Idiopathic pulmonary fibrosis Department of Pulmonology and Critical Care of Medicine R4 김연주 1

2 Summary of IIPEpidemiologyDefinitionDiagnosis PathophysiologyTreatmentAcute exacerbation

 Idiopathic Interstitial Pneumonia comprise a number of clinicopathological entities, which are sufficiently differ from one another to be designated as separate disease entities 3 Summary of Idiopathic Interstitial Pneumonia AJRCCM Vol 165. pp 277–304, 2002

Diffuse Parenchymal Lung Diseases DPLD of known causes (CVD, drug, environ) Idiopathic interstitial pneumonia (IIP) Granulomatous DPLD (sarcoidosis) Other forms of DPLD (LAM, HX, EP) IPF = idiopathic UIP IIP other than IPF DIP AIP NSIP RB-ILD COP LIP 2002 ATS/ERS classification

5 Histologic and clinical classification of IIP AJRCCM Vol 165. pp 277–304, 2002

6 Differential diagnosis of IIP

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Epidemiology of IPF 8 Incidence and Prevalence –13~20/10 5 person-years –onset is usually greater than 50 yr Sex and Age –males>females (31.5/10 5 vs 26.1/10 5 ) –40 ~70 yr(mean age at diagnosis of 66yr) –rare in children, but increase with advancing age 35~ 44 yr : 2.7/10 5 ≥75yr : exceeded 175/10 5 for individuals 5-yr survival : 20% median survival : 2.8~4.2 yrs

Definition of IPF 9  usual interstitial pneumonia (UIP) on surgical lung biopsy + unknown etiology 1. Exclusion of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases 2. Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1/FVC ratio) and/or impaired gas exchange [increased P A-a DO 2 with rest or exercise or decreased DLco 3. Abnormalities on conventional chest radiographs or HRCT scans

Diagnosis 10 Clinical criteria for IPF in absence of surgical lung Bx Major criteria (all must be present) –exclusion of other known causes of ILD (drug toxicity, environmental exposures, connective tissue dz) –abnormal PFT (  VC, ↑FEV1/FVC,  DLco,  P A-a DO 2 ) –bibasilar reticular abnormality with minimal GGO on HRCT –no features of an alternative Dx in TBLB or BAL Minor criteria (  three) –age > 50 yr –insidious onset of otherwise unexplained DOE –duration of illness  3 months –Bibasilar, inspiratory crackles (“dry” or “Velcro” type) 2002 ATS/ERS classification

Diagnostic process in DPLD 11 AJRCCM Vol 165. pp 277–304, 2002

12  Hx –gradual onset of a nonproductive cough and dyspnea –Progressive, for >6 mo –Occupational Hx : exposure to asbestos, silica, respirable toxin –paroxysmal dry cough that is refractory to antitussive agents  P/Ex –Crackles (≥ 80%) : “dry,” end-inspiratory, and “Velcro” –Clubbing(25~50%), Cyanosis, cor pulmonale, peripheral edema –Weight loss, malaise, fatigue –Fever is rare  Laboratory and Serological Tests –not helpful except to “rule out” other causes of diffuse parenchymal lung disease –LDH↑, ANA(+) : 10~20%, not high titer

13  Chest Radiograph –Usually bilateral peripheral reticular opacities at lung base –With decreased lung volumes –DDx : asbestosis, connective tissue disease(scleroderma, RA) –Pleural disease or lymphoadenopahy : not usually  High Resolution CT Scanning –patchy, predominantly peripheral, subpleural, bibasal reticular abnormalities –GGO, traction bronchiectasis, subpleural honeycombing –Accuracy : about 90% –DDx : pleural plaque(asbestosis), GGO(>30% DIP)

Chest x-ray and CT 14 NEJM, Vol. 345, No. 7, 2001

15  Pulmonary Function Testing –parenchymal restrictive ventilatory defect (VC ↓, TLC↓, FRC↓, RV↓, DLco ↓, FEV1/FVC NL or ↑)  ABGA –NL or mild hypoxemia, resp.alkalosis  Bronchoalveolar Lavage –diagnostic usefulness : limited –Neutrophil ↑(70~90%), eosinophil ↑(40~60%), lymphocyte ↑ –Neutrophil and eosinophil : worse prognosis

16  Lung Biopsy –confident clinicopathologic diagnosis –Open thoracotomy or VATS lung Bx –transbronchial lung biopsies Used only to rule out other disorders smaller biopsies(2~5mm) are not adequate to establish a pathological diagnosis

Pathology 17 Х 15 Х 150 Fibroblast foci NEJM, Vol. 345, No. 7, 2001

Pathogenesis 18 (1)loss of alveolar-capillary barrier basement membrane (BM) integrity (2) failure of reepithelialization and reendothelialization of BM results in pathologic fibrosis (3) TGF-β is necessary but not entirely sufficient to promote permanent fibrosis (4) persistent injury/antigen/irritant is necessary for the propagation of fibrosis (5) epithelial-to-mesenchymal transition(EMT) and bone marrow-derived progenitor cells(fibrocyte) are critical cellular mechanism in regulation of fibrosis CHEST 2009; 136:1364–1370

Pathogenesis 19 CHEST 2009; 136:1364–1370

Pathogenesis 20 Allergy 2010 CHEST 2009; 136:1364–1370

Pathogenesis 21 ERJ 2007; 30: 835–839 & Allergy 2010

Prognosis of IPF 22  Indicators of longer survival among patients with IPF –Younger age ( <50 yr) –Female sex –Shorter symptomatic period (≤ 1 yr) with less dyspnea, relatively preserved lung function –Presence of ground glass and reticular opacities on HRCT –↑ lymphocytes (20 ~25%) in BAL fluid –A beneficial response or stable disease 3 to 6 mo after initial corticosteroid therapy –A history of “current” cigarette smoking at the time of diagnosis has been associated with improved survival– This finding remains unexplained

Treatment 23  ATS/ERS consensus statement in 2000 –exact time that therapy should be started is unknown –before irreversible fibrosis : response rates may be higher –combined therapy (corticosteroid + azathioprine or cyclophosphamide) Corticosteroids Prednisone 0.5mg/kg/D for 4 wks  0.25mg/kg/D for 8 wks  0.125mg/kg/D or 0.25mg/kg every other day Azathioprine 2~3mg/kg/D (< 150mg/D orally) or Cyclophosphamide 2mg/kg/D (< 150mg/D orally) –Length of therapy : for at least 6 months

24  Anti-fibrotic medications –Colchicine and penicillamine –Pirfenidone novel anti-inflammatory, antifibrotic compound pulmonary function improve  Immune modulators –Interferon-gamma : inhibit collagen formation by fibroblasts

NEJM ;21,  Antioxident therapy –N-acetylcysteine : molecular precursor to the naturally occurring antioxidant glutathione

26  Lung transplantation –only option for end stage pulmonary fibrosis and for patients who fail to respond to medical treatment –Age limitation : <60yrs –Five-year survival : 50–60% –Alleviate requirement for supplemental oxygen Lung vol. and DLco ↑ pulmonary HTN and Rt.HF reverse –Waiting – list mortality(>30%) Limitation of the donor lungs Difficulty in predicting survival and frequent AE → early referral for lung transplantation is important

Acute exacerbation 27  Definition –rapid deterioration during the course of the disease that is not due to infection, pulmonary embolism, or heart failure  Etiology : unknown –represent a distinct, pathobiological manifestation of the primary disease process, characterized by idiopathic lung injury –represent clinically occult but biologically distinct conditions that go undiagnosed(e.g., viral infection, aspiration) : Herpesviruses, Gastroesophageal reflux –sequelae of an acute direct stress to the lung, with a subsequent acceleration of the already abnormal fibroproliferative process intrinsic to IPF

28  Clinical features –Progressive dyspnea over the course of <1 month –Worsening hypoxemia ( a fall in PaO 2 > 10 mm Hg or P/F ratio<225) –Cough –Mild fever –Flue like symptom Many patients present with severe hypoxemia respiratory failure requiring mechanical ventilation(45%) Eur Respir J 2006; 27: 143–150

AE-IPF Diagnosis 29 AJRCCM Vol 176. pp 636–643, 2007

30  Incidence of AE-IPF in Reported Trials  The time from the diagnosis of IPF to an AE ranged from 3 to 60 months

Acute exacerbation IPF 31 pathogenesis

AE-IPF HRCT 32  High-resolution CT (HRCT) is a useful modality –new-onset ground glass opacities and/or –consolidation in a background of fibrosis (intralobular septal thickening, traction bronchiectasis, and bronchiolectasis) and –honeycomb opacities At baseline during acute exacerbation

AJRCCM Vol 176. pp 636–643, 2007

34  Surgical lung biopsy –most sensitive and specific diagnostic procedure –change in the original diagnosis in about 50–70%  fiber-optic bronchoscopy and bronchoalveolar lavage (BAL) –to exclude the possibility of infections –BAL fluid culture were negative, with neutrophilia

35 appearance of diffuse alveolar damage, the histological lesion of acute interstitial pneumonia

Mortality of AE-IPF 36 European Journal of Internal Medicine 19 (2008) 227– % 67.1%

AE-IPF Treatment 37 Anti-inflammatory treatment –Pulse corticosteroid therapy (0.5~1g/D of MPD for 3 days) –Cyclosporine A : 1.0 ~2.0 mg/kg/d –Cyclophosphamide Antifibrotic agent –Pirfenidone Anticoagulation –prevention of in situ thrombosis –prevention of fibrin deposition in the alveolar space Lung transplantation –young and middle-aged patients : treatment option