Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

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 toxicityNarcoticsPrimary (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



Idiopathic Pulmonary Fibrosis, Gross and Huninghake, NEJM, 2001.


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.”

1. A distinct type of chronic fibrosing interstitial pneumonia 2. Unknown cause 3. Limited to the lungs 4. 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


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 à 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 penetranceThose with IPF had mutant telomerase and short telomeresTelomeres shorten with each cell division and ultimately lead to apoptosisProposed 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 à 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

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S

urv

ival

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

Documents

Idiopathic Pulmonary Fibrosis