1、1,兒童閉塞性細支氣管炎Bronchiolitis Obliterans （BO）in children,張云峰,2,病歷摘要,患兒，男，2歲。 2009.12，曾因發(fā)熱，喘息1周入PICU。診斷毛細支氣管炎，EB病毒感染，呼吸衰竭，中毒性腦病。20天后出院。出院口服順爾寧，但一直有咳嗽，喘息癥狀。 出院1個月后，因咳嗽、喘息，診斷：兒童哮喘。吸入普米克/可必特治療。咳嗽減輕，但仍喘息，每于活動后喘息明顯，休息后緩解。 既往史：患兒有濕疹史（較重），曾有2次喘息史； 家族史：其小姨的孩子有哮喘。,病例（1）,3,輔助檢查,輔助檢查： 血常規(guī)：WBC: 4.510（9）/L,NE: 66.2%，

2、 Hb: 128g/L CRP:3.29mg/L。 MP-IgM：1:40；CP-IgM：陰性 血總 Ig E： 679U/ML， 血食物+呼吸特異性Ig E: 牛羊肉 2.0 血氣： PH7.32，PaO2 66. 8mmHg ， PaCO2 54.1mmHg,BE 2.4mmol/l.,4,5,病歷摘要,患兒，男，2歲 因發(fā)熱5天，皮疹1天住院。診斷麻疹。住院第4天咳嗽，住院后6天家長要求出院。出院5天后，再次出現(xiàn)發(fā)熱39.8度，咳嗽加重，再次入院，診斷：重癥肺炎。MPP(1:1280)，住院20余天，癥狀好轉出院?；丶液箪F化吸入普米克和可必特治療?；顒雍笕源ⅰ?三個月后，再次因發(fā)熱，咳

3、嗽、喘息加重住院，診斷大葉肺炎，肺膿腫，兒童哮喘，住院20天好轉出院，出院后仍喘息，咳嗽。 既往史：濕疹（+），既往無喘息史。不愛揉鼻、眼 家族史：無喘息家族史。 IgE 14.5U/ml 血食物+呼吸特異性Ig E:陰性。,病例（2）,6,入院時（2009-05-23） 發(fā)熱，喘重，雙肺密集水泡音,7,出院2月后（2009-08-04） ，輕咳、活動后喘促， 雙肺散在水泡音,8,1年后（2010-08-23），輕咳、活動后喘促， 左肺散在水泡音,9,10,11,Bronchiolitis obliterans (BO) is an irreversible obstructive lung

4、disease 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 tra

5、nsplantation (LT).,Introduction,12,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 . P

6、ostinfectious bronchiolitis obliterans in children: lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation Review article Korean J Pediatr 2015;58(12):459-465 Current research on pediatric patients with bronchiolitis obliterans in Brazil Intracta

7、ble Rare Dis Res. 2015 February; 4(1): 711.,13,Epidemiology,Although 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

8、with allogeneic HSCT 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.,14,Pathogenesis,15,BO相關病因和基礎疾病,感染性閉塞性細支氣管炎,常見病毒 （腺病毒、呼吸道合胞病毒、流感病毒、副流感病毒） 支原體 結締組織?。愶L濕性關節(jié)炎和嗜酸性筋膜炎） 吸入性損傷（二氧化氮、二氧化硫、氨、氯、光氣、灼熱氣體、

9、飛灰等）毒物服入 異體移植物受者（心肺聯(lián)合移植或肺移植、骨髓移植） 藥物（青霉胺、洛莫司汀、可卡因、金等） 其他并發(fā)癥：炎癥性腸病、神經內分泌細胞增生、多發(fā)性類癌樣微瘤、副腫瘤天皰瘡,16,Etiology in children,PIBO與 腺病毒（ADV） 呼吸道合胞病毒（RSV） 支原體感染 麻疹病毒 流感病毒 副流感病毒 巨細胞病毒,17,Risk Factor,PIBO發(fā)生的危險因素 ADV毛細支氣管炎 （OR=49.9） 住院時間超過30天 （OR=27.2） 多病灶肺炎 （OR=26.6） 需機械通氣治療 （OR=11.9） 高碳酸血癥 （OR=5.6）。,18,Patholog

10、y,病因不同，但組織病理學改變相似 縮窄性細支氣管炎和增殖性細支氣管炎 增殖性細支氣管炎以肉芽組織在氣道內呈息肉團塊增生為特征 肺泡腔內亦出現(xiàn)肉芽組織時，則稱為 閉塞性細支氣管炎伴機化性肺炎(BOOP）,19,Childhood PIBO 絕大多數為縮窄性 早期上皮細胞壞死，氣道炎癥細胞浸潤 相鄰肺實質正?；騼H有輕微改變 細支氣管變形，膠原沉積，黏液滲出 后期形成黏膜下纖維化，管腔進行性變窄，最終形成閉塞,20,氣道阻塞間接征象 黏液潴留 巨噬細胞聚集 肺過度充氣 細支氣管變形擴張 支氣管上皮細胞肥大，上皮層變厚，管腔可出現(xiàn)阻塞甚或閉塞,21,Constrictive bronchioliti

11、s in SLE,22,23,肺泡灌洗液中以中性粒細胞增多為主 部分區(qū)域淋巴細胞增多 中性粒細胞趨化因子IL-8濃度增高 這些變化仍存在于肺損傷數年之后,24,Clinical symptoms and signs,The initial symptoms and signs of BO are similar to acute viral bronchiolitis: fever, cough, tachypnea, and wheezing (1,3). But the disease does not progress as expected and symptoms and signs

12、 persist for weeks or months. 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). In a previous study by the current authors (10), the most common symptoms and signs of BO in 40 pati

13、ents were wheezing, dyspnea, and coughing (Table 1).,25,high-resolution chest tomography (HRCT),Brazilian studies (6,9,10,18) found that characteristic findings in HRCT were: a mosaic pattern of perfusion bronchiectasis bronchial wall thickening air trapping atelectasis,26,Cardinal Features Areas of

14、 decreased attenuation Reduced number / calibre of vessels Bronchial dilatation No parenchymal distortion No zonal predilection,CT in Obliterative Bronchiolitis,27,28,250例兒童及青少年CT改變,29,Diagnosis,Although a diagnosis of PIBO should be confirmed by histopathology, most pediatric pulmonologists diagnos

15、e PIBO based on history and clinical findings according to the following criteria:,30,(1) acute severe respiratory infection during childhood, especially early childhood; (2) persistent airway obstruction after initial insult and unresponsiveness to systemic steroids and bronchodilators, as demonstr

16、ated by clinical symptoms and signs, and a lung function test, if it can be performed; (3) mosaic perfusion, air trapping, and/or bronchiectasis in chest computed tomography; and,31,(4) exclusion of other chronic lung diseases such as severe asthma, bronchopulmonary dysplasia, chronic aspiration, pr

17、imary ciliary dyskinesia, cystic fibrosis, immunodeficiency, and alpha-1-antitrypsin deficiency (Table 1).,32,Recent studies of clinical prediction rules to diagnose PIBO in children found that typical clinical history, adenovirus infection, and high-resolution computed tomography with mosaic perfus

18、ion were highly predictable variables32).,33,History of lower respiratory infection, particularly adenovirus, mycoplasma, or measles. Persistent airway obstruction symptoms and signs, or recurrent airway obstruction symptoms and signs in a mild form. Sign of obstruction: FEV1/FVC 0.8 or FEV1 percent

19、 predicted 80%. Irreversible airway obstruction demonstrated by lung function test: absent BDR, but positive BDR in some patients. CT (inspiration and expiration): mosaic perfusion, air trapping, and/or bronchiectasis. Exclusion of other chronic lung disease (asthma, BPD, chronic aspiration, PCD, cy

20、stic fibrosis, and immunodeficiency). Postinfectious bronchiolitis obliterans is clinically diagnosed when all of the above criteria are met. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BDR, bronchodilator response; BPD, bronchopulmonary dysplasia; CT, computed tomography

21、; PCD, primary ciliary dyskinesia.,Table 1. Diagnosis of postinfectious bronchiolitis obliterans,34,Treatment,Although the optimal treatment of PIBO has not been established, corticosteroids have been used to combat the inflammatory component. Systemic steroids can be used rather than inhaled steroi

22、ds in consideration of the obliteration of the small airways. Prolonged oral steroid therapy over a period of 2 months to 2 years was applied to about 70% of children with PIBO in a relatively long-term observational study13),35,Some studies have used pulse therapy with methylprednisolone (30 mg/kg/

23、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). Systemic steroids should be given in the early period of the disease, before fibrosis is established.,36,By the time a diagnosis of PIBO is made, the small airways

24、might already be obliterated with fibrosis. Furthermore, after the start of systemic steroids to treat PIBO, the question arises as to 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 st

25、eroid therapy. Although the timing of the decision to treat the disease and the duration of small airway inflammation differs between 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 declin

26、e of lung function39).,37,Although, theoretically, a bronchodilator response should be absent in children with fixed airway obstruction such 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

27、 should be applied on an individual basis according to the bronchodilator response.,38,In addition, it has been suggested that azithromycin, 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).,39,LT remains the final option for children with BO after LT or HSCT who have progressed to end-s