Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) in children, with high mortality and morbidity (1, 2). The neurological disability due to TBM has significant long-term consequences for children, their families and healthcare systems (3); prevention and early diagnosis are therefore critical. For programmes to effectively respond to this public health emergency, improved surveillance data are required to better define the burden of TBM in children and to inform interventional research (4). We address this critical need for improved surveillance, review current TB surveillance strategies and their limitations, and present practical guidelines for strengthening global pediatric TBM surveillance.

Children (<15 years old) account for 12% of the estimated global TB burden (5). Young children (<5 years) or those living with HIV are at high risk for TB and TB-related mortality (6, 7). Despite availability of effective treatment, an estimated 1.19 million children globally developed TB in 2019 and 230,000 children died, most <5 years old, making TB a top ten cause of under-5 mortality (5, 8).

Children aged <2 years are at particularly high risk of disseminated TB including TBM (6). TBM frequently presents with non-specific symptoms during the early stages of disease, resulting in frequent delayed diagnosis and advanced clinical disease at eventual presentation. Although early diagnosis and treatment are key to reducing mortality and improving functional outcomes (9, 10), a systematic review found that nearly 50% of children with TBM were diagnosed at an advanced disease stage (2). Without treatment, TBM is fatal (1); undiagnosed cases, or those diagnosed late, likely make a substantial but unquantified contribution to global pediatric TB deaths.

Furthermore, TBM in children is preventable. First, Bacille Calmette-Guérin (BCG) vaccination at birth remains an effective intervention in high TB-burden countries to prevent TBM in young children (pooled efficacy of 73% (95% CI: 67–79%), (11). Second, TB transmission often occurs amongst family members and contact tracing combined with prompt provision of TB preventive therapy (TPT) following exposure to Mycobacterium tuberculosis (M.tb) also reduces the risk of developing TB, including TBM (12, 13). TPT is safe, effective (12), widely available and universally recommended for high-risk child contacts after M.tb exposure. However, implementation in high TB-burden settings remains poor (14), with TPT initiated in only one third of the estimated 1.3 million eligible child TB contacts in 2019 (5).

Therefore, the resulting mortality and morbidity in pediatric TBM often reflects health system failures. Every TBM diagnosis should be considered an opportunity to evaluate the health system and assessment of every child with TBM should be a standard quality control activity for TB programmes.

Pediatric TBM can provide insights into the broader epidemiology of child and adult TB. Figure 1 provides an overview of population and health system factors influencing the relationship between all TB, pediatric TB, and pediatric TBM.

Historically, TB control strategies and surveillance have focused primarily on patients contributing most to TB transmission: adults with infectious sputum smear-positive pulmonary TB (19). Young children typically develop paucibacillary TB disease, and because they contribute little to transmission, they have been largely neglected in TB control strategies and surveillance (39). In 2012, the WHO requested that countries report age-disaggregated TB data and in 2020 requested 5-year age-band disaggregated reporting for children. Despite this recent progress, substantial challenges remain for the routine surveillance of pediatric TB (40). Only 44% of the estimated number of pediatric TB cases globally were reported to WHO in 2019. Underlying challenges include under-detection of cases, incomplete reporting of detected cases, and undiagnosed deaths (40, 41).

TB programmes globally have been urged to adopt a care cascade approach for TB surveillance (42). Reporting surveillance data in a care cascade framework is a valuable tool for monitoring and evaluation of TB services by quantifying patient losses along the care cascade and informing evidence-based interventions to improve patient care. India and South Africa have both used cascade analysis to evaluate TB care (43, 44). However, these studies did not focus on children and there are limited data investigating pediatric TB using a care cascade approach. Cascade and patient pathway analysis has recently been proposed for TBM to investigate healthcare system gaps (45).

TB surveillance data should also capture the full spectrum of TB disease. However, all patients with pulmonary TB, irrespective of whether they also have extra-pulmonary TB, are currently grouped into one category when countries report disease spectrum. It is therefore impossible to distinguish TBM from other TB forms using routine TB surveillance data, and population-based estimates of the TBM burden at any age are very limited (21, 46).

In many high TB-burden countries, TB care and reporting are decentralized; hospitals do not routinely report data to TB programmes. This results in incomplete reporting of hospital-diagnosed patients, posing challenges for pediatric TB surveillance (47–50) and even more so for TBM surveillance (48). The diagnosis of TBM almost always occurs in hospital, and given the high in-hospital mortality and often in-hospital treatment completion for children with TBM, there is substantial under-reporting of pediatric TBM cases and deaths to TB programmes.

Current reporting indicators do not measure morbidity and disability post-TBM, critically important factors to comprehensively capture the pediatric TB burden. Surveillance data on delays in health care seeking, diagnosis or treatment initiation are not available and the impact of these on severity of pediatric TB and TBM disease at diagnosis is also not routinely reported.

Of key importance is that existing routine TB surveillance data are limited to only diagnosed and reported cases and do not reflect undiagnosed deaths. In high TB-burden settings, many children with TBM die undiagnosed or are misdiagnosed as having other conditions. A post-mortem study from Mozambique reported a high proportion of undiagnosed TB deaths in children at a tertiary hospital (51); In high TB-burden countries, autopsies are rare, and mortality data seldom quantify undiagnosed TB and TBM deaths accurately.

The devastation of TBM has likely been compounded by the COVID-19 pandemic. Although children appear to have been spared from severe COVID-19 disease, little is known regarding the biological impact of SARS-CoV-2 on TB pathogenesis or the impact of COVID-19 public health control measures on pediatric TB services (52). Diagnosing and treating TB in children requires functional and accessible health services. If pediatric TB is diagnosed early and appropriate treatment is started, outcomes for most TB-forms are excellent (53).

WHO reported a 21% reduction in global TB case notifications between 2019 and 2020, estimating that disruptions to TB care due to COVID-19 could result in 500,000 additional TB deaths (54). The effect of COVID-19 on healthcare-seeking behavior and access to routine healthcare services is poorly understood. Reduced health seeking behavior or access to care in turn could result in children presenting with advanced TBM and could lead to more missed opportunities for TBM prevention including reduced BCG vaccination coverage (55). A recent modeling study estimated between 886 and 33,074 additional pediatric TB deaths due to COVID-19 related disruption of BCG vaccination services globally (56). Alternatively, social distancing and mask wearing to reduce COVID-19 transmission may also have reduced TB transmission, potentially lowering the rates of pediatric TB and TBM. Research to measure and understand the impact of the COVID-19 pandemic on pediatric TB and TBM is needed, especially to inform mitigation strategies for improved prevention and care of TBM in children.

Accurate and complete pediatric TBM surveillance along the care cascade is a critical first step toward an effective response to end pediatric TB, and we therefore propose a cascade approach for children with TBM (Figure 2), including reporting of key indicators. In addition to adopting a care cascade approach, we propose the following practical recommendations to strengthen the surveillance of TBM in children (Table 1).

Improved data regarding the number of children affected by TBM throughout the care cascade would have a positive impact on multiple levels (41), and is critical for advocating for the needs of children with TBM.

TBM is the most devastating form of pediatric TB. It is preventable and treatable, yet still contributes substantially to child TB deaths and morbidity. A TBM diagnosis should be seen as a public health emergency and should be reported and monitored as such. Without surveillance data and a framework of reporting indicators, we will not be able to monitor trends, measure the impact of interventions, or effectively respond to this devastating form of TB in children. Surveillance data can help us identify opportunities for prevention, early diagnosis, and improved care to minimize the impact of TBM on child health globally.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

KDP and JS prepared the original draft of the manuscript. All authors were involved with conceptualization of the idea, reviewed, edited the manuscript drafts, critically reviewed, and approved the final version of the manuscript.

KDP is supported by the Fogarty International Center of the National Institutes of Health under Award Number K43TW011006. AH is financially supported by the South African National Research Foundation through a South African Research Chairs Initiative (SARChI). JS is supported by a Clinician Scientist Fellowship jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (MR/R007942/1). HJ is supported by the U.S. National Institutes of Health, National Institute of Allergy and Infectious Diseases (R03AI164123 and R01AI152126).

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