Interpretation of Clinical Efficacy of Biologics in Chronic Rhinosinusitis With Nasal Polyps via Understanding the Local and Systemic Pathomechanisms

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease treated with medication or surgery. For recalcitrant type 2 CRSwNP, biological agents have been effectively used to improve nasal polyp score, nasal congestion score, daily symptoms related to CRSwNP, and time to systemic corticosteroid use or revision surgery. Although general guidelines for using biologics to treat CRSwNP were proposed by the European Position Paper on Rhinosinusitis and Nasal Polyps in 2020 and various studies have tested their efficacy, there is much more to learn about biologics—specific indication and choice of biologics based on the endotypes, for instance. Understanding the vascular distribution of monoclonal antibodies and the differences in the vascularity of the non-polyp mucosa and nasal polyp tissue will not only aid understanding of each biologic’s clinical effect but also provide insights to establishing a more personalized approach to treating recalcitrant CRSwNP with biologics.     

Availability of Preoperative Systemic Steroids on Endoscopic Sinus Surgery for Chronic Rhinosinusitis with Nasal Polyposis

Purpose

To analyze the outcome of endoscopic sinus surgery (ESS) after preoperative systemic steroid (PSS) treatment for chronic rhinosinusitis (CRS) with nasal polyposis (NP) and to investigate and compare clinicopathological factors associated with the outcome.

Materials and Methods

We performed a retrospective chart review of 468 patients with CRS with NP who underwent primary ESS between January 2005 and October 2011. 124 patients who met the inclusion criteria were included. Beginning from 2008, our clinic administered steroid preoperatively in patients of CRS with NP, thus there were 84 patients with preoperative systemic steroid (PSS group) and another 40 patients without such regimen (no PSS group). To evaluate the outcome after ESS, poor outcome and complication were analyzed according to the following parameters: age, sex, follow-up duration, eosinophilic infiltration, atopy, asthma, Lund-Mackay score, and polyp grade.

Results

There was no significant difference in poor outcome rates between the PSS and no PSS group (35.0% vs. 47.6%, p=0.185). There was no significant difference in complication rates between the PSS and no PSS group (10% vs. 6%, p=0.468). As with the multivariate analysis of the clincopathological factors to the poor outcome rate, presence of asthma and eosinophilic infiltration were significantly related (odds ratio as 6.555 and 4.505, respectively), whereas PSS was confirmed as less likely related (odds ratio 0.611).

Conclusion

Low dose PSS administration does not seem to have an effect on the outcome after ESS in patients who have CRS with NP. Eosinophilic infiltration and presence of asthma are important predictors of surgical outcome.     

鼻内镜术后联合置管冲洗治疗真菌性上颌窦炎的疗效观察

目的 探究鼻内镜术后联合置管冲洗治疗真菌性上颌窦炎安全性和临床效果。方法 选择2013年3月~2017年3月我院用鼻内镜术后行鼻腔冲洗的真菌性上颌窦炎患者840例,随机分为实验组440例和对照组400例。实验组术后配合常规治疗的同时给予生理盐水500 ml置管冲洗术腔,1次/d,持续14 d;对照组则在术后配合常规治疗的同时给予生理盐水500 ml常规冲洗术腔,1次/d,持续14 d。比较两组患者鼻内镜术后1月、2月、3月及6月鼻腔恢复情况。结果 实验组术后第1、2、3及6月痊愈率与对照组比较,差异有统计学意义（P＜0.05）,第6月实验组痊愈率为45.45%,显著高于对照组的27.50%,差异有统计意义（P＜0.05）。结论 真菌性上颌窦炎患者在鼻内镜手术术后,采用常规综合治疗配合置管冲洗术腔,能够很好地把术腔分泌物及痂皮冲出,减轻鼻腔、鼻窦的炎性反应,缩短鼻窦上皮化的时间,恢复保护和防御功能。     

Artificial Intelligence and Machine Learning in Chronic Airway Diseases: Focus on Asthma and Chronic Obstructive Pulmonary Disease

Chronic airway diseases are characterized by airway inflammation, obstruction, and remodeling and show high prevalence, especially in developing countries. Among them, asthma and chronic obstructive pulmonary disease (COPD) show the highest morbidity and socioeconomic burden worldwide. Although there are extensive guidelines for the prevention, early diagnosis, and rational treatment of these lifelong diseases, their value in precision medicine is very limited. Artificial intelligence (AI) and machine learning (ML) techniques have emerged as effective methods for mining and integrating large-scale, heterogeneous medical data for clinical practice, and several AI and ML methods have recently been applied to asthma and COPD. However, very few methods have significantly contributed to clinical practice. Here, we review four aspects of AI and ML implementation in asthma and COPD to summarize existing knowledge and indicate future steps required for the safe and effective application of AI and ML tools by clinicians.     

Effect of one hour of passive cigarette smoking on lung function and airway responsiveness in adults and children with asthma

Summary We exposed 18 adults with bronchial asthma, 16 healthy controls and 11 children with asthma for 1 h either to ambient air (AA) or to environmental tobacco smoke (ETS). Exposure was performed at rest in an exposure chamber. Before and after exposure symptom scores and lung function were determined. After exposure bronchoprovocation tests with methacholine (adults) or histamine (children) were performed to determine the concentrations causing a 100% increase in SRaw (PC₁₀₀SRaw), and a 20% fall in FEV₁ (PC_2OFEV₁). In adult asthmatics mean (SD) SRaw before and after Sham was 8.8 (3.6) and 8.4 (3.6) cmH₂O · s, and mean FEV₁ (SD) was 3.18 (0.97) and 3.14 (0.9) 1, respectively. Before and after passive smoking mean SRaw (SD) was 7.5 (3.0) and 7.2 (2.7) cmH₂O · s, and mean FEV₁ (SD) was 3.31 (1.0) and 3.21 (0.88) 1, respectively. Geometric mean (SD) PC₁₀₀SRaw and PC_2OFEV₁ after Sham were 0.38 (4.5) and 0.29 (4.1) mg/ml, after passive smoking 0.39 (5.1) and 0.36 (4.7) mg/ ml, respectively. In healthy controls there was no consistent effect on the respective parameters during exposure. In children mean (SD) SRaw before and after Sham was 8.7 (3.6) and 9.0 (3.2) cmH₂O · s, and mean FEV₁ (SD) was 1.97 (0.32) and 1.98 (0.40) 1, respectively. Before and after passive smoking mean SRaw (SD) was 10.4 (5.3) and 9.4 (3.3) cmH₂O · s, and mean FEV₁ (SD) was 1.95 (0.37) and 1.94 (0.35) 1, respectively. Geometric mean (SD) PC₁₀₀SRaw and PC₂₀FEV₁ after Sham were 1.39 (3.0) and 0.70 (2.7) mg/ml, and after passive smoking 1.65 (2.5) and 0.96 (2.3) mg/ml, respectively. There were no significant differences in lung function and airway responsiveness between exposure to ambient air or ETS. The main symptoms during passive smoking were eye and nasopharyngeal irritation. Our observations suggest that in children and adults with mild to moderate bronchial asthma, 1 h of passive cigarette smoking does not cause airway obstruction or con sistent changes in bronchial responsiveness.Abbreviations AA ambient air (Sham) - ETS environmental tobacco smoke - SRaw specific airway resistance - FEV₁a one-second forced expiratory volume - PC₂₀FEV₁a provocative concentrations of histamine/methacholine to decrease FEV₁ by 20% - PC₁₀₀SRaw provocative concentrations of histamine/methacholine to increase SRaw by 100% Supported by Forschungsrat Rauchen und Gesundheit, Hamburg, Federal Republic of Germany     

基于聚类分析对慢性肺部疾病表型的研究进展

慢性肺部疾病包括慢性阻塞性肺疾病（COPD）、支气管哮喘、支气管扩张、间质性肺病、肺结节病、尘病和慢性肺曲霉菌病等。这些疾病具有不同的临床表型,同一治疗方案对不同表型的疗效可能存在很大区别,因此准确分析表型对制定个体化治疗方案意义重大。聚类分析是依据研究对象距离远近与相似程度的差异,将它们分成不同亚型的统计学方法。近年来,学术界发现聚类分析可用于包括慢性肺部疾病在内多种疾病的表型研究。本文对慢性肺部疾病表型的聚类分析研究作一综述,总结出该类疾病表型研究的进展和聚类分析的常用研究策略。     

肺弥散功能测定在支气管哮喘和慢性阻塞性肺疾病鉴别诊断中的应用

目的:探讨肺弥散功能测定在支气管哮喘和慢性阻塞性肺疾病鉴别诊断中的意义.方法:收集我院2010年1月～2011年3月呼吸科门诊、住院患者共112例,其中哮喘患者(A组)21例,慢阻肺患者(B组)47例,肺功能正常者44例作对照组(C组),检测3组患者的肺通气功能(RV/TLC、FEV1/预计值)和弥散功能(Dlco/VA、DLco SB),对结果进行分析比较.结果:哮喘组和慢阻肺组FEV1/预计值均低于对照组(P＜0.05);哮喘组弥散功能(Dlco/VA、DLco SB)值与对照组比较无明显差异(P﹥0.05),而慢阻肺组弥散功能值明显低于对照组及哮喘组(P＜0.05).结论:肺弥散功能测定对哮喘与慢阻肺的鉴别诊断有重要价值.     

Hemodynamic Reactivity to Laboratory Stressors in Healthy Subjects: Influence of Gender and Family History of Cardiovascular Diseases

Although laboratory stressor tests have been applied as a preliminary protocol in some cardiovascular studies, there is a lack of data comparing the pressor and chronotropic responses among the main stressor tests. Therefore, the aim of this study was to evaluate the variability in hemodynamic responsiveness to the main stressor tests, establish a hyperresponsiveness cutoff criterion and analyze the influence of gender and family history of cardiovascular diseases (CVDs) in healthy subjects. We examined hemodynamic responses to physical (cold pressor and handgrip tests) and mental (Stroop color-word test) stressors in 98 subjects (48 males and 50 females) without CVDs. All stressor tests resulted in increased blood pressure (BP) levels, which were lower and less dispersed in the handgrip test compared to the cold pressor test. Adopting the 75^th percentile as the cutoff in our data, we classified subjects exhibiting absolute pressor changes equal to or higher than 14, 24 and 36 mmHg in systolic and 9, 13 and 24 mmHg in diastolic BP during the handgrip, Stroop and cold pressor test, respectively, as hyperresponsives. Males exhibited greater (p<0.05) increases in systolic BP in the handgrip (11% vs. 8%) and cold pressor (25% vs. 21%) tests and in diastolic BP in the handgrip (12% vs. 7%) and Stroop (22% vs. 19%) tests than females. A positive association between family history of CVDs and pressor hyperreactivity to stressor tests was observed. We propose using the 75^th percentile of hemodynamic sample values as a cutoff criterion to classify individuals as pressor or chronotropic hyperreactives. We conclude that hemodynamic responsiveness to stressor tests in healthy subjects is positively influenced by male gender and family history of CVDs.     

The Quality of Health Information on Allergic Rhinitis,Rhinitis, and Sinusitis Available on the Internet

PurposeThe internet has become one of the most important media outlets used to obtain health information. Therefore, the quality of health information available on the internet is very important. We evaluated the quality of internet-derived health information on allergic rhinitis, rhinitis and sinusitis and compared these results to those of previous studies performed five years ago.MethodsThe terms "allergic rhinitis (AR)", "rhinitis" and "sinusitis" were searched among the four most commonly used search engines in South Korea. These websites were evaluated according to the author, the Journal of the American Medical Association (JAMA) benchmarks, the DISCERN questionnaire and the Allergic rhinitis and its Impact on Asthma (ARIA) 2008 Update.ResultsA total of 120 websites were obtained and analyzed. For all diseases, "Oriental physician" had the largest portion (almost half of all websites), followed by "Western physician". Based on analyses using the JAMA benchmark, "Attribution" and "Disclosure" were ignored in almost all surveyed websites. According to the scores of the DISCERN question, the majority of websites did not supply appropriate references for their health information, and information on the negative aspects of treatment such as risks and uncertainty was not provided in several websites. In an analysis based on the ARIA 2008 Update concepts, 65% of websites pertaining to health information on AR contained unreliable information.ConclusionsThe quality of health information on the internet was not acceptable. Thus, governmental regulation or control to improve the quality of health information is required.     

功能性鼻内镜手术后术腔两种冲洗液对疗效的影响

目的探讨功能性鼻内镜手术后术腔冲洗应用改进的冲洗液对术腔恢复的影响。方法将我院耳鼻喉科2008年2至12月收住的302例确诊为慢性鼻窦炎患者随机分为对照组和实验组,均行功能性鼻内镜手术,术后在给予相同药物治疗的基础上行术腔冲洗。实验组为0.02%呋喃西林500 mL加复方薄荷油20 mL加地塞米松10 mg;对照组冲洗液为生理盐水50 mL加庆大霉素32万IU加地塞米松10 mg,依据内窥镜鼻窦手术疗效评定标准对两组患者症状改善及术腔恢复情况进行疗效评定。结果实验组和对照组行术腔冲洗前各组疾病分期、分型无统计学差异（P〉0.05）,术腔冲洗后实验组患者症状改善及术腔恢复情况明显优于对照组,差异有统计学意义（P〈0.05）。结论呋喃西林、地塞米松和复方薄荷油冲洗液能有效改善功能性鼻内镜手术后患者的症状,促进患者术腔的恢复。     

鼻腔内一氧化氮分布的实验及数值研究进展

一氧化氮(nitric oxide,NO)在鼻腔内参与抗菌、抗病毒、促进鼻黏膜纤毛摆动、调节鼻黏膜血管扩张等多种生理功能。 NO 浓度异常会导致多种鼻腔疾病的发生,已成为临床常规检测气道炎症的生物学指标。 随着医学与力学等领域的深入交叉,运用数值研究方法,与传统的实验方法相结合,对鼻腔内 NO 浓度分布进行分析,可量化鼻腔内各处 NO 浓度,获得鼻腔内 NO 的分布规律,辅助相关鼻腔疾病的临床诊疗,有助于推动精准医疗的发展。 本文对鼻腔内 NO 浓度分布实验研究及数值研究的进展进行综述,并对未来研究方向进行展望。     

Effects of Neutrophil and Eosinophil Extracellular Trap Formation on Refractoriness in Chronic Rhinosinusitis With Nasal Polyps

PurposeThis study investigated the clinical implications of neutrophil extracellular trap (NET) formation (NETosis) and eosinophil extracellular trap (EET) formation (EETosis) regarding refractoriness in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP).MethodsNasal polyp specimens were obtained from 117 patients with CRSwNP who received endoscopic sinus surgery. Disease control status at postoperative 1 year was assessed. Refractory cases were defined as partly controlled or uncontrolled cases according to the EPOS 2020 guidelines. NETosis and EETosis were evaluated through immunofluorescence staining (citrullinated histone H3-human neutrophil elastase and citrullinated histone-galectin-10, respectively) followed by manual counting. The z-score of NET and EET counts was used to define the following four groups: low extracellular trap formation (ETosis), NETosis-predominant, EETosis-predominant, and high-ETosis.ResultsThe refractory and non-refractory groups showed significant differences in the tissue eosinophil count (P = 0.005) and EET count (P = 0.029). The tissue neutrophil count and the NET/neutrophil ratio were significantly different between the refractory and non-refractory groups of patients with neutrophilic CRS (P = 0.045, 0.031, respectively). Refractoriness significantly differed among the low-ETosis (30.77%), NETosis-predominant (47.83%), EETosis-predominant (56.67%), and high-ETosis (83.33%) groups (P = 0.005).ConclusionsThe results of this study suggest that tissue Eosinophilia and EETosis may play a prognostic role, primarily in CRSwNP and thattissue neutrophilia and NETosis can play as prognostic biomarkers in neutrophilic CRSwNP.     

A 1-year study of salmeterol powder on pulmonary function and hyperresponsiveness to methacholine

BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have been proved safe and effective for the treatment of asthma. However, controversy still exists as to the appropriateness of scheduled long-term therapy with these agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by treatment with salmeterol for a period of 52 weeks and evaluated bronchial hyperresponsiveness to methacholine during and after the treatment period. METHODS: Three hundred fifty-two patients with mild to moderate asthma were assessed by 12-hour serial spirometry and serial methacholine challenge tests. RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after drug at day 1 was significantly greater with salmeterol powder compared with placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1 year. The mean increase in the log(2) of the provocative cumulative methacholine dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was significantly higher in the salmeterol-treated patients than in the placebo group (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs 0.41 doubling doses at week 24). At week 52 the increase from baseline in log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1) was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10 doubling doses for placebo (P =.031). Long-term salmeterol use was not associated with a deleterious effect on asthma control during and after treatment. CONCLUSION: This study demonstrates that the bronchodilator properties of salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to methacholine is decreased to a modest degree during treatment. Clinically significant increases in hyperresponsiveness did not develop after discontinuation of salmeterol treatment.     

Effects of ketotifen on symptoms and on bronchial mucosa in patients with atopic asthma

Ketotifen is marketed throughout the world as an antiallergy drug, but whether it affects infiltration of inflammatory cells into airway mucosa is not known. We studied the effects of ketotifen on symptoms, pulmonary function, and airway inflammation in 25 patients with atopic asthma. Patients took ketotifen (1 mg twice daily) or a matching placebo for 8 weeks in a double-blind, parallel-group study. Data recorded on diary cards were used for 2 weeks before treatment began, and they were used for the last 2 weeks of treatment to study asthma symptoms, use of β2–agonists, and peak expiratory flow (PEF). Pulmonary function tests, bronchial responsiveness to methacholine, and fiberoptic bronchoscopy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. Specimens were stained immunohistochemically with monoclonal antibodies against stored eosinophil cationic protein (EG1), the secreted form of eosinophil cationic protein (EG2), mast-cell tryptase (AA1), neutrophil elastase (NP57), CD3, CD4, CD8, and CD25. The numbers of positively stained cells in the lamina propria were counted. Compared with the placebo, the ketotifen-treated group exhibited significant improvement of asthma symptoms ( P <0.05) and bronchial responsiveness (P<0.05). This was accompanied by a reduction of EG2+ eosinophils ( P <0.05), CD3+ T cells ( P <0.001), CD4+ T cells (P<0.01), and CD25+ activated T cells ( P <0.01) in the bronchial mucosa. These results suggested that the beneficial effects of ketotifen in bronchial asthma may result from consequent inhibition of activated eosinophils and T-cell recruitment into the airway. Moreover, ketotifen may relieve allergic inflammation in bronchial asthma.     

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin‐1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)‐induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c‐deficient (Fbln1c^–/–) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild‐type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c^–/– mice with AAD also had reduced numbers of α‐smooth muscle actin‐positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)‐5, IL‐13, IL‐33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL‐5, IL‐33 and TNF levels in lung‐draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3‐positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL‐5 and IL‐13 from co‐cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium‐treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

基于CT扫描模型的胸腔气道测量方法研究

基于二维CT图像的胸腔气道高精度测量对肺部疾病的诊断具有重要意义。但是由于CT图像在成像过程中不可避免的模糊,使得气道内外壁无明显边界,导致确定内外壁位置的难度加大,测量误差大。本研究分析了CT扫描数学模型,然后采用优化技术合理设置参数调整模型,并与真实气道灰度轮廓进行最大程度匹配,以实现一定精度范围内气道的精确测量。模型对比实验表明,本方法与目前流行的半高宽法相比具有较高的测量精度和稳定性。将该方法应用于19例慢性阻塞性肺炎(COPD)患者实际胸部CT气道测量实验,测量正确率为96.2%,能较好地满足临床测量要求。     

特布他林联合N-乙酰半胱氨酸治疗AECOPD的疗效及对患者免疫功能的影响

目的观察特布他林联合N-乙酰半胱氨酸治疗慢性阻塞性肺疾病急性加重(AECOPD)的疗效及对患者免疫功能的影响。方法选取我院60例AECOPD患者,以数字表法随机分为3组,各20例,均接受常规治疗,在此基础上,A组予以特布他林,B组予以N-乙酰半胱氨酸,C组予以特布他林联合N-乙酰半胱氨酸治疗,比较3组治疗前后氧化应激反应[超氧化物转化酶(SOD)与丙二醛(MDA)]、肺功能[用力肺活量(FVC)、1s用力呼气容积(FEV1)与FEV1/FVC]、免疫功能(CD3+、CD4+、CD4+/CD8+)、外周血嗜酸性粒细胞(EOS)计数,观察3组症状改善时间及疗效。结果C组总有效率100.00%,明显高于A组70.00%与B组65.00%(P<0.05);C组治疗后SOD明显高于A组与B组(P<0.05),MDA明显低于A组与B组(P<0.05);C组治疗后FVC、FEV1、FEV1/FVC、CD3+、CD4+、CD4+/CD8+显著高于A组与B组(P<0.05),EOS计数显著低于A组与B组(P<0.05);C组呼吸困难消失、咳嗽消失、喘息改善与哮鸣音消失时间明显短于A组与B组(P<0.05)。结论特布他林联合N-乙酰半胱氨酸可有效改善AECOPD患者免疫功能与肺功能,减轻炎症及氧化应激反应,促进临床症状恢复,获得良好疗效。