Scientific progress: New and important developments in paediatric tuberculosis
The screening, diagnosis, and treatment of tuberculosis (TB) in children remain far from optimal. Elri Voigt rounds up key developments in paediatric TB presented at the 52nd Union World Conference on Lung Health.
The screening, diagnosis, and treatment of tuberculosis (TB) in children remain far from optimal – and in many respects lag behind what can be done for adults.
We pick out five developments in paediatric TB presented at the 52nd Union World Conference on Lung Health recently held online. It is a big conference and we no doubt missed some interesting studies – you can browse the conference abstracts for yourself here.
While, in our view at least, there were no obvious stand-out results like last years’ landmark SHINE treatment shortening study, which we reported on here, it has nevertheless been another year of important advances.
Treatment for kids
Using bedaquiline and delamanid in children
Over the past decade, drugs like bedaquiline, and to a lesser extent delamanid and pretomanid, have transformed the treatment of drug-resistant TB (DR-TB) in adults. As often happens, it has arguably taken far too long to do the studies required to establish how to best use these medicines in children. Fortunately, a number of studies presented at the conference looked at different treatment options for children.
Quality assurance manager for the endTB clinical trials in Pakistan, Saman Ahmed presented findings on the safety and efficacy of DR-TB regimens containing bedaquiline and delamanid in children and adolescents.
The findings were part of the endTB observational study and looked at 190 children and adolescents who were treated for TB with regimens containing bedaquiline and delamanid. The study showed a high success rate of 85%, which is classified as the TB being cured or treatment is completed.
She says there were several adverse events of interest, the most common being peripheral neuropathy, (which occurred in 16% of participants), electrolyte depletion (which occurred in 15% of participants), and hearing loss (which occurred in 7% of patients). Most of these side effects improved with time.
Based on the study, Ahmed says that the treatment of DR-TB with regimens containing bedaquiline and delamanid is not only effective but also well-tolerated among children and adolescents. She argues that all oral regimens, including bedaquiline and delamanid, should be scaled up for these age groups, as has already been recommended by the World Health Organisation (WHO).
New combination dispersible tablet
Apart from delays in studies testing new TB drugs in children, other challenges include medicines that taste bad and difficulties in getting the dosages right for growing kids. Some promising results addressing both these issues in the treatment for drug-sensitive TB in kids were presented at the conference.
Infectious diseases specialist Dr Awewura Kwara told attendees that for children on standard first-line therapy, insufficient plasma concentrations of the drugs isoniazid, rifampicin, and pyrazinamide are contributing to death and treatment failure.
To this end, Kwara presented interim findings from a small study in Ghana to verify that a new child-friendly isoniazid, rifampicin (which is a pyrazinamide fixed-dose combination or FDC dispersible tablet for TB treatment in children) achieved target drug concentrations.
The FDC tablet was developed based on the revised WHO dosing guidelines for children. Kwara said the tablet is water dispersible, palatable and unlike the previous formulation, does not require supplemental isoniazid/rifampicin tablets to achieve the recommended dosages.
The study enrolled 92 children aged younger than 15 years with clinical confirmation of TB with or without HIV coinfection. Sixty-eight completed PK testing and were included in the analysis.
According to Kwara, the FDC tablet achieved dosages within the recommended ranges for each drug in most children in the study, and results suggest that the isoniazid and pyrazinamide dosages in the FDC tablet are adequate. However, in nearly 60% of the participants rifampicin levels weren’t as good as hoped, suggesting that a higher dosage is needed. Malnutrition was also a risk factor for insufficient rifampicin levels.
Diagnosis and screening in kids
This year’s conference showcased a variety of studies and presentations that focused on ways to diagnose or screen for TB in children that did not involve collecting sputum. The current gold standard TB tests all rely on sputum – which most children struggle to produce.
Head of the TB research group at the MRC Unit in The Gambia, Dr Jayne Sutherland explained, “What you want is a test where you can have your answer quite quickly, you want a test that does not rely on sputum because a lot of children, a lot of people living with HIV cannot produce sputum or they have a very low pathogen load in there.”
Promising fingerstick blood test
Sutherland presented interim findings for a new blood test for TB. The screening test, called Xpert MTB-HR prototype, is a fingerstick blood test that works by analysing the expression of three different genes. The interim results were only from adults, but Sutherland says that children are also taking part in the study and these findings will be included when the full study is reported.
So far, the interim results show that the screening test provides a sensitivity of 87% and specificity of 94%, which meets the WHO target product profile for a triage test for TB. Spotlight has unpacked the fingerstick findings in more detail here.
Sutherland says that the GBP5 gene signature, which is one of the three genes the test looks for, is particularly promising for childhood TB diagnosis. Spotlight will keep a close eye on future findings from this study.
Testing for TB in stool
Infectious diseases epidemiology researcher at the University of Bordeaux, France, and international trial manager for the TB-Speed project Aurélia Vessière presented findings from the TB-Speed Pneumonia study. It assessed the feasibility and yield of systematic TB detection using Xpert MTB/RIF Ultra on nasopharyngeal aspirate (NPA) and stool samples in children with severe pneumonia. Xpert MTB/RIF Ultra is already widely used to detect TB and some TB drug resistance from sputum.
“Our hypothesis was that systematic, early molecular TB detection in children with severe pneumonia could increase TB case detection and eventually reduce mortality,” she says.
The study enrolled 2,570 children, between the ages of two to 59 months, from March 2019 to March 2021. The participants were divided into a control group, which received the WHO standard of care for children with severe pneumonia, and an intervention group.
Vessière says the intervention group (1,169 children) received the WHO standard of care as well as systematic early detection of TB using Xpert Ultra. One stool sample and one NPA sample were taken from each child and tested using Xpert Ultra within 24 hours of hospitalisation. TB treatment was initiated immediately if the result was positive for TB.
She says in terms of the feasibility of sample collection and testing with Ultra, NPA collection was done successfully on 97% of the intervention group, and of those children, 96% had a valid Ultra result. For the stool collection, 81% of the intervention arm had their stool collected, and of those 79% had a valid Ultra result.
Of those children in the intervention group, 89 children (or just over 8%) tested positive for TB, according to Vessière, which was a lower than expected yield. She adds that not all the children were diagnosed with TB based on the Ultra test, as some were diagnosed based on radiological or clinical features based on the clinician’s decisions.
The results showed that the percentage of diagnoses that were based on a positive Ultra result on an NPA was around 24%, while a positive Ultra result on a stool sample was about 18%, and 27% for either of the samples.
According to Vessière, the results demonstrated a high feasibility of combined NPA and stool sample collection. “Ultra testing on either stool or NPA contributed to microbiological confirmation in a quarter of TB diagnosis,” she says.
A new battery-powered mucus aspirator
Research director in the TRANSVIH MI research unit at the French National Research Institute for Sustainable Development (IRD) Dr Maryline Bonnet presented study findings on a battery-operated mucus aspirator, as well as an alternative manual system for NPA to test for TB in children. This was part of her presentation on results from the TB-speed project, which is evaluating different diagnostic approaches. One such approach is NPA for Ultra testing (i.e. testing NPA samples with Ultra, as discussed above). Using Xpert MTB/RIF Ultra to test NPA samples is now recommended by the WHO as a method of TB diagnosis in children.
Mucus aspirators are devices used to suck mucus samples, in this case from the upper part of the throat behind the nose.
Bonnet says that the TB-Speed project has a component where it seeks to improve equipment used for implementation of NPA at a primary health care level. She explains that the target product profile identified for this aspect of the project is a mucus aspirator that can be safely used on children younger than 10 years old. Other specifications for the device include being battery operated so it can be used in primary healthcare in resource-limited countries with irregular access to electricity, and aspirate at least 1ml or more of nasopharyngeal mucus. Based on this, Bonnet recommends the use of the ATMOS LC27.
In parallel, she says, the team also developed a manual operating aspirate pump that can be used by nurses. There have been five prototypes, with the latest having been assessed for end-user feedback, function, and longevity. The feasibility assessment in healthy adult volunteers is ongoing.
She says that NPA is feasible and acceptable in highly vulnerable children with pneumonia and at low-level healthcare facilities, but tolerability of this semi-invasive test remains a challenge. DM/MC
This article was produced by Spotlight – health journalism in the public interest.