Consolidated Guidelines

Algorithms included in the operational handbook: In the follow-up to the GDG meeting, new integrated treatment decision algorithms for specific populations and settings have been developed and internally validated, using regression modelling with pre-determined cut-off values for sensitivity and specificity against the reference standard (using updated clinical case definitions to define pulmonary TB, outlined in Graham S et al. (31)), based on the individual patient data set used for the evidence review conducted to answer this PICO question.

For HIV-infected children under the age of 10 years, the pooled sensitivity of the algorithms reviewed ranged from 24% (Marais et al. criteria) to 92% (Uganda NTLP algorithm), and the pooled specificity from 15% (Uganda NTLP algorithm) to 87% (Stegen-Toledo score, cut-off 5).

For children with SAM the pooled sensitivity varied between 33% (Marais et al. criteria) and 93% (Uganda NTLP algorithm and Keith Edward score), while the pooled specificity varied between 10% (Keith Edward score) and 88% (Stegen-Toledo score, cut-off 5).

TB diagnosis in children relies on a thorough assessment of all evidence derived from a careful history of exposure, clinical examination and relevant investigations. While various algorithms and scoring systems for TB diagnosis in children exist, these have not been systematically evaluated. There is a need for evidence-based, practical treatment decision algorithm(s), ideally for different settings with varying access to diagnostic tests and CXR.

Interim recommendation

In children with presumptive pulmonary TB attending health care facilities, integrated treatment decision algorithms may be used to diagnose pulmonary TB.
(Conditional recommendation, very low certainty of evidence).

Remarks

Local monitoring of specimen collection by specimen type, diagnostic test, result and clinical diagnosis in a TB Laboratory Register (or equivalent) is recommended. Results should be recorded in a TB Register.

Routine recording and reporting of child and adolescent notifications in five-year age brackets (i.e. 0-4, 5-9, 10-14, 15-19 years) is recommended by WHO for countries with case-based electronic recording and reporting systems.

Specimen collection and the quality thereof needs to be ensured to optimize accurate diagnosis for all specimen types.

Children with severe acute malnutrition (SAM): four studies (with 259 participants, of whom 9 had TB disease) were identified for children with SAM using Xpert Ultra on gastric aspirates and three studies (428 participants, 19 with TB) using Xpert Ultra on stool specimens. The meta-analysis on stool samples in children with SAM showed similar accuracy as in the overall analysis (sensitivity 63.2%, specificity 98.5%). A meta-analysis on gastric aspirates could not be performed due to insufficient data.

The development of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, United States of America (United States)) was a significant step forward in improving the diagnosis of TB and the detection of rifampicin resistance globally. However, Xpert MTB/RIF sensitivity is suboptimal, particularly among people (including children) with smear-negative TB and people (including children) living with HIV. The Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States), hereafter referred to as Xpert Ultra, was developed by Cepheid as the next-generation assay to overcome these limitations.

Recommendation:

In children with signs and symptoms of pulmonary TB, Xpert Ultra should be used as the initial diagnostic test for TB and detection of rifampicin resistance on sputum, nasopharyngeal aspirate, gastric aspirate or stool, rather than smear microscopy/culture and phenotypic drug susceptibility testing (DST).

Of the estimated 1.1 million children who developed TB annually, only 399 000 (36.5%) were notified to NTPs in 2020. Under-notification is worst among children below 5 years of age, with only 27.5% of children with TB being notified (1). These 'missing' children are not diagnosed and/or not reported. TB-related mortality among children below 15 years of age was estimated at 226 000 for 2020 (1). Modelling has shown that 80% of TB-related deaths are among children under 5 years of age, and that 96% of children who die of TB, did not access treatment (15).