MAJOR CREDIT SEMINAR

Management of Idiopathic
Pulmonary Fibrosis (IPF)

Submitted by
Dr.Prakash GV
M-5926
Division of Surgery
 Overview
1. Introduction
2. Prevalence
3. Risk factors of IPF
4. Pathogenesis
5. Clinical signs
6. Diagnosis
7. Management
 Introduction
• Hamman and Rich are generally considered to have
been the first to describe idiopathic pulmonary
fibrosis (IPF)
J Homolka, 1987

• Chronic, progressive disease characterized by the

aberrant accumulation of fibrotic tissue in the lungs
parenchyma, associated with significant morbidity
Sgalla et al., 2018

• Idiopathic pulmonary fibrosis (IPF) is a rapidly fatal

condition of unknown cause
Ian M Rogers, 2017
• Progressive life-threatening disease that is
characterized anatomically by scarring of the lungs
and symptomatically by exertional dyspnea
Weycker et al., 2007

• IPF a fibrotic lung disease characteristically

demonstrates a progressive reduction in lung
volumes, impaired gas exchange, dyspnea, and death
Daniels et al., 2010

• Chronic, progressive, irreversible, and usually lethal

lung disease of unknown cause
Selman et al., 2011
 Prevalence
• Annual incidence is 4.6 and 16.3 per 100 000 and the
prevalence is 13 to 20 cases per 100000
Selman et al., 2011

• Prevalence is estimated to be 14 - 42 per 100000

Nalysnyk et al., 2012

• Estimated to range between 3 and 18 cases per

100000 people per year.
Seibold et al., 2011

• Males are more affected than females

Coultas et al., 1994
 Incidence varies according to
age and gender
Incidence rates
120
Cases per 100,000 person-years

101.9
100 Males Females

80
57
60 48.6

40
21.1
14.2
20
10
4 2.2 4
Age group
0
35-44 45-54 55-64 65-74 ≥ 75

Coultas et al., 2005

Risk Factors of PF
Generti
c
factors

Chronic
viral
GERD
infectio
ns
IPF
Environ
Comorb mental
idities exposur
es

Raghu G, 2011
Environmental and Gastroesophageal
occupational Reflux Disease Comorbidities
exposure (GERD)
• Exposure to metal • GERD is • Pulmonary
dusts or wood associated with hypertension
dusts microaspiration • Pulmonary
• Agriculture & • 66%-87% of IPF neoplasia
farming patients suffer • COPD
• Inorganic dust from GERD • Ischemic heart
• Organic dust • 33%-53% of disease
• Gases and fumes patients are
asymptomatic
• Viruses

Raghu G, 2011
Immunologic Drug Neoplastic
• Rheumatoid • Antibiotics • Lymphangitic
arthritis (nitrofurantoin, carcinomatosis
• lupus
Lerythematosus
sulfasalazine) • Bronchoalveolar
• Scleroderma • Antiarrhythmics carcinoma
• Polymyositis/ (amiodarone,
dermatomyositis propranolol)
• Anticonvulsants
(phenytoin)

Fulton B G and Ryerson C J, 2015

 Pathogenesis
• Development and progression of the healing response has
slipped out of control, disrupting many delicate balances
Maria Angel, 2006
• Understanding of IPF pathogenesis remains elusive
Sgalla et al., 2018

• Hallmark lesions of idiopathic pulmonary fibrosis are the

fibroblast foci
Myers et al., 1998

• If the inflammatory cascade was interrupted before

irreversible tissue injury occurred, fibrosis might be
avoided
Thomas et al., 2013
MS Wilson and TA Wynn, 2009
Richeldi et al., 2017
 Pathogenesis of IPF
aberrant wound healing response to injury
AEC damage and activation

Secretion of growth factors;

activation of multiple inflammatory,
cell signaling and repair pathways

Fibroblast-to- Formation of
myofibroblast Disruption of fibroblast foci Accumulation
Fibroblast transition; EBM/AECs (aggregates); of ECM
migration and Epithelial-to- apoptosis apoptosis (scarring)
proliferation mesenchymal resistant
transition

FIBROSIS

AEC: alveolar epithelial cell; EBM: Epithelial basement membrane; ECM: extracellular matrix.

King et al., 2011

 Clinical signs
• May not present early in the disease and may not
occur until the disease has progressed
• Non-specific symptoms of exertional dyspnoea with
or without dry cough
• Exercise intolerance, cough or laborious breathing
Richeldi et al., 2017

• In established disease, pulmonary function tests

identify restrictive disease (reduced total lung
capacity) and abnormal gas exchange
Collard et al., 2011
 Clinical signs
• Progresses slowly and clinical condition
progressively deteriorates
Richeldi et al., 2017

• Physical examination, fine, high-pitched bibasilar

inspiratory crackles are usually heard (audio) and
digital clubbing is present in roughly 30% of patients
King et al., 2001
 Diagnosis
• History - it is paramount to obtain a complete history
of exposure to environmental, occupational
recreational/medically related substances
Maria Angel, 2006

• Radiography - Identification of a pattern of interstitial

pneumonia on basis of radiological/histological
criteria without evidence of an alternative cause
Collard et al., 2017
• Radiographically evident interstitial infiltrates
predominantly affecting the lung bases
Gross et al., 2001
 Diagnosis
• Standard chest radiography is still the most frequently used
tool for diagnostic purposes concerning the lung
Raoof et al., 2012
• Diagnosis of fibrosis remains challenging using conventional
X-ray imaging, especially in early and moderate stages of the
disease
Hellbach et al., 2017

• Due to its low sensitivity and specificity, a considerable

number of diagnoses are missed in projection radiography
Wielputz et al., 2014
• Dark-field imaging is a valuable tool to improve the diagnosis
of fibrosis on projection images compared to conventional
transmission-based radiographs alone
Hellbach et al., 2017
Dark-field and transmission images of fibrotic and healthy murine lungs

Hellbach et al., 2017

 Diagnosis
• CT - High-resolution CT of the chest enables detailed
assessment of lung parenchyma revolutionised the
investigation

Diffuse bilateral parenchymal fibrosis

with honeycombing and loss of lung volume

Collard et al., 2017

 Biopsy
Older patients with comorbidities cause clinically significant
physiological impairment/risk is greater and surgical lung biopsy
Should generally be avoided

C - Typical spatial and temporal heterogenicity with subplueral fibrosis and microscopic
honeycombing
D – fibroblast b/w fibrotic and less involved lung tissue
Jones et al., 2017
 Biomarkers for IPF

• Candidates
– Serum CCL18
– LOXL2
– Telomerase
– Surfactant proteins A & D
– KL-6
– Matrix Metallo-Proteases (MMP1/MMP7)
– Circulating fibrocytes
– Clinical parameters
• Pending validation
• Not widely available
Prasse et al., 2009
Management
 Pillars of care in IPF

Comprehensive care
Disease Symptom
Patient
specific based
education
therapy therapy

Mortality risk of 6%, 16%, and 39% incorporates gender, age,

lung physiology variables respectively
Ley et al., 2012
 Disease management

Early disease Advanced

• Disease • Oxygen disease
modifying assesment • Lung
therapy • Pulmonary transplantation
• Treatment of rehabilitation • Supplemental
comorbidites oxygen
• Palliative care

Richeldi et al., 2017

 Antifibrotic agents
Imatinib mesylate
• Tyrosine kinase inhibitor with activity against
platelet-derived growth factor receptors, discoidin
domain receptors
Spiegel et al., 2008

• Potent inhibitor of lung fibroblast - myofibroblast

transformation and proliferation

• Inhibits extracellular matrix production by inhibition

of PDGF and transforming growth factor - b
signalling
PDGF – Platelet Derived Growth Factor Uehara et al., 2007
• Safety and efficacy of imatinib given orally at a dose
of 600 mg daily versus placebo over 96 weeks in
patients with mild to moderate IPF

• Blinded dose reduction from 600 mg - 400 mg daily

imatinib was associated with higher incidence of AE
related drop-outs 22% compared with placebo (10%)
Daniels et al., 2010
 Pirfenidone
• Orally administered pyridine with combined anti-
inflammatory, antioxidant, and antifibrotic actions
Lee BS et al., 1998
• Regulation of TGF β in vitro, and inhibition of fibroblast
and collagen synthesis has been shown in animal models
of lung fibrosis
Schaefer et al., 2011

• Both high-dose (1,800 mg/day) and low-dose 1,200

mg/day) pirfenidone groups improved vital capacity (VC)
• Treatment with pirfenidone decrease the rate of decline in
VC and may increase the PFS time over 52 weeks
Ebina et al., 2010
 GERD treatment
• Management of GERD may involve lifestyle
modification, medical therapy and surgical therapy
• Antiacid medication is recommended for most patients
with IPF, including those without symptoms of reflux
Fulton B G and Ryerson C J, 2015
• Complete healing with PPIs vs H2RA occurs nearly twice
as fast, healing rate 11.7%/week and 11.5%/week vs
5.9%/week and 6.4%/week
• Surgical therapy is treatment for longterm therapy in
GERD and has become more appealing since the
introduction of laparoscopic anti-reflux surgery
GERD – Gastroesophageal Reflux Disease Badillo et al., 2014
PPI – Proton Pump Inhibitors
H2RA – H2 Receptor Anatagonists
GERD therapy is associated with
improved survival

Lee JS, et al., 2011

 Treatment of comorbidities
• Sildenafil, a phosphodiesterase-5 inhibitor, showed
some positive effects on PH treatment
Zisman et al., 2010

• Lung neoplasia - Increased mortality and acute

exacerbation of IPF following surgical resection,
chemotherapy, or radiation
• Long-acting beta-agonists and anti-cholinergics
primarily exert their benefits in COPD
Fulton B G and Ryerson C J, 2015
THANK YOU