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) 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
epithelium.

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

INTERSTIAL LUNG DISEASES

Connective Tissue Diseases
Scleroderma
Polymyositis-Dermatomyositis
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Mixed Connective Tissue Disease
Ankylosing Spondyitis
Primary (Unclassified)
Sarcoidosis
Langerhans cell histiocytosis
Amyloidosis
Pulmonary vasculitis
Lipoid pneumonia
Lymphangitic carcinomatosis
Bronchoalveolar carcinoma
Pulmonary lymphoma
Gauchers Disease
Niemann-Pick Disease
Hermansky-Pudlak syndrome
Neurofibromatosis
Lymphangioleiomyomatosis
Tuberous Sclerosis
ARDS
AIDS
Bone Marrow Transplantation
Postinfectious
Eosinophilic pneumonia
Alveolar Proteinosis
Diffuse Alveolar Hemorrhage Syndromes
Alveolar microlithiasis
Metastatic calcification

Treatment-Related / Drug-Induced
Antibiotics nitrofurantoin, sulfasalazine
Antiarrhythmics amiodarone, propanolol
Anti-inflammatories gold, penacillamine
Anti-convulsants dilantin
Chemotherapeutic agents bleomycin, cyclophosphamide,
methotrexate, azathioprine
Therapeutic radiation
Oxygen toxicity
Narcotics
Occupational and Environmental Diseases
Inorganic

Organic

Silicosis
Asbestosis
Hard-metal pneumoconiosis
Coal workers pneumoconiosis
Berylliosis
Aluminum oxide fibrosis
Talc pneumoconiosis
Siderosis (arc welder)
Stannosis (tin)

Bird breeders lung

Farmers lung
Bacteria e.g. NTB mycobacteria
Fungi e.g. Aspergillus
Animal protein e.g. Avian
Chemical sensitizers e.g. isocyanates

Idiopathic Fibrotic Disorders

Acute interstitial pneumonitis (Hamman-Rich syndrome)
Idiopathic Pulmonary Fibrosis
Familial Idiopathic Pulmonary Fibrosis
Desquamative intersitial pneumonitis
Respiratory bronchiolitis
Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonitis
Lymphocytic interstitial pneumonia (Sjgrens Syndrome, AIDS, Hashimotos)
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 IPF
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

UIP IPF

USUAL INTERSTITIAL PNEUMONIA PATTERN

Key histologic features:

1. Dense fibrosis with remodeling of lung architecture , frequent honeycomb
fibrosis
2. Fibroblastic foci usually at the edge of scarring
3. Patchy lung involvement
4. Usually subpleural distribution

Important negative findings:

1.
2.
3.
4.
5.

No active lesions typical of other ILDs

Lackof marked interstitial chronic inflammation
No (or rare) granulomas
No evidence of inorganic dust deposits (e.g. asbestos bodies)
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.

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
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

EPIDEMIOLOGY

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

Pathogenesis IPF

- Progressive fibrotic reaction is associated with an

epithelial-dependent fibroblast-activated process
- Deregulatred adaptative immune mechanisms and
subsequent inflammation
- Two different cellular routes lead to lung fibrosis:
- the inflammatory pathway, and
- the epithelial pathway

1. Epithelial injury and activation

- mutations in surfactant protein C (expressed exclusively
by AEC II)
- polymorphism in the promoter region of mucin 5B gene
(MUC5B). MUC5B is a gel-forming mucin expressed by
bronchial epithelial cells
- gene ELMOD2 (4q31): essential for cellular processes
and an antiviral effect in AEC (is less expressed in IPF)
- deregulation of some embryological pathways might
explain the abnormal behavior of AEC and fibroblasts in
IPF:
- Wnt- -catenin pathway is switched on in both cell
types

1. Epithelial injury and activation

- phosphatase and tensin homologue (PTEN) is
downregulated in myofibroblasts within fibroblastic foci
(resistance to apoptosis)
- sonic hedgehog (enables cells to evade apoptosis and
cell cycle arrest) is strongly expressed in epithelial cells
lining honeycomb cysts
- bone morphogenetic proteins (belong to TGF
superfamily) is inhiited by gremlin, a strong protein
antagonist attenuate phosphorylation mediated by bmp
increased TGF 1-induced EMT and decreased
myofibroblast apoptosis

2. Profibrotic effects of aberrantly activated AECs in the lung

microenvironment
- the activation of the coagulation cascade:

- FT-F VIIa-F X assembles on the alveolar epithelium

stimulates fibroblasts. Fibrin and fibronectin stimulate
EMT

- AEC are the primary source of chemotactic factors or

mitogenes for mesenchymal cells (PGF, TGF , TNF,
endotelin1)
- there is an influx of circulating fibrocytes into lungs.
Fibrocytes markers of hemopoietic cells (CD45, CD34),
mesenchymal (collagen I, fibronectin) and CXCR4

2. Profibrotic effects of aberrantly activated AECs in the lung

microenvironment
- EMT: epithelial cells acquire mesenchymal properties
and increase their capability to move and to synthesise
interstitial matrix. Myofibroblasts: prosurfactant proteins
(epithelial), alpha-SMA, N-cadherin (mesenchymal),
keratin 18 (epithelial)
- three main factors drive the differentiation of fibroblasts
to myofibroblasts: high mechanical stress, local increase
of active TGF 1, presence of specialized matrix proteins
(fibronectin). TGF 1 and endothelin 1 promote fibroblast
resistance to apoptosis through P13K/AKT pathway and
deficiency of PGE2

3. The absent type I pneumocytes

- AEC type I cover more than 90% of the alveolar surface
area
- patients with IPF have an important loss of type I
pneumocytes reduction of some important antifibrotic
molecules (caveolin 1)
- loss of RAGE (AEC type I) decreased binding of AEC
type I to the basement membrane, thus prevetniong the
proper re-epithelialisation of alveoli during fibrogenesis

4. Matrix metalloproteinases
- MMP7, MMP1 and MMP2 genes are highly expressed in
IPF
- most of these MMP are localized in the AEC
- MMP2 is increased in alveolar and bronchiolar epithelial
cells and in fibroblastic foci
- increased expression of MMP1 is associated with two
gene polymorphisms

5. Angiogenesis
- an aberrant vascular remodelling occurs in lungs
affected by IPF: fibrotic areas have fewer blood vessels,
whereas adjacent non-fibrotic tissue is highly
vascularized

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

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!

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 TNF and TGF1

PATHOGENESIS

CLINICAL PRESENTATION
Middle age 50-70s
New onset of progressive exertional dyspnea and nonproductive 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)
Tachypnea
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

CXR
16% of patients with
ILD have normal
chest x-rays

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

Courtesy of W. Richard Webb, MD.

CXR

CXR

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

PFTs
PFTs

= Restrictive pattern

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

Normal or increased FEV1/FVC
Decreased DLCO

Source: images.md

ABG
ABG

Hypoxemia, respiratory alkalosis

Decreased PaO2 with rest or exercise

Increased A-a gradient

Other lab tests that might be useful?

Elevated ESR
Hypergammaglobulinemia
Low-titer positive ANA (21% patients with IPF)
RF
Circulating immune complexes
Cryoimmunoglobulins

HIGH RES CT
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
Honeycombing
Traction bronchiectasis
Later stages - more diffuse
reticular pattern prominent in
lower lung zones associated
with thickened interlobular
septa

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

HIGH RES CT

Am J Respir Crit Care Med Vol 183. pp 788824, 2011

BAL in IPF
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
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.

LUNG BIOPSY
Gold Standard for diagnosis of IPF (and IIPs)
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 V

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

Histopathological Criteria

Am J Respir Crit Care Med Vol 183. pp 788824, 2011

Surgical lung biopsy specimens demonstrating

UIP pattern

(A) Scanning power microscopy showing a patchy process with honeycomb

spaces (thick arrow), some preserved lung tissue regions (thin arrow), and
fibrosis extending into the lung from the subpleural regions. (B) Adjacent
to the regions of more chronic fibrosis (thick arrow) is a fibroblast focus
(asterisk), recognized by its convex shape and composition of edematous
fibroblastic tissue, suggestive of recent lung injury
Am J Respir Crit Care Med Vol 183. pp 788824, 2011

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 / PROGNOSIS

Worst prognosis of all the ILDs
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
infections
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 PFTs
advanced fibrosis

Clinical phenotypes and prognosis

- patients with IPF have a median survival of 2.5-3.5 years

after diagnosis
- worse prognosis is associated with old age (>70 years of
age), smoking history, low body-mass index, severe
physiological impairment, large radiological extent of
disease and pulmonary hypertension

Clinical phenotypes and prognosis

Stable or slowly progressive course

- patients have decreased lung volumes and capacities,
with hypoxemia at rest that worsens with exercise

Clinical phenotypes and prognosis

Accelerated variant
- a subgroup of patients, mainly male cigarette smokers,
has a rapidly progressive course with shortened survival
- the upregulated genes in the group whose disease
progressed rapidly included members of the MAPK-EGR1HSP70 (mitogen-activated protein kinase-early growth
response gene protein-heat shock protein 70) pathway,
which regulate cigarette smoke-induced inflamation

Clinical phenotypes and prognosis

Acute exacerbation
- acute exacerbation of IPF is defined by rapid
deterioration of the disease in the absence of infection,
heart failure, pulmonary embolism, or other identifiable
causes
- diagnosis is made by a combination of clinical,
physiological and radiographical findings

RISK OF MORTALITY IN IDIOPATHIC

PULMONARY FIBROSIS

Am J Respir Crit Care Med Vol 183. pp 788824, 2011

ACUTE EXACERBATIONS OF IPF

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-1b (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
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)

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

Probability of
Survival

1.0

P = 0.16
P = 0.02 (age adjusted)

0.8

Azathioprine +
Prednisone (n = 14)

0.6
0.4

Prednisone (n = 13)

0.2
0

0 1 2 3 4 5 6 7 8 9

Years

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

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?

Mortality, P =
NS
NAC+Pred+Aza
Pred+Aza+
Placebo

7/80 (9%)
8/75 (11%)

LUNG TRANSPLANT
IPF is the most common ILD among referrals for transplant and the 2 nd
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)

PERFENIDONE
Mechanism of Action:

inhibits TGF--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

OTHER TREATMENT OPTIONS

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- blocker

Phase II

Imatinib

C-Abl and PDGF Phase II

TK-inhibitor

FG-3019

Anti-CTGF
monoclonal Ab

Limited data:

Methotrexate
Cyclosporine
Colchicine
Penicillamine

Phase II
planned

SUMMARY
IPF is the most common ILD with the worst prognosis
The most important distinction is differentiate IPF from the other IIPs
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, PFTs, 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
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

References
Mason: Murray & Nadels Textbook of Respiratory Medicine, 4 th 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,
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.
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, 646664, 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 UpdateA 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.

Noutati terapeutice in IPF

PIRFENIDON
studiu faza 3 (ASCEND study group);
555 pts cu IPF- pirfenidon (2403mg/zi) sau placebo;
End-point-uri primare modificari FVC sau deces la 52 de
saptamani;
End-pointu-uri secundare: testul distantei parcurse in 6 min,
supravietuire fara progresie, dispneea si deces de orice forma;
Rezultate: (grup pirfenidon)
-scaderea cu 47.9% a nr. de pacienti care au avut o reducere cu
peste 10% a FVC sau au decedat;
- crestere cu 132.5% a proportiei de pacienti care nu au avut un
declin al FVC (p<0.001). Pirfenidonul a redus declinul in testul
distantei (p=0.04) si a imbunatatit supravietuirea (p<0.001)
Ef. secundare: gastrointestinale si cutanate;

NINTEDANIB
inhibitor intracelular pentru multiple tyrosin kinaze (VEGF,
FGF, PDGF);
STUDIU FAZA 3 (INPULSIS 1 si 2)
1066 pts randomizati 3:2 nintedanib (150mg x 2/zi) sau
placebo 52 sapt;
End-point primar: rata anuala de declin FVC
End-point secundar: timpul pana la prima exacerbare acuta
si scorul total al St. George`s Respiratory Questionnaire
(simptome, activitate si impact).
Rezultate:
Nintedanib reduce declinul FVC (hazard value: 0.38; 95%
0.19-0.77, p<0.005)
Ef. Secundare: diaree.