ATS 2015. Poster Board P832. Physiological Mechanisms of Dyspnea Relief Following Ivacaftor in Cystic Fibrosis

American Thoracic Society 2015


Cystic Fibrosis Transmembrane Regulator (CFTR) targeting therapy with ivacaftor has been shown to result in improved lung function, respiratory symptoms, sinus disease, nutritional parameters, CF related diabetes, as well as exercise tolerance in patients with certain CFTR mutations. The two reports by Bickel and Schaeffer et al. presented at ATS (Poster Boards P832 & P854), demonstrate improvement of structural lung disease on CT imaging following the treatment with ivacaftor. This not only suggests that reversibility of lung damage on ivacaftor treatment can be achieved and visualized, but also that structural improvement contributes to the functional benefits seen on CFTR-targeting therapy. Potential therapeutic benefit for ivacaftor was also demonstrated in COPD, where it was shown to overcome cigarette smoke-induced mucus clearance abnormalities (Lin et al., Poster Board P607).

- CARE Respirology Faculty 

Please see the abstracts that follow for full details on these abstracts:

ATS 2015. Poster Board P832. Physiological Mechanisms of Dyspnea Relief Following Ivacaftor in Cystic Fibrosis, [Publication Number: A1461]
M.R. Schaeffer et al. 

Description: We performed detailed pulmonary function and cardiopulmonary cycle exercise testing 2 weeks pre- and 8 weeks post-initiation of ivacaftor in a 27-year old male with CF (CFTR genotype F508del/G551D). Serial inspiratory capacity maneuvers were performed throughout exercise to examine operating lung volumes and expiratory flow limitation. Both the intensity and qualitative dimensions of dyspnea were monitored throughout exercise. Chest computed tomography (CT) scans were obtained 13 months pre- and 10 weeks post-ivacaftor.

Post-ivacaftor CT scan demonstrated a marked reduction in bronchial wall thickening and mucus plugging. The patient’s degree of airflow obstruction, gas trapping, gas transfer, body mass, and sweat choloride improved by 16%, 12%, 22%, 8%, and 40%, respectively following treatment. Exercise duration, peak work rate, and peak oxygen consumption increased by 33%, 25%, and 14%, respectively. Exertional dyspnea was reduced at standardized absolute work rates by up to 5 Borg scale units. The dominant qualitative descriptor of dyspnea prior to treatment was a heightened sensation of “unsatisfied inspiration”. In contrast, following treatment, dyspnea was primarily described as a heightened sense of increased “work/effort”. Minute ventilation was consistently reduced for any given submaximal work rate and this was achieved using a less rapid and shallow breathing pattern with corresponding improvements in ventilatory efficiency (VE/VCO2) by 9%. Flow-volume loop analysis revealed an attenuation of expiratory flow limitation for a given submaximal work rate and a reduction in dynamic hyperinflation at peak exercise.

Discussion: Augmentation of mucociliary clearance leads to an improvement in exercise capacity and favorable alterations in both the intensity and qualitative dimensions of exertional dyspnea in our patient. The improvement in resting airflow obstruction and reduction in gas trapping had direct beneficial effects on the ventilatory response to exercise. Decreases in ventilatory requirements coupled with a more mechanically efficient breathing pattern likely played an important role in reducing dyspnea and improving exercise tolerance in our patient.

ATS 2015. Poster Board P854. Chest Computerized Tomography (CT) Improvement After Initiating Treatment with Ivacaftor, [Publication Number: A5902]
S. Bickel et al. 

Introduction: Ivacaftor has been used successfully in patients with cystic fibrosis to help reverse the underlying gating defect associated with the G551D mutation. There is limited data with regards to ivacaftor’s impact on chest CT imaging in young pediatric patients.

Case: We report on a 6 year old girl with cystic fibrosis (CF) (deltaF508/G551D) with a history of severe, progressive lung disease, complete collapse of her left lung, and subsequent improvement after starting therapy with ivacaftor. At the time of initiating therapy, the patient had 14 prior admissions for CF exacerbations. A chest CT scan done 4 months prior to starting ivacaftor revealed collapse of the entire left lung with corresponding overexpansion of the right lung and mediastinal shift. The left lung was reduced to a small crescent shape object, sandwiched between the overinflated right lung, which filled the entire left chest cavity, and the thoracic cage. A thoracic surgery consult found no viable option to salvage both lungs, and recommended referral for future lung transplantation. Spirometry at this time demonstrated baseline FEV1 in the mid-40s. The patient began taking ivacaftor at age 5 and began having considerable improvement in her symptoms. Over the next year, her FEV­1 steadily increased into the low 60s and she had only one exacerbation requiring admission over that time period (about 3 months into therapy). A repeat chest CT performed about 7 months after starting therapy demonstrated significant partial re-expansion of the left lower lobe which seemed to correlate with the patient’s improved clinical status. 

Discussion: Information in the literature regarding ivacaftor’s effect on pediatric imaging remains scarce. This case provides radiologic evidence suggesting ivacaftor may play a role in reversing prior lung damage due to CF. In addition, trials of ivacaftor were conducted in patients with mild to moderate disease. This case provides a useful reference in younger patients with severe lung disease as evidenced by gains in FEV1, weight gain, and overall clinical improvement. Finally, ivacaftor is currently approved for patients 6 years of age and greater. While studies are on-going for use in younger children, this case suggests it is effective and well tolerated in this age range.

Conclusion: Ivacaftor therapy can improve findings on chest CT in pediatric patients with severe lung disease. Further research is needed to characterize these improvements over long time periods and in different groups.

ATS 2015. Poster Board 607. CFTR Potentiator Ivacaftor, a Novel Mucus Clearance Therapy in COPD, [Publication Number: A3871]
V.Y. Lin et al. 

Results: In HBE cells, cigarette smoke reduced ASL height by 36% (Veh 13.3 ± 0.7, CSE 8.4 ± 0.6 µm), CBF by 15% (Veh 5.9 ± 0.2, CSE 5.0 ± 0.1 Hz), and MCT by 98% (Veh 0.25 ± 0.03, CSE 0.004 ± 0.002 mm/min). Ivacaftor rescued these smoke-induced effects on ASL (18.8 ± 1.3 µm, p < 0.001), CBF (6.62 ± 0.2 Hz, p < 0.001), and MCT (0.25 ± 0.03 mm/min, p < 0.001). In contrast to HBE, smoke exposure caused mucus release from glands in normal human bronchus, increasing ASL (baseline 23.0 ± 2.4, post-smoke 65.7 ± 14.2 µm), but severely reducing MCT (by 99%; baseline 0.22 ± 0.06, post-smoke 0.017 ± 0.003 mm/min), with no effect on PCL or CBF. Ivacaftor increased MCT in smoked tissues by 2.5-fold (Veh 0.02 ± 0.005, ivacaftor 0.05 ± 0.011 mm/min) without affecting ASL or PCL, suggesting altered mucus viscoelasticity caused delayed MCC. FRAP indicated ivacaftor reduced mucus viscosity in airway tissues from non-smokers and healthy smokers by 56% (Veh 14.9 ± 0.3, ivacaftor 6.4 ± 0.6 s, p < 0.0001).

Conclusions: CFTR activation by ivacaftor overcomes cigarette smoke-induced mucus clearance abnormalities. In contrast to observations in primary cells, smoking induced glandular mucus hypersecretion and did not deplete ASL. Ivacaftor conferred marked improvements in MCT in smoke-exposed bronchial tissue by reducing mucus viscosity, indicating its potential as a novel COPD therapy.

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