IDIOPATHIC

PULMONARY
FIBROSIS (IPF)
PROF A
HAMMANGABDO
MBBS, FWACP
 OUTLINE
• INTRODUCTION
• CLASSIFICATION
• EPIDEMIOLOGY
• AETIOLOGY
• PATHOPHYSIOLOG
Y
• CLINICAL
FEATURES
• DIAGNOSIS
• DIFFERENTIALS
• COMPLICATIONS
• PROGNOSIS
• CONCLUSION
 INTRODUCTION
• Idiopathic pulmonary fibrosis (IPF) a.k.a
cryptogenic fibrosing alveolitis, is a specific
form of chronic, progressive fibrosing interstitial
pneumonia of unknown cause,
– primarily occurring in older adults,
– limited to the lungs,
– associated with histopathologic and/or
radiologic pattern of usual interstitial pneumonia
(UIP)
• IPF portends a poor prognosis
• No proven effective therapies are available for
its treatment beyond lung transplantation.
 INTODUCTION2
• IPF is an interstitial lung disease (ILD)
• ILDs represent a large number of conditions that
involve the parenchyma of the lung—the
alveoli, the alveolar epithelium, the capillary
endothelium, and the spaces between these
structures, as well as the perivascular and
lymphatic tissues.
• Heterogeneous group of disorders classified
together because of similar clinical,
roentgenographic, physiologic, or
pathologic manifestions
 CLASSIFICATION
• ILD can be broadly classified based on major
histo-pathological finding into
(1)those associated with predominant inflammation
and fibrosis and
(2)those with a predominantly granulomatous
reaction
• Each can be subdivided into
– Known cause
– Unknown cause
 Inflammation/Fibrosis
Known Cause • Smoking-related
• Asbestosis – Desquamative
interstitial pneumonia
• Fumes, gases (DIP)
• Drugs (antibiotics, – Respiratory bronchiolitis–
amiodarone, gold) associated interstitial lung
and chemotherapy disease
drugs – Langerhans cell
granulomatosis
• Radiation (eosinophilic granuloma of
• Aspiration pneumonia the lung)
• Residual of acute
respiratory
distress syndrome
 Inflammation/Fibrosis
• Unknown Cause • Connective tissue diseases
• Idiopathic – Systemic lupus
interstitial erythematosus, rheumatoid
arthritis, ankylosing
pneumonias (IIP) spondylitis, systemic
– Idiopathic sclerosis, Sjögren's syndrome,
pulmonary fibrosis polymyositis-
– Acute interstitial dermatomyositis
pneumonia • Pulmonary hemorrhage
– Cryptogenic organizing syndromes
pneumonia (bronchiolitis – Goodpasture's
obliterans with syndrome, idiopathic
organizing pneumonia) pulmonary
– Nonspecific interstitial hemosiderosis, isolated
pneumonia pulmonary capillaritis
 Inflammation/Fibrosis
• Lymphocytic infiltrative
disorders (lymphocytic
interstitial pneumonitis
assd with CTD)
• Eosinophilic pneumonias
• Lymphangioleiomyomatosis
• Amyloidosis
• Inherited diseases
– Tuberous sclerosis,
neurofibromatosis,
Niemann- Pick disease,
Gaucher's disease,
Hermansky-Pudlak syndrome
• Gastrointestinal or liver
diseases (Crohn's disease,
primary biliary cirrhosis,
chronic active hepatitis,
ulcerative colitis)
• Graft-versus-host disease
(bone marrow
transplantation; solid
organ transplantation)
 Granulomatous
•Known Cause • Lymphomatoid
• Hypersensitivity • granulomatosis
pneumonitis • Sarcoidosis
(organic dusts) • Granulomatous
• Inorganic dusts: • vasculitides
• beryllium, silica
• Langerhans'
• Unknown cause cell
• Bronchocentric granulomatosis
• granulomatosis • Wegener's
• granulomatosis
• Allergic granulomatosis
of Churg-Strauss
 EPIDEMIOLOGY
• IPF is the commonest of all Idiopathic Interstitial
Pneumonias (IIPs)
• Worldwide incidence
– 10.7 cases per 100,000 person-years for males and
7.4
cases per 100,000 person years for females.
• Worldwide prevalence
– 20 cases per 100,000 persons for males and 13 cases
per 100,000 persons for females.
• Kim DS, Collard HR, King TE., Jr Classification and natural history of the idiopathic interstitial pneumonias. Proc Am
Thorac Soc 2006;3:285–92 .
 EPIDEMIOLOGY
USA
• Age and sex adjusted incidence
– 8.8-17.4 per 100,000 person-years a
• Prevalence
– 27.4-63/100,000 person years a

• Nigeria – case reportb

• a-Fernandez Perez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. Jan 2010;137(1):129-37
• b-A rare case of cor pulmonale secondary to idiopathic pulmonary fibrosis in Nigeria Raphael Chinedu Anakwue et al
 EPIDEMIOLOGY
• Age
– >50yrs

• Sex prevalence
– >M:F (55yrs and older)

• Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence

of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. Oct 1 2006;174(7):810-
6
 AETIOLOGY
• Remains undefined
• However, some inciting agents have
been implicated
– Cigarette smoking
– Smoke
– Environmental pollutants
– Viral infections
– Gastroesophageal reflux disease
– Chronic aspiration
– Genetic basis : <5%
 PATHOGENESIS
• Previous theory - generalized inflammation
progressed
to widespread parenchymal fibrosis.
• Current theory - IPF is an epithelial-fibroblastic
disease, in which unknown endogenous or
environmental stimuli disrupt the homeostasis of
alveolar epithelial cells, resulting in diffuse
epithelial cell activation and aberrant epithelial cell
repair.

 Re-establishing an intact epithelium following injury

is a key component of normal wound healing.
 PATHOGENESIS
• In IPF, exposure to an inciting agent in a
susceptible host may lead to the initial
alveolar epithelial damage
• Following injury, aberrant activation of
alveolar
epithelial cells leading to
– 1) release of potent fibrogenic cytokines and
growth factors, eg. TNF-α, TGF-β, platelet-derived
growth factor, insulin-like growth factor-1
– These are involved in the migration and
proliferation of fibroblasts and the transformation
of fibroblasts into myofibroblasts
 PATHOGENESIS
– 2) provokes the
migration, proliferation,
and activation of
mesenchymal cells with
the formation of
fibroblastic/myofibrobla
s tic foci
– myofibroblasts
secrete extracellular
matrix proteins
 PATHOGENESIS
• Failure of apoptosis leads to myofibroblast
accumulation, exuberant extracellular
matrix protein production, persistent tissue
contraction, and pathologic scar formation
 PATHOGENESIS
• TGF-β has been shown to promote an
antiapoptotic phenotype in fibroblasts
• Research has shown that apoptosis
resistance in the fibroblasts and
myofibroblasts participating in the repair of
the alveolar epithelium may contribute to
the persistent and/or progressive fibrosis in
idiopathic pulmonary fibrosis.
 PATHOGENESIS
Genetic basis
– Mutant telomerase
• Telomerase is a specialized polymerase
that adds telomere repeats to the ends of
chromosomes, helping to offset shortening
that occurs during DNA replication.
• TGF-β negatively regulates
telomerase activity- mutation
 PATHOGENESIS
• This telomere shortening could promote the
loss of alveolar epithelial cells, resulting in
aberrant epithelial cell repair, and therefore
should be considered as another potential
contributor to the pathogenesis of
idiopathic pulmonary fibrosis
 PATHOGENESIS
– Surfactant protein C
• Genetic mutations in serum surfactant
protein C have been discovered in some
individuals with familial pulmonary fibrosis.
• These mutations in serum surfactant protein
C may damage type II alveolar epithelial cells
 PATHOGENESIS
– Caveolin-1
• Caveolin-1 limits TGF-β–induced production
of extracellular matrix proteins and restores
the alveolar epithelial-repair process.
• It has been observed that the expression of
caveolin-1 is reduced in lung tissue from
patients with idiopathic pulmonary
fibrosis.
 CLINICAL FEATURES
• SYMPTOMS Systemic
• Gradual onset, often symptoms
greater than 6 months, (uncommon)
Weight loss
• of dyspnea – Low-grade
exertional, fevers
• progressive Fatigue
Arthralgias
•
Myalgias
• and/or a nonproductive

•
cough
 CLINICAL FEATURES
• Approximately 5% of patients are
asymptomatic at diagnosis – routine
chest radiograph/lung biopsy
• In these group however, symptoms
developed approximately 1000 days after the
recognition of the radiographic abnormality a

• a-Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic
interstitial pneumonias. Proc Am Thorac Soc. Jun 2006;3(4):285-92.
 CLINICAL FEATURES
• It is critical to obtain a complete history,
including
– medication history – amiodarone,
bleomycin, nitrofurantoin
– social history
– occupational history
– exposure history
– Review of systems
• To exclude other causes of interstitial
lung disease.
 CLINICAL FEATURES
SIGNS
• Evidence of respiratory distress
• fine bibasilar inspiratory crackles (Velcro
crackles).
• digital clubbing(25-50%)
• Cyanosis
• Aside features of pulm HTN/cor pulmonale,
extra pulmonary involvement does not occur
with idiopathic pulmonary fibrosis
Clubbing of the fingers in idiopathic
pulmonary fibrosis
 CLINICAL FEATURES
• FEATURES OF PULM HTN (20-40%)
– loud P2
– fixed split S2,
– holosystolic tricuspid regurgitation
murmur,
– pedal edema.
– right ventricular heave
– elevation of the jugular venous pressure
 DIAGNOSIS

• If IPF is suspected, diagnosis can be

challenging
 DIAGNOSIS
• A Multidisciplinary Consensus Statement on
the Idiopathic Interstitial Pneumonias
published by the American Thoracic Society
(ATS) and the European Respiratory Society
(ERS) in 2000 proposed specific major and
minor criteria for establishing the diagnosis of
IPF.
• However, in 2011, new simplified and updated
criteria for the diagnosis and management of
IPF were published by the ATS, ERS, together
with the Japanese Respiratory Society (JRS) and
Latin American Thoracic Association (LATA)
 DIAGNOSIS
Currently, a diagnosis of IPF requires:
• Exclusion of known causes of ILD, e.g.,
domestic and occupational environmental
exposures, connective tissue disorders, or drug
exposure/toxicity
• The presence of a typical radiological Usual
Interstitial Pneumonia (UIP) pattern on
HRCT.
• Specific combinations of HRCT and surgical
lung biopsy pattern in patients subjected to
surgical lung biopsy
 IMAGING
High-resolution computed tomography
• an essential component of the
diagnostic pathway in IPF
• IPF is characterized by patchy,
predominantly peripheral, predominantly
subpleural, and bibasilar reticular opacities
• Subpleural honeycombing (< 5-mm round
translucencies with a density equal to that
of air) is also a common finding
Classic subpleural honeycombing (red circle) in
a patient with a diagnosis of idiopathic
pulmonary fibrosis
 IMAGING
• Ground-glass opacities can be found but
are
less extensive than reticular abnormalities.
• Traction bronchiectasis could also be found
A patient with IPF and a confirmed histologic diagnosis of usual interstitial
pneumonia. Note the reticular opacities (red circle) distributed in both lung
bases and the minimal ground-glass opacities (blue circle)
High-resolution computed tomography
scans of the chest of a patient with IPF. The
main features are of a peripheral,
predominantly basal pattern of coarse
reticulation with honeycombing
 IMAGING
• Reticular opacities and honeycombing seen
on HRCT imaging correlates histologically with
fibrosis and honeycombing.
• The presence of subpleural honeycombing,
traction bronchiectasis, and thickened
interlobular septae increase the specificity
of HRCT for diagnosing idiopathic pulmonary
fibrosis
 IMAGING
• Multiple studies have documented that the
accuracy of a confident diagnosis of usual
interstitial pneumonia made on the basis
of HRCT imaging findings by an
experienced observer exceeds 90%a

• a-Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum
of abnormalities, and temporal progression. Proc Am Thorac Soc. Jun 2006;3(4):307-14.
 IMAGING
HRCT Criteria for UIP Pattern:
– UIP pattern requires all 4 features below.
• Subpleural, basal predominance
• Reticular abnormality
• Honeycombing with or without traction
bronchiectasis
• Absence of features listed as inconsistent
with UIP pattern
 IMAGING
Inconsistent with UIP pattern requires any of the 7
features below.
– Upper or mid-lung predominance
– Peribronchovascular predominance
– Extensive ground-glass abnormality (extent greater than
reticular abnormality)
– Profuse micronodules (bilateral, predominantly
upper lobes)
– Discrete cysts (multiple, bilateral, away from areas of
honeycombing)
– Diffuse mosaic attenuation/air-trapping (bilaterally, in 3
or more lobes)
– Consolidation in bronchopulmonary segment(s)/lobe(s)
 IMAGING
Chest Radiography
• Virtually all patients with IPF have an
abnormal chest radiograph at the time
of diagnosis
• lacks diagnostic specificity for
idiopathic pulmonary fibrosis.
 IMAGING
The typical findings :
• Peripheral reticular opacities (netlike
linear and curvilinear densities)
predominantly at the lung bases.
• Honeycombing (coarse reticular pattern)
and lower lobe volume loss can also be
seen.
Chest radiograph of a patient with idiopathic
pulmonary fibrosis showing bilateral lower
lobe reticular opacities (red circles)
A chest radiograph of a patient with IPF. Note
the small lung fields and peripheral pattern of
reticulonodular opacification
 OTHER TESTS
Pulmonary function testing
• Findings are nonspecific and should be used in
conjunction with clinical, radiologic, and
pathologic information to ensure an accurate
diagnosis
• Good for prognostication
• Ventilatory pattern –
Restrictive
– Vital capacity, functional residual capacity, total
lung capacity, and forced vital capacity (FVC) all are
reduced
– Obstructive ventilatory defect, not common; if
present, may suggest the coexistence of COPD.
• Diffusion Capacity of Carbon monoxide (DLco)
–
Reduced
– In IPF, reduced DLCO may precede the development
of abnormal lung volumes
6-Minute walk testing (6MWT)
• marker of functional exercise capacity that
is being increasingly used in the initial and
longitudinal clinical assessment of patients
with idiopathic pulmonary fibrosis
• Markers of increased
mortality
– Patients who have >10% decline in FVC (percent
predicted) over 6 months, have a 2.4-fold
increased risk of death.
– Baseline DLCO below 35% is correlated with
increased mortality.
– So also decline in DLCO greater than 15%
over 1
year
– Desaturation below the threshold of 88% during
the 6MWT
Note:
• in patients who do not desaturate to less
than 88% during a 6-minute walk test
(6MWT), the only strong predictor of
mortality is a progressive decline in FVC
(>10% after 6 mo)
• in patients who desaturate to less than 88%
during a 6MWT, a progressive decline in
DLCO (>15% after 6 mo) is a strong predictor
of increased mortality
• Bronchoalveolar Lavage
(BAL)
– not required for the diagnosis of IPF
– can be useful to exclude other alternative
diagnoses
– may demonstrate the presence of infection,
malignancy, alveolar proteinosis,
eosinophilic pneumonia, or occupational
dusts.

BAL fluid neutrophilia has been demonstrated to

predict early mortality.
• Transthoracic Echocardiography – pulm
• HTN,
ECG – pulmonary HTN
• Up to 30% of patients with IPF have positive
tests for ANA or rheumatoid factor;
however, these titers are generally not high.
– Presence of high titers may suggest the
presence
of a connective-tissue disease.
• CRP, ESR – may be elevated (60-94%)
 LUNG BIOPSY
• According to the updated 2011 guidelines, in
the absence of a typical UIP pattern on HRCT, a
surgical lung biopsy is required for confident
diagnosis
i.e, in patients with possible UIP pattern
or inconsistent with UIP pattern
• Histologic specimens for the diagnosis of IPF must
be taken at least in three different places and be
large enough that the pathologist can comment
on the underlying lung architecture
• Hence, surgical lung biopsy specimen are
obtained through either an open lung biopsy
or video-assisted thoracoscopic surgery
(VATS)
HISTOLOGY
• The histopathological lesion associated with
idiopathic pulmonary fibrosis is -Usual
interstitial pneumonia(UIP).
• characterized by a heterogeneous,
variegated appearance with alternating areas
of healthy lung, interstitial inflammation,
fibrosis, and honeycomb change
• resulting in a patchwork appearance at
low magnification
Photomicrograph of the histopathological appearances of usual
interstitial pneumonia. High-power magnification (on the right) shows a
focus of fibroblastic proliferation, close to an area of fibrosis within which
a mild, non-specific, chronic inflammatory cell infiltrate can be observed.
In the subpleural space, a typical honeycombing aspect can be
recognized.
DIFFERENTIAL DIAGNOSIS
• These are numerous. A few
include
• Other Idiopathic Interstitial
Pneumonias (IIPs)
– nonspecific interstitial pneumonia,
– cryptogenic organizing pneumonia,
– acute interstitial pneumonia
– lymphoid interstitial pneumonia
DIFFERENTIAL DIAGNOSIS
• Other causes of UIP pattern
– Systemic sclerosis/Scleroderma
– Hypersensitivity Pneumonitis
– Rheumatoid Arthritis
– Fibronodular Sarcoidosis
– Asbestosis
– Drug induced fibrosis
DIFFERENTIAL DIAGNOSIS
• Other causes of Ground Glass Appearance on
HRCT
– Heart Failure
– Non Specific Idiopathic Pneumonia (NSIP)
– Desquamative Interstitial Pneumonia
– Hypersensitivity Pneumonitis
 TREATMENT
Can be divided into

Non-pharmacologic

Pharmacologic

Surgical
 TREATMENT
Non-pharmacologic
• Smoking cessation
• Diet: healthy diet/ideal body weight
improves QOL
• Long term Oxygen therapy – when
SpO2<88%
or PaO2< 55mmHg
• Vaccination against influenza
and pneumoccocal infections
 TREATMENT
Pharmacologic
• Novel approaches to treatment are being
developed based on the new theories of
IPF pathogenesis
• No optimal medical treatment of IPF is yet
to be identified
• Hence, risk-benefit ratio important.
 TREATMENT
Antioxidants
• N-acetyl cysteine (NAC) –
gluthathione precursor
• Study of the Effects of High-Dose N-
Acetylcysteine (NAC) in IPF (IFIGENIA
Idiopathic Pulmonary Fibrosis International
Group Exploring N-Ace-tylcysteine I
Annual)
– showed improvement in Dlco and VC over
12 months of follow up
 TREATMENT
• Prednisone, Azathioprine, and N-
acetylcysteine: A Study That Evaluates
Response in IPF(PANTHER-IPF) however,
worsened outcome, and increased admission
rate
Biological response modulators
• Etanercept (anti TNF-alpha) – no improvement
Endothelin receptor antagonists
• Bosentan showed no improvement in 6MWT over
placebo
 TREATMENT
Phosphodiesterase inhibitors
• Sidenafil - no significant difference in
the 6MWT
• However, statistically significant differences
in the change in dyspnea, PaO2, diffusing
capacity, and quality of life were noted.
 TREATMENT
Tyrosine kinase inhibitors
• Imatinib mesylate: potent inhibitor of lung
fibroblast-myofibroblast transformation and
proliferation, through inhibition of platelet-
derived growth factor and transforming
growth factor-β signaling – showed no
significant improvement in lung function
over placebo
 TREATMENT
Antifibrotic agents
• Pirfenidone(Esbriet): a novel compound with
combined anti-inflammatory, antioxidant,
and antifibrotic effects – first approved in
Japan
• Approved by USA FDA in Oct 15 2014
• Colchicine: no improvement in clinical
outcome
Anticoagulant: worsened outcome
 TREATMENT
•Surgical
• Lung transplantation – definitive treatment
– Any patient diagnosed with IPF or probable IPF
should be referred for lung transplantation
evaluation, regardless of the vital capacity
• Indication for listing
– DLCO <39% predicted,
– 10% or greater decrement in FVC during 6 months
of
• follow-up,
– decrease in pulse oximetry below 88% during a
 COMPLICATIONS
Acute exacerbation of IPF (AE-IPF)
• Commonest/most dreaded
• Worsens prognosis
• Rate – 10-57%
• Usually secondary to infections,
pulmonary
embolism, or pneumothorax
 COMPLICATIONS
Diagnostic criteria for an AE-IPF:
• Previous or concurrent diagnosis of idiopathic pulmonary
fibrosis
• Unexplained worsening or development of dyspnea within
30 days
• HRCT scan with new bilateral ground-glass abnormality
and/or consolidation superimposed on a background
reticular or honeycomb pattern consistent with a usual
interstitial pneumonia pattern
• Worsening hypoxemia from a known baseline arterial
blood
gas measurement
• No evidence of pulmonary infection by endotracheal
aspiration or BAL
 OTHER COMPLICATIONS
• Pulmonary hypertension
• Respiratory infection
• Acute coronary syndrome
• Thromboembolic disease
• Adverse medication
effects
• Lung cancer
 PROGNOSIS
•Prognosis is poor
•5yr survival rate – 20-40%
Poor prognostic factors
– >10% decline in FVC (%
predicted) over 6 months
– DLCO <35%
– A decline in DLCO >15%
over 1 year
– Desaturation below the threshold of 88% during the
6MWT
– Progressive decline in DLCO (>15% after 6 mo)
– BAL fluid neutrophilia
– Male sex
– Age >65
 CONCLUSION
• IPF is a chronic progressive fibrosing IP
• Aetiology is unknown
• It’s uncommon but invariably fatal
• Bears semblance to a host of other disease entities
• Diagnosis relies on the clinician integrating the
clinical, laboratory, radiologic, and/or pathologic
features to make a clinical-radiologic-pathologic
correlation that supports its diagnosis.
• No proven effective medical therapy save
lung transplantation.
Thank
You