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婴幼儿喘息早期诊断评价及干预性治疗的可行性研究

发布时间:2018-08-04 20:42
【摘要】:婴幼儿喘息是全世界范围内儿童常见的临床症候群,反复发作的婴幼儿喘息多与急性呼吸道病毒感染有关,基于喘息临床表型而制定个体化治疗策略,是达到喘息/哮喘最优化临床控制的关键。大多数哮喘儿童的首次喘息症状发生在学龄前期,但约50%左右的喘息到6岁时可完全缓解,与呼吸道病毒感染高峰年龄一致,对病毒感染与婴幼儿喘息之间关系的深入了解,有助于认识感染与变态反应相关炎症之间内在的免疫学机制,能够帮助大家更好地理解婴幼儿喘息与哮喘的异同点,最终达到哮喘的个体化治疗方案推行。已证实诱发婴幼儿喘息急性发作最常见的病毒是RSV,与年长儿和成人不同。病毒感染相关的婴幼儿喘息因其与支气管哮喘的密切相关性而日益受到重视,反复发作的喘息是哮喘的高危因素,患有反复喘息的婴幼儿,哮喘的发生率是没有喘息症状儿童的5~10倍。因此,观察喘息婴幼儿病情发展变化特点,并进行准确的评估及早期干预性治疗,是降低哮喘发病率、提高儿童健康水平的有效措施之一。但是,始终困扰临床医生的问题是目前临床缺乏婴幼儿哮喘早期诊断的标准,也没有提示早期治疗必要性的客观依据,究其根源,是缺乏对婴幼儿慢性气道炎症及功能评价的行之有效的临床判定方法。 近年来,哮喘患病率呈明显上升趋势,严重影响着儿童的身心健康。嗜酸细胞被认为是哮喘的主要效应细胞,嗜酸性粒细胞炎症反应是哮喘的基本特征,已证实嗜酸性粒细胞炎症是哮喘加重的很好的预测指标,并且认为嗜酸性粒细胞对病毒感染无反应。然而,有研究揭示嗜酸性粒细胞可以促进病毒清除和增强宿主的防御能力,提出了嗜酸性粒细胞可以在获得性免疫反应不足的情况下在某种程度上激发原发性宿主抗病毒防御反应。已有国内外许多研究证实,哮喘患儿痰液细胞分型能客观反映气道炎症变化,但与成人哮喘不同,儿童哮喘不具有两种特有的稳定炎症表型,即嗜酸性粒细胞和非嗜酸性粒细胞型,虽然在成人依据这两种表型而制定的哮喘治疗策略在临床工作中都获得了成功,但是,儿童哮喘的诊断远比成人复杂,儿童哮喘治疗方案的确定也较成人有很大不同。人们越来越认识到针对哮喘儿童采用单一的治疗方法不太可能获得临床成功,因为有一大群“儿童哮喘”并不是真正意义上的哮喘,而一部分被当成呼吸道反复感染而治疗的患者却极有可能是被忽视的哮喘,因此,确定儿童哮喘和/或喘息性疾病的临床表型,可以为儿童喘息相关性疾病提供潜在的治疗目标和更个性化的治疗方法。因此,我们采用液基薄层细胞制片技术研究哮喘的高危人群,即具有特应性体质的反复发作喘息的婴幼儿,采集诱导痰液进行痰炎症细胞表型检测,并按病情严重程度研究结果进行了比较。参照以往研究结果,拟定痰液EOS%>2.5%为痰液EOS增高,痰液NEU%>54%为NEU增高,结合两者将研究对象分为4组:①嗜酸性粒细胞型(EOS%>2.5%);②中性粒细胞型(NEU%>54%);③少中性粒细胞型(NEU%≤54%+EOS%≤2.5%);④混合粒细胞型(EOS%>2.5%+NEU%>54%)。同时对反复喘息患者进行气道炎症标志物血清EDN水平检测,及婴幼儿潮气肺功能检测,并对比孟鲁司特钠干预性治疗前后婴幼儿喘息气道炎症指标及肺功能的变化,以期探讨婴幼儿喘息与哮喘之间发病机制的异同,对婴幼儿哮喘做到早期诊断、合理治疗,提高儿童的健康水平。 本研究联合应用液基薄层细胞制片技术、血清EDN酶联免疫吸附测定及婴幼儿潮气肺功能检测技术,对反复喘息婴幼儿临床表现、气道炎症表型及气道功能进行综合评价,以期证实婴幼儿喘息不同于典型哮喘的发病机制及其与哮喘密切相关的共同特征,以期发现婴幼儿喘息的治疗折点并探索早期治疗的重要性。 研究结果如下: 1婴幼儿喘息与呼吸道病毒感染密切相关,7种常见呼吸道病毒病原筛查发现约76.0%的喘息患儿鼻咽抽吸物中可检出呼吸道病毒,其中单一感染RSV为主要病毒(占48.0%),副流感病毒1、2、3占16.0%,流感病毒A、B占4.5%,腺病毒占7.5%,混合感染常占9.0%,并可见三重病毒感染者,仅15.0%的患儿未检出病毒病原体。 2890例患者共采集合格痰液标本867例,其中至少表现为一种炎症细胞型为504例(占58.1%),分别为中性粒细胞型(占65.2%),嗜酸细胞型(占30.6%),混合细胞型(占4.2%)。中性粒细胞型是婴幼儿炎症细胞型的主要类型,嗜酸性粒细胞型在重症组更具有优势,与轻症组相比差异有统计学意义(P<0.05)。重症组诱导痰液标本炎症细胞计数显示更高计数值,与轻症组相比,中性粒细胞和嗜酸性粒细胞差异均有显著性(P<0.05)。 3血清EDN水平在不同炎症细胞组有差异,以嗜酸细胞型组为最高(112.6±41.2)μg/l,其次依次为混合性细胞组(104.8±39.4)μg/l、中性粒细胞组(88.2±36.6)μg/l和少中性粒细胞型(60.9±34.6)μg/l,各组间血清EDN水平差异有统计学意义(P<0.05)。 4虽然外周血嗜酸细胞计数在各炎症组中并没有显著差异,但血清EDN水平显示与外周血嗜酸细胞增高有显著正相关性(γ=0.781,P<0.05)。 5潮气肺功能提示反复喘息儿童潮气量减低,低潮气量与血清EDN水平增高相关(γ=0.499,P<0.05)。 6婴幼儿喘息发作期患儿呼吸频率比同龄对照组明显增快,潮气量明显减少,反映气道阻塞的指标TPTEF/TE和VPEF/VE也低于对照组,差异均有显著性(P<0.05)。缓解期患儿呼吸频率下降,VT/kg、TPTEF和VPEF、TPTEF/TE、VPEF/VE均明显回升,治疗前后各项指标差异均有显著性(P<0.05);缓解期VT/kg与对照组无明显差异(P>0.05),但TPTEF/TE、VPEF/VE差异显著(P<0.05)。 7应用孟鲁司特钠治疗106例患者12周临床症状改善42.5%(45/106),治疗后4周、12周时患儿喘息、咳嗽、活动后咳嗽/喘息(活动力)、潮气肺功能等与基础值相比差异均有统计学意义(P<0.05),与对照组相比,两组在喘息发作次数、年平均住院天数、年均使用β2AG天数、肺功能改善等方面相比均有统计学差异(P<0.05),经随访2年治疗组11例(占10.4%)诊断为哮喘,对照组19例(占39.6%),两组差异有统计学意义(χ2=38.3967,P<0.05)。 8在3个月的治疗观察结束时(观察终点),未予孟鲁司特钠治疗组嗜酸细胞型喘息患者血清EDN水平较相比治疗组显著增高的(P<0.05),且较初始水平相比明显增高(P<0.05);而治疗组血清EDN水平较治疗前显着下降(P<0.05)。 9治疗前喘息患儿潮气量明显减少,反映气道阻塞的指标TPTEF/TE和VPEF/VE明显减低。经12周孟鲁司特钠治疗后,治疗组患儿PTEF(ml/s)、VT/kg、TPTEF和VPEF、TPTEF/TE、VPEF/VE均明显回升,治疗前后各项指标差异均有显著性(P0.05);与对照组相比有显著性(P0.05),而未经治疗者,12周后PTEF(ml/s)也有改善(P0.05),但TPTEF/TE、VPEF/VE差异显著下降,观察前后无明显变化,差异无统计学意义(P0.05)。 本研究应用DFA方法对婴幼儿喘息进行常见7种呼吸道病毒进行筛查,并首次采用液基薄层细胞制片技术对患者进行炎症分型,并用EDN作为气道炎症标志物作为评价,同时应用潮气肺功能对婴幼儿阻塞性气道疾病进行诊断及预后评估,,发现婴幼儿喘息与成人典型哮喘相比炎症分型不同且不稳定,嗜酸细胞活化很难及早发现,所以嗜酸细胞活化的标志物因其更敏感,可以作为非侵袭性气道功能评价的标记物,而潮气肺功能动态监测及评估气道功能值得推广。孟鲁司特钠能够阻断嗜酸细胞脱颗粒,是婴幼儿喘息早期干预性治疗的有效地可选方案。
[Abstract]:Infantile wheezing is a common clinical syndrome in children worldwide. Repeated onset wheezing is associated with acute respiratory virus infection. An individualized treatment strategy based on a wheezing clinical phenotype is the key to optimal clinical control of wheezing / asthma. The first wheezing symptom in most children of asthma occurs in school. At the beginning of the age, about 50% of the wheezing can be completely relieved at the age of 6. It is consistent with the peak age of the respiratory virus infection. The deep understanding of the relationship between the virus infection and the infantile breather helps to understand the inherent immunological mechanism between infection and allergy related inflammation, which can help us to better understand the wheezing and asthma of infants. It has been proved that the most common virus that induces acute asthma attacks in infants is RSV, which is different from the older and adult. The asthma associated with virus infection is becoming more and more important because of its close correlation with bronchial asthma. Repeated attacks of wheezing are the high risk of asthma. The incidence of asthma in infants and young children with repeated wheezing is 5~10 times as high as that of children without wheezing symptoms. Therefore, it is one of the effective measures to reduce the incidence of asthma and improve the health level of children. The problem of birth is the standard for the lack of early diagnosis of infant asthma in clinical, and there is no objective basis for the necessity of early treatment. The root of this problem is the lack of effective clinical judgement on the evaluation of chronic airway inflammation and function in infants.
In recent years, the incidence of asthma is on the rise, which seriously affects the physical and mental health of children. Eosinophil is considered to be the main effect cell of asthma. Eosinophil inflammation is the basic characteristic of asthma. Eosinophil inflammation is a good predictor of asthma aggravation and is considered to be eosinophil. There is no response to viral infection. However, studies have revealed that eosinophils promote the clearance of viruses and enhance the defense ability of the host. It is suggested that eosinophils can stimulate the anti viral defense against the primary host to some extent under the condition of acquired immune response. Many studies have confirmed that children with asthma have been diagnosed with asthma. Phlegm cell typing can objectively reflect the changes in airway inflammation, but unlike adult asthma, children with asthma do not have two specific stable inflammatory phenotypes, eosinophils and non eosinophilic granulocytes. Although the asthma treatment strategy based on these two phenotypes in adults has been successful in clinical work, however, children The diagnosis of asthma is far more complex than that of adults, and the treatment for asthma is very different from that in adults. It is increasingly recognized that a single treatment for asthma children is not likely to be clinically successful because a large group of "child asthma" is not a true sense of asthma, and a part is treated as a respiratory tract. Patients treated with reinfection are highly likely to be neglected asthma. Therefore, the clinical phenotype of asthma and / or asthmatic disease in children can provide potential treatment targets and more individualized treatment for asthma related diseases in children. Therefore, we use liquid based thin layer cell technique to study high-risk groups of asthma, In the case of recurrent wheezing infants with atopic constitution, the sputum induced sputum was collected to detect the phlegm phenotype of phlegm cells, and the results were compared according to the severity of the disease. According to the previous research results, the sputum EOS% > 2.5% was increased in sputum EOS, and the sputum NEU% > 54% was higher in NEU, and the study object was divided into 4 groups. (1) Eosinophil type (EOS% > 2.5%); (2) neutrophils (NEU% > 54%); (3) neutrophils (NEU% < < 54%+EOS% < 2.5%); (EOS% > 2.5%+NEU% > 54%); (EOS% > 2.5%+NEU% > 54%). Serum EDN level of airway inflammation markers in patients with repeated wheezing, and detection of tidal lung function in infants and infants, and compared to montelukast The changes of airway inflammation index and lung function in infants and young children before and after intervention treatment are discussed in order to explore the similarities and differences between infant wheezing and asthma, early diagnosis, rational treatment and improvement of children's health.
This study combined with liquid based thin layer cell production, serum EDN enzyme linked immunosorbent assay and infant tidal lung function testing technology to evaluate the clinical manifestations, airway inflammation phenotypes and airway function of infants and young children with repeated wheezing, in order to confirm that infant wheezing is different from that of typical asthma and is closely related to asthma. The common characteristics are to find out the treatment points of infant wheezing and to explore the importance of early treatment.
The results of the study are as follows:
1 infantile wheezing is closely related to respiratory virus infection. 7 common respiratory virus pathogens screening found that about 76% of the nasopharyngeal aspirates in children with wheezing can detect respiratory virus, of which single infection RSV is the main virus (48%), parainfluenza virus 1,2,3 accounts for 16%, flow virus A, B account for 4.5%, adenovirus 7.5%, mixed infection often 9. %, and three cases of viral infection were found. Only 15% of children did not detect viral pathogens.
In 2890 cases, 867 cases of qualified sputum were collected. At least one inflammatory cell type was found in 504 cases (58.1%), which were neutrophil type (65.2%), eosinophil type (30.6%) and mixed cell type (4.2%). Neutrophil type was the main type of infantile inflammatory cell type, and eosinophil type was more in severe group. The difference was statistically significant compared with the light disease group (P < 0.05). The inflammatory cell count of the sputum specimens induced by the severe group showed a higher count value. Compared with the light disease group, there were significant differences in neutrophils and eosinophils (P < 0.05).
3 the level of serum EDN was different in the different inflammatory cells group, and the eosinophil group was the highest (112.6 + 41.2) mu g/l, followed by mixed cell group (104.8 + 39.4) mu g/l, neutrophils group (88.2 + 36.6) mu g/l and less neutrophil type (60.9 + 34.6) mu g/l, and the difference of serum level between each group was statistically significant (P < 0.05).
4 although there was no significant difference in the eosinophil count of peripheral blood in the inflammatory groups, there was a significant positive correlation between the serum EDN level and the increase of eosinophils in the peripheral blood (gamma =0.781, P < 0.05).
5 tidal pulmonary function indicates that tidal volume decreases in children with recurrent wheezing, and low tidal volume is associated with increased serum EDN level (gamma =0.499, P < 0.05).
6 the respiratory rate in children with wheezing attack was significantly faster than that in the same age control group, and the volume of tidal gas decreased significantly. The index of TPTEF/TE and VPEF/VE reflecting airway obstruction were also lower than those in the control group. The difference was significant (P < 0.05). The respiratory frequency of children in remission stage decreased, VT/kg, TPTEF and VPEF, TPTEF/TE, VPEF/VE all increased significantly, and all the fingers before and after treatment. There was no significant difference in VT/kg between remission group and control group (P > 0.05), but there was significant difference in TPTEF/TE and VPEF/VE between remission group and control group (P < 0.05).
7 the clinical symptoms of 106 patients with montelukast were improved by 42.5% (45/106), 4 weeks after treatment, 12 weeks of asthma, cough, coughing / wheezing (activity), and tidal gas and lung function, compared with the basic values (P < 0.05). Compared with the control group, the number of breathing attacks, the annual average hospitalization days, and the years were compared with the control group. There were statistically significant differences in the use of beta 2AG days and the improvement of lung function (P < 0.05). After 2 years of follow-up, 11 cases (10.4%) were diagnosed as asthma and 19 cases in the control group (39.6%). The two groups were statistically significant (x 2=38.3967, P < 0.05).
8 at the end of the 3 month treatment observation (observation point), the level of serum EDN in the patients with eosinophilic wheezing in the montelukast group was significantly higher than that in the treatment group (P < 0.05), and was significantly higher than the initial level (P < 0.05), while the serum level of EDN in the treatment group was significantly lower than that before the treatment (P < 0.05).
9 the tidal volume of children with wheezing before treatment was significantly reduced, and the index of TPTEF/TE and VPEF/VE of airway obstruction decreased obviously. After 12 weeks of montelukast treatment, PTEF (ml/s), VT/kg, TPTEF and VPEF, TPTEF/TE, VPEF/VE all increased significantly after 12 weeks of treatment (P0.05), and there was a significant difference compared with the control group (P) 0.05), but without treatment, PTEF (ml/s) was also improved after 12 weeks (P0.05), but the difference of TPTEF/TE and VPEF/VE decreased significantly. There was no significant change before and after observation, and there was no significant difference (P0.05).
In this study, the DFA method was used to screen 7 common respiratory viruses for infants and infants, and the liquid based thin layer cell technique was used for the first time to classify the patients, and EDN was used as a marker for airway inflammation. At the same time, the diagnosis and prognosis evaluation of the obstructive airway disease in infants and infants was evaluated by using the tidal lung function. Infant wheezing is different and unstable compared with adult asthma. Eosinophil activation is difficult to detect early. Therefore, the markers of eosinophil activation can be used as a marker for noninvasive airway function evaluation. Dynamic monitoring and assessment of airway function are worth promoting. Montelukast sodium. Blocking eosinophils degranulation is an effective alternative to early intervention in infants with wheezing.
【学位授予单位】:吉林大学
【学位级别】:博士
【学位授予年份】:2013
【分类号】:R725.6

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