囊性纤维化患者在接受Elexacaftor/Tezacaftor/Ivacaftor治疗前的基线鼻窦表型：一项横断面分析。

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中文摘要

背景： 鼻窦疾病在囊性纤维化（CF）中高度普遍，但治疗前疾病负担在不同CFTR基因型类别中仍未得到充分描述。随着CFTR调节剂治疗重塑疾病轨迹，在启动elexacaftor/tezacaftor/ivacaftor（ETI）之前建立按基因型分层的气道疾病基线，对于理解后续鼻窦反应至关重要。
方法： 在这项横断面研究中，45名CF患者接受了ETI前评估，包括SNOT-22问卷、鼻塞视觉模拟量表（VAS）、Lund-Kennedy（LK）内镜评分、Lund-Mackay（LM）CT分期以及CCCRC嗅觉识别测试。比较了杂合子与F508del纯合子基因型之间的疾病负担。杂合子患者进一步根据致囊性纤维化突变的遗传类别（按突变类型分为I至VI类）进行分层，并根据外分泌胰腺状态额外比较鼻窦结局。使用Spearman相关性评估症状、结构和功能指标之间的关联。
结果： 鼻塞VAS平均为4.15 ± 2.30，SNOT-22评分平均为14.4 ± 11.2，提示轻至中度症状负担。LK内镜显示轻至中度疾病（4.09 ± 1.54），LM CT显示明显混浊（14.17 ± 4.62）。嗅觉评分差异很大（8.63 ± 3.08，D+E复合）。在任何领域均未发现基因型组之间的显著差异。VAS与SNOT-22强相关（ρ = 0.54，p < 0.001），与嗅觉呈负相关（ρ = -0.42，p = 0.02），但与内镜或影像学严重程度无关。在杂合子中，最小功能类与残余功能类之间任何领域均无差异（VAS p = 0.129；SNOT-22 p = 0.177；LK p = 0.878；LM p = 0.225；嗅觉 p = 0.357），且经错误发现率校正后均无统计学意义。鼻窦评分同样不因外分泌胰腺状态而异，但该分析仅限13名患者，因此把握度明显不足。
结论： CF患者在ETI治疗前表现出可测量的鼻窦疾病，涉及症状、结构和功能领域。按基因型、按CFTR功能类别以及按胰腺状态均无显著差异，表明基线气道疾病在很大程度上独立于按传统分类的CFTR功能严重程度。这些发现为未来纵向评估鼻窦和嗅觉对CFTR调节剂治疗的反应建立了多领域治疗前参考。

英文摘要

BACKGROUND: Sinonasal disease is highly prevalent in cystic fibrosis (CF), yet pre-treatment disease burden remains incompletely characterized across CFTR genotype classes. As CFTR modulator therapy reshapes disease trajectories, establishing a genotype-stratified baseline of upper-airway disease before elexacaftor/ tezacaftor/ivacaftor (ETI) initiation is essential for contextualizing subsequent sinonasal responses.
METHODS: In this cross-sectional study, 45 individuals with CF underwent pre-ETI evaluation, including the SNOT-22 questionnaire, visual analog scale (VAS) for nasal obstruction, Lund-Kennedy (LK) endoscopic scoring, Lund-Mackay (LM) CT staging, and CCCRC olfactory identification testing. Disease burden was compared between heterozygous and F508del homozygous genotypes. Heterozygous patients were further stratified by the genetic class of the cystic fibrosis-causing mutation, ranging from class I to class VI, according to the type of mutation, and sinonasal outcomes were additionally compared by exocrine pancreatic status. Associations among symptoms, structural, and functional measures were assessed using Spearman correlations.
RESULTS: Mean VAS nasal obstruction was 4.15 ± 2.30 and mean SNOT-22 score 14.4 ± 11.2, indicating mild to moderate symptom burden. LK endoscopy showed mild to moderate disease (4.09 ± 1.54) and LM CT substantial opacification (14.17 ± 4.62). Olfactory scores varied widely (8.63 ± 3.08, D+E composite). No significant differences were found between genotype groups across any domain. VAS correlated strongly with SNOT-22 (ρ = 0.54, p < 0.001) and inversely with olfaction (ρ = -0.42, p = 0.02), but not with endoscopic or radiologic severity. Among heterozygotes, no domain differed between minimal-function and residual-function classes (VAS p = 0.129; SNOT-22 p = 0.177; LK p = 0.878; LM p = 0.225; olfaction p = 0.357), and none survived false-discovery-rate correction. Sinonasal scores likewise did not differ by exocrine pancreatic status, an analysis limited to 13 patients and therefore substantially underpowered.
CONCLUSIONS: Individuals with CF exhibit measurable sinonasal disease across symptomatic, structural, and functional domains before ETI therapy. The absence of significant differences by genotype, by CFTR functional class, and by pancreatic status indicates that baseline upper-airway disease is largely independent of CFTR functional severity as conventionally classified. These findings establish a multidomain pre-treatment reference for future longitudinal assessment of sinonasal and olfactory responses to CFTR modulator therapy.