Research Uncovers Early Vascular Component in CF, Opening Doors to Earlier Diagnosis

For decades, cystic fibrosis (CF) research has focused primarily on the effect of CFTR in the lining of the airways. However, a new study led by the Division of Pulmonary Medicine at Cincinnati Children’s reveals that vascular pathology is also a fundamental component of CF lung disease, beginning in childhood and evolving alongside airway changes. These findings not only deepen understanding of CF pathophysiology but also suggest new strategies for earlier diagnosis and treatment.

Evidence of Early and Independent Vascular Changes

The prospective study, published in the Journal of Cystic Fibrosis, examined 160 children and young adults with CF, ages 5–25, and compared them with age-matched healthy controls. Using high-resolution CT imaging, investigators measured the fraction of small pulmonary blood vessels (BV5) relative to total vessel volume (BV5/TBV%). This promising marker enabled them to track vascular morphology across different age groups, lung function categories and treatment exposures.

The results were striking. Loss of small blood vessels began as early as the first decade of life—often when spirometry readings such as FEV1 still appeared normal. In fact, children with CF showed an initial increase in small vessel density compared with controls, followed by a steady decline as the disease progressed. Significantly, this vascular attrition was associated not just with FEV1 decline, but also with reduced diffusion capacity, impaired exercise performance and abnormal lung clearance index results.

“These findings tell us that pulmonary vascular changes are not simply a late complication of CF,” explains study senior author Raouf Amin, MD, division director of Pulmonary Medicine. “They emerge early, in parallel with airway pathology, and may represent an independent disease process that we can target.”

The Role of CFTR Modulator Therapy

Another key finding centered on CFTR modulator therapy. Patients treated with first-generation modulators (ivacaftor, Orkambi or Symdeko) continued to show age-related small-vessel loss. In contrast, those treated with Trikafta (elexacaftor/tezacaftor/ivacaftor) did not demonstrate the same progressive decline. Their vascular patterns remained stable over time, resembling those of healthy controls.

However, Trikafta did not reverse vascular damage once advanced disease was present. This suggests that early initiation of highly effective therapy may be critical for preserving vascular—and ultimately pulmonary—health.

“Before this study, we didn’t know Trikafta could have the same effect on the airway as it does on vascular cells involved in lung disease in CF,” says Dr. Amin. “Further study is needed, but for now this discovery provides additional support for starting Trikafta as soon as possible in eligible patients, because the drug may prevent vascular pathology that otherwise progresses silently in childhood.”

Implications for Diagnosis and Monitoring

The study also suggests that BV5/TBV% may represent a promising new imaging marker for CF disease activity. Although not yet a clinical tool, it shows potential to complement spirometry, lung clearance index and diffusion capacity in both routine care and clinical trials. Its role in predicting long-term outcomes remains an important area for further investigation.

Looking Ahead to What’s Next

This study underscores the innovative research culture at Cincinnati Children’s Division of Pulmonary Medicine, where clinicians and scientists work to redefine pediatric CF care. By uncovering early, parallel pathways of vascular and airway pathology, the team has opened the door to novel diagnostics and therapeutic strategies.

“Our team plans to do a longitudinal study to explore the role of pulmonary vasculature in CF,” Dr. Amin says. “If that study produces similar results to our prospective study, it will underscore the importance of monitoring the progression of vascular changes in patients with CF.”