【作者】 王超；

【导师】 于振坤；

【作者基本信息】 东南大学 ， 临床医学（专业学位）， 2025， 博士

【摘要】 第一部分儿童阻塞性睡眠呼吸暂停的文献计量学分析与系统评价背景:阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)是儿童中最常见的睡眠呼吸障碍疾病。如未能及时诊断并有效治疗,可能导致一系列严重的并发症。目前尚无专门针对儿童OSA的文献计量学分析。方法:我们通过Web of Science核心合集中的科学引文索引扩展版(SCI-EXPANDED)收集了2015年至2024年所有关于儿童OSA的英文论著与综述。利用Vosviewer和在线文献计量分析平台对国家、机构、作者等发文情况进行可视化分析,使用Citespace对关键词进行“Burst Detection”分析,以确定研究趋势和研究热点。结果:近10年的年度发文量整体呈上升趋势,美国(1934篇,占44.64%)和中国(674篇,占15.56%)为主要贡献国家。研究机构方面,辛辛那提大学(196篇)发文最多,排名前10的机构中有8家位于美国。期刊分析显示,《International Journal of Pediatric Otorhinolaryngology》为发表相关文献数量最多的期刊,共计发表287篇文献,而《Sleep》期刊的总被引用次数最高(6891次)。在研究者贡献方面,David Gozal教授以182篇文章成为发文量最多的作者。突现词分析(Burst detection)显示,2023-2024年的研究热点主要包括“腺样体肥大”、“21三体综合征”、“舌扁桃体切除术”、“护理”和“变应性鼻炎”等。结论:过去十年间全球在儿童OSA领域取得了显著的研究进展,美国在此领域占据主导地位。通过文献计量学的可视化分析,本研究清晰揭示了儿童OSA研究热点的演化趋势,并明确了近期研究关注的重点领域(特别是合并变应性鼻炎的儿童OSA)。这些发现不仅为本博士课题的二、三、四部分研究奠定了坚实基础,也为研究人员提供了重要的参考文献和新的研究方向,有助于推动该领域未来的学术进步与临床实践创新。第二部分变应性鼻炎与慢性腺扁疾病的因果关联:中介孟德尔随机化研究背景:变应性鼻炎(allergic rhinitis,AR)与慢性腺扁疾病(chronic adenotonsillar diseases,CATD)之间的关联已被广泛关注,但二者是否存在明确的因果关系尚不清楚。本研究旨在探讨AR对CATD的潜在因果效应,并评估慢性鼻窦炎(chronic rhinosinusitis,CRS)在二者关系中的中介作用。方法:本研究采用两样本孟德尔随机化(mendelian randomization,MR)研究设计,利用遗传工具变量进行分析。其中AR的遗传数据来自MRC IEU Open GWAS数据库,CATD的数据来自Finn Gen R12生物库,CRS的数据来源于GWAS Catalog数据库。运用多种MR分析方法分析暴露与结局之间的因果关联,并采用MR两步法检验CRS在AR与CATD之间的中介效应。结果:MR分析结果显示,AR对CATD具有显著的正向因果关系(IVW,β=0.556,95%CI:0.263 to 0.848,P<0.001),反之,CATD对AR不存在显著因果效应(IVW,β=0.003,95%CI:-0.010 to 0.017,P=0.630)。AR对CRS也表现出显著的正向因果关系(IVW,β=1.385,95%CI:0.783 to 1.987,P<0.001),且CRS对CATD同样具有显著的正向因果关联(IVW,β=0.154,95%CI:0.060 to 0.248,P=0.001)。中介效应分析显示,CRS在AR对CATD的总体效应中起38.4%的中介作用(中介效应=0.213,95%CI:0.047 to 0.379,P=0.011)。结论:本研究通过孟德尔随机化分析证实了AR与CATD之间存在正向因果关系,并揭示了CRS在这一过程中发挥的中介作用。这些发现为理解疾病之间的潜在因果联系提供了新的视角,但仍需进一步研究以揭示背后的生物学机制,并在不同人群中进行验证。第三部分变应性鼻炎与儿童持续性OSA:基于CHAT数据库的二次分析背景:儿童持续性阻塞睡眠呼吸暂停(Obstructive sleep apnea,OSA)近年受到广泛关注。OSA患儿常伴发变应性鼻炎(allergic rhinitis,AR),但目前尚不清楚合并AR的OSA儿童腺扁切除术后(adenotonsillectomy,AT)是否较未合并AR的儿童更可能出现持续性OSA。方法:本研究为一项多中心随机对照试验儿童腺样体扁桃体切除术试验(childhood adenotonsillectomy trial,CHAT)的二次分析。根据AR患病情况将患儿分为AR组与non-AR组。采用Hodges-Lehmann方法计算中位数差值及95%置信区间。通过广义线性混合模型控制潜在混杂因素,以评估组别与研究结局之间的关联。结果:本研究共纳入372例患儿,其中AR组93例,non-AR组279例。患儿中位年龄为6.0岁(IQR:5.0~8.0岁),男性占54.3%,女性占45.7%。两组患儿的基线人口学特征差异无统计学意义,但AR组中PSQ评分>0.33(百分比差值=14%,95%CI:5%~21%)和OSA-18评分≥60(百分比差值=18%,95%CI:6%~29%)的比例显著高于non-AR组。治疗后,AR组的OAHI显著高于non-AR组(中位数差值:0.29;95%CI:0.01~0.57),最低血氧饱和度显著低于non-AR组(中位数差值:-1.00;95%CI:-2.00~-1.00)。并且,AR组发生持续性OSA的风险显著高于non-AR组(a OR:2.31;95%CI:1.10~4.85)。结论:本研究表明,合并AR的OSA患儿,其睡眠呼吸的症状负担及生活质量损害更为显著,且术后更易出现持续性OSA。这提示AR患儿在AT术后,仍需积极规范管理AR症状。未来亟需开展更为严谨的前瞻性队列研究,结合吸入性变应原检测确诊AR,并采用标准化鼻塞症状评估量表,明确合并AR患儿术后鼻塞症状的改善情况。临床试验注册:Clinical Trials.gov;识别号:NCT00560859第四部分腺扁切除术后OSA儿童鼻部症状的评估:一项前瞻性队列研究背景:儿童鼻塞多由腺样体肥大与变应性鼻炎(allergic rhinitis,AR)引发,二者均可引发或加重阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)病情。腺扁切除术(adenotonsillectomy,AT)作为儿童OSA的主要治疗手段,其对鼻部症状(包括鼻塞、鼻痒、喷嚏和流清水涕)的改善效果尚不明确。方法:本研究是一项前瞻性队列研究,纳入经II级多导睡眠监测确诊的OSA患儿。据术前吸入性变应原检测结果,将患儿分为AR组与non-AR组。分别于术前和术后3个月,采用由患儿父母填写的鼻塞症状评估量表(nasal obstruction symptom evaluation,NOSE)评估患儿的鼻塞症状;同时采用由患儿自行填写的视觉模拟评分(visual analog scale,VAS)评估鼻部症状。组内差异使用配对样本t检验,组间比较使用独立样本t检验。结果:最终纳入58例行AT治疗的OSA患儿(AR组29例,non-AR组29例)。基线数据显示,AR组患儿NOSE总分及鼻部症状VAS评分均显著高于non-AR组。两组在年龄、性别、BMI、PSQ评分、OAHI、ODI及最低血氧饱和度等指标上均无统计学差异。术后3个月随访发现,non-AR组呈现显著改善(均值差=27.93,95%CI:23.34~32.52),AR组NOSE总分亦显著下降(均值差=18.28,95%CI:13.24~23.32),但AR组评分改善幅度小于non-AR组(均值差=-9.66,95%CI:-16.32~-2.99)。术后AR组患儿各项鼻部症状VAS评分均有明显改善,包括鼻塞(均值差=1.28,95%CI:0.70~1.85)、鼻痒(均值差=0.93,95%CI:0.53~1.53)、清水样涕(均值差=1.17,95%CI:0.63~1.71)及喷嚏(均值差=0.72,95%CI:0.35~1.11)。结论:本研究表明,AT显著改善了OSA儿童的鼻塞症状,但AR限制了其改善程度,这一点在家长填写的NOSE问卷和儿童填写的VAS评分中得到了验证。此外,AT还在短期内有效改善了AR的其他鼻部症状,包括鼻痒、喷嚏和流清水涕。未来研究可适当延长随访周期,动态评估手术对鼻部症状的持续影响。临床试验注册:Chictr.org.cn;识别号:Chi CTR2500095586更多还原

【Abstract】 Part Ⅰ Global trends and hotspots on childhood obstructive sleep apnea:a10-year bibliometric analysis and systematic reviewObjective:Obstructive sleep apnea(OSA)is the most common sleep-related breathing disorder among children.It may develop a wide range of severe complications if not diagnosed promptly and treated effectively.However,childhood OSA has not yet been analyzed using a dedicated bibliometric approach.Methods:We collected the research results of childhood OSA from 2015 to 2024 through Web of Science.Vosviewer,Cite Space,and bibliometric online analysis platforms were used for visualizing and analyzing the literature.Publication outputs by country,institution,and author were visualized using Vosviewer and an online bibliometric analysis platform.Cite Space was employed for“burst detection”of keywords to identify emerging trends and research hotspots.Results:Annual publication counts showed a general upward trend.The United States(1934articles,44.64%)and China(674 articles,15.56%)were the primary contributors.In terms of research institutions,the University of Cincinnati produced the largest number of publications(196).Journal analysis revealed that the International Journal of Pediatric Otorhinolaryngology published the highest number of articles(287),whereas Sleep accrued the most total citations(6891).Professor David Gozal ranked first among authors,with 182 publications.Burst detection indicated that recent research hotspots include“adenoid hypertrophy,”“trisomy 21,”“lingual tonsillectomy,”“nursing,”and“allergic rhinitis”.Conclusion:Global research on childhood OSA has grown significantly over the past decade,with the United States playing a leading role.This bibliometric analysis clarifies the evolution of research hotspots and identifies emerging areas of focus.These findings not only lay a foundation for more in-depth investigations in this paper but also provide researchers with valuable references and future research directions.Part Ⅱ The association of allergic rhinitis with chronic adenotonsillar diseases: a mediation Mendelian randomization studyObjectives: The relationship between allergic rhinitis(AR)and chronic adenotonsillar diseases(CATD)has long been noted,but the causal relationship between them has not been clearly established.This study aims to investigate the potential causal effect of AR on CATD and to assess whether chronic sinusitis(CRS)mediates this relationship.Methods: A two-sample Mendelian randomization(MR)design was employed,utilizing genetic instrumental variable analysis.Genetic data for AR were obtained from the MRC IEU Open GWAS data infrastructure,CATD data from the Finn Gen biobank,and CRS data from the GWAS Catalog.Multiple MR methods,including inverse-variance weighted(IVW)and weighted median analyses,were applied.Additionally,a two-step MR approach was used to examine the mediating role of CRS in the association between AR and CATD.Results: MR analysis revealed a significant positive causal effect of AR on CATD(IVW,β = 0.556,95% CI: 0.263 to 0.848,p < 0.001),whereas no causal influence of CATD on AR was observed(IVW,β = 0.003,95% CI:-0.010 to 0.017,p = 0.630).AR was also positively associated with CRS(IVW,β = 1.385,95% CI: 0.783 to 1.987,p < 0.001).Furthermore,CRS showed a significant positive association with CATD(IVW,β = 0.154,95% CI: 0.060 to 0.248,p = 0.001).Mediation analysis indicated that CRS accounted for 38.4% of the total effect of AR on CATD(mediation effect = 0.213,95% CI: 0.047 to 0.379,p = 0.011).Conclusion: This study confirmed a positive causal relationship between AR and CATD through Mendelian randomization analysis and revealed the mediating role of CRS in this process.These findings provide new insights into the potential causal relationship between these diseases.Part Ⅲ Association of allergic rhinitis with persistent obstructive sleep apnea:A secondary analysis of the CHATObjectives: Persistent pediatric obstructive sleep apnea(OSA)has garnered increasing attention.Allergic rhinitis(AR)frequently coexists with pediatric OSA;however,it remains unclear whether AR predisposes children to persistent OSA following adenotonsillectomy(AT)compared with those without AR.Methods: This study is a secondary analysis of the multicenter randomized controlled trial(CHAT).Participants were categorized into AR and non-AR groups according to medical history record.The Hodges-Lehmann method was used to calculate median differences and 95% confidence intervals(CIs).A generalized linear mixed model was employed to adjust for potential confounders and assess the association between group status and clinical outcomes.Results: A total of 372 children were included: 93 in the AR group and 279 in the non-AR group.The median age was 6.0 years(interquartile range [IQR],5.0–8.0),with a male-tofemale ratio of approximately 54.3% to 45.7%.No significant differences in baseline demographics were found between the two groups.However,a higher proportion of children in the AR group had a Pediatric Sleep Questionnaire(PSQ)score > 0.33(percentage difference = 14%,95% CI: 5% to 21%)and an OSA-18 score ≥ 60(percentage difference = 18%,95% CI: 6–29%).After treatment,the AR group had significantly higher OAHI compared with the non-AR group(median difference,0.29;95% CI,0.01 to 0.57)and significantly lower minimum oxygen saturation(median difference,-1.00;95% CI,-2.00 to-1.00).Additionally,the AR group had a significantly increased risk of persistent OSA compared with the non-AR group(a OR: 2.31;95% CI: 1.10 to 4.85).Conclusions: In this study,children with AR were more likely to experience persistent OSA,highlighting the importance of effective AR management even post-adenotonsillectomy.Future studies should adopt rigorous prospective cohort designs,using allergen testing for AR diagnosis and standardized scales to evaluate postoperative nasal obstruction.Trial Registration: Clinical Trials.gov;Identifier: NCT00560859Part Ⅳ Evaluation of Nasal Symptoms After Adenotonsillectomy in Children with Obstructive Sleep Apnea: A Prospective Cohort StudyBackground: Nasal obstruction in children is often caused by adenoid hypertrophy and allergic rhinitis(AR),both of which contribute to obstructive sleep apnea(OSA).Adenotonsillectomy(AT)is commonly performed to cure OSA,but its effect on nasal obstruction,especially in children with AR,remains unclear.Methods: A prospective cohort study was conducted at Nanjing BenQ Medical Center with children diagnosed with OSA by level II polysomnography.Participants were divided into AR and non-AR groups according to serum-specific Ig E test.Nasal symptoms were assessed using the Nasal Obstruction Symptom Evaluation(NOSE)scale and Visual Analog Scale(VAS)at baseline and 3-month follow-up.Results: A total of 58 children with OSA(29 in each group: AR and non-AR)who underwent AT were included.At baseline,children in the AR group had significantly higher NOSE and VAS scores for nasal symptoms compared to the non-AR group,whereas there were no significant differences in the Obstructive Apnea-Hypopnea Index(OAHI)or minimal oxygen saturation.After three months,both groups showed significant reductions in NOSE scores,with a mean difference of 18.28(95% CI: 13.24 to 23.32)for the AR group and 27.93(95% CI: 23.34 to 32.52)for the non-AR group.However,the AR group exhibited a smaller decline than the non-AR group(mean difference =-9.66,95% CI:-16.32 to-2.99).Furthermore,the AR group reported marked improvements in VAS scores for nasal obstruction(mean difference = 1.28,95% CI: 0.70 to 1.85),nasal itching(0.93,95% CI: 0.53 to 1.53),clear rhinorrhea(mean difference = 1.17,95% CI: 0.63 to 1.71),and sneezing(0.72,95% CI: 0.35 to 1.11).Conclusions: AT significantly reduced nasal obstruction symptoms in children with OSA,although this improvement was less pronounced in those with AR compared to those without AR.Additionally,AT improved other AR-related nasal symptoms,including nasal itching,sneezing,and clear rhinorrhea.Future studies should consider longer follow-up periods to dynamically evaluate the long-term effects of surgery on nasal symptoms.Trial Registration: Chictr.org.cn;Identifier: Chi CTR2500095586更多还原