Steroid resistant BOOP (Bronchiolitis Obliterans Organizing Pneumonia) 호흡기 내과 노태준

Order 1. Introduction 2. Classification 3. Review of Korean case reports – Efficacy of Steroid 4. Pathogenesis and Role of steroid in BOOP 5. Refractory BOOP 6. Relationship between Relapse and Steroid resistant BOOP

Introduction Clinico-radiological-pathologic entity Subacute clinical course – flu like illness, cough, fever, DOE… Davison et al (1983) : “ COP (Cryptogenic organizing pneumonia)” Epler et al (1985) : “ BOOP (Bronchiolitis Obliterans Organizing Pn) ” → organized granulation tissue plug 70% : idiopathic, 20% : connective tissue disease Organized granulation tissue plug within alveolar duct / alveoli

Classification Idiopathic Rapidly progressive Focal nodular Post infection Chlamydia, Legionella, Adenovirus, CMV, Influenza Malaria, PCP… Drug Antibiotics: Amphotericin B, Cephalosporin, sulfasalazine Bleomycin, Gold, amiodarone Carbamazepine, Phenytoin… Connetive tissue disease Polymyositis, SLE, RA… Immunologic disorder Organ transplantation BM, Lung, kidney Radiotherapy Environmental exposures Miscellaneous IBD, Lymphoma, cancer T-Cell CLL, HIV infection MDS, Chr thyroiditis alcholoic LC CABG… Arch Intern Med 2001;161:158-164

이대목동병원 5예+ Case reports 19예

외국 저널은 steroid 효과를 63-96%로 보고 ( 특히 NEJM 1985 찾아볼것 ) Good response

Pathogenesis Injury to capillary endothelial cells and alveolar epithelial cell Leakage of plasma proteins ( especillay, coagulation factors ) Into Alveolar lumen, activaion of extrinsic coagulation ptwy Fibrin deposit : fibrinolytic process ↓ Biological activity on fibroblast : chemotactic, activating

Role of cytokines in BOOP Role in organised fibrotic intraalveolar buds ?? Degradation of connective matrix : Requires of enzymes MMP ( Metalloproteinases), Gelatinases, stromelysins ← produce by leukocytes & fibroblasts Cytokines J Clin Invest 1996;98:2739-2745

Mechanisms of steroid Inhibit transcription of several inflammatory cytokines ( IL-1,3,4,5,6,8, TNF-α, GM-CSF ) AP-1, NF-κB : upregulation of cytokines Inhibit of ICAM-1, E-selectin Synthesis of SLPI (Secretory leukocyte protease inhibitor) : reduce airway inflammation Inhibit of MIP-1α (Macrophage Inflammatory protein-1) MCP-1 (Monocyte chemotactic protein-1) Am J Crit Care Med 1999;160:1079-1100

Mechanisms of steroid Inhibit transcription of several inflammatory cytokines ( IL-1,3,4,5,6,8, TNF-α, GM-CSF ) AP-1, NF-κB : upregulation of cytokines Inhibit of ICAM-1, E-selectin Synthesis of SLPI (Secretory leukocyte protease inhibitor) : reduce airway inflammation Inhibit of MIP-1α (Macrophage Inflammatory protein-1) MCP-1 (Monocyte chemotactic protein-1) Am J Crit Care Med 1999;160:1079-1100

Corticosteroids in Acute Respiratory Failure ARDS PCP Acute eosinophilic pneumonia Alveolar hemorrhage syndromes SLE, Wegener’s granulomatosis, Microscopic polyangiitis Good pasture’s syndrome, BMT Acute lupus pneumonitis BOOP Radiation pneumonitis Miliary TB Pul. Toxicity to2ndary Drugs or toxins - Bleomycin, Amiodarone Am J Crit Care Med 1999;160:1079-1100

Treatment Corticosteroids : standard Improve within 48 hrs, but radiologic findings – several wks Dose : 1-1.5 mg/kg/day for 1-3 Mo – tapering for 6 – 12 Mo Relapse

Self limited BOOP Vascular growth factor in BOOP Apoptotic activity ↑in fibromyxoid lesion of BOOP compared with IPF Lung 1999;177:2739-2745

PI) progressive dyspnea (o/s: 3 wks) with nonproductive cough 49/M, nonsmoker PI) progressive dyspnea (o/s: 3 wks) with nonproductive cough Drug Hx) imipramine and carbamazepine for depression Chest PA) bilat. Sym. Interstitial and alveolar shadow at lung base HRCT ) multiple air space consolidation with ground glass opacity Serology ) negative TBLB ) lymphocytic infiltration & fibroblastic tissue filling with alveoli and alveolar duct 이 약때문에 BOOP가 생겼다는 report도 없다. Respir Med 1997;91:175-177

Cont’d Prednisolone 1 mg/kg/day ( 60 mg ) and Drug continued But, Worsening respiratory failure and progression of X-ray over 3 wks : FiO2 60% and MV considered Added Cyclophosphamide 150 mg/day Day 7 – improve Over 6 wks – dramatic recovery ( lab, X-ray ) CP and PDL – continued for 6 Mo, PDL tappering by 5 mg every 2 wks No relapse over 18 Mo Definitive한 recommendation은 아직 보고된바가 많지 않아 아직 고려할수 없지만, 저자들은 호전을 보고한다. Respir Med 1997;91:175-177