Breath analysis helps monitor lung function in CF children: Study
VOCs in breath may be biomarkers of lung function, treatment response
Volatile organic compounds (VOCs) found in breath may be used as biomarkers of lung function and treatment response in children with cystic fibrosis (CF) and mild lung disease, a pilot study in France showed.
The study compared breath composition before and up to six months after children initiated Kaftrio (elexacaftor/tezacaftor/ivacaftor) treatment, and found that the levels of 12 VOCs were altered after treatment. Six of them were significantly associated with lung-function measurements.
“This highlights the feasibility of breath analysis in young children and underscores its potential for monitoring lung function,” the researchers wrote. “It may also offer novel non-invasive options to predict therapeutic response.”
The study, “Short-term modification of breathprint by Elexacaftor/Tezacaftor/Ivacaftor in a paediatric cohort,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the CFTR gene that result in no or faulty production of the CFTR protein. This leads to the accumulation of thick and sticky mucus in the lungs and other organs, clogging the airways and providing a fertile breeding ground for infectious bacteria.
Checking for VOCs
Kaftrio, sold as Trikafta in the U.S., is a CFTR modulator that helps defective CFTR protein work more effectively. It is approved in the European Union, in combination with Kalydeco, to treat patients 2 and older with at least one F508del mutation in the CFTR gene. In adults and adolescents with CF, the treatment was shown to improve lung function and ease sputum (phlegm) production. However, “these endpoints prove insufficiently sensitive in patients with a mild disease and a normal basal respiratory function such as school-age children,” the researchers wrote.
They analyzed whether changes in breath composition, particularly VOCs, occurred in children with CF after initiating treatment with Kaftrio. VOCs originate from respiratory cell metabolic processes that commonly derive from the degradation of other compounds related to digestion, aging, or inflammatory reactions.
The study enrolled 11 children with a median age of 8.6 at Necker pediatric hospital in Paris. Nine children had a F508del mutation in one CFTR gene copy and a minimal function mutation (a mutation in which the resulting CFTR protein works minimally) in the other copy, and two had the F508del mutation in both CFTR copies. One had been previously treated with Orkambi (lumacaftor/ ivacaftor), another CFTR modulator also marketed by Vertex Pharmaceuticals.
All children had chronic infections with Staphylococcus aureus before Kaftrio initiation. The infection persisted in eight children after one month of treatment. Infections by other bacteria, including Pseudomonas aeruginosa, were no longer detected after treatment.
Overall, pulmonary function tests mild airway obstruction in most of the children who performed lung function tests before and after treatment initiation. At the study’s start, percent predicted forced expiratory flow (ppFEF) — the rate at which air is forcefully exhaled from the lungs during a specific time period — was moderately low, whereas lung clearance index (LCI, a measure of the time it takes for a tracer gas to be cleared from the lungs) was elevated. Percent predicted forced expiratory volume in one second (ppFEV1), which measures the amount of air a person can forcefully exhale in one second, was normal.
After one week of treatment, measures of lung function improved, while sweat chloride levels decreased. Assessing sweat chloride levels is a standard approach to diagnosing and monitoring CF.
From 30 breath samples, a total of 1,395 VOCs were retained after processing the data. Twelve of them were significantly changed after starting Kaftrio. Six of these compounds were significantly associated with measurements of lung function.
Increases in dimethyl sulfide and tetradecene were associated with improvements in ppFEV1 and ppFEF, while 2,6-dimethylundecane had the oppposite correlation with these measures. Increases in another component, 2-butanone, was associated with lower ppFEV1 and forced vital capacity, also a lung function measure.
Additionally, 3-methyldecane and 3-(chloromethyl)-heptane were predictive of changes in LCI, “making these VOCs potential predictive biomarkers of lung function evolution,” the team wrote.
“This study reports for the first time a very short-term impact of [Kaftrio] on breath composition in children with a mild lung disease and lays the groundwork for identifying early VOC biomarkers modified by CFTR correction,” the researchers wrote. The study was limited by “the small number of participants and the presence of confounding factors, such as infection and concomitant treatments, which limit the generalisability of the findings,” they added.
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