1、 儿童闭塞性细支气管炎儿童闭塞性细支气管炎Bronchiolitis Obliterans （BO）in children 张云峰张云峰病历摘要病历摘要v 患儿，男，患儿，男，2岁。岁。v 2009.12，曾因发热，喘息，曾因发热，喘息1周入周入PICU。诊断毛细支气。诊断毛细支气管炎，管炎，EB病毒感染，呼吸衰竭，中毒性脑病。病毒感染，呼吸衰竭，中毒性脑病。20天后天后出院。出院口服顺尔宁，但一直有咳嗽，喘息症状。出院。出院口服顺尔宁，但一直有咳嗽，喘息症状。v 出院出院1个月后，因咳嗽、喘息，诊断：儿童哮喘。吸入个月后，因咳嗽、喘息，诊断：儿童哮喘。吸入普米克普米克/可必特治疗。咳嗽减轻，
2、但仍喘息，每于活动可必特治疗。咳嗽减轻，但仍喘息，每于活动后喘息明显，休息后缓解。后喘息明显，休息后缓解。v 既往史：患儿有湿疹史（较重），曾有既往史：患儿有湿疹史（较重），曾有2次喘息史；次喘息史；v 家族史：其小姨的孩子有哮喘。家族史：其小姨的孩子有哮喘。病例（1）辅助检查辅助检查辅助检查：辅助检查：v 血常规：血常规：WBC: 4.5WBC: 4.51010（9 9）/L,NE: 66.2%/L,NE: 66.2%， Hb: Hb: 128g/L128g/Lv CRP:3.29mg/LCRP:3.29mg/L。v MP-IgMMP-IgM：1:401:40；CP-IgMCP-IgM：阴性
3、：阴性v 血总血总 Ig EIg E： 679U/ML679U/ML，v 血食物血食物+ +呼吸特异性呼吸特异性Ig E: Ig E: 牛羊肉牛羊肉 2.02.0v 血气：血气： PH7.32PH7.32，PaOPaO2 2 66. 8mmHg 66. 8mmHg ， PaCOPaCO2 2 54.1mmHg,BE 2.4mmol/l. 54.1mmHg,BE 2.4mmol/l.病历摘要病历摘要v 患儿，男，患儿，男，2 2岁岁v 因发热因发热5 5天，皮疹天，皮疹1 1天住院。诊断麻疹。住院第天住院。诊断麻疹。住院第4 4天咳嗽，天咳嗽，住院后住院后6 6天家长要求出院。出院天家长要求出院
4、。出院5 5天后，再次出现发热天后，再次出现发热39.839.8度，咳嗽加重，再次入院，诊断：重症肺炎。度，咳嗽加重，再次入院，诊断：重症肺炎。MPP(1:1280)MPP(1:1280)，住院，住院2020余天，症状好转出院。回家后雾化余天，症状好转出院。回家后雾化吸入普米克和可必特治疗。活动后仍喘息。吸入普米克和可必特治疗。活动后仍喘息。v 三个月后，再次因发热，咳嗽、喘息加重住院，诊断大叶三个月后，再次因发热，咳嗽、喘息加重住院，诊断大叶肺炎，肺脓肿，儿童哮喘，住院肺炎，肺脓肿，儿童哮喘，住院2020天好转出院，出院后仍天好转出院，出院后仍喘息，咳嗽。喘息，咳嗽。v 既往史：湿疹（既往史
5、：湿疹（+ +），既往无喘息史。不爱揉鼻、眼），既往无喘息史。不爱揉鼻、眼v 家族史：无喘息家族史。家族史：无喘息家族史。v IgE 14.5U/ml IgE 14.5U/ml 血食物血食物+ +呼吸特异性呼吸特异性Ig E:Ig E:阴性。阴性。病例（2）入院时（2009-05-23） 发热，喘重，双肺密集水泡音出院2月后（2009-08-04） ，轻咳、活动后喘促，双肺散在水泡音1年后（2010-08-23），轻咳、活动后喘促，左肺散在水泡音 Bronchiolitis obliterans (BO) is an irreversible obstructive lung disease
6、characterized by subepithelial inflammation and fibrotic narrowing of the bronchioles1) In the pediatric clinical field, three main categories of BO are generally encountered: (1) postinfectious BO (PIBO), (2) BO after hematopoietic stem cell transplantation (HSCT), and (3) BO after lung transplanta
7、tion (LT). Introduction Postinfectious bronchiolitis obliterans (PIBO) is an irreversible obstructive lung disease characterized by subepithelial inflammation and fibrotic narrowing of the bronchioles after lower respiratory tract infection during childhood, especially early childhood . Postinfectio
8、us bronchiolitis obliterans in children: lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation Review article Korean J Pediatr 2015;58(12):459-465Current research on pediatric patients with bronchiolitis obliterans in BrazilIntractable Rare Dis
9、Res. 2015 February; 4(1): 711. EpidemiologyAlthough the prevalence of PIBO has not been estimated accurately, 0.6% of 3,141 autopsies and lung biopsies performed at a single center were diagnosed as BO, and most of these cases were PIBO). The prevalence of BO after HSCT among cases with allogeneic H
10、SCT is 2%6%). The prevalence of BO after LT was markedly higher, up to 35% within 5 years posttransplant13), than the prevalence of PIBO and BO after HSCT.PathogenesisBO相关病因和基础疾病相关病因和基础疾病v感染性闭塞性细支气管炎感染性闭塞性细支气管炎, ,常见病毒常见病毒v（腺病毒、呼吸道合胞病毒、流感病毒、副流感病毒腺病毒、呼吸道合胞病毒、流感病毒、副流感病毒） 支原体支原体v结缔组织病（类风湿性关节炎和嗜酸性筋膜炎）结缔组
11、织病（类风湿性关节炎和嗜酸性筋膜炎）v吸入性损伤（二氧化氮、二氧化硫、氨、氯、光气、吸入性损伤（二氧化氮、二氧化硫、氨、氯、光气、灼热气体、飞灰等）毒物服入灼热气体、飞灰等）毒物服入v异体移植物受者（心肺联合移植或肺移植、骨髓移植）异体移植物受者（心肺联合移植或肺移植、骨髓移植）v药物（青霉胺、洛莫司汀、可卡因、金等）药物（青霉胺、洛莫司汀、可卡因、金等）v其他并发症：炎症性肠病、神经内分泌细胞增生、多其他并发症：炎症性肠病、神经内分泌细胞增生、多发性类癌样微瘤、副肿瘤天疱疮发性类癌样微瘤、副肿瘤天疱疮Etiology in childrenPIBO与与 腺病毒（腺病毒（ADV） 呼吸道合胞病
12、毒（呼吸道合胞病毒（RSV） 支原体感染支原体感染 麻疹病毒麻疹病毒 流感病毒流感病毒 副流感病毒副流感病毒 巨细胞病毒巨细胞病毒Risk FactorPIBO发生的危险因素 ADV毛细支气管炎 （OR=49.9） 住院时间超过30天 （OR=27.2） 多病灶肺炎 （OR=26.6） 需机械通气治疗 （OR=11.9） 高碳酸血症 （OR=5.6）。Pathology病因不同，但组织病理学改变相似病因不同，但组织病理学改变相似缩窄性细支气管炎和增殖性细支气管炎缩窄性细支气管炎和增殖性细支气管炎增殖性细支气管炎以肉芽组织在气道内呈息肉团块增殖性细支气管炎以肉芽组织在气道内呈息肉团块增生为特征增
13、生为特征肺泡腔内亦出现肉芽组织时，则称为肺泡腔内亦出现肉芽组织时，则称为闭塞性细支气管炎伴机化性肺炎闭塞性细支气管炎伴机化性肺炎(BOOP）Childhood PIBO 绝大多数为缩窄性绝大多数为缩窄性早期上皮细胞坏死，气道炎症细胞浸润早期上皮细胞坏死，气道炎症细胞浸润相邻肺实质正常或仅有轻微改变相邻肺实质正常或仅有轻微改变细支气管变形，胶原沉积，黏液渗出细支气管变形，胶原沉积，黏液渗出 后期形成黏膜下纤维化，管腔进行性变窄，后期形成黏膜下纤维化，管腔进行性变窄，最终形成闭塞最终形成闭塞气道阻塞间接征象气道阻塞间接征象 黏液潴留黏液潴留 巨噬细胞聚集巨噬细胞聚集 肺过度充气肺过度充气 细支气管
14、变形扩张细支气管变形扩张 支气管上皮细胞肥大，上皮层变厚，管腔可出现支气管上皮细胞肥大，上皮层变厚，管腔可出现阻塞甚或闭塞阻塞甚或闭塞Constrictive bronchiolitis in SLE肺泡灌洗液中以中性粒细胞增多为主部分区域淋巴细胞增多中性粒细胞趋化因子IL-8浓度增高这些变化仍存在于肺损伤数年之后Clinical symptoms and signsv The initial symptoms and signs of BO are similar to acute viral bronchiolitis: fever, cough, tachypnea, and wheez
15、ing (1,3). But the disease does not progress as expected and symptoms and signs persist for weeks or months. v Patients with BO have tachypnea, dyspnea, hypoxemia, crackles, wheezing, an increased antero-posterior diameter of the chest, digital clubbing, and cyanosis (3,7,12,17).v In a previous stud
16、y by the current authors (10), the most common symptoms and signs of BO in 40 patients were wheezing, dyspnea, and coughing (Table 1).high-resolution chest tomography (HRCT) vBrazilian studies (6,9,10,18) found that characteristic findings in HRCT were: a mosaic pattern of perfusion bronchiectasis b
17、ronchial wall thickening air trapping atelectasisCardinal FeaturesCardinal FeaturesAreas of decreased attenuationReduced number / calibre of vesselsBronchial dilatationNo parenchymal distortionNo zonal predilectionCT in Obliterative BronchiolitisCT改变改变例数（例数（N）构成比构成比马赛克灌注马赛克灌注空气滞留空气滞留支气管壁增厚支气管壁增厚支气管扩
18、张支气管扩张肺不张肺不张支气管黏液栓支气管黏液栓220230195240165145889278966658250例儿童及青少年CT改变DiagnosisvAlthough a diagnosis of PIBO should be confirmed by histopathology, most pediatric pulmonologists diagnose PIBO based on history and clinical findings according to the following criteria: (1) acute severe respiratory infec
19、tion during childhood, especially early childhood; (2) persistent airway obstruction after initial insult and unresponsiveness to systemic steroids and bronchodilators, as demonstrated by clinical symptoms and signs, and a lung function test, if it can be performed; (3) mosaic perfusion, air trappin
20、g, and/or bronchiectasis in chest computed tomography; and (4) exclusion of other chronic lung diseases such as severe asthma, bronchopulmonary dysplasia, chronic aspiration, primary ciliary dyskinesia, cystic fibrosis, immunodeficiency, and alpha-1-antitrypsin deficiency (Table 1).vRecent studies o
21、f clinical prediction rules to diagnose PIBO in children found that typical clinical history, adenovirus infection, and high-resolution computed tomography with mosaic perfusion were highly predictable variables32).vHistory of lower respiratory infection, particularly adenovirus, mycoplasma, or meas
22、les.vPersistent airway obstruction symptoms and signs, or recurrent airway obstruction symptoms and signs in a mild form.vSign of obstruction: FEV1/FVC 0.8 or FEV1 percent predicted 80%.vIrreversible airway obstruction demonstrated by lung function test: absent BDR, but positive BDR in some patients
23、. vCT (inspiration and expiration): mosaic perfusion, air trapping, and/or bronchiectasis.vExclusion of other chronic lung disease (asthma, BPD, chronic aspiration, PCD, cystic fibrosis, and immunodeficiency). vPostinfectious bronchiolitis obliterans is clinically diagnosed when all of the above cri
24、teria are met. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BDR, bronchodilator response; BPD, bronchopulmonary dysplasia; CT, computed tomography; PCD, primary ciliary dyskinesia.Table 1. Diagnosis of postinfectious bronchiolitis obliteransTreatmentvAlthough the optimal t
25、reatment of PIBO has not been established, corticosteroids have been used to combat the inflammatory component. vSystemic steroids can be used rather than inhaled steroids in consideration of the obliteration of the small airways. vProlonged oral steroid therapy over a period of 2 months to 2 years
26、was applied to about 70% of children with PIBO in a relatively long-term observational study13)vSome studies have used pulse therapy with methylprednisolone (30 mg/kg/day) for 3 days per month to treat PIBO, and this strategy is expected to have fewer side effects compared to daily oral steroids5,38
27、). vSystemic steroids should be given in the early period of the disease, before fibrosis is established.v By the time a diagnosis of PIBO is made, the small airways might already be obliterated with fibrosis. Furthermore, after the start of systemic steroids to treat PIBO, the question arises as to
28、 how long inflammation lasts after the development of PIBO. Since the answer to this question is unknown, it is difficult to know when to start and finish systemic steroid therapy. Although the timing of the decision to treat the disease and the duration of small airway inflammation differs between
29、BO after HSCT and PIBO, seven of nine patients after HSCT receiving up to six cycles of methylprednisolone pulse therapy were clinically stable without further decline of lung function39).vAlthough, theoretically, a bronchodilator response should be absent in children with fixed airway obstruction s
30、uch as in PIBO, a positive bronchodilator response ranging from 10% to 42.9% was present in children with PIBO13,30,45). The use of a bronchodilator beta-2-agonist should be applied on an individual basis according to the bronchodilator response.vIn addition, it has been suggested that azithromycin,
31、 a macrolide antibiotic with anti-inflammatory properties, may be beneficial for the progression of BOS after LT or HSCT, however, the results are controversial47-50). In children with PIBO, azithromycin has been used clinically without supporting evidence31).v LT remains the final option for childr
32、en with BO after LT or HSCT who have progressed to end-stage lung disease.v LT should be considered for children with PIBO who have progressed to end-stage lung disease.Outcome and prognosisvIn a study by Zhang et al. (7), 22.6% of patients had clinical remission, 67.7% of patients continued to have
33、 symptoms, and 9.7% of patients died.(31例随访例随访3.5年，前瞻性年，前瞻性研究研究)ConclusionsvPIBO is an irreversible obstructive lung disease that is characterized by subepithelial inflammation and fibrotic narrowing of the bronchioles after lower respiratory tract infection during childhood, especially early childh
34、ood. Although diagnosis of PIBO should be confirmed by histopathology, it is generally based onvhistory and clinical findings. The optimal treatment for PIBO has not been established, but corticosteroids have been used with the aim of reducing the inflammatory component. LT remains the final option for children with PIBO who have progressed to end-stage lung disease.THANKS
