Idiopathic Pulmonary Fibrosis.ppt
Transcript of Idiopathic Pulmonary Fibrosis.ppt
Idiopathic Pulmonary Fibrosis
Brian D. Southern
Senior Talk August 2008
OBJECTIVES
Know the definitions of ILD, IIP, and IPF
Understand the pathogenesis of IPF
Appreciate the clinical features
Realize how the diagnosis of IPF is made
Know current therapies
Become aware of areas of current research and novel therapeutic approaches
Be able to summarize current thinking about IPF
Interstitial Lung Disease (ILD) orDiffuse Parenchymal Lung Disease (DPLD)
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
Any process that results in inflammatory-fibrotic infiltration of the alveolar septa resulting in effects on the capillary endothelium and alveolar epithelium.
“Death occurred about three months and a half after the onset of the acute disease and the lung was two thirds of the normal size, grayish in color, and hard as cartilage. Microscopically these areas showed advanced fibrotic changes and great thickening of the alveolar walls.” - Sir William Osler, 1892
Generic term used to describe many conditions that cause breathlessness and/or cough and are associated with radiographic bilateral lung abnormalities.
INTERSTIAL LUNG DISEASESConnective Tissue DiseasesSclerodermaPolymyositis-DermatomyositisSystemic Lupus ErythematosusRheumatoid ArthritisMixed Connective Tissue DiseaseAnkylosing Spondyitis
Treatment-Related / Drug-InducedAntibiotics – nitrofurantoin, sulfasalazineAntiarrhythmics – amiodarone, propanololAnti-inflammatories – gold, penacillamineAnti-convulsants – dilantinChemotherapeutic agents – bleomycin, cyclophosphamide, methotrexate, azathioprineTherapeutic radiationOxygen toxicityNarcotics
Primary (Unclassified) SarcoidosisLangerhans cell histiocytosisAmyloidosisPulmonary vasculitisLipoid pneumoniaLymphangitic carcinomatosisBronchoalveolar carcinomaPulmonary lymphomaGaucher’s DiseaseNiemann-Pick DiseaseHermansky-Pudlak syndromeNeurofibromatosisLymphangioleiomyomatosisTuberous SclerosisARDSAIDSBone Marrow TransplantationPostinfectiousEosinophilic pneumoniaAlveolar ProteinosisDiffuse Alveolar Hemorrhage SyndromesAlveolar microlithiasisMetastatic calcification
Occupational and Environmental Diseases
Inorganic Organic
Silicosis Bird breeder’s lungAsbestosis Farmer’s lungHard-metal pneumoconiosis Bacteria – e.g. NTB mycobacteriaCoal worker’s pneumoconiosis Fungi – e.g. AspergillusBerylliosis Animal protein – e.g. AvianAluminum oxide fibrosis Chemical sensitizers - Talc pneumoconiosis e.g. isocyanatesSiderosis (arc welder)Stannosis (tin)
Idiopathic Fibrotic DisordersAcute interstitial pneumonitis (Hamman-Rich syndrome)Idiopathic Pulmonary FibrosisFamilial Idiopathic Pulmonary FibrosisDesquamative intersitial pneumonitisRespiratory bronchiolitisCryptogenic organizing pneumoniaNonspecific interstitial pneumonitisLymphocytic interstitial pneumonia (Sjögrens Syndrome, AIDS, Hashimoto’s)Autoimmune pulmonary fibrosis (inflammatory bowel disease, PBC, ITP, AIHA)
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med. 2002
QUICK HISTORY OF IIP
In 1969, Liebow and Carrington described 5 types of chronic interstitial pneumonias based on histology:
1.Usual interstitial pneumonia (UIP)2.Bronchiolitis obliterans interstitial pneumonia and diffuse alveolar damage (BIP)3.Desquamative interstitial pneumonia (DIP)4.Lymphocytic interstitial pneumonia (LIP)5.Giant cell interstitial pneumonia (GIP)
In 2002, the ATS/ERS published their consensus classification of IIP based on Clinical-Radiologic-Pathologic categories:
Clinical-Radiologic-Pathologic Diagnosis Histologic Pattern
Idiopathic Pulmonary Fibrosis (Cryptogenic fibrosing alveolitis)
Usual interstitial pneumonia
Nonspecifiic interstitial pneumonia (provisional)
Nonspecific interstitial pneumonia
Cryptogenic organizing pneumonia Organizing pneumonia
Acute interstitial pneumonia Diffuse alveolar damage
Respiratory bronchiolitis ILD Respiratory bronchiolitis
Desquamative interstitial pneumonia Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia Lymphoid interstitial pneumonia
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias, Am J Respir Crit Care Med.
USUAL INTERSTITIAL PNEUMONIA PATTERN
The UIP pattern can be seen in the following conditions:o IPFo Familial IPFo Collagen vascular diseaseso Drug toxicityo Chronic hypersensitivity pneumonitiso Asbestosiso Hermansky-Pudlak syndrome
The term UIP is usually reserved for patients in whom the lesion is idiopathic
UIP ≈ IPF
Key histologic features:
1. Dense fibrosis with remodeling of lung architecture , frequent honeycomb fibrosis
2. Fibroblastic foci usually at the edge of scarring3. Patchy lung involvement4. Usually subpleural distribution
Important negative findings:
1. No active lesions typical of other ILD’s2. Lackof marked interstitial chronic inflammation3. No (or rare) granulomas4. No evidence of inorganic dust deposits (e.g. asbestos bodies)5. Lack of marked eosinophilia
USUAL INTERSTITIAL PNEUMONIA PATTERN
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
Idiopathic Pulmonary Fibrosis, Gross and Huninghake, NEJM, 2001.
USUAL INTERSTITIAL PNEUMONIA PATTERN
HONEYCOMB PATTERN
Pictures taken from http://mediswww.meds.cwru.edu/ecsample/yeartwo/pulmonary/interstitial.html
IDIOPATHIC PULMONARY FIBROSIS
ATS definition: “IPF is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause limited to the lungs and associated with a surgical lung biopsy showing a histologic pattern of UIP.”
• A distinct type of chronic fibrosing interstitial pneumonia
• Unknown cause
• Limited to the lungs
• Associated with a histologic pattern of usual interstitial pneumonia (UIP)
EPIDEMIOLOGY
Raghu et. al., Am J of Resp Crit Care Med 2006
Estimated to affect approx 5 million people worldwide
Most cases are sporadic, but rare cases of familial IPF have been described
The most common (and deadly) interstitial lung disease
EPIDEMIOLOGY
Raghu et. al., Am J of Resp Crit Care Med 2006
CLINICAL PRESENTATION
Middle age 50-70s
New onset of progressive exertional dyspnea and non-productive cough
Most have symptoms for 12-18 months prior to definitive evaluation
Constitutional symptoms are uncommon
Weight loss, fever, fatigue, myalgias, or arthralgias occasionally present
Detailed occupational and exposure history
PHYSICAL EXAM
Bibasilar late inspiratory fine crackles (Velcro rales)
Clubbing – 40-75% - late in disease course
Cardiac exam usually normal until middle-late stages- augmented P2, right-sided heave, S3 gallop
Cyanosis
Rash, arthritis, myositis should suggest an alternate diagnosis
Tachypnea
CXR
Idiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.
16% of patients with ILD have normal chest x-rays
Courtesy of W. Richard Webb, MD.
CXR
CXR
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.
PFTs
PFT’s
Source: images.md
Restrictive pattern
Reduced TLC, VC, and/or RV (decreased compliance)
Normal or increased FEV1/FVC
Decreased DLCO
=
ABG
ABG = Hypoxemia, respiratory alkalosis
Decreased PaO2 with rest or exercise
Increased A-a gradient
Other lab tests that might be useful?
Elevated ESRHypergammaglobulinemiaLow-titer positive ANA (21% patients with IPF)RFCirculating immune complexesCryoimmunoglobulins
HIGH RES CT
Can now be used to differentiate IPF from other ILD
Can determine extent and severity of disease activity
Can be used to detect disease, especially in pts with no or minimal changes on CXR
Idiopathic Pulmonary Fibrosis, Gross and Hunninghake, NEJM, 2001.
Peripheral, subpleural fibrosis
Alternating areas of normal tissue
Honeycombing
Traction bronchiectasis
Later stages - more diffuse reticular pattern prominent in lower lung zones associated with thickened interlobular septa
BAL in IPF Role and value of serial BAL in IPF previously unknown
Increased inflammatory cells in IPF, but no predominant type
156 subjects with biopsy proven UIP/IPF enrolled between 1982-1996
BAL within 3 weeks of lung biopsy
Linear relationship between increasing neutrophil percentage and the risk of mortality
Each doubling in the neutrophil percentage was associated with a nearly 30% increased risk of death or transplantation in adjusted analysis ([HR] 1.28; 95% CI, 1.01 to 1.62; p = 0.04). There was no association with lymphocyte or eosinophil percentage.
Suggests that BAL fluid neutrophil percentage at the time of diagnosis of IPF is an independent predictor of time to death.
Kinder et al, Chest, Jan 2008
LUNG BIOPSY
Gold Standard for diagnosis of IPF (and IIP’s)
Large piece of lung parenchyma is required, optimally from several sites
Transbronchial biopsy is only useful for ruling out other disorders
Can be performed by thoracotomy, thorascopy, or VATS
OTHER STUDIES IN IPF
Gallium Scanning (67Ga) used for staging “alveolitis” in ILD, e.g sarcoidosis
Not useful – difficult to interpret, very low specificity
VQ scan reveals patchy, non-segmental areas of decreased Vdecreased perfusion in lower lung zonesincreased perfusion of upper lung zones (due to PH)
ATS/ERS CRITERIA FOR DIAGNOSIS OF IPF IN ABSENCE OF SURGICAL LUNG BIOPSY
Major Criteria:
Exclusion of other known causes of ILD
Abnormal PFTs that include evidence of restriction and impaired gas exchange
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT
Transbronchial lung biopsy or BAL showing no features to support alternative dx
Minor Criteria:
Age > 50
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness greater than 3 months
Bibasilar inspiratory crackles (dry or “Velcro”-type in quality)
ALL of the major criteria plus at least THREE minor criteria.
NATURAL HISTORY / PROGNOSISWorst prognosis of all the ILD’sDisease course is variable5-year survival rate is 30-50%
40% IPF patients die of respiratory failureOthers die of complicating illnesses, mainly CAD and infectionsEnd-stage disease is characterized by severe PH with cor pulmonale that does not improve with oxygenIncidence of bronchogenic carcinoma is increased in patients with IPF
Median survival after diagnosis is less than 3 years
Factors associated with shortened survival:Increased neutrophil countolder agepoor pulmonary function at presentationrecent deterioration in results of PFT’sadvanced fibrosis
ACUTE EXACERBATIONS OF IPF
Several recent clinical trials have shown that multiple subclinical andacute exacerbations lead to decline in pulmonary function
Traditional view: slow, steady decline in lung fuction respiratory failure
Martinez et al, Ann Intern Medicine, 2005
168 patients in the placebo group of a trial evaluating interferon-γ1b (mild-mod IPF)
Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks.
Minimal physiologic deterioration or worsening severity of dyspnea over time
Frequent hospitalizations for respiratory disorders (23%, 21% died)
IPF was the primary cause of death in 89% who diedAcute clinical deterioration preceded death in 47%
Kim et al, Eur Resp J, 2006
Analysis of 147 IPF patients demonstrated 2-year frequency of acute exacerbations was 9.6%
ACUTE EXACERBATIONS OF IPF
Consensus group in 2007 defined acute exacerbation:
Diagnosis of IPF Unexplained development of worsening of dyspnea within 30 days HRCT with new ground-glass abnormalities No evidence of pulmonary infection by ET aspirate or BAL Exclusion of alternative causes, e.g. HF, PE
Treatment: Broad-spectrum antibiotics High-dose steroids (prednisone 1 mg/kg)
GENETIC SUSCEPTIBILITY?
Up to 3% of cases of IPF appear to cluster in families (Familial IPF)
Armanios et al, NEJM 2007.
73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for
mutations in hTERT and hTR (telomerase RT and telomerase RNA) Demonstrated that mutation was inherited in autosomal dominant fashion
with variable penetrance Those with IPF had mutant telomerase and short telomeres Telomeres shorten with each cell division and ultimately lead to apoptosis Proposed that fibrosis occurs due to death of alveolar cells
ASSOCIATED RISK FACTORS
Up to 75% of index patients with IPF are current or former smokers
Latent viral infections have also been reported to have an association
Given the similarity between asbestosis and IPF, is there a causative environmental agent?
Chronic aspiration?
GERD AND IPF
Raghu et al, Eur Resp J, Oct 2006.
65 consecutive patients with IPF were subjected to 24-h pH monitoring and esophageal manometry
133 patients with intractable asthma and GERD used for comparison Prevalence of GERD in IPF patients was 87% but only 47% had symptoms GERD was higher in IPF patients (76% versus 57%; p = 0.020) Despite tx with standard dose PPI, 12/19 still had abnormal pH
Conclusion: GERD is highly prevalent and often clinically occult in patients with IPF, and often does not respond entirely to standard dose PPI
PATHOGENESIS
Originally thought inflammation fibrosis
Animal models
Early IPF is dominated by inflammatory cells
Asymptomatic relatives of patients with familial IPF have evidence of alveolitis in the absence of disease
PROBLEMS: 1) Little inflammation is seen histologically2) Measurements of inflammation do not correlate3) Anti-inflammatory therapies DO NOT WORK!
Alveolar macrophage thought to play a major role
Secretes proinflammatory and profibrotic cytokines
Promote collagen deposition
PATHOGENESIS
Starting around 1998, studies began to demonstrate that inflammation is NOT a prominent finding in most cases of IPF/UIP.
These sites are typical in alveolar epithelial injury
Abnormal wound healing involving epithelial cells and fibroblasts
Activated epithelial cells release potent fibrogenic molecules and cytokines, such as TNFα and TGFβ1
PATHOGENESIS
PATHOGENESIS
TREATMENT
ATS recommendation (2000):
Prednisone + Azathioprine or Cyclophosphamide
Consensus recommendation (2008):
Prednisone + Azathioprine + N-acetylcysteine
STEROIDS
Cochrane Systematic Review in 2003
Fifteen studies were selected as potentially eligible for meta-analysis. After further analysis of full text papers, no RCTs or CCTs were identified as suitable and therefore no data was available for inclusion in any meta-analysis. All studies were excluded due to inadequate methodologies.
Currently there is no evidence to support the routine use of corticosteroids alone in the management of IPF.
AZATHIOPRINE Raghu et al, Am Rev Respir Dis 1991.
• 27 newly diagnosed patients with IPF• Prednisone + Azathioprine vs. Prednisone + Placebo, follow-up 9 years• After 1 year, P+A had better lung function, but was not significant • 43% (6/14) died vs. 77% (10/13)
Side effects: leukopenia,
GI-related
Pro
bab
ility
of
Su
rviv
al
Years
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6 7 8 9
Azathioprine + Prednisone (n = 14)
Prednisone (n = 13)
Raghu G, et al. Am Rev Respir Dis. 1991;144:291-296.
P = 0.02 (age adjusted)
P = 0.16
CYCLOPHOSPHAMIDE Collard et al, Chest, 2004
• Retrospective study looking at 164 patients with IPF from 1984-2002• 82 patients on prednisone and oral cyclophosphamide vs. 82 patients on prednisone alone• No difference in survival from time of initial visit
Multiple other small studies have been unimpressive Toxicity is major (pancytopenia, hemorrhagic cystitis, GI-related)
N-acetylcysteine (NAC)
Demedts et al, NEJM, 2005.
• 182 patients with UIP• Prednisone + Azathioprine + High-dose NAC (600mg TID) vs. P/A• Significant difference in the deterioration of VC and DLCO
at 12 months
Relative difference of 9% and 24% respectively• Oxidant-antioxidant imbalance?
8/75 (11%)Pred+Aza+Placebo
7/80 (9%)NAC+Pred+Aza
Mortality, P = NS
LUNG TRANSPLANT
IPF is the most common ILD among referrals for transplant and the 2nd most frequent disease for which lung transplantation is performed
Criteria: Evidence of UIP plus any of the following:
DLCO < 39% predicted Decrement in FVC > 10% during 6 months Decrease in pulse ox below 88% during 6-minute walk test Honeycombing on HRCT
5-year survival for lung transplant in IPF is 40-50%
SLT has been the standard treatment
Living donor lobar lung transplant (LDLLT) - Date et al, Chest 2005
9 patients with IIP dependent on systemic steroids (up to 50mg/day)Transplant of two lower lobes from two healthy relativesAfter 10-48 months of follow-up 8/9 still alive (one died of acute rejection)
PERFENIDONE
Mechanism of Action:
Included 267 patients in 73 different centers Pirfenidone 1800 mg/day vs. 1200 mg/day vs. placebo VC, SpO2 on exertion, number of acute exacerbations were primary endpoints
At week 52: Difference in VC between groups was 70mL and 80mLNo significant difference in lowest SaO2 on exertion
No significant difference in the number of acute exacerbations Significant difference in progression-free survival
Currently in Phase III trials in the U.S. (CAPACITY)
Phase III trial in Japan ended last month:
inhibits TGF-β-stimulated collagen synthesis decreases the extracellular matrix blocks fibroblast proliferation in-vivo
Adverse effects: rash, GI effects, fatigue
OTHER TREATMENT OPTIONS
Limited data: Methotrexate Cyclosporine Colchicine Penicillamine
Interferon gamma-1b: important in “wound healing” PCRT suggested a possible mortality benefit Large multinational trial (INSPIRE) was stopped when the primary endpoint of mortality benefit was not achieved
Drug Mechanism Status
Bosentan(BUILD-1)
Endothelin receptor agonist
Phase III
Etanercept TNF-α blocker Phase II
Imatinib C-Abl and PDGF TK-inhibitor
Phase II
FG-3019 Anti-CTGF monoclonal Ab
Phase II planned
SUMMARY
IPF is the most common ILD with the worst prognosis
The most important distinction is differentiate IPF from the other IIP’s
Biopsy is the gold standard for diagnosis, histology = UIP pattern with fibroblast foci (hallmark of IPF)
Most common presentation is 50-60 y.o. male with progressive dyspnea and non-productive cough
Most common physical exam findings are “Velcro” rales +/- clubbing
Most important diagnostic studies are CXR, PFT’s, ABG, and HRCT
Higher BAL neutrophil percentage at time of diagnosis = worse prognosis?
If certain clinical criteria are met, can diagnose IPF without biopsy
Acute exacerbations are now recognized to be an important target for therapy
SUMMARY
Possible genetic component involving mutant telomeres, resulting in apoptosis of alveolar cells
There is a high correlation with GERD in IPF
Newly accepted hypothesis that fibrosis is a result of aberrant “wound healing” resulting from repeated injury of unknown cause
There is still no effective therapy for IPF
Current recommendation is steroids + azathioprine + NAC
SLT improves 5-year survival, LDLLT shows promise in advanced disease
Perfenidone will likely be the next option in therapy for IPF
There are a number of novel therapies on the horizon
References
Kinder BW et al. , Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. Vol 133(1): pp 226-32, Jan 2008.
Martinez FJ et al. (IPF Study Group). The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis. Ann Intern Med. Vol 142: pp 963-967, 2005.
Kim DS et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Resp J. Vol 27: pp143-150, 2006.
Selman et al. Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy. Annals of Internal Medicine. Vol 134: 2, pp. 136-151, 2001.
Raghu, G et al . Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, double-blind randomized, placebo-controlled clinical trial. Am. Rev. Respir. Dis. 144: 291-296, 1991.
Collard et al, Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest. 125(6):2169-74, 2004.
Maurits Demedts et al, High-dose acetylcysteine in Idiopathic Pulmonary Fibrosis. NEJM, Vol 353: 2229-2242, 2005.
Armanios MY et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. NEJM 356: 1317-26, 2007.
Mason: Murray & Nadel’s Textbook of Respiratory Medicine, 4th ed. Chapter 53 – Approach to Diagnosis and Management of the Idiopathic Interstitial Pneumonias. King and Schwarz, 2005.
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. Vol 165, pp 277-304, 2002.
Gross and Hunninghake, Idiopathic Pulmonary Fibrosis. NEJM. Vol 345, No 7: pp 517-525, 2001.
Verma and Slutsky , Idiopathic Pulmonary Fibrosis – New Insights. NEJM. Vol 356, No 13: pp 1370-1372, 2007.
Noth and Martinez. Recent Advances in Idiopathic Pulmonary Fibrosis. Chest 132: 637-50, 2007.
Noble PW. Idiopathic Pulmonary Fibrosis: Natural History and Prognosis. Clin Chest Med 27, S11-16, 2006.
American Thoracic Society, Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment. Am. J. Respir. Crit. Care Med., Volume 161, Number 2, 646-664, 2000.
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database of Systematic Reviews 2003, Iss 3.
Raghu G et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. Vol 28(4): 884-5, 2006.
Orens et al. International Guidelines for the Selection of Lung Transplant Candidates: 2006 Update—A Consensus Report From the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. The Journal of Heart and Lung Transplantation. Volume 25, Issue 7, Pages A1-A20, 745-868 (July 2006)
Date et al. A New Treatment Strategy for Advanced Idiopathic Interstitial Pneumonia*: Living-Donor Lobar Lung TransplantationChest, Sep 2005; 128: 1364 – 1370.