Childhood Tuberculosis: Historical Perspectives, Recent Advances, and a Call to Action

As the world focuses on the COVID-19 pandemic, it is important not to lose sight of other infectious and noninfectious diseases that continue to exact a major toll on the health of children. Childhood tuberculosis (TB) stands among the most serious of these, with an estimated 1.1 million cases of TB disease and more than 200,000 TB deaths in children less than 15 years of age in 2020 [1]. The COVID-19 pandemic has markedly decreased the global capacity to diagnose and treat TB in children and adults, resulting in decreased numbers of persons treated for TB in 2020, and the first increase in TB mortality in more than a decade [1]. Increased transmission from adults with untreated infectious TB is anticipated to reverse the previous slow but steady decline in TB in both children and adults. As global efforts to manage the COVID-19 pandemic continue, it is important to take stock of the state of childhood TB and evaluate what needs to be done, not just to reach the rate of progress that existed prior to the pandemic, but to advance efforts on multiple fronts to reduce morbidity and mortality from TB in children.

In this series of articles, experts in childhood TB will address several aspects of the TB epidemic in children, including the interaction of TB with both HIV infection and with COVID-19, medication interactions and adherence, diagnostics, new treatments, systems and programmatic approaches to TB care and services, and vaccine development. These articles will identify the challenges in controlling childhood TB in 2022 and beyond, and highlight areas that can accelerate the prevention, diagnosis, and treatment of this longstanding global pandemic.

Historical and Artistic Perspectives

This supplement focuses on recent advances to treat and prevent one of the earliest widespread human pathogens. The first molecularly-confirmed case of pediatric tuberculosis appears in the archeological record approximately 9000 years ago, in an infant buried in a neolithic grave site in Atlit-Yam, off the Mediterranean coast of Israel [2]. Genetic and archeological evidence suggest that TB infected humans for tens of thousands of years prior to this child’s burial [3–5]. TB disease appears in the first illustrations of and writings about human health and medicine. Syndromes consistent with TB were given the names of yaksma in the Indian Atharvaveda [6], phthisis in the writings of the Greek physicians Hippocrates, Soranus of Ephesus, and their contemporaries [7], and schachepheth in the Old Testament [8]. Some scholars argue that funerary pre-Dynastic and Dynastic Egyptian depictions of musculoskeletal deformities illustrate sequelae of Pott’s disease [9, 10].

In Europe, the deformities caused by extrapulmonary TB lent the disease to early representations of the intersection of health, myth, and power in art. Clovis of France (487-511 CE) was credited with the first application of the “Royal Touch,” whereby monarchs would touch—and thereby miraculously heal—the scrofulous lesions of their subjects. Creators of Medieval manuscripts to Baroque oil paintings portrayed these monarchs’ divinely ordained power to rule through their representations of this thaumaturgic power to cure TB [11].

As urbanization progressed in the 18th and 19th centuries, representations of TB evolved. The romantic metaphors attached to consumptive TB were highlighted in the poems of George Gordon Byron and John Keates, Giacomo Puccini’s and Giuseppe Verdi’s operas, and Henry David Thoreau’s essays. These fantastical views of TB death, in which the ill are (as Robert Louis Stevenson explained) “tenderly weaned from the passion of life…that when at last the end comes, it will come quietly and fitly” [12], contrasted with the realities of the disease, which thrived in burgeoning, impoverished, urban environments, and which killed as many as 1 in 100 Europeans per year in the early 19th century [13, 14]. Susan Sontag, in Illness as Metaphor, argues that the romantic view of TB dissipated only with the introduction of streptomycin and isoniazid in the 1940s and 50s [15], though the private devastation of the disease is captured in the funereal, chiaroscuro paintings of Edvard Munch, Cristobal Rojas, Claude Monet, and others who appeared to represent their personal grief through their art (Figure 1).

Figure 1.

“La Miseria” (“The Misery”), by Cristóbal Rojas. 1886. Oil on canvas. Galería de Arte Nacional, Caracas, Venezuela. (Reproduced with permission.).

Tuberculosis and Modern Medicine

On March 24, 1882, Robert Koch announced the discovery of the bacteria that causes TB [16]. Building on new insights in microbiology, the first decades of the 20th century saw advances in the diagnosis and prevention of TB. Driven by a search for a cure, Koch extracted tuberculin from heat-concentrated cultures of Mycobacterium tuberculosis [17]. While tuberculin did not cure TB, it formed the foundation of the first peripheral test for TB, developed by Charles Mantoux in 1908 [17]. The Bacille Calmette-Guerin (BCG) vaccine (first administered to humans in 1921) followed shortly after [18]. Through careful observation in the 1930s, Wallgren and others defined the natural history of untreated TB in children, including the extreme susceptibility to severe TB in infants and young children [19].

Treatment of TB was a major focus of the early antibiotic era. Streptomycin and para-aminosalicyclic acid were introduced in 1945, isoniazid in 1952, ethambutol in the early 1960s, and rifampin in the 1970s [20]. Along with other clinicians and investigators, Edith Lincoln, an American pediatrician working in the early to mid-20th century, made major contributions to understanding TB infection in children, including the treatment with isoniazid to prevent progression to TB disease [21]. Her quote, “wherever there are tuberculous adults there are infected children…no one is immune,” remains important today [21].

Starting in the 1980s, the emergence of drug-resistant TB and the HIV epidemic began to reverse the previous decades’ gains, leading the World Health Organization to declare TB a global health emergency in 1993 [22]. Renewed interest in ­pediatric TB has followed slowly.

Recent Progress

In 2011, there was a call to action to address childhood TB [22–24], and recent years have seen substantial progress in addressing gaps in the management of TB in children. The articles in this supplement will highlight the current state of the art and what is needed to accelerate the fight against childhood TB. Together with identifying areas where progress has been slow, the recent advances in many aspects of the management of childhood TB can provide a framework for future efforts to prevent, diagnose and treat TB in children.

Recognition of the lack of accurate age-disaggregated data for pediatric TB has led to new efforts to better define the burden of TB in children. Diagnostics, particularly host response biomarkers, has been one of the most active areas of TB translational research. Moving beyond multi-feature signatures to diagnose TB disease, recent work has demonstrated the potential to identify those at risk for progression from TB infection to TB disease [25, 26], or those with TB disease who are likely to achieve cure.

Important progress in TB treatment has also been made in many areas. Examples include (1) recognition that higher doses of rifampin are well-tolerated, may accelerate time to eradication, and may be required to achieve optimal serum and CSF concentrations [27–31], (2) demonstration that a 4-month fluoroquinolone and rifapentine-containing regimen that allows cure of pulmonary TB in adolescents and adults [32], and (3) evidence that new drugs and a 6-month oral regimen for drug-resistant TB achieves cure with much less toxicity than prior regimens [33]. In addition, a shortened regimen for limited pulmonary disease in children has been shown to be as effective as the standard 6-month treatment course [34], and several groups are working to carefully define the pharmacokinetics and pharmacodynamics of new and existing TB drugs in children with and without HIV infection. These efforts to inform rational dosing are particularly important to ensure that advances in TB treatment are available to children. Progress in preventing TB has been made using old tools, such as expanded treatment of TB infection in children with HIV [35, 36] and expanding the reach of TB infection treatment and prophylaxis in high-burden settings. Ultimately, these approaches may be replaced by the development of new vaccines that effectively prevent TB infection and/or TB disease in children.

Conclusion

This supplement provides a review of major advances in the diagnosis and management of childhood TB. These articles provide reviews on several important aspects of childhood TB including the impact of the COVID-19 pandemic, HIV, and social determinants of health on TB care; advances in TB diagnostics and therapeutics; implementation science and the TB infection care cascade; TB vaccines; and programmatic approaches to TB services. Yet despite the advances described in the supplement’s articles, the remaining gaps in knowledge, resources, and access continue to cause children to suffer and die from this disease. There remains a need to quantify the burden of childhood TB, including obtaining age-disaggregated data. Diagnostics must be improved. Appropriate drugs must be made available globally. Integrated, family-centered models of care should be expanded. COVID-19 and its accompanying social and economic harms have put even more children at risk of TB, and threaten to undo the progress that could and should end TB. Thus, we view this supplement not only as a tool to highlight recent strides but also as a call to action for childhood TB. There is a need, now more than ever, to redouble our efforts to stop this epidemic.

Notes

Acknowledgments.We would like to acknowledge the Galería de Arte Nacional, Caracas, Venezuela, for providing the image of La Miseria by Cristóbal Rojas for this article.

Financial support. Dr. Campbell was supported by Agency for Healthcare Research and Quality grant number T32 HS000063 as part of the Harvard-wide Pediatric Health Services Research Fellowship Program. Dr. Dubois was supported by Grant Number T32 AI007433 from the National Institute of Allergy and Infectious Diseases.

Supplement sponsorship. This article appears as part of the supplement “What’s New in Childhood Tuberculosis?” sponsored by the Stop TB Partnership.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Author notes

These authors contributed equally.