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Idiopathic Pulmonary Fibrosis

Brian D. Southern

Senior Talk August 2008


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
Interstitial Lung Disease (ILD) or
Diffuse Parenchymal Lung Disease (DPLD)

 Any process that results in

inflammatory-fibrotic infiltration of the
alveolar septa resulting in effects on the
capillary endothelium and alveolar

 Generic term used to describe many

conditions that cause breathlessness
and/or cough and are associated with
radiographic bilateral lung abnormalities.
Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.

“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
Connective Tissue Diseases Treatment-Related / Drug-Induced
Scleroderma Antibiotics – nitrofurantoin, sulfasalazine
Polymyositis-Dermatomyositis Antiarrhythmics – amiodarone, propanolol
Systemic Lupus Erythematosus Anti-inflammatories – gold, penacillamine
Rheumatoid Arthritis Anti-convulsants – dilantin
Mixed Connective Tissue Disease Chemotherapeutic agents – bleomycin, cyclophosphamide,
Ankylosing Spondyitis methotrexate, azathioprine
Therapeutic radiation
Oxygen toxicity
Primary (Unclassified)
Langerhans cell histiocytosis
Occupational and Environmental Diseases
Pulmonary vasculitis
Inorganic Organic
Lipoid pneumonia
Lymphangitic carcinomatosis
Silicosis Bird breeder’s lung
Bronchoalveolar carcinoma
Asbestosis Farmer’s lung
Pulmonary lymphoma
Hard-metal pneumoconiosis Bacteria – e.g. NTB mycobacteria
Gaucher’s Disease
Coal worker’s pneumoconiosis Fungi – e.g. Aspergillus
Niemann-Pick Disease
Berylliosis Animal protein – e.g. Avian
Hermansky-Pudlak syndrome
Aluminum oxide fibrosis Chemical sensitizers -
Talc pneumoconiosis e.g. isocyanates
Siderosis (arc welder)
Tuberous Sclerosis
Stannosis (tin)
Bone Marrow Transplantation Idiopathic Fibrotic Disorders
Postinfectious Acute interstitial pneumonitis (Hamman-Rich syndrome)
Eosinophilic pneumonia Idiopathic Pulmonary Fibrosis
Alveolar Proteinosis Familial Idiopathic Pulmonary Fibrosis
Diffuse Alveolar Hemorrhage Syndromes Desquamative intersitial pneumonitis
Alveolar microlithiasis Respiratory bronchiolitis
Metastatic calcification Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonitis
Lymphocytic 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
 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
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 Usual interstitial pneumonia

fibrosing alveolitis)
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.

The UIP pattern can be seen in the following conditions:

o Familial IPF
o Collagen vascular diseases
o Drug toxicity
o Chronic hypersensitivity pneumonitis
o Asbestosis
o Hermansky-Pudlak syndrome

The term UIP is usually reserved for patients in whom the

lesion is idiopathic


Key histologic features:

1. Dense fibrosis with remodeling of lung architecture , frequent honeycomb

2. Fibroblastic foci usually at the edge of scarring
3. Patchy lung involvement
4. Usually subpleural distribution

Important negative findings:

1. No active lesions typical of other ILD’s

2. Lackof marked interstitial chronic inflammation
3. No (or rare) granulomas
4. No evidence of inorganic dust deposits (e.g. asbestos bodies)
5. Lack of marked eosinophilia

Mason: Murray & Nadel's Textbook of Respiratory

Medicine, 4th ed.

Idiopathic Pulmonary Fibrosis, Gross and

Huninghake, NEJM, 2001.

Pictures taken from


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

• Unknown cause
• Limited to the lungs
• Associated with a histologic pattern of usual interstitial
pneumonia (UIP)
 Estimated to affect approx 5 million people worldwide

 The most common (and deadly) interstitial lung disease

 Most cases are sporadic, but rare cases of familial IPF have
been described

Raghu et. al., Am J of Resp Crit Care Med 2006


Raghu et. al., Am J of Resp Crit Care Med 2006


Middle age 50-70s

New onset of progressive exertional dyspnea and non-

productive cough

Most have symptoms for 12-18 months prior to definitive


Constitutional symptoms are uncommon

Weight loss, fever, fatigue, myalgias, or arthralgias

occasionally present
Detailed occupational and exposure history

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


Rash, arthritis, myositis should suggest an alternate


16% of patients with

ILD have normal
chest x-rays

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

Courtesy of W. Richard Webb, MD.


Mason: Murray & Nadel's Textbook of Respiratory Medicine, 4th ed.

PFT’s = Restrictive pattern

Reduced TLC, VC, and/or RV (decreased compliance)

Normal or increased FEV1/FVC

Decreased DLCO

ABG = Hypoxemia, respiratory alkalosis

Decreased PaO2 with rest or exercise

Increased A-a gradient

Other lab tests that might be useful?

Elevated ESR
Low-titer positive ANA (21% patients with IPF)
Circulating immune complexes
Can be used to detect disease, especially in pts with no
or minimal changes on CXR
Can determine extent and severity of disease activity
Can now be used to differentiate IPF from other ILD

Peripheral, subpleural fibrosis

Alternating areas of normal tissue


Traction bronchiectasis

Later stages - more diffuse

reticular pattern prominent in
lower lung zones associated
with thickened interlobular

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

 Role and value of serial BAL in IPF previously unknown

 Increased inflammatory cells in IPF, but no predominant type

 Kinder et al, Chest, Jan 2008

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


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.
 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


 Gallium Scanning (67 Ga) 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 V

decreased perfusion in lower lung zones
increased perfusion of upper lung zones (due to PH)
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.

Worst prognosis of all the ILD’s
Disease course is variable
5-year survival rate is 30-50%
Median survival after diagnosis is less than 3 years
40% IPF patients die of respiratory failure
Others die of complicating illnesses, mainly CAD and
End-stage disease is characterized by severe PH with cor
pulmonale that does not improve with oxygen
Incidence of bronchogenic carcinoma is increased in
patients with IPF
Factors associated with shortened survival:
Increased neutrophil count
older age
poor pulmonary function at presentation
recent deterioration in results of PFT’s
advanced fibrosis
 Traditional view: slow, steady decline in lung fuction  respiratory failure
 Several recent clinical trials have shown that multiple subclinical and
acute exacerbations lead to decline in pulmonary function

 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 died

Acute 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
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)
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

 Up to 75% of index patients with IPF are current or former


 Latent viral infections have also been reported to have an


 Given the similarity between asbestosis and IPF, is there a

causative environmental agent?

 Chronic aspiration?

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

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

Alveolar macrophage thought to play a major role

Secretes proinflammatory and profibrotic cytokines

Promote collagen deposition

PROBLEMS: 1) Little inflammation is seen histologically

2) Measurements of inflammation do not correlate
3) Anti-inflammatory therapies DO NOT WORK!
 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

ATS recommendation (2000):

Prednisone + Azathioprine or Cyclophosphamide

Consensus recommendation (2008):

Prednisone + Azathioprine + N-acetylcysteine


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.
 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)
P = 0.16
1.0 P = 0.02 (age adjusted)

Probability of
 Side effects: Azathioprine +
leukopenia, Survival 0.6 Prednisone (n = 14)
Prednisone (n = 13)

0 1 2 3 4 5 6 7 8 9

Raghu G, et al. Am Rev Respir Dis. 1991;144:291-296.

 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?

Mortality, P =

7/80 (9%)

Pred+Aza+ 8/75 (11%)

 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 relatives
After 10-48 months of follow-up 8/9 still alive (one died of acute rejection)

Mechanism of Action:  inhibits TGF-β-stimulated collagen synthesis

 decreases the extracellular matrix
 blocks fibroblast proliferation in-vivo

Currently in Phase III trials in the U.S. (CAPACITY)

Phase III trial in Japan ended last month:

 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 80mL

No significant difference in lowest SaO2 on exertion
No significant difference in the number of acute exacerbations
Significant difference in progression-free survival

Adverse effects: rash, GI effects, fatigue

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 Endothelin Phase III
(BUILD-1) receptor agonist

Etanercept TNF-α blocker Phase II

Imatinib C-Abl and PDGF Phase II
FG-3019 Anti-CTGF Phase II planned
monoclonal Ab

Limited data:  Methotrexate

 Cyclosporine
 Colchicine
 Penicillamine

 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


 Possible genetic component involving mutant telomeres, resulting in

apoptosis of alveolar cells
 Newly accepted hypothesis that fibrosis is a result of aberrant “wound
healing” resulting from repeated injury of unknown cause
 There is a high correlation with GERD in IPF
 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
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.

Verma and Slutsky , Idiopathic Pulmonary Fibrosis – New Insights. NEJM. Vol 356, No 13: pp 1370-1372, 2007.

Gross and Hunninghake, Idiopathic Pulmonary Fibrosis. NEJM. Vol 345, No 7: pp 517-525, 2001.

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,

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.

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,
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 Transplantation
Chest, Sep 2005; 128: 1364 – 1370.