1、婴幼儿期哮喘的早期诊断思路及治疗策略,中国医科大学附属盛京医院小儿呼吸内科尚云晓,2,World map of the prevalence of clinician-diagnosed asthma adapted to demonstrate disease trends over the period 19902008,Anandan C,et al. Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy 2010; 65: 152167.,3,0- 1-
2、2- 3- 4- 5- 6- 7- 8- 9- 10- 11- 12- 13- 14-,year,First onset age (yr) n (6672),(n),A nationwide survey in China on prevalence of asthma in urban children,全国儿科哮喘协作组. 中华结核和呼吸杂志2004,4,Most cases of chronic asthma begin in preschool age.Adults with chronic asthma had a median age of symptom onset of 3 y
3、ears and 80% to 90% of cases had onset before the age of 5 years.,Bisgaard H,et al. Long-term studies of the natural history of asthma inchildhood. J ALLERGY CLIN IMMUNOL 2010,126(2):187-197,GINA,2011,6,The diagnosis of asthma in early childhood is challenging and difficult,No specific diagnostic to
4、ols or surrogate markers for detecting asthma in infancy. Therefore, asthma should be suspected in any infant with recurrent wheezing and cough episodes.,Bacharier LB, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus reportAllergy. 2008;63(1):534.,7,诊断困难的原因,（1）婴幼儿期气道的发育尚未成
5、熟，在气道的生理、解剖及免疫等方面有其特殊性；（2）在婴幼儿期引起喘息的疾病种类繁多，增加了鉴别诊断的难度；（3）喘息性疾病的临床自然表型在婴幼儿期尚未充分显现，是暂时性喘息还是哮喘尚需日后观察；（4）对哮喘诊断有一定帮助的辅助检查，如肺功能、气道激发试验、呼出气NO测定、诱导痰液分析等，在婴幼儿期受到设备条件及配合的限制。,尚云晓.婴幼儿期哮喘的诊断思路.中国小儿急救医学,2009,16：104-106.,将近2/3的儿童哮喘患者被延迟诊断,Lynch BA, et al. Allergy Asthma Proc. 2010;31:e48e52.,延迟诊断导致哮喘患儿的急诊率上升,Lynch
6、 BA, et al. Allergy Asthma Proc. 2010;31:e48e52.,延迟治疗可降低儿童哮喘患者的肺功能,Bisgaard H,et al. Respir Med. 2007 Jul;101(7):1477-82,自诊断后每延迟治疗1年FEV1的预计值下降 0.25% (P=0.039).,11,建立一个良好的临床诊断思路对早期诊断至关重要,A,B,C,个人临床体会，对疑诊为哮喘的婴幼儿，可采用以下5种诊断模式：,D,E,12,诊断依据充分，就诊时可明确诊断,A,B,C,D,E,喘息病史的婴幼儿,“哮喘” ?,需要结合自然表型和危险因素分析才能诊断,需要观察实验性治
7、疗后的反应才能诊断,需要日后较长时间随诊观察才能诊断,需要进一步的辅助检查除外其它疾病才能诊断,尚云晓.婴幼儿期哮喘的诊断思路.中国小儿急救医学,2009,16：104-106.,13,A. 就诊时可明确诊断,就诊时可明确诊断哮喘的婴幼儿是具有典型哮喘病史、体征等的患儿； 完全符合我国最新制定的儿童哮喘诊断标准的一类患儿；该诊断标准适合于任何年龄的哮喘儿童（勿认为只适合于5岁以上儿童）； 只要与诊断标准的各项条件符合即可做出诊断,14,B.需要结合自然表型和危险因素分析才能诊断,对于那些临床考虑为哮喘但是与上述诊断标准并不完全符合的婴幼儿，在确诊为哮喘前，尚需要仔细分析本患儿的哮喘表型和危险因
8、素；如果后者证据充分，也可做出确定诊断。,15,Martinez FD,Prevalence of wheezing,16,Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (57 years), stratified for atopy at school age .,Illi S, et al. Lancet 2006;368:763770.,17,The following categories of symptoms ar
9、e highly suggestive of a diagnosis of asthma,GINA,2011,18,A simple clinical index based on the presence of a wheeze before the age of 3,GINA,2011,one major risk factoror two of three minor risk factorshas been shown to predict the presence of asthma in later,major risk factor, parental history of as
10、thmaeczema, eosinophiliawheezing without coldsallergic rhinitis,minor risk factors,19,Asthma prognostic index number (National asthma education and prevention program 2007),4 Wheezing during the previous year+1 of major criterion or 2 of minor criterion,Guilbert TW, et al. Atopic characteristics of
11、children with recurrent wheezing at high risk for the development of childhood asthma. J Clin Immunol 2004;114:12827, Parental history of asthma Physician diagnosis of atopic dermatitis Allergic sensitization to at least one aeroallergen,Major Criterion,Minor Criterion, Allergic sensitization to egg
12、s, milk, or peanuts Blood Eosinophilia(4%) Wheezing apart from viral illnessesallergic rhinitis,20,过敏性疾病史(A) 和运动诱发性喘息(B) 是2个最重要的哮喘预测因素,10.9%,53.2%,17.2%,Frank等对628名5岁以下儿童进行为期10年的研究发现,Frank et al. Long term prognosis in preschool children with wheeze: Longitudinal postal questionnaire study 1993-2004
13、. BMJ, 2008,336:1387-8.,A,B,A simple tool to identify infants at high risk of mild to severe childhood asthma: the persistent asthma predictive score,Three parameters independently predicted persistent asthma: family history of asthma, personal atopic dermatitis, multiple allergen sensitizations. 42
14、% sensitivity, 90% specificity, 67% positive predictive value, 76% negative predictive value for the prediction of persistent asthma.,J Asthma. 2011 ;48(10):1015-21,22,23,Carlsen KCL,et al. Allergy 2010; 65: 11341140.,24,s-IgE and severity score at 2 years predicts asthma at 10 years,Predicted proba
15、bility of current asthma at 10 years by the sum of specific IgE antibodies (PAU/L) (left curve) and Severity score (right curve) at 2 years corrected for gender interaction (boys red line, girls blue line).,Carlsen KCL,et al. Allergy 2010; 65: 11341140.,25,26,Carlsen KCL,et al. Allergy 2010; 65: 113
16、41140.,27,Carlsen KCL,et al. Allergy 2010; 65: 11341140.,28,C.需要观察实验性治疗后的反应才能诊断,临床上还有一类疑诊哮喘的婴幼儿，哮喘诊断依据按第二种模式亦不很充分，因此难以在就诊当时予以哮喘诊断。但是该类有喘息症状或长期咳嗽患儿按照一般常见的“感冒”治疗无效，按“下呼吸道感染”经过较长时间抗生素治疗亦无效，而应用支气管舒张剂及抗炎（激素、白三烯调节剂）治疗则有效。,GINA,2011,30,C.需要观察实验性治疗后的反应才能诊断, A useful method for confirming the diagnosis of as
17、thma in children 5 years and younger is a trial of treatment with short-acting bronchodilators and inhaled glucocorticosteroids.Marked clinical improvement during the treatment and deterioration when treatment is stopped supports a diagnosis of asthma.,对于5岁及以下儿童，确定哮喘诊断的有效方法是应用短效支气管舒张剂和吸入糖皮质激素； 如果按照哮
18、喘治疗临床症状明显改善，而当治疗停止后症状又恶化，则支持哮喘的诊断。,GINA,2011,31,C.需要观察实验性治疗后的反应才能诊断,如果用吸入糖皮质激素、白三烯受体拮抗剂或支气管舒张剂治疗无效，则哮喘的诊断需要重新审定。,Treatment response should be considered. If therapy with ICS, leukotriene receptor antagonists (LTRA) or bronchodilators fails, the asthma diagnosis should be reconsidered.,2011.British G
19、uideline on the Management of Asthma A national clinical guideline,33,D.需要日后随诊观察才能诊断,喘息症状在婴幼儿期并非哮喘特有，许多非哮喘疾病也可出现喘息症状，尤其在1岁以内更为常见。据一项前瞻性的出生群组研究显示，50%的3岁以下婴幼儿童至少有过1次喘息发作。可见绝大多数3岁内的喘息将来并不发展成哮喘。, Martinez FD, Wright AL, Taussig LM, et al.Asthma and wheezing in the first six years of life. N Engl J Med,1
20、995,332:133138.,34,D.需要日后随诊观察才能诊断,需要日后随诊观察才能诊断的该类患儿早期诊断较为困难，主要原因是症状或体征多不典型，或者有助于诊断的危险因素（哮喘预测指数）尚不充分等。（1） 婴幼儿期第1次喘息诊断较为困难哮喘的第1次发作？RSV诱发的喘息？RSV毛细支气管炎？RSV肺炎？其它？,35,D.需要日后随诊观察才能诊断,（2）过敏性疾病体征有时尚未表现，第三种喘息表型评估困难有一些日后发展成哮喘的儿童，在婴幼儿期并无典型的湿疹或过敏性鼻炎（后期才明显）；还有部分哮喘患儿至儿童期亦无湿疹或过敏性鼻炎等。因此，对第一次喘息发作的婴幼儿很难在就诊时予以诊断或排除哮喘，必
21、须通过日后随诊观察才能确定。,36,E.需要进一步的辅助检查除外其它疾病才能诊断, “除外其他疾病所引起的喘息、气急、胸闷和咳嗽”是儿童哮喘诊断标准中的重要条件。但是，由于不同级别医院的检查手段所限，在临床实践中很难将所有相关喘息性疾病都除外后再诊断哮喘，这仅是理论上的，在具体临床诊断中很难操作。通常情况下，如果婴幼儿其它条件皆符合哮喘诊断标准，亦无其它特殊病史及体征，则做一些临床常规检查项目除外常见的相关疾病后即可诊断。,37,E.需要进一步的辅助检查除外其它疾病才能诊断,有些喘息婴幼儿，哮喘的病史及症状都不典型，既有哮喘的可能，但也有其它疾病的可疑，而后者通过一般的辅助检查难以确诊或除外。
22、该类患儿诊断最为困难，虽然实验性治疗对哮喘的确定或排除可能有一定帮助，但是如果病史或体征可疑有其它疾病时，首先除外其它相关疾病是非常必要的。可根据鉴别诊断需要做进一步的相关检查，如肺部HRCT、螺旋CT三维成像、食道PH值监测、纤维支气管镜等。,38,E.需要进一步的辅助检查除外其它疾病才能诊断,喘息出现的年龄越小，越要注意除外其它疾病，尤其是对抗哮喘治疗反应不佳者,生后12个月 出现喘息,3岁既往健康小儿出现喘息（除外气道异物）,首先除外有无气道发育方面的异常等，而不能首先考虑哮喘,首先考虑哮喘，然后再考虑其它疾病,39,E.需要进一步的辅助检查除外其它疾病才能诊断,2岁以下婴幼儿 急性喘息
23、(第1次),2岁以下婴幼儿 反复喘息,急性毛细支气管炎、气道异物、支气管炎/ 肺炎、过敏症 (如食物过敏等)等,支气管哮喘 咽/ 气管软化 慢性肺疾病 (新生儿期呼吸系统疾病后) 先天异常造成的气道狭窄(如血管环等) 胃食管反流 闭塞性细支气管炎 肺结核等,常见于,常见于,40, Chronic rhino-sinusitis Gastroesophageal refluxRecurrent viral lower respiratory tract infectionsCystic fibrosisBronchopulmonary dysplasiaTuberculosisCongenita
24、l malformation causing narrowing of theintrathoracic airways Foreign body aspirationPrimary ciliary dyskinesia syndromeImmune deficiencyCongenital heart disease,GINA,2011,Alternative causes of recurrent wheezing must be considered and excluded,41,Upper airway diseases Allergic rhinitis and sinusitis
25、 Obstructions involving large airwaysForeign body in trachea or bronchusVocal cord dysfunction Vascular rings or laryngeal webs Laryngotracheomalacia, tracheal stenosis, or bronchostenosis Enlarged lymph nodes or tumor Obstructions involving small airways Viral bronchiolitis or obliterative bronchio
26、litis Cystic fibrosis Bronchopulmonary dysplasia Heart disease Other causes Recurrent cough not due to asthma Aspiration from swallowing mechanism dysfunction or gastroesophageal reflux,Alternative causes of recurrent wheezing must be considered and excluded for Infants and Children,(National asthma
27、 education and prevention program 2007),2011.British Guideline on the Management of Asthma A national clinical guideline,Clinical assessment,43,婴幼儿期哮喘诊断中应注意的问题,哪些患儿需要喘息3次可以诊断？,哪些患儿喘息1次可以诊断？,哪些患儿喘息2次可以诊断？,？,44,婴幼儿期哮喘诊断中应注意的问题,1. Transient heezing: 2. Nonatopic wheezing3. Persistent asthma,注意婴幼儿喘息的第4种
28、临床类型,4. Severe intermittent wheezing Infrequent acute wheezing episodes associated with the following: Minimal morbidity outside of time of respiratory tract illness Atopic characteristics, including eczema, allergic sensitization and peripheral blood eosinophilia,Bacharier LB, et al. Allergy. 2008;
29、63(1):534,45,婴幼儿期哮喘诊断中应注意的问题,注意婴幼儿喘息的第4种临床类型,4. Severe intermittent wheezing 即“严重的间歇性喘息” 该临床表型的特点是喘息发作不频繁，在呼吸道疾病以外极少发作，有过敏体质，包括湿疹、变应原致敏性和外周血嗜酸性粒细胞增多。,鉴于严重哮喘在病理学上有其独特的特征，由此将其作为一个是独特的临床表型而被考虑。,Bacharier LB, et al. Allergy. 2008;63(1):534,46,婴幼儿期哮喘诊断中应注意的问题,注意婴幼儿喘息的肺内不典型体征,1.来诊时哮鸣音听不到或不确切2.哮鸣音被掩盖3.哮喘时“
30、水泡音”的特征,尚云晓. 婴幼儿期哮喘的诊断思路.中国小儿急救医学,2009,16：104-106.,？,？,？,47,注意不典型体征,哮喘时“水泡音”的特征多于吸气早、中期出现（于气道内）较粗大哭闹或活动后明显，安静睡眠时或拍背吸痰后可明显减少或消失 临床无感染迹象未合并感染的哮喘患儿则较少发热胸部X线（胸片或CT）无炎症征像,尚云晓. 婴幼儿哮喘的特征及诊断策略 中国实用儿科杂志,2006,4期,治疗策略,48,（1）年龄 （2）病情 （3）病程（4）既往治疗反应（5）吸入装置（6）吸入方法（7）初始治疗恰当药 物的选择,个性化的治疗方案,（8）选择药物要考虑 的因素（9）联合治疗的选择（
31、10）对各方案及指南的正 确理解和灵活运用(11) 关注小气道炎症（12）难治性哮喘的对策（13）关注夜间哮喘,Asthma Treatment Guidelines and Recommendations for Young Children based on,GINA 2011, NIH/NAEPP, BTS 2011, ERS and EAACI / AAAAI (PRACTALL),Asthma Management for Children 5 years,*Oral glucocorticosteroids should be used only for treatment of
32、acute severe exacerbations of asthma.Shaded boxes represent the preferred treatment options. Recommendations may include uses not consistent with product labeling.,GINA Pediatric Guidelines 2010,Stepwise Approach for Managing Asthma in Children Aged 511 Years,Step up if needed(first, check adherence
33、, environmental control, and comorbid conditions)Assess controlStep down, if possible(and asthma is well controlled for at least 3 months),NAEPP, NHLBI, NIH. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 2007. Recommendations may include uses not consistent wit
34、h product labeling.,NIH/NAEPP Guidelines 2007,Stepwise Approach for Managing Asthma in Children Aged 4 Years,Step up if needed(first, check adherence, inhaler technique, and environmental control)Assess controlStep down, if possible(and asthma is well controlled for at least 3 months),NAEPP, NHLBI,
35、NIH. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 2007.,Recommendations may include uses not consistent with product labeling.,NIH/NAEPP Guidelines 2007,British Guideline on the Management of Asthma A national clinical guideline (2011),British Thoracic Society
36、 Scottish Intercollegiate Guidelines Network 2008,British Guideline on the Management of Asthma. Thorax 2008;63(suppl IV):iv1-iv121.,Stepwise Management in Children 5-12 years,*BDP (beclometasone) or equivalent. All doses of inhaled steroids refer to BDP given via CFC MDIs metered dose inhaler). Rec
37、ommendations may include uses not consistent with product labeling.,BTS Guidelines 2008,Stepwise Management in Children Less Than 5 Years,*BDP (beclometasone) or equivalent. Higher nominal doses may be required if dug delivery is difficult Recommendations may include uses not consistent with product
38、 labeling.,BTS Guidelines 2008,儿童哮喘的诊断和治疗 PRACTALL 共识报告,PRACTALL=变态反应工作; EAACI=欧洲变态反应临床免疫学会; AAAAI=美国变态反应、哮喘和临床免疫学会.,Diagnosis and Treatment of Asthma in Childhood: a PRACTALL consensus report,57,02 岁儿童,（1）间歇使用2-激动剂应为首选，尽管仍存在争议； （2）病毒性喘息的每日控制治疗 (长期或短期治疗)可选用白三烯受体拮抗剂； （3）吸入糖皮质激素（雾化吸入或使用储雾罐装置吸入）可作为持续性哮
39、喘的每日控制治疗药物，尤其是重度或需要频繁口服糖皮质激素治疗的哮喘； （4）存在过敏体质的哮喘患儿，吸入糖皮质激素要及早，应作为一线药物给予； （5）在哮喘急性期和反复发作时，可给予强的松1 2 mg/kg/d治疗3 5 天。,PRACTALL consensus report. Allergy, 2008, 63(1):534.,58,35岁儿童,（1）首选吸入糖皮质激素，布地奈德（budesonide）100200g2，或氟替卡松（fluticasone）50125g2； （2）短效2-激动剂沙丁胺醇（salbutamol）0.1 mg/喷，或特布他林（terbutaline） 0.25
40、mg/喷，每4h一次，每次12喷； （3）对于间歇或轻度持续性哮喘儿童，LTRA可替代ICS单独给予；,PRACTALL consensus report. Allergy, 2008, 63(1):534.,59,35岁儿童,(4）如果ICS控制不理想，需加用LTRA（montelukast）4 mg/d。 （5）如上述治疗仍未控制，则需要考虑以下措施：增加LABA（至少是间歇性使用；虽然在该年龄组缺乏已发表的证据）；增加ICS剂量；加用茶碱；应注意，以上为非顺序性选择。,PRACTALL consensus report. Allergy, 2008, 63(1):534.,关注夜间性哮喘
41、,Nocturnal exacerbation of asthma affects more than two-thirds of asthma patients and contributes to asthma relatedmorbidity and mortality.,60,Greenberg H. Nocturnal asthma. Curr Opin Pulm Med 2012, 18:5762,夜间哮喘的原因,(1) sleep state induced increased airway parasympathetic tone;(2) decreased lung volu
42、me;(3) airway smooth muscle unloading:(a) perturbed actinmyosin binding;,61,Greenberg H. Nocturnal asthma. Curr Opin Pulm Med 2012, 18:5762,夜间哮喘的原因,(4) circadian modulation of respiratory function:(a) decreased expiratory flow rate;(b) reduced catecholaminergic activity;(c) reduced nonadrenergic, no
43、ncholinergicnervous system activity;(d) decreased cortisol;(e) increased inflammatory mediators;,62,Greenberg H. Nocturnal asthma. Curr Opin Pulm Med 2012, 18:5762,夜间哮喘的原因,(5) sleep-related environmental factors:(a) allergens;(b) cold air;(6) comorbid disease:(a) obstructive sleep apnea (OSA);(7) ga
44、stroesophageal reflux (GER) disease.,63,Greenberg H. Nocturnal asthma. Curr Opin Pulm Med 2012, 18:5762,夜间哮喘的治疗,(1) 制定治疗方案时要充分考虑生理节奏的变化；（2）给药时间与生理节奏同步，使药效在夜间最大化；（3）低剂量茶碱或缓释茶碱（夜间给予）；（4）睡前吸入激素或长效2激动剂；（5）经皮吸收的2激动剂在睡前给予可改善夜间哮喘症状；,64,Greenberg H. Nocturnal asthma. Curr Opin Pulm Med 2012, 18:5762,难治性哮喘的新
45、分类,1. Untreated severe asthma（未治疗的重度哮喘）2. Difficult-to-treat severe asthma（难治疗的重度哮喘）3. Treatment-resistant severe asthma（治疗抵抗的重度哮喘）,Bousquet JUniform definition of asthma severity, control and exacerbations.J Allergy Clin Immunol 2010;126:926-38.,asthma that is easily controlled once the appropriate
46、 medication and adequate adherence and technique are set in place. This may enable them to achieve a less severe form of asthma in the presence of adequate therapy to which they respond.,Bousquet JUniform definition of asthma severity, control and exacerbations.J Allergy Clin Immunol 2010;126:926-38
47、.,1. Untreated severe asthma（未治疗的重度哮喘）,characterized by a partial or poor response to treatment that reflects the presence of factors other than asthma alone, such as poor access to treatment, poor adherence, poor inhalation technique, environmental exposures, psychosocial issues.,Bousquet JUniform
48、definition of asthma severity, control and exacerbations.J Allergy Clin Immunol 2010;126:926-38.,2. Difficult-to-treat severe asthma（难治疗的重度哮喘）,（1) Those who are partially or poorly controlled despite high-dose inhaled corticosteroid or a high-dose inhaled corticosteroid/long-acting -adrenergic agoni
49、st combination and frequent or chronic use of systemic corticosteroids.(previously called refractory or severe asthma).,Bousquet JUniform definition of asthma severity, control and exacerbations.J Allergy Clin Immunol 2010;126:926-38.,3. Treatment-resistant severe asthma（治疗抵抗的重度哮喘）,依据对药物的反应分为两类,即使应用高剂量ICS或高剂量ICSLABA,以及反复或长期使用全身性糖皮质激素，仍控制不良。（以前称为顽固性或严重哮喘）,
