氧增强mri （OE-MRI）和短时间延长多次呼吸冲洗（MBWShX）显示接受elexaftor /tezcaftor/ivacaftor （ETI）治疗的患者的“沉默”肺部疾病进展

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.528

C. Short , T. Semple , M. Abkir , M. Tibiletti , M. Rosenthal , S. Padley , G.J.M. Parker , J.C. Davies

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We hypothesised that in the context of improved clinical status, any lung disease progression would be observed more clearly using OE-MRI and MBW<sub>ShX</sub> than conventional measures.</div></div><div><h3>Methods</h3><div>PwCF were recruited as part of a large observational study to determine the clinimetric properties of OE-MRI; all were on ETI therapy (>6 months at baseline). Participants performed OE-MRI, MBW<sub>ShX</sub>, and spirometry whilst clinically stable on the same day at baseline and at 6-monthly intervals over 18 months. <em>OE-MRI parameters</em>: ventilation defect percentage (VDP) and ∆R<sub>2</sub>* (ventilation signal). <em>MBW<sub>ShX</sub> parameters</em>: UVLU and LCI<sub>ShX</sub> (LCI<sub>2.5</sub> + UVLU) a measure of global lung health. Data is presented as mean (SD) and ∆baseline (95%CI) and assessed using a mixed effects model with Tukey's test for multiple comparisons.</div></div><div><h3>Results</h3><div>Thirty-six pwCF aged 20.3 (±12.7) completed the baseline visit. FEV<sub>1</sub> and LCI<sub>2.5</sub> appeared stable, whereas significant deterioration in the novel MBW<sub>ShX</sub> and MRI parameters could be observed, with OE-MRI measures demonstrating sensitivity at 12 months.<span><div><div><table><thead><tr><th>Parameter</th><th>Baseline (N=36) Mean (SD)</th><th>6 months (N=32) Mean (SD)</th><th>∆ (95%CI) P value</th><th>12 months (N=32) Mean (SD)</th><th>∆ (95%CI) P value</th><th>18 months (N=28) Mean (SD)</th><th>∆ (95%CI) P value</th></tr></thead><tbody><tr><td><strong>ppFEV<sub>1</sub></strong></td><td>89.5% (±19.4%)</td><td>88.9% (±19.2%)</td><td>-0.5% (-3.8 to 2.7) P>0.05</td><td>88.7 (±19.7%)</td><td>-0.8% (-4.0 to 2.4%) P>0.05</td><td>88.1% (±19.2%)</td><td>-1.3% (-4.6 to 2.0%) P>0.05</td></tr><tr><td><strong>LCI<sub>2.5</sub></strong></td><td>9.1 (±4.2)</td><td>9.1 (±4.0)</td><td>0.02 (-0.62 to 0.58) P>0.05</td><td>9.1 (±3.9)</td><td>0.02 (-0.61 to 0.57) P>0.05</td><td>9.4 (±3.9)</td><td>0.25 (-0.36 to 0.87) P>0.05</td></tr><tr><td><strong>LCI<sub>ShX</sub></strong></td><td>12.7 (±9.0)</td><td>13.3 (±9.8)</td><td>0.58 (-0.5 to 1.7) P>0.05</td><td>13.6 (±9.7)</td><td>0.91 (-0.2 to 2.0) P>0.05</td><td>14.2 (±8.5)</td><td>1.54 (0.4 to 2.7) <strong>P<0.01</strong></td></tr><tr><td><strong>UVLU</strong></td><td>3.6 (±5.2)</td><td>4.2 (±6.3)</td><td>0.62 (-0.3 to1.6) P>0.05</td><td>4.5 (±6.0)</td><td>0.90 (0.0 to 1.8) P>0.05</td><td>4.7 (±4.6)</td><td>1.1 (-0.2 to 2.1) <strong>P<0.05</strong></td></tr><tr><td><strong>∆R<sub>2</sub>*<sub>MS-1</sub></strong></td><td>0.076 (±0.025)</td><td>0.072 (±0.025)</td><td>-0.004 (-0.010 to 0.002) P>0.05</td><td>0.069 (±0.025)</td><td>-0.006 (-0.013 to 0.00) <strong>P<0.05</strong></td><td>0.065 (±0.025)</td><td>-0.011 (-0.017 to 0.00) <strong>P<0.001</strong></td></tr><tr><td><strong>VDP%</strong></td><td>8.2% (±7.7%)</td><td>9.9% (±8.9%)</td><td>1.6% (0.3 to 3.6%) P>0.05</td><td>10.6% (±8.4%)</td><td>2.4% (0.5 to 4.4%) <strong>P<0.01</strong></td><td>12.7% (±10.6%)</td><td>4.5% (2.5 to 6.6%) <strong>P<0.0001</strong></td></tr></tbody></table></div></div></span></div></div><div><h3>Conclusions</h3><div>Reliance on conventional OMs may lead to false reassurance about disease stability over time; particularly in relation to assessing safe withdrawal of standard treatments. 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FEV<sub>1</sub> and LCI<sub>2.5</sub> appeared stable, whereas significant deterioration in the novel MBW<sub>ShX</sub> and MRI parameters could be observed, with OE-MRI measures demonstrating sensitivity at 12 months.<span><div><div><table><thead><tr><th>Parameter</th><th>Baseline (N=36) Mean (SD)</th><th>6 months (N=32) Mean (SD)</th><th>∆ (95%CI) P value</th><th>12 months (N=32) Mean (SD)</th><th>∆ (95%CI) P value</th><th>18 months (N=28) Mean (SD)</th><th>∆ (95%CI) P value</th></tr></thead><tbody><tr><td><strong>ppFEV<sub>1</sub></strong></td><td>89.5% (±19.4%)</td><td>88.9% (±19.2%)</td><td>-0.5% (-3.8 to 2.7) P>0.05</td><td>88.7 (±19.7%)</td><td>-0.8% (-4.0 to 2.4%) P>0.05</td><td>88.1% (±19.2%)</td><td>-1.3% (-4.6 to 2.0%) P>0.05</td></tr><tr><td><strong>LCI<sub>2.5</sub></strong></td><td>9.1 (±4.2)</td><td>9.1 (±4.0)</td><td>0.02 (-0.62 to 0.58) P>0.05</td><td>9.1 (±3.9)</td><td>0.02 (-0.61 to 0.57) P>0.05</td><td>9.4 (±3.9)</td><td>0.25 (-0.36 to 0.87) P>0.05</td></tr><tr><td><strong>LCI<sub>ShX</sub></strong></td><td>12.7 (±9.0)</td><td>13.3 (±9.8)</td><td>0.58 (-0.5 to 1.7) P>0.05</td><td>13.6 (±9.7)</td><td>0.91 (-0.2 to 2.0) P>0.05</td><td>14.2 (±8.5)</td><td>1.54 (0.4 to 2.7) <strong>P<0.01</strong></td></tr><tr><td><strong>UVLU</strong></td><td>3.6 (±5.2)</td><td>4.2 (±6.3)</td><td>0.62 (-0.3 to1.6) P>0.05</td><td>4.5 (±6.0)</td><td>0.90 (0.0 to 1.8) P>0.05</td><td>4.7 (±4.6)</td><td>1.1 (-0.2 to 2.1) <strong>P<0.05</strong></td></tr><tr><td><strong>∆R<sub>2</sub>*<sub>MS-1</sub></strong></td><td>0.076 (±0.025)</td><td>0.072 (±0.025)</td><td>-0.004 (-0.010 to 0.002) P>0.05</td><td>0.069 (±0.025)</td><td>-0.006 (-0.013 to 0.00) <strong>P<0.05</strong></td><td>0.065 (±0.025)</td><td>-0.011 (-0.017 to 0.00) <strong>P<0.001</strong></td></tr><tr><td><strong>VDP%</strong></td><td>8.2% (±7.7%)</td><td>9.9% (±8.9%)</td><td>1.6% (0.3 to 3.6%) P>0.05</td><td>10.6% (±8.4%)</td><td>2.4% (0.5 to 4.4%) <strong>P<0.01</strong></td><td>12.7% (±10.6%)</td><td>4.5% (2.5 to 6.6%) <strong>P<0.0001</strong></td></tr></tbody></table></div></div></span></div></div><div><h3>Conclusions</h3><div>Reliance on conventional OMs may lead to false reassurance about disease stability over time; particularly in relation to assessing safe withdrawal of standard treatments. 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引用次数: 0

摘要

后调节剂时代提出了几个新的挑战，特别是需要敏感的肺结局测量（OM）。目前的工具是次优的；为了解决这个问题，我们的团队开发了MBWShX来评估以前被忽视的通气下肺单位（UVLU），但它不能提供空间信息。功能性肺部MRI有可能成为追踪CF肺部疾病的敏感OM。我们假设，在临床状况改善的情况下，使用e - mri和MBWShX比常规方法更清楚地观察到任何肺部疾病的进展。方法招募spwcf作为大型观察性研究的一部分，以确定OE-MRI的临床特性；所有患者均接受ETI治疗（基线为6个月）。在临床稳定的情况下，参与者在同一天进行e - mri、MBWShX和肺活量测定，并在18个月内每隔6个月进行一次。e - mri参数：通风缺陷百分比（VDP）、通风信号∆R2*。MBWShX参数：UVLU和LCIShX （LCI2.5 + UVLU）是衡量全球肺部健康的指标。数据以均数（SD）和∆基线（95%CI）表示，并使用混合效应模型和Tukey检验进行多重比较。结果36例pwCF患者完成基线访诊，年龄20.3（±12.7）岁。FEV1和LCI2.5表现稳定，而新型MBWShX和MRI参数明显恶化，OE-MRI测量显示12个月时的敏感性。ParameterBaseline (N = 36)意味着(SD) 6个月(N = 32)意味着(SD)∆P value12 (95% ci)个月(N = 32)意味着(SD)∆P value18 (95% ci)个月(N = 28)意味着(SD)∆P (95% ci) valueppFEV189.5%(±19.4%)88.9%(±19.2%)-0.5% (-3.8 - 2.7)P> 0.0588.7(±19.7%)-0.8% (-4.0 - 2.4%)P> 0.0588.1%(±19.2%)-1.3% (-4.6 - 2.0%)P> 0.05 lci2.59.1(9.1±4.2)(0.02±4.0)(-0.62 - 0.58)P> 0.059.1(0.02±3.9)(-0.61 - 0.57)P> 0.059.4(0.25±3.9)(-0.36 - 0.87)P> 0.05 lcishx12.7(13.3±9.0)(0.58±9.8)(-0.5 - 1.7)P> 0.0513.6(0.91±9.7)(-0.2 - 2.0)P> 0.0514.2(1.54±8.5)(0.4 - 2.7)术;0.01 uvlu3.6(4.2±5.2)(0.62±6.3)(-0.3 to1.6) P> 0.054.5(0.90±6.0)(0.0 - 1.8)P> 0.054.7(1.1±4.6)(-0.2 - 2.1)术;0.05∆R2 *女士- 10.076(0.072±0.025)(-0.004±0.025)(-0.010 - 0.002)P> 0.050.069(-0.006±0.025)(-0.013 - 0.00)术;0.050.065(-0.011±0.025)(-0.017 - 0.00)术;0.001 vdp % 8.2%(±7.7%)9.9%(±8.9%)1.6% (0.3 - 3.6%)P> 0.0510.6%(±8.4%)2.4%(0.5 - 4.4%)术;0.0112.7%(±10.6%)(2.5到4.5%结论对传统OMs的依赖可能导致对疾病稳定性的错误保证；特别是在评估标准治疗的安全停药方面。相比之下，OE-MRI和MBWShX似乎具有额外的敏感性，可以显示在后调节剂时代可能占主导地位的细微疾病进展。这可以允许早期干预，量身定制的护理，并提供更可靠的未来试验结果。由CF基金会资助

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WS07.01‘Silent' lung disease progression in people receiving elexacaftor/tezcaftor/ivacaftor (ETI) therapy revealed by Oxygen Enhanced-MRI (OE-MRI) and Multiple breath washout with Short extension (MBWShX)

Objectives

The post modulator era is raising several new challenges, particularly with a need for sensitive pulmonary outcome measures (OM). Current tools are suboptimal; to address this our group developed MBW_ShX to assess previously overlooked under ventilated lung units (UVLU), but it cannot provide spatial information. Functional lung MRI has the potential to be a sensitive OM to track CF lung disease. We hypothesised that in the context of improved clinical status, any lung disease progression would be observed more clearly using OE-MRI and MBW_ShX than conventional measures.

Methods

PwCF were recruited as part of a large observational study to determine the clinimetric properties of OE-MRI; all were on ETI therapy (>6 months at baseline). Participants performed OE-MRI, MBW_ShX, and spirometry whilst clinically stable on the same day at baseline and at 6-monthly intervals over 18 months. OE-MRI parameters: ventilation defect percentage (VDP) and ∆R₂* (ventilation signal). MBW_ShX parameters: UVLU and LCI_ShX (LCI_2.5 + UVLU) a measure of global lung health. Data is presented as mean (SD) and ∆baseline (95%CI) and assessed using a mixed effects model with Tukey's test for multiple comparisons.

Results

Thirty-six pwCF aged 20.3 (±12.7) completed the baseline visit. FEV₁ and LCI_2.5 appeared stable, whereas significant deterioration in the novel MBW_ShX and MRI parameters could be observed, with OE-MRI measures demonstrating sensitivity at 12 months.

Parameter	Baseline (N=36) Mean (SD)	6 months (N=32) Mean (SD)	∆ (95%CI) P value	12 months (N=32) Mean (SD)	∆ (95%CI) P value	18 months (N=28) Mean (SD)	∆ (95%CI) P value
ppFEV₁	89.5% (±19.4%)	88.9% (±19.2%)	-0.5% (-3.8 to 2.7) P>0.05	88.7 (±19.7%)	-0.8% (-4.0 to 2.4%) P>0.05	88.1% (±19.2%)	-1.3% (-4.6 to 2.0%) P>0.05
LCI_2.5	9.1 (±4.2)	9.1 (±4.0)	0.02 (-0.62 to 0.58) P>0.05	9.1 (±3.9)	0.02 (-0.61 to 0.57) P>0.05	9.4 (±3.9)	0.25 (-0.36 to 0.87) P>0.05
LCI_ShX	12.7 (±9.0)	13.3 (±9.8)	0.58 (-0.5 to 1.7) P>0.05	13.6 (±9.7)	0.91 (-0.2 to 2.0) P>0.05	14.2 (±8.5)	1.54 (0.4 to 2.7) P<0.01
UVLU	3.6 (±5.2)	4.2 (±6.3)	0.62 (-0.3 to1.6) P>0.05	4.5 (±6.0)	0.90 (0.0 to 1.8) P>0.05	4.7 (±4.6)	1.1 (-0.2 to 2.1) P<0.05
*∆R₂_MS-1**	0.076 (±0.025)	0.072 (±0.025)	-0.004 (-0.010 to 0.002) P>0.05	0.069 (±0.025)	-0.006 (-0.013 to 0.00) P<0.05	0.065 (±0.025)	-0.011 (-0.017 to 0.00) P<0.001
VDP%	8.2% (±7.7%)	9.9% (±8.9%)	1.6% (0.3 to 3.6%) P>0.05	10.6% (±8.4%)	2.4% (0.5 to 4.4%) P<0.01	12.7% (±10.6%)	4.5% (2.5 to 6.6%) P<0.0001

Conclusions

Reliance on conventional OMs may lead to false reassurance about disease stability over time; particularly in relation to assessing safe withdrawal of standard treatments. In contrast, OE-MRI and MBW_ShX appear to have the additional sensitivity required to demonstrate subtle disease progression that may predominate in the post-modulator era. This could allow earlier intervention, tailored care and provide a more reliable future trial outcome.

Funded by the CF Foundation

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.