Transcript Idiopathic Pulmonary Fibrosis & other Interstitial Lung
Idiopathic Pulmonary Fibrosis & other Interstitial Lung Diseases
Dr. Samir Nusair, MD Rokach Inst. for Lung Dis. & TB Prevention, Clalit Health Services Tel: 02-5017547, E-mail: [email protected]
twitter.com/samirnus Nusair 2013
References:
• Raghu G, et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
• Travis WD, et al. ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-48.
• Collard HR, et al. Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):636-43.
• Antoniou KM, et al. Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future. Eur Respir Rev. 2013;22:281-91.
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Restrictive Lung Diseases
• Parenchymal lung disease – Idiopathic interstitial pneumonias • Idiopathic pulmonary fibrosis – Granulomatous (sarcoidosis, hypersens. pneumonitis) – Occupational – Autoimmune (collagen vasc. Dis. Related) • Extra-pulmonary process – Chest wall deformity – Neuromuscular dis. – Pleural disease – Abdominal process (pregnancy, ascites, obesity) Nusair 2013
Restrictive Lung Diseases
•
Parenchymal lung disease
– Idiopathic interstitial pneumonias •
Idiopathic pulmonary fibrosis
– Granulomatous (sarcoidosis, hypersens. pneumonitis) – Occupational – Autoimmune (collagen vasc. Dis. Related) • Extra-pulmonary process – Chest wall deformity – Neuromuscular dis. – Pleural disease – Abdominal process (pregnancy, ascites, obesity) Nusair 2013
REVISED AMERICAN THORACIC SOCIETY/EUROPEAN RESPIRATORY SOCIETY CLASSIFICATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS: MULTIDISCIPLINARY DIAGNOSES
– Major idiopathic interstitial pneumonias • Idiopathic pulmonary fibrosis (IPF) • Idiopathic nonspecific interstitial pneumonia (NSIP) • Respiratory bronchiolitis–interstitial lung disease • Desquamative interstitial pneumonia • Cryptogenic organizing pneumonia • Acute interstitial pneumonia – Rare idiopathic interstitial pneumonias • Idiopathic lymphoid interstitial pneumonia • Idiopathic pleuroparenchymal fibroelastosis • Unclassifiable idiopathic interstitial pneumonias*
Am J Respir Crit Care Med. 2013;188:733
REVISED AMERICAN THORACIC SOCIETY/EUROPEAN RESPIRATORY SOCIETY CLASSIFICATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS: MULTIDISCIPLINARY DIAGNOSES
– Major idiopathic interstitial pneumonias • Idiopathic pulmonary fibrosis (IPF) • Idiopathic nonspecific interstitial pneumonia (NSIP) • Respiratory bronchiolitis–interstitial lung disease • Desquamative interstitial pneumonia • Cryptogenic organizing pneumonia • Acute interstitial pneumonia – Rare idiopathic interstitial pneumonias • Idiopathic lymphoid interstitial pneumonia • Idiopathic pleuroparenchymal fibroelastosis • Unclassifiable idiopathic interstitial pneumonias*
Am J Respir Crit Care Med. 2013;188:733
Physiologic changes in Interstitial Lung Disease Nusair 2013
Physiologic changes in Interstitial Lung Disease • • • • • • Reduced airflow values High FEV 1 /FVC ratio Reduced lung volumes (FVC, FRC, TGV) Reduced gas exchange due to: -increased ventilatory-perfusion mismatch -thickened alveolar-vascular barrier => (decreased diffusion capacity TL CO ) Increased respiratory rate at rest (also on effort) • • Widened P A O 2 -P a O 2 gradient Normal to Decreased O 2 – saturation These are more marked with increased exercise intensity Nusair 2013
FEV 1 /FVC ratio Nusair 2013
Obtained From: http://www.spirxpert.com/
Obstructive Nusair 2013 Restrictive
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Hypoxemia
• The major cause of hypoxemia is ventilation-perfusion mismatching • Decreased diffusion capacity contributes further to hypoxemia evident during effort Nusair 2013
A Measurements During Exercise Testing Jones NL
. N Engl J Med
1975;293: 541 –544, 647–650 B
A Measurements During Exercise Testing Jones NL
. N Engl J Med
1975;293: 541 –544, 647–650 B
Parenchymal vs. extra-parenchymal restrictive lung disease
FVC FEV1/FVC RV Parnchymal RLD Decreased Normal/ Increased Decreased MVV/ MIP/MEP TLCO Normal Decreased A-a O2 gradient Widened
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Extraparenchymal RLD Decreased Variable Normal/ Increased Decreased Normal Normal
Idiopathic Pulmonary Fibrosis
Definition Nusair 2013
IPF definition:
•
IPF
is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP. (Excluding environmental exposure, medication, or systemic disease is important).
Am J Respir Crit Care Med. 2011;183(6):788-824.
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Idiopathic Pulmonary Fibrosis
Epidemiology Nusair 2013
Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000.
•
Prevalence:
14-42 /100,000 in US depending on criteria used •
Annual Incidence
: 6.8-16.3/100,000 Raghu G et al. Am J Respir Crit Care Med 2006; 174:810-816 Nusair 2013
Diagnosis of IPF
• Exclusion of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).
• UIP pathology pattern on surgical lung biopsy • The presence of a UIP pattern on high-resolution computed tomography (HRCT) in patients who are not subjected to surgical lung biopsy.
Am J Respir Crit Care Med. 2011;183(6):788-824.
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HISTOPATHOLOGIC ELEMENTS OF UIP Nusair 2013
Anatomy of the Lower Respiratory System
Main bronchi Trachea Left Right Bronchus rigid because of C-shaped cartilage rings Bronchioles Acinus Alveolus Acinus Capillary Attenuated epithelium Alveolar space
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Alveolus Capillaries
Normal lung histology Nusair 2013
MACROPATHOLGY OF UIP Nusair 2013
TEMPORAL HETEROGENEITY OF UIP Nusair 2013 Slide courtesy of KO Leslie, MD.
FIBROBLASTIC FOCI IN UIP
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Histologic UIP Pattern
(All Four Criteria) • Evidence of marked fibrosis/ architectural distortion, +/- honeycombing in a predominantly subpleural/ paraseptal distribution • Presence of patchy involvement of lung parenchyma by fibrosis • Presence of fibroblast foci • Absence of features against a diagnosis of UIP suggesting an alternate diagnosis Nusair 2013
Histologic features against a diagnosis of UIP suggesting an alternate diagnosis • Hyaline membranes (except for acute exacerbation IPF) • Organizing pneumonia • Granulomas • Marked interstitial inflammatory cell infiltrate away from honeycombing • Predominant airway centered changes Nusair 2013
Imaging in UIP Nusair 2013
Imaging in UIP Nusair 2013
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Imaging
Normal HRCT Nusair 2013
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Imaging
Normal HRCT Nusair 2012
HRCT FINDINGS IN IPF Nusair 2012
AJRCCM 2011
HRCT UIP Pattern
(All Four Criteria) • Subpleural, basal predominance • Reticular abnormality • Honeycombing with or without traction bronchiectasis • Absence of features listed as inconsistent with UIP pattern Nusair 2013
HRCT findings inconsistent with UIP Pattern • Upper or mid-lung predominance • Peribronchovascular predominance • Extensive ground glass abnormality • Profuse micronodules (bilateral, predominantly upper lobes) • Discrete cysts (multiple, bilateral, away from areas of honeycombing) • Diffuse mosaic attenuation/air-trapping • Lobar/segmental Consolidation Nusair 2013
Combined Pulmonary Fibrosis and Emphysema (CPFE) • Heterogeneous population of patients • Combined Restrictive and obstructive pattern with “normal” lung volumes, and low diffusion capacity • Increased risk of developing pulmonary hypertension Nusair 2013
Clubbing
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Sounds of IPF “Velcro” Crackles
http://www.soundsofipf.com/ Nusair 2013
Idiopathic pulmonary fibrosis
Pathogenesis Nusair 2013
Pathogenesis & 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.
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Molecular Biology of IPF
Triggering event
Slide courtesy of RM Strieter, MD.
Molecular Biology of IPF
Triggering event
Slide courtesy of RM Strieter, MD.
Pulmonary Hypertension in IPF Nusair 2013
Genetics of IPF
• Possible candid gene polymorphisms – Surfactant proteins C or A2 – Telomere length –
MUC5B
promoter gene Nusair 2013
MUC5B
promoter gene
• Discovered by genomewide linkage scan • Increased expression of MUC5B on the p terminus of Chromosome 11 • More associated w/ patients older than >50yrs (Framingham cohort,
NEJM 2013
) • Associated with IPF but not scleroderma or sarcoidosis fibrosis (
Thorax 2013
) • Hypothesized Mechanisms: by increased Mucin5B production – Increased epithelial injury – Slowed clearance of airway toxins Nusair 2013
Idiopathic pulmonary fibrosis (IPF)
APPROACH TO THERAPY Nusair 2013
Anti-inflammatory Nusair 2013
Anti-fibrotic
N-Acetylcysteine
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N-Acetylcysteine
• A daily dose of 600mgX3/d • Exp and Placebo group received Azathioprin+prednisone • VC and TLCO differences are not considered clinically significant (less than 10%) • Mortality in placebo recipients similar to other control groups in other studies • NAC may have relieved the toxic effects of AZA+PDN Nusair 2013
Pirfenidone
• In Vitro and animal studies show: TNF-α, PDGF and TGF β signal transduction inhibition • Initial Clinical studies based on which the drug was authorized in Japan have not been published • At a later stage drug authorized in Europe but not is USA or Israel (up to date Nov 2013)
Pirfenidone
High dose vs. placebo p=0.028
Low dose vs. placebo p=0.065
Pirfenidone
p=0.0416
p=0.0394
Problem of inconsistent results at 60 weeks 004 study 006 study
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pooled study results
004 study Kaplan-Meir distribution of Progression-free survival 006 study pooled study results
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Therapeutic Approaches to IPF (1) • Evidence to date suggests that pharmacologic therapy for IPF is without definitive, proven benefit • Azathioprine and Prednisone is no longer a treatment option in IPF (since 2012)
Raghu G, et al. ATS/ERS/JRS/ALAT Committee on IPF. AJRCCM, 2011
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Therapeutic Approaches to IPF (2) • A reasonable choice of drug therapy in a minority of patients: – acetylcysteine monotherapy – Pirfenidone (?)
Raghu G, et al. ATS/ERS/JRS/ALAT Committee on IPF. AJRCCM, 2011
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Therapeutic Approaches to IPF (3) • These agents could be a consideration in a minority of patients (despite a strong recommendation against the following regimens): – corticosteroid monotherapy, – colchicine monotherpay, • There is a strong recommendation against the use of Interferon gamma-1b, bosentan, & etanercept
Raghu G, et al. ATS/ERS/JRS/ALAT Committee on IPF. AJRCCM, 2011
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Idiopathic pulmonary fibrosis (IPF)
Prognosis and Course of Disease Nusair 2013
Median Survival of patients with IPF 1.00
Median survival of patients who died (N=41/74) = 28.2 mo
0.75
0. 50 0.25
0.00
0 20 40 60 80 100
Time from Onset of Symptoms (mo)
120 Nusair 2013 Schwartz DA et al. Am J Respir Crit Care Med. 1994;149:450.
Cause of Death in IPF
IPF [N=543] 1-7 year FU 60% Died [N=326] Respiratory failure 39% Lung cancer 10% Pulmonary embolism 3% Pulmonary infection 3% Cardiovascular disease 27% Other 18%
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Acute Exacerbation of IPF
Am J Respir Crit Care Med 2007;176:636 –643.
Diagnostic Criteria • Previous or concurrent diagnosis of idiopathic pulmonary fibrosis • Unexplained worsening or development of dyspnea within 30 days • High-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern • No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage • Exclusion of alternative causes, including the following: Left heart failure Pulmonary embolism Identifiable cause of acute lung injury Nusair 2013
Baseline IPF Exacerbation
IPF exacerbation: acute diffuse alveolar damage with well-developed eosinophilic hyaline membranes Nusair 2012
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Lung Transplantation for Idiopathic Pulmonary Fibrosis
• Timing of Listing for LTX –Acceptable Criteria
(ATS, 1998; ERJ 2004)
– Patient symptomatic & FVC 60-70% and/or TLCO < 50-60% – Failure to achieve / maintain disease stability: • Symptomatic (incl. rest or Ex desaturation) disease with progression despite treatment (PDN + CTX)- 3 month follow-up recommended • Regardless to symptom severity, if PFT becomes abnormal - refer to Tx program Nusair 2013
REVISED AMERICAN THORACIC SOCIETY/EUROPEAN RESPIRATORY SOCIETY CLASSIFICATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS: MULTIDISCIPLINARY DIAGNOSES
– Major idiopathic interstitial pneumonias • Idiopathic pulmonary fibrosis (IPF) • Idiopathic nonspecific interstitial pneumonia (NSIP) • Respiratory bronchiolitis–interstitial lung disease • Desquamative interstitial pneumonia • Cryptogenic organizing pneumonia • Acute interstitial pneumonia – Rare idiopathic interstitial pneumonias • Idiopathic lymphoid interstitial pneumonia • Idiopathic pleuroparenchymal fibroelastosis • Unclassifiable idiopathic interstitial pneumonias*
Am J Respir Crit Care Med. 2013;188:733
NSIP Nusair 2013
NSIP Nusair 2013
Leslie, K. O. Chest 2005;128:513S-519S
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NSIP
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Rheumatoid arthritis Nusair 2013
DIP Nusair 2012
DIP Nusair 2013
DIP Nusair 2013
RB-ILD
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RB-ILD
Copyright ©2004 BMJ Publishing Group Ltd.
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RB-ILD
Mavridou, D et al. Thorax 2004;59:910-911
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CONTRASTING PATHOLOGIC FEATURES OF IIP
Feature Temporal appearance Interstitial inflammation Collagen fibrosis UIP Variegated Scant Patchy DIP/RBILD Uniform Scant Variable, diffuse in DIP; focal, mild in RBILD No AIP Uniform Scant No NSIP Uniform Usually prominent Variable, diffuse Fibroblast proliferation Organizing pneumonia Honeycomb changes Intraalveolar macrophage accumulation Fibroblastic foci No Yes Occasional, focal No No No Diffuse in DIP; peribronchiolar in RBILD No Diffuse No No No Occasional, diffuse, or rare fibroblastic foci Occasional, focal Rare Occasional, patchy Hyaline membranes Occasional, focal No
Leslie, K. O. Chest 2005;128:513S 519S
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