Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Berlin Institute of Health, Berlin, Germany.
Ann Am Thorac Soc. 2021 Jun;18(6):971-980. doi: 10.1513/AnnalsATS.202008-1054OC.
Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of CFTR (cystic fibrosis [CF] transmembrane conductance regulator) activity and a moderate improvement of spirometry in Phe508del homozygous patients with CF. However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown. To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation. In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome, and proinflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy. Lumacaftor-ivacaftor had no effects on forced expiratory volume in 1 second (FEV% predicted) (1.7%; 95% confidence interval [CI], -1.0% to 4.3%; = 0.211) but improved LCI (-1.6; 95% CI, -2.6 to -0.5; < 0.01) and MRI morphology (-1.3; 95% CI, -2.3 to -0.3; < 0.05) and perfusion score (-1.2; 95% CI, -2.3 to -0.2; < 0.05) in our study cohort. Furthermore, lumacaftor-ivacaftor decreased the total bacterial load (-1.8; 95% CI, -3.3 to -0.34; < 0.05) and increased the Shannon diversity of the airway microbiome (0.4; 95% CI, 0.1 to 0.8; < 0.05), and reduced IL-1β (interleukin-1β) concentration (median change, -324.2 pg/ml; 95% CI, -938.7 to 290.4 pg/ml; < 0.05) in sputum of Phe508del homozygous patients. This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology, and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV% predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).
先前的研究表明，lumacaftor-ivacaftor 疗法可部分恢复 CFTR（囊性纤维化跨膜电导调节因子）的活性，并可使 Phe508del 纯合子 CF 患者的肺活量测定值得到适度改善。然而，lumacaftor-ivacaftor 对肺清除指数（LCI）、胸部磁共振成像（MRI）检测到的肺形态和灌注、气道微生物组和炎症的影响仍不清楚。 为了研究 lumacaftor-ivacaftor 对 LCI、肺 MRI 评分以及气道微生物组和炎症的影响。 在这项前瞻性观察性研究中，我们评估了 30 名年龄在 12 岁及以上的 Phe508del 纯合子 CF 患者的临床结局，包括肺活量测定值和体重指数、LCI、肺 MRI 评分、痰微生物组和促炎细胞因子，在开始 lumacaftor-ivacaftor 治疗前和 8-16 周后。 lumacaftor-ivacaftor 对 1 秒用力呼气量（FEV%预测值）没有影响（1.7%；95%置信区间[CI]，-1.0%至 4.3%； = 0.211），但改善了 LCI（-1.6；95%CI，-2.6 至 -0.5； < 0.01）和 MRI 形态（-1.3；95%CI，-2.3 至 -0.3； < 0.05）和灌注评分（-1.2；95%CI，-2.3 至 -0.2； < 0.05）。此外，lumacaftor-ivacaftor 降低了总细菌负荷（-1.8；95%CI，-3.3 至 -0.34； < 0.05）和气道微生物组的 Shannon 多样性增加（0.4；95%CI，0.1 至 0.8； < 0.05），并降低了痰中 IL-1β（白细胞介素-1β）浓度（中位数变化，-324.2 pg/ml；95%CI，-938.7 至 290.4 pg/ml； < 0.05）。 这项研究表明，lumacaftor-ivacaftor 对 Phe508del 纯合子患者的肺通气、形态和灌注以及气道微生物组和炎症有有益的影响。我们的结果表明，LCI 和 MRI 可能比 FEV%预测值更敏感，可用于检测慢性 CF 肺部疾病患者对 CFTR 调节剂治疗的反应。临床试验在 ClinicalTrials.gov 注册（NCT02807415）。
