London, UK – Researchers in Europe have identified two highly sensitive lung tests that can detect subtle worsening of cystic fibrosis (CF) lung disease—even when conventional breathing tests suggest patients are stable.
The findings indicate that oxygen-enhanced MRI (OE-MRI) and multiple breath washout with Short extension (MBWShX) may provide a more accurate picture of ongoing lung disease than current monitoring methods. Researchers believe these tools could play an important role in tracking disease progression in the era of highly effective CFTR modulator therapies.
The study, “Oxygen-enhanced MRI and multiple breath washout with Short extension reveal cystic fibrosis lung disease progression despite triple modulator therapy,” was published in Thorax. Larger multicenter studies are now being planned to further validate these techniques.
Lead author Christopher Short, PhD, from Imperial College London’s National Heart and Lung Institute, said:
“Our findings suggest that oxygen-enhanced MRI and MBWShX may provide additional information beyond conventional tests and could help us better understand what is happening in the lungs over time.”
Why Better Monitoring Is Needed
Cystic fibrosis causes thick, sticky mucus to accumulate in the lungs, blocking airways, promoting chronic infections, and leading to progressive lung damage and declining respiratory function.
Traditionally, lung health in CF is monitored using spirometry, particularly the measurement of forced expiratory volume in one second (FEV₁), which evaluates how much air a person can forcefully exhale. Another commonly used test is the multiple breath washout (MBW), which measures the lung clearance index (LCI)—an indicator of how efficiently air is distributed throughout the lungs. Higher LCI values indicate poorer lung function.
While these tests have long been effective, the widespread use of CFTR modulators, such as Trikafta, has significantly improved lung function and slowed disease progression in many patients. As a result, traditional monitoring methods may no longer be sensitive enough to detect subtle, ongoing lung damage.
According to Short:
“CFTR modulators have had a transformative impact on the lives of people with cystic fibrosis. As patients become healthier, it becomes increasingly important that our monitoring tools are sensitive enough to detect subtle changes in lung disease.”
The Two New Tests
Multiple Breath Washout with Short Extension (MBWShX)
Researchers enhanced the standard MBW test by adding a slow, forced exhalation at the end of the procedure, known as the Short extension.
This modification generates two additional measurements:
- LCIShX, an expanded version of the traditional lung clearance index.
- UVLU (Under-Ventilated Lung Unit), which estimates the amount of poorly ventilated lung tissue, previously described as trapped air.
These measurements are designed to detect subtle ventilation abnormalities that conventional MBW may miss.
Oxygen-Enhanced MRI (OE-MRI)
To visualize where lung abnormalities occur, researchers paired MBWShX with oxygen-enhanced MRI (OE-MRI).
Unlike standard lung function tests, OE-MRI shows how effectively different regions of the lungs receive oxygen by using inhaled medical oxygen as a contrast agent. The technique works on standard MRI scanners, requires no radiation exposure, and provides detailed regional information about lung ventilation.
Study Design
Researchers from the United Kingdom, Ireland, and the Netherlands followed 46 people with cystic fibrosis, aged 6 to 55 years, over an 18-month period.
A subgroup consisting of 20 people with CF and 20 healthy volunteers repeated testing within six weeks to evaluate the reliability of the new methods.
Most participants completed both tests successfully. Only two individuals were unable to finish the MRI because of claustrophobia.
Repeated testing showed highly consistent results, demonstrating that the new measurements are reliable enough to detect genuine disease progression rather than normal measurement variability.
New Tests Were More Sensitive Than Standard Assessments
The new techniques detected lung abnormalities in substantially more patients than conventional tests.
At the beginning of the study:
- 41% had abnormal FEV₁.
- 50% had abnormal LCI.
- 80% had abnormal LCIShX.
- 85% had abnormal UVLU.
These findings suggest that MBWShX identifies early lung impairment that standard spirometry and conventional MBW may overlook.
Detecting Early Response to Trikafta
Researchers also evaluated 11 school-age children who had recently begun treatment with Trikafta.
During the first six months:
- FEV₁ and conventional LCI showed no significant improvement.
- LCIShX improved by 2.5 units.
- UVLU improved by 1.8 units.
- OE-MRI showed a 1.6% reduction in ventilation defect percentage (VDP).
- Overall lung ventilation signals also improved.
These results indicate that the new tests were able to detect treatment-related improvements that standard assessments failed to identify.
Hidden Disease Progression Despite Stable Standard Results
Among participants who had already been receiving Trikafta for at least six months, traditional monitoring suggested stable disease over the 18-month follow-up.
No significant changes were observed in:
- FEV₁
- Forced vital capacity (FVC)
- Conventional LCI
- Structural MRI scores
However, the more sensitive tests revealed continued deterioration.
Over 18 months:
- LCIShX worsened by 1.53 units, with 54% of participants experiencing changes greater than 10%.
- UVLU increased by 1.1 units.
- Ventilation defect percentage (VDP) increased by 2.5% after 12 months and 4.5% after 18 months.
- OE-MRI also demonstrated progressively weaker ventilation signals over time.
These findings suggest that lung disease may continue to progress even when standard clinical assessments indicate stability.
Patients at Higher Risk
The researchers found that disease progression was greatest among patients who already had poorer lung function at the start of the study, regardless of whether it was measured using FEV₁, conventional LCI, or LCIShX.
Greater decline was also observed in participants who had:
- Chronic Pseudomonas aeruginosa infection.
- Pulmonary exacerbations at baseline.
Study Conclusions
The researchers concluded that MBWShX and oxygen-enhanced MRI are sensitive, reliable tools for monitoring cystic fibrosis lung disease and may provide clinically meaningful information beyond conventional lung function testing.
Importantly, this study provides the first evidence suggesting that lung disease may continue to progress in people with cystic fibrosis despite treatment with highly effective triple-modulator therapy such as Trikafta.
The authors believe these findings challenge the current reliance on standard lung function tests alone and highlight the need for more sensitive monitoring strategies as cystic fibrosis care continues to evolve.
Contact
Christopher Short, PhD
Imperial College of London
Phone: +44 020 7574 7949
Email: [email protected]