there was no difference in the proportion of unfavourable outcomes between the two arms. The SHINE trial also found that 16 weeks of treatment was non-inferior compared to 24 weeks of treatment among children with both peripheral lymph node disease and pulmonar y disease (N=182 in the 16-week arm and N=171 in the 24-week arm).

The majority of children with TB have less severe forms of the disease than adults. Treatment regimens that are shorter than those for adults may be effective in treating children with TB, however solid evidence to substantiate this has been lacking to date. Shorter treatment regimens can result in lower costs to families and health services, potentially less toxicity, lower risks of drug-drug interactions in children living with HIV, and fewer problems with adherence.