The incidence recorded in children reflects the failure to control TB in adults [29]. Children are most vulnerable to TB infection because of their immaturity and ultimately impaired immune system [8]. Research has shown that the impaired innate pulmonary defense mechanisms in neonates and children are attributable to the reduced killing of microbes and diminished recruitment of monocytes to the infection site, thus disabling the ability of the immune system to induce necessary responses against the Mtb pathogen [8,30]. Furthermore, children are born with ineffective and immature antigen-presenting cells and T helper cells, which disable them from being able to produce interleukin-12 [8,31], which is essential for the initial phase of Type 1 T helper cells (Th1) polarization and for maintaining the efficiency of interferon-γ transcription [32]. This makes children particularly vulnerable to TB infection, accounting for the estimated 10% of all TB cases being those of children under the age of five [27].

About 1.1 million children fall ill with TB annually and approximately 230,000 deaths (including those living with HIV) were recorded in 2020 [2,20,33]. Studies have shown that reported statistics do not provide a true reflection of the global pediatric TB burden because most often, many cases go undiagnosed or unreported and as such, the global statistics could be much higher [6,20,33,34]. It has been observed that most reported pediatric fatalities occur in children who are not receiving any TB treatment, meaning that efforts geared towards identifying groups at risk of infection, effective diagnosis, and appropriate treatment require urgent improvement and implementation to significantly reduce TB mortality in children. Tuberculosis is considered one of the top ten causes of death in children under 15 years, but an important component of the past analysis is the focus on under 5-year-old mortalities. Mathematical estimates of available epidemiological data predicted that TB may be the sixth highest cause of death among children ages one to fifty-nine months, resulting in more mortalities than even meningitis, HIV/AIDS, measles, and pertussis. Moreover, some deaths, often thought to originate from pneumonia, meningitis, or AIDS, may have been caused by TB infection. Thus, some TB-related fatalities were probably not represented in the available global estimates and overall reported numbers are lower than what they really are [35,36,37].

Despite this, pulmonary TB in children remains in the shadows because most incidents are smear-negative and are thus said to have a minor contribution to the spread of the disease [10,38]. Although TB in children is not regarded as a major contributing factor to community spread, it is a key cause of high mortality and morbidity rates among this group largely due to the unlikelihood of early detection, especially in those under 5 years of age, thus accounting for an estimate of over 500,000 new TB cases each year. Most deaths due to active TB infection in pediatric patients are frequently attributed to other diseases such as pneumonia, which is the leading cause of death in children under 5 years [39,40,41]. Although this is underdiagnosed in most cases of pneumonia in children, Mtb is a causative agent for both tuberculosis and pneumonia. Literature has reported autopsy results showing that approximately 1–23% of all pneumonia-related cases also presented with TB [40]. This then further supports the notion that pediatric TB cases are underreported. Without a proper estimate of the global TB burden, there would be inadequate allocation of resources for diagnosis, treatment, vaccination, and the market size for potential drug development, which would ultimately motivate pharmaceutical industries to prioritize anti-TB drug development. All these factors are essential tools for the advocacy and control of TB in children [36].

The spectrum of the disease in children ranges from paucibacillary lymphadenitis to severe disseminated disease [23]. Children under 2 years of age, especially fetuses and neonates, are most susceptible to TB infection and are more prone to developing severe disease because their immune systems are underdeveloped. Typically, they have no protection against harmful pro-inflammatory cytokine responses because they are still transitioning from the supposedly sterile intrauterine environment into the antigen-exposed external environment [34,42]. Children less than 5 years are often known not to develop active disease immediately post Mtb infection but have a 10% chance of experiencing active disease reactivation during their adulthood [43,44,45]. Moreover, pediatric patients are at greater risk of becoming infected and developing active disease following contact with adult patients who have TB. Children therefore form an important group of patients requiring latent TB infection (LTBI) testing and therapy [23]. Children serve as potential reservoirs for active TB later in their lifetime and this is evidenced by the fact that globally, around 67 million children are carriers of latent TB infection. This poses a significant threat to the success of the World Health Organization’s global “END-TB” strategy [6,27].

When children are infected with Mtb, they are often more susceptible to getting sick faster than adults who are equally exposed. Relative to the pediatric population, TB disease in adults is typically associated with a previous dormant infection that subsequently develops into an active illness years later, due to immune system weakening often resulting from underlying diseases, drugs, or other environmental factors [46]. In most instances, the transmission of TB amongst pediatrics is because of close and lengthy contact with adults who have infectious pulmonary TB [47,48]. Since children, especially those under the age of two years, are dependent on extensive adult supervision, they will most likely get the TB infection from a close household member, caregiver, or an older child with whom they spend a lot of time. Older children, however, are less dependent on adults and are more social; hence, they usually become infected from an outside source. It can therefore be inferred that transmission in children is not only dependent on social factors such as poverty and overpopulation, but also on the prevalence within communities and the age of the child [42,49,50]. Studies have identified a bimodal risk profile for TB infection in children, which shows that the risk of transmission is highest in those in their late teenage ages and under two years, while the risk decreases significantly for children between five and ten years old [42]. Although it is not considered a major contributing factor toward the spread of infection within the community [39], pediatric TB spread is synonymous with recent infections in societies. The burden of pediatric TB thus provides a more accurate indication of the transmission rates of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium [49,51,52]. Children often require approximately twelve months post-infection to progress to an active disease state, which frequently develops into severe forms of extrapulmonary infection such as TB meningitis or miliary TB that may end up being fatal [42,53]. Host-specific factors such as age, history of Bacillus Calmette–Guérin (BCG) vaccination, malnutrition, HIV/AIDS status, etc., can significantly impact the rate and extent of transmission, risk of infection, and progression to active or latent TB [48,54].