The probability of TB progression and poor outcomes is higher in CALHIV than their peers without HIV, partly due to diagnostic delays and non-specific presentation. One recommended vital strategy for early TB case detection is systematic TB screening, especially for high-risk groups such as CALHIV. However, evidence to inform the design of pediatric TB screening strategies is limited. As a result, the implementation of TB screening in children remains a challenge and has contributed to the significant gap in TB case detection.

Advances in TB screening approaches for children generally lag behind that of adults due to limited evidence, often leading to the adaptation of evidence-based adult recommendations despite differences in disease characteristics. More recently, the World Health Organization recommended that systematic screening for TB disease be conducted using a symptom screen including any one of current cough, fever, poor weight gain, or close contact with a TB patient among children <10 years who are living with HIV at each care encounter. Any child living with HIV with a positive symptom screen should undergo further diagnostic evaluation [16], but programmatic data from Kenya suggests attendance at pediatric-focused HIV clinics may be associated with a lower likelihood of appropriate diagnostic follow up [17]. Additionally, as this approach misses up to 40% of children with HIV-associated TB, research on new strategies for TB screening in this high-risk population is urgently needed [18].

Advancement in HIV care, including the provision of differentiated service delivery approaches, has created new opportunities to effectively integrate TB screening within routine HIV services and ensure uninterrupted care. Similarly, systematic screening for TB disease should be conducted using a symptom screen including any one of cough, fever or poor weight gain; or chest radiography; or both for children <15 years with TB exposure. The yield of symptom screening is higher among close contacts of TB patients than other risk groups. If available, CXR may be used as a TB screening tool for children <15 years with TB exposure [19]. Direct comparisons of these strategies in CALHIV were not performed. The use of C-reactive protein in TB screening is currently limited to adolescents and adults living with HIV [16]. Commercially available tests of TB infection (TST and IGRA) cannot differentiate between TB infection and disease, may be affected by conditions unrelated to TB infection, and are often inaccessible in TB high-burden settings. Hence, tests of infection have a limited role in TB screening in high-burden settings, particularly among CALHIV.

The elevated TB risk among CALHIV despite anti-retroviral therapy (ART) indicates the ongoing need for effective and widespread implementation of TB preventive treatment (TPT) in this population. Data on drug–drug interactions between rifamycins and dolutegravir is urgently needed so that CALHIV may also benefit from the increasing availability of shorter TPT treatment regimens. Recent data suggests that 1 month of isoniazid and rifapentine is safe and feasible in children and adolescents two years and above [20]. This data, combined with efficacy data in adults living with HIV suggests that this very short TPT regimen, is appropriate for CALHIV [21]. However, there is limited evidence to inform whether adjustments in dolutegravir dosing are needed in children receiving daily or weekly rifapentine for TPT.

While more data is needed to optimize TPT delivery for CALHIV, existing data on TPT uptake and completion is encouraging. While TPT uptake is more robust in adults than children, rates of TPT adherence and completion have been quite good when evaluated within observational cohorts of CALHIV. Evidence demonstrates that differentiated service delivery models, TPT education, and seamless integration with HIV care are important predictors of TPT completion [22,23,24]. Given persistently high rates of TB disease among CALHIV, TPT scale up is essential and will benefit from shorter TPT regimens, child-friendly formulations, and patient-centered TPT administration integrated within ART to minimize increased burden on patients and health systems.

The TB case detection gap in CALHIV remains problematic and is exacerbated by the COVID-19 pandemic [1]. However, new developments in diagnostics may reduce this gap. Building on years of work supporting the value of stool and nasopharyngeal aspirates for child TB diagnosis, the WHO now endorses both specimen types for TB diagnosis in CALHIV [25,26]. Stool specimens and nasopharyngeal aspirates have similar sensitivity to respiratory specimens when combined or only slightly lower than respiratory specimens as stand-alone tests. However, as these specimens are easier for nurses to collect and require less equipment, more children, including CALHIV, should be evaluated for TB. Additional implementation science work is urgently needed to evaluate the impact of collecting these non-traditional specimens in CALHIV. New diagnostic approaches will certainly be needed as only a small minority of CALHIV on TB treatment have a confirmation by Xpert [26]. Additionally, there is emerging data for urine as a useful specimen for TB diagnosis with the new SILVAMP-LAM point-of-care assay.

One report from a South African pediatric cohort demonstrated a 24% increase in sensitivity in CALHIV (60%, 95%CI 40.7–76.6 for SILVAMP-LAM vs. 36%, 95%CI, 20.2–55.5 for Alere-LAM) against a microbiologic reference standard [27]. SILVAMP-LAM performed equally well in stored urine specimens from 4 African pediatric TB clinics. Sensitivity was 64.9%, 95% CI 43.7–85.2; positive in 40 of 63 confirmed samples versus 30.7% (95% CI 8.6–61.6; 19 positive of 63 confirmed samples) for Alere-LAM [28]. The specificity was similar for both tests in each study; however, additional data using prospectively collected specimens is needed to confirm these promising results.

While new bacteriological tests are important, they are unlikely to identify all cases of paucibacillary TB in CALHIV. Fortunately, emerging approaches to support clinical diagnosis have great promise. Leveraging data from a diagnostic study of 438 CALHIV, a treatment-decision score was developed based on detailed symptom assessments and radiographic data, including CXR and ultrasound; the resultant score had an AUC of 0.861 with a sensitivity of 88.6% and a specificity of 61.2% compared to a composite tuberculosis diagnosis using the NIH consensus definitions [29]. Although CXR was an important component of the algorithm, many high-risk children with exposure to TB and prolonged TB symptoms, can be diagnosed correctly with this algorithm without a CXR. Further, this study also highlighted poor agreement between local radiologists, pediatric pulmonologists and pediatric radiologists and limited overall diagnostic accuracy (55.3%) in CALHIV [30]. Hence, while CXR may play a role in TB screening or diagnosis for CALHIV, new strategies, perhaps including computer aided detection, are needed to increase the accuracy of this important tool. Preliminary data on complementary approaches using monocyte-to-lymphocyte ratios as a diagnostic aid also merits additional exploration [31].