A dearth of diagnostic tools for childhood TB
New diagnostic tests for tuberculosis (TB) represent a major advance over existing technology. However, the advances also highlight a significant gap in TB research generally: the paucity of diagnostic research for TB in children.
In late 2009, a young, underweight boy with a hacking cough arrived in the paediatric ward of the Lagos University Teaching Hospital (LUTH), one of the city’s largest public providers. Based on his symptoms, doctors decided that the probable culprit was pulmonary tuberculosis (PTB) - the most common form of childhood TB and a not uncommon result of growing up in one of Lagos’ squalid, overcrowded shantytowns.
Nigeria, after all, has the world’s fourth highest TB burden, and children account for an estimated 11 percent of the country’s incident cases every year. (In some high-burden settings, children account for more than 25 percent of incident cases). According to WHO, of the 9 million annual TB cases worldwide, roughly 1 million occur in children under 15 years of age, with three quarters of those occurring in 22 high-burden countries.
Still, as with the vast majority of childhood TB cases, the LUTH doctors’ diagnosis amounted to a shot in the dark. Due to the difficulty of obtaining samples--young children are often incapable of expelling sputum—microbiological confirmation of TB is rarely attempted in children. “And even when you’re able to demonstrate organisms, the yield is low,” says Dr JK Renner, chief of paediatric medicine at LUTH. “Usually between 10 and 20 percent.”
That low yield requires a prolonged mycobacterial culture, which can delay microbiological confirmation by several weeks, he says. In the meantime, the infection can spread. “TB in children tends to cause more problems than it does in adults,” says Renner. “You have TB meningitis, TB spondylitis, and disseminate TB in infants, all of which can progress very quickly. It’s a big problem.”
Moreover, because mycobacterial culture is frequently negative in children with clinically diagnosed PTB, clinicians are often wary of discontinuing therapy based on a negative culture result. And since there is no reference standard that is both highly sensitive and specific to which results can be compared, researchers cannot accurately assess the performance of new diagnostics or clinical algorithms.
After treating the boy for several months with little effect, the LUTH doctors began to worry that they’d guessed wrong. A CT scan confirmed it. “We found it was a foreign body that had created a fibrosis in the lungs,” says Renner. A simple surgery solved the problem. “And it was just because of this extra investigation, which was very expensive for the parents, that we weren’t able to come to that conclusion earlier than we did.”
The boy turned out to be fine. But paediatric TB is in a grave state, and not least for the dearth of diagnostic tools at clinicians’ disposal. Even as a new automated test promises to revolutionize the diagnosis of TB in adults, the sensitivity of smear microscopy, the most accurate test currently available for paediatric TB in most resource-limited settings, is less than 15 percent.
“Our ability to even assess the magnitude of the problem is severely hampered by the lack of diagnostics in children,” says TDR scientist Luis Cuevas, who with other TDR scientists and experts on paediatric TB co-authored a letter published in the New England Journal of Medicine last December.
That letter, a response to the study by Boehme et al reporting the high degree of accuracy of the new “game-changing” automated test, argued that despite the lack of a sensitive reference standard, “high-quality studies of new diagnostics that use rigorous and standardized approaches should be conducted in children.” The game-change is welcome, they wrote, “but the new strategies should also prioritize tuberculosis research in children.”
In addition to advocating for greater research, that TDR-led expert group is working to prepare the common reference standard needed to assess the performance of new diagnostics, specimen sampling methods and comparative testing in different country settings. The group has also joined forces with the WHO Stop TB Partnership and Stop TB Department, among other international experts on paediatric TB, to promote the adoption of the common reference standard by researchers evaluating new diagnostics in children.
In addition to advocating for greater research, that TDR-led expert group is working to reach a consensus for which reference standard to use to assess the performance of new diagnostics, specimen sampling methods and comparative testing in different country settings. The group has also joined forces with the WHO Stop TB Partnership and Stop TB Department, among other international experts on paediatric TB, to promote the adoption of the agreed reference standard by researchers evaluating new diagnostics in children.
On March 17, scientists met in Stockholm to advocate for increased research on paediatric TB at a conference organized by the European Centre for Disease Prevention and Control (ECDC) and the Stop TB Partnership. And in June, the U.S. National Institutes of Health (NIH) will hold a meeting to establish a standard method for evaluating and defining priorities for research on diagnostics for paediatric TB.