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NEW APPROACHES TO MANAGING IDIOPATHIC PULMONARY FIBROSIS Presented By: Magd Mohamed Galal Professor Of Chest Diseases Al Azhar University Faculty Of Medicine For Girls Interstitial Lung Disease (ILD) Diffuse parenchymal lung diseases (DPLDs). Definition: A group of disorders that involve the distal lung parenchyma,or space between the epithelial and endothelial basement membranes. Diffuse Parenchymal Lung Disease DPLD of known Idiopathic Granulomatous Other forms of cause eg drugs Interstitial DPLDs eg DPLD Or association eg Pneumonia (IIP) sarcoidosis Eg LAM ,HX ect. Collagen vascular disease Idiopathic pulmonary IIP other than IPF Fibrosis (IPF) Desquamative interstitial Respiratory bronchiolitis pnumonia Interstitial lung disease Acute interstitial Cryptogenic organizing pneumonia pneumonia Non specific interstitial Lymphocytic interstitial Pneumonia (provisional) pneumonia General Diagnostic Approach Of DPLDs IDIOPATHIC PULMONARY FIBROSIS (Cryptogenic Pulmonary Fibrosis) OVERVIEW Prevalence: 13–20/100,000 in US (approximately 35,000-55,000 cases) Onset: Usually between 50 and 70 yr Clinical presentation Progressive dyspnea on exertion Paroxysmal cough, usually nonproductive Abnormal breath sounds on chest auscultation Abnormal chest x-ray or HRCT Restrictive pulmonary physiology with reduced lung volumes and DLCO and widened A-aPO2 Coultas DB et al. Am J Respir Crit Care Med. 1994;150:967. ATS/ERS. Am J Respir Crit Care Med. 2000;161:646. CLASSIFICATION OF IIP (IMMUNOCOMPETENT HOST) Idiopathic interstitial pneumonia (IIP) Idiopathic Respiratory pulmonary Desquamative bronchiolitis- Acute Nonspecific fibrosis/Usual interstitial associated interstitial interstitial interstitial pneumonia interstitial lung pneumonia pneumonia pneumonia (DIP) disease (AIP) (NSIP) (UIP) (RBILD) ATS/ERS. Am J Respir Crit Care Med. 2000;161:646. INTERNATIONAL CONSENSUS STATEMENT ON IPF: HISTOLOGY UIP is essential to diagnosis of IPF Idiopathic, progressive, diffuse fibrosing inflammatory process Involves lung parenchyma Surgical lung biopsy recommended in patients with suspected IPF, especially those with atypical clinical or radiographic features Major purpose of histologic examination is to distinguish UIP from other histologic subsets ATS/ERS. Am J Respir Crit Care Med. 2000;161:646. of IIP DIAGNOSIS OF IPF Major criteria Exclusion of other known causes of ILD Abnormal pulmonary function studies Bibasilar reticular abnormalities on HRCT scan No histologic or cytologic features on transbronchial lung biopsy or BAL analysis supporting another diagnosis ATS/ERS. Am J Respir Crit Care Med. 2000;161:646. DIAGNOSIS OF IPF Minor criteria Age >50 yr Insidious onset of otherwise unexplained exertional dyspnea Duration of illness 3 mo Bibasilar, dry (“Velcro”) inspiratory crackles Pulmonary Function Reduction in all lung volume Increased static elastic recoil Rapid shallow rapid breathing Impaired single –breath diffusing capacity (DLco) Impaired oxygenation at rest and exercise Exercise induced alveolar –arterial O2 gradient correlates better with histologic abnormalities than do lung volumes or DLco. Exercise testing with arterial cannulations: Widening A-aPo2 Respiratory alkalosis Decreased O2 consumption Increased dead space (VD/VT) Increased MV for level of O2consumption Low O2 pulse 6 walk test + oximetry easier ,better for disease progression and regression. HRCT in IPF Bibasilar interstitial and intra lobular reticular opacities. Interlobular septal thickening Sub pleural honeycomb changes , Traction bronchiectasis in lower lobes, Without pleural abnormalities. HRCT FINDINGS IN IPF Slide courtesy of G Raghu, MD. BAL Normally contains 95-98% macrophages and very few neutrophils, lymphocytes, or eosinophils. The predominance of certain subgroups of cells in patients with DPLD might be helpful in the differential diagnosis. Neutrophils are often predominant in smokers and in patients with IPF, Hypersensitivity pneumonitis, or Collagen vascular diseases Lymphocytic predominance is seen mainly in patients with sarcoidosis or Hypersensitivity pneumonitis. Eosinophils predominate in patients with chronic eosinophilic pneumonia, Loeffler syndrome, or Churg- Strauss angiitis .On the other hand, BAL may yield a specific diagnosis in DPLD, patients with certain findings such as:- Asbestos bodies (which indicate asbestosis). Silica-filled macrophages (silicosis). Periodic acid-Schiff (PAS)-stained lipoproteinaceous material (pulmonary alveolar proteinosis). X bodies (eosinophilic granuloma). HISTOPATHOLOGIC ELEMENTS OF UIP Heteroganous areas of end stage fibrosis and honeycombing, with areas of active proliferation of fibroblast (suggesting diffuse ongoing microscopic alveolar epithelial injury. Fibroblastic foci Minimal interstitial inflammation (primary proliferative process) Honey combing (common) cystic space is lined by bronchial epithelium. UIP interstitial inflammation mild &patchy. The fibro tic zones are composed mainly of dense collagen, & oldest disease is seen peripherally in lung lobule or acinus. Slide courtesy of KO Leslie, MD. TEMPORAL HETEROGENEITY OF UIP Slide courtesy of KO Leslie, MD. INFLAMMATION AND FIBROSIS IN UIP Interstitial inflammation and fibrosis with alveolar wall thickening Temporal heterogeneity Slide courtesy of KO Leslie, MD. Peripheral accentuation of fibrosis CHRONIC INTERSTITIAL INFLAMMATION IN UIP Alveolar septal infiltrate of lymphocytes & plasma cells Hyperplasia of type 2 pneumocytes. of KO Leslie, MD. Slide courtesy FIBROBLASTIC FOCI IN UIP Slide courtesy of KO Leslie, MD. Evidence Of Pulmonary Hypertension CONTRASTING PATHOLOGIC FEATURES OF IIP . Feature UIP DIP/RBILD AIP NSIP Temporal appearance Variegated Uniform Uniform Uniform Interstitial inflammation Scant Scant Scant Usuallyprominent Collagen fibrosis Patchy Variable, diffuse No Variable, diffuse in DIP; focal, mild in RBILD Fibroblast proliferation Fibroblastic foci No Diffuse Occasional, diffuse, r rare fibroblastic foci Organizing pneumonia No No No Occasional, focal Honeycomb changes Yes No No Rare Intraalveolar macrophage Occasional, focal Diffuse in DIP; No Occasional, patchy accumulation peribronchiolar in RBILD Hyaline membranes No No Occasional, No focal Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301. NSIP Either pure inflammatory or dense fibrosis (predominance of cellular pattern or fibro tic pattern). Must exclude (HSP, drug, and collagen vascular disease). Pathology, uniform of same age (as a result of single insult). Fibroblastic foci & Honey combing are rare PATHOGENESIS OF PULMONARY FIBROSIS PATHOGENESIS AND COURSE OF UIP UIP Multiple microscopic foci of injury occurring over many years Focal fibroblast proliferation (fibroblastic foci) Collagen deposition Recurrent microscopic injury Progressive clinical course Death Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301. MOLECULAR BIOLOGY OF PULMONARY REPAIR Triggering Cellular phase Fibrotic phase event Endothelial cell Angiostasis Monocyte + ELR- CXC ELR- CXC TNF-a ELR+ CXC IL-1 ELR- CXC MØ ELR+ CXC IL-1 Extracellular TNF-a matrix + fibroblast Normal alveoli Cellular phase – ELR+ CXC IFN-g Angiogenesis IL-12 Lymphocyte IL-18 Endothelial cell ELR+ CXC ELR- CXC ELR- CXC ELR+ CXC Slide courtesy of RM Strieter, MD. Homeostasis Fibro tic phase INFLAMMATORY RESPONSE OF THE LUNG Circulating Fixed leukocyte macrophage Recognition Capillary Antigen endothelial cell Capillary Recruitment Monocyte Removal Infiltrating Phagocytic Fibrous matrix leukocyte leukocyte (scar issue) (macrophage) Activated Resolution leukocyte Chemotactic cytokine wave Fibroblast Slide courtesy of RM Strieter, MD. Th1 AND Th2 RESPONSES Th1 TISSUE Increased IFN-g Increased IFN-g Increased IL-2 Increased IL-2 Cell-Mediated RESTORATION Increased IL-12 Increased IL-12 Immunity Increased IL-18 IFN-g Increased IL-18 Increased IL-2 Increased IL-12 Increased IL-18 Fibroblast Activation Th2 and Increased IL-4 Matrix Deposition Increased IL-5 Antibody-Mediated Increased IL-10 Immunity Increased IL-13 FIBROSIS Slide courtesy of RM Strieter, MD. ROLE OF Th1 AND Th2 RESPONSES IN REPAIR PROCESS Cytokine Activation Fibrotic Phase Phase Th2 Type ExtracellularMatrix IL-4/IL-13 (Fibrosis) (+) Chemokines IL- Fibroblast 10 (-) IFN-g IL-12 IL-18 (-) Th1 Type Resolution Slide courtesy of RM Strieter, MD. ROLE OF TGF-b AND IFN-g IN REPAIR PROCESS TGF-b receptor IFN-g receptor Activation of Jak/STAT1 Smad3-4 IFN-g inhibits Smad7 activation of Smad3-Smad4 and induces Smad7 Increase of TGF-b–dependent gene transcription Inhibition of TGF-b–dependent gene transcription Ulloa L et al. Nature. 1999;397:710. MOLECULAR BIOLOGY OF IPF: SUMMARY Shift to increased production of Th2 cytokines and decreased production of Th1 cytokines resulting from unknown lung injury Over expression of Th2 cytokine TGF-b stimulates angiogenesis, fibroblast activation, deposition of ECM, and fibro genesis Th1 cytokine IFN-g counters effects of TGF-b, but IFN-g production decreased in IPF IFN-g may have therapeutic role in management of IPF PROGNOSTIC FACTORS IN IPF Figure 4. Kaplan-Meier survival curves for patients grouped by combining HRCT and histopathologic features as follows: histopathologic pattern showing NSIP and HRCT interpreted as indeterminate or NSIP (n=23, dotted line); histopathologic pattern showing UIP and HRCT interpreted as indeterminate or NSIP (n=46, dashed line); and histopathologic pattern showing UIP and HRCT interpreted as UIP (n=27, solid line), p=0.001. + = last follow-up visit; circle = death. CAUSE OF DEATH IPF [N=543] 1-7 year FU 60% Died [N=326] Respiratory Lung Pulmonary Pulmonary Cardiovascular Other failure cancer embolism infection disease 18% 39% 10% 3% 3% 27% Panos RJ et al. Am J Med. 1990;88:396. RISK FACTORS FOR PROGRESSIVE DISEASE Age: >50 yr Gender: male Dyspnea: moderate to severe with exertion History of cigarette smoking Lung function: moderate to severe loss (especially gas exchange with exercise) BAL fluid: neutrophilia or eosinophilia at presentation HRCT scan: reticular opacities or honeycomb changes Response to corticosteroids: poor Pathology: more fibrosis, fibroblastic foci HRCT ABNORMALITIES AND CHANGES IN LUNG FUNCTION 100 Frequency of Improvement in 75 Lung Function (%) 50 25 N=4 N=12 N=11 0 Ground Glass Mixed Reticular HRCT Appearance Wells AU et al. Am Rev Respir Dis. 1993;148:1076. HRCT APPEARANCE VS SURVIVAL IN IPF 100 90 CT appearance atypical of CFA Survival (%) 70 60 50 40 30 20 10 CT appearance typical of CFA 0 0 1 2 3 4 5 6 7 Time from Presentation (yr) Daniil ZD et al. Am J Respir Crit Care Med. 1999;160:899. BAL CELLULARITY AND STEROID RESPONSIVENESS Responders (N=8) 100 * Non responders (N=19) * p<0.05 * Prevalence (%) 75 * 50 25 0 Lymphocytes Neutrophils Eosinophils >11% >4% >3% Rudd RM et al. Am Rev Respir Dis. 1981;124:1. APPROACHES TO THERAPY The hope of achieving stability as scarred lung cannot regenerate. Start treatment in patient who are symptomatic : In those with a 30-40% reduction in lung function indices. With evidence of disease progression on serial lung function testing. THERAPEUTIC APPROACHES TO IPF Corticosteroids Antioxidant agents Other Glutathione immunosuppressives N-acetylcysteine Azathioprine Others Cyclophosphamide Agents that block Antifibrotic agents neutrophil adhesion Colchicine molecules D-Penicillamine Inhibitors of specific IFN-g fibrogenic cytokines IFN-b and growth factors Pirfenidone ATS/ERS. Am J Respir Crit Care Med. 2000;161:646 CLINICAL RESPONSE TO THERAPY IN IPF 100 Stable or Improved (%) Prednisolone + Cyclophosphamide Prednisolone 50 0 1 3 12 24 36 Months Johnson MA et al. Thorax. 1989;44:280. EFFECT OF THERAPY ON SURVIVAL IN IPF 100 Prednisone Prednisone + Colchicine 80 Prednisone + D-Penicillamine Prednisone + Colchicine Survival (%) + D-Penicillamine 60 40 20 0 0 10 20 30 40 50 60 70 Months Selman M et al. Chest. 1998;114:507. NEW TARGETS FOR THERAPEUTIC INTERVENTION Greater insight into pathogenesis of IPF using molecular biological approaches Wide range of potential mediators identified Targets might include Initial injurious agent Earliest pathogen tic event Final common pathway leading to fibrosis Lung Transplantation Indication: Severe ,end stage lung disease. Medical therapy ineffective. Substantial limitation in activities of daily life. Limited life expectancy(<18 months) End stage lung disease: Severe dyspnoea Honeycombing or pulmonary hypertension. Severe physiologic derangement TLC<60%- (A-a)Po2 at rest >30 Severe exercise desaturation or (A-a)Po2 widening. Clinical /radiological/physiologic score >70. Treatment Of Complications Supportive therapy to minimize morbidity. O2 therapy Oxygen concentrators Portable liquid oxygen Diuretic therapy Opiate. Treatment of PE ,infection.
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