Changes in Low Attenuation Regions and Arterial and Venous Blood Volume Distribution in Response to CFTR Modulator Therapy in People With Cystic Fibrosis

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Abstract Rationale: The most important structural lung abnormalities that can be observed on inspiratory chest CTs of people with cystic fibrosis(PwCF) are bronchial widening and thickening, mucus plugs and, on expiratory scans, large low attenuation regions (LAR). LAR are most likely reflecting the combination of hypoventilation and hypoperfusion secondary to airways obstruction and hypoxic pulmonary vasoconstriction. Using sensitive visual scoring techniques and sensitive AI-based image analysis algorithms we previously demonstrated important improvements in airway wall thickening, mucus plug number and in LAR in PwCF aged 12 years and over after 12 Months(M12) and 24 Months(M24) of Elexacaftor-Tezacaftor-Ivacaftor(ETI) therapy. For the current study we sought to establish the impact of ETI on arterial and venous blood volume distribution and LAR. We hypothesized that a reduction in LAR would correlate with a reduction in the upstream arterial blood volumes reflecting reduced upstream pulmonary arterial pressures. Methods: Standardized spirometry-controlled CT scans were performed at baseline (M0), M12, and M24. CTs were fully automatically analyzed (Thirona, Nijmegen) using: LungQ-VERA: measurement of LAR (% total lung volume); LungQ-AVX: Total arterial and venous blood volumes were computed based on the outer diameter and length of pulmonary arteries and veins. Results were divided in bins: 0.2-1mm, 1-2mm, and >2mm. Blood volume in each bin is expressed as % of total lung blood volume. Differences in arterial blood volumes for each bin were compared between M0 vs M12 and between M0 and M24 (mixed model) and between changes(Δ) M0-M12 in arterial blood volumes vs Δ%LAR. Results are shown as: median [Q1, Q3]. Results: Number CT scans: M0=65, M12=43, M24=38. Arterial blood volumes for M0, M12, M24: Bin 0.2-1 mm: 6.7[6.0,7.6], 6.6[5.7-7.5], 6.5[5.7,7.1]% (differences ns); Bin 1-2mm: 10.9[10.0,12.2], 9.4[8.7,10.2], 9.6[8.8, 10.4]% (differences P<0.001); Bin>2; 38.4 [35.6,41.7], 37.4[34.8, 39.2], 37.7[34.8, 39.7] (differences p<0.001). For all venous bins an increase in %volumes were observed for M12 and M24 (all p<0.001). %LAR for M0, M12, M24 were 13.1[7.9, 20.7], 4.9[2.6, 10.4], 6.2[3.6,12.6] (differences <0.001). Δblood volumes versus Δ%LAR showed a positive correlation(r=0.27, p=0.09) in the arterial bin>2mm, and an negative correlation for the 0.2-1 bin (r=-0.39, p=0.014). Discussion: Substantial changes are seen in the pulmonary arterial and venous blood volume distribution in response to ETI therapy. The reduction in upstream large vessel %arterial blood volume suggests a reduction in pulmonary arterial pressures. Furthermore, the increase of the %venous blood volume suggests improved pulmonary perfusion.

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