Transcript INTERSTITIAL - Department Of Pulmonary Medicine

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INTERSTITIAL PULMONARY FIBROSIS
ATS Definition
Interstitial Pulmonary Fibrosis is defined as a
specific form of chronic fibrosing interstitial pneumonia of
unknown causes, limited to the lungs and associated with
a histologic pattern of usual interstitial pneumonia (UIP).
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EPIDEMIOLOGY
• Estimated to affect approximated 5 million people world wide.
• The most common (and deadly) interstitial lung disease.
• Most cases are sporadic, but rare cases of familial IPF have been
described.
• 15 % of pulmonary physician’s practice.
• Mortality from IPF continues to increase in many countries.
• Earlier, considered to be rare in India.
• In 1979, Jindal et al published 65 cases of DPLD seen over a period of 5
years. Recently the same center published data on 76 patients with IPF
diagnosed over a 16 months period- increase in frequency of diagnosis.
• Increase in number of studies in India due to increase in incidence or due to
availability of better diagnostic facilities like HRCT and fibreoptic
bronchoscopy.
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RISK FACTOR OF IPF
• Cigarette smoking.
• Environmental Exposure – metal dust, wood dust,
solvents associated with increased risk of developing
pulmonary fibrosis.
• Viruses (EBV, influenza, CMV, HCV), chronic aspiration
secondary to GERD.
• Hereditary factors do contribute but no specific genetic
marker has been identified.
• Familial
IPF
–
autosomal
dominant
–
variable
penetrance.
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PATHOLOGY
• Interstitial pneumonia classified by Hamman and Rich
followed by Liebow.
Pathological Classification
• Usual interstitial pneumonia.
• Desquamative interstitial pneumonia.
• Respiratory Bronchiolitis Interstitial Lung Diseases.
• Acute Interstitial pneumonia (Hamman-Rich Disease)
• Non-specific Interstitial pneumonia.
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PATHOLOGY (Contd.)
• Pathological
changes
characterized
by
UIP
–
distinguished by variation in location and age of lesions,
with predilection for peripheral subpleural parenchyma.
• Fibrotic zones with associated honey-combing alternate
with areas of relatively unaffected Lung tissue. Fibrotic
areas vary in age and activity.
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MULTIPLE HYPOTHESES FOR THE
PATHOGENESIS OF IPF

Inflammation causes fibrosis

Noninflammatory (multiple hit) hypothesis:
fibrosis results from epithelial injury and
abnormal wound healing in the absence of
chronic inflammation

Vascular remodeling: aberrant vascular
remodeling supports fibrosis, and may contribute
to increased shunt and hypoxemia
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INFLAMMATORY HYPOTHESIS

Inflammation causes fibrosis


Inflammatory concept was dominant in the 1970s and
1980s
 IPF resulted from unremitting inflammatory response
to injury culminating in progressive fibrosis
Role of inflammation remains controversial
 Lack of efficacy of corticosteroids
Injury
Inflammation
Fibrosis
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Progression of Lung Fibrosis
Injury
Epithelial cells
?
Endothelial
cells
Capillary
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Tissue Model of Lung Fibrosis
Epithelial cells
Cell death
Endothelial
cells
Growth factors and other
products of epithelial
cell Injury
Capillary
Myofibroblast
Collagen
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NON INFLAMMATORY (MULTIPLE HIT)
HYPOTHESIS

Fibrosis results from epithelial/endothelial injury
and abnormal wound healing in the absence of
chronic inflammation



Recurrent, unknown injury to distal pulmonary parenchyma
causes repeated epithelial cell injury and apoptosis
Loss of alveolar epithelium exposes basement membrane
to oxidative injury and degradation
Failure of re-epithelialization/re-endothelialization provides
stimulus for persistent profibrotic growth factor production,
persistent fibroblast proliferation, excessive deposition of
ECM, and progressive fibrosis
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NONINFLAMMATORY (MULTIPLE HIT) HYPOTHESIS
Recurrent
pulmonary
injury
Epithelial/
endothelial
injury and
apoptosis
TGF-b = transforming growth factor-beta
PDGF = platelet derived growth factor
IGF-1 = insulin-like growth factor-1
Loss of basement
membrane
Failure of reepithelialization/ reendothelialization
Fibroblast
proliferation
ECM
deposition
Release of
profibrotic growth
factors (TGF-b,
PDGF, IGF-1)
Progressive fibrosis with loss of lung
architecture
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VASCULAR REMODELING HYPOTHESIS
• Aberrant vascular remodeling supports fibrosis and may
contribute to increased shunt and hypoxemia
 Increased angiogenesis results from imbalance of pro-angiogenic
chemokines (IL-8, ENA-78) and anti-angiogenic, IFN-inducible chemokines
(IP-10)
 Vascular remodeling leads to anastomoses between the systemic/pulmonary
microvasculature, increasing right-to-left shunt, contributing to hypoxemia
Fibrosis
Chemokine
imbalance
Increased
angiogenesis
Aberrant
vascular
remodeling
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DEFECTS IN HOST DEFENSE MECHANISMS MAY
CONTRIBUTE TO FIBROSIS
• Defects in endogenous host defense
mechanisms (eg, IFN-g, PGE2 production) that
limit fibrosis after acute lung injury may
contribute to progressive fibrosis
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American Thoracic Society (ATS)
Diagnostic Criteria (IPF)
• According to ATS, in immunocompetent adult, the
presence of all of the major diagnostic criteria as well as
at least 3-4 minor criteria
increase the likelihood of
correct diagnosis of IPF.
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American Thoracic Society (ATS)
Major Criteria
• Exclusion of other known causes of ILD such as certain drug
toxicities, environmental exposures and connective tissue disorders.
• Abnormal pulmonary function studies that include restriction
(reduced VC, increase FEV1 / FVC ratio) and impaired gas
exchange.
• Bibasilar reticular abnormalities with minimal ground glass opacities
on HRCT scan.
• Transbronchial Lung biopsy or BAL showing no feature to support
alternative diagnosis.
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Minor Criteria
• Age > 50 years.
• Insidious onset of otherwise unexplained dyspnoea on
exertion.
• Duration of illness more or equal to 3 months.
• Bibasilar, inspiratory crackles (dry/velcro type in quality)
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CLINICAL PRESENTATION
• Middle age 50 - 70.
• Progressive dyspnoea on exertion.
• Non-productive cough.
• Most have symptoms for 12-18 month prior to definitive
evaluation.
• Constitutional symptoms are uncommon.
• Weight loss, fever, fatigue, myalgias, or arthralgias
occasionally present.
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PHYSICAL EXAMINATION
• Bibasilar late inspiratory fine crackles (velcro rales).
• Tachypnea.
• Clubbing 40-70% late in disease course.
• Cardiac examination normal until middle-late stages –
augmental P2, Right sided heave, S3 gallop.
• Cyanosis
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Diagnosis of Pulmonary Fibrosis
Investigation:
• FBC show mild anemia.
• ESR and C-reactive protein may be raised.
• Autoantibodies including antinuclear antibodies, RA factors.
• Arterial blood gases – Oxygen desaturation is common.
Lung Function Test :
• Shows Restrictive Pattern (But obstructive of airway may also be
present)
• Reduced total lung capacity.
• Reduced residual capacity.
• Reduced residual volume.
• Reduced gas transfer.
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X-ray Chest
• Bilateral
basal symmetrical peripheral reticular opacities with
decreased lung volumes.
• Volume loss evident by diaphragmatic elevation and depression of
fissures.
• Progressive fibrosis ultimately leads to cystic dilatation of distal air
spaces, which is visible as peripheral honey combing.
• Alternative diagnosis/ super-imposed complicated illness should be
suspected if X-ray shows bronchogram, confluent shadows or hilar
adenopathy.
• Most of patient with IPF have abnormalities on X-ray. Rarely patients
can have a normal X-ray, but have evidence of IPF either in HRCT or
surgical lung biopsy.
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HRCT
Patchy, predominantly peripheral, sub-pleural, bibasilar
reticular abnormalities and area of traction bronchiectasis
with limited amount of ground glass opacity.
• The areas of severe involvement show sub-pleural
honeycombing.
• When certain diagnosis is not able to made by HRCT
then a lung biopsy is needed for diagnosis.
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This 50-year-old man presented with end-stage lung fibrosis
PA chest radiograph shows medium to coarse reticular
B: CT scan shows multiple small cysts (honeycombing) involving
predominantly the subpleural peripheral regions of lung. Traction
bronchiectasis, another sign of end-stage lung fibrosis.
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Classic idiopathic pulmonary fibrosis in 70-year-old man.
High-resolution CT shows bilateral subpleural reticulation,
traction bronchiectasis (curved arrow), and honeycombing
(straight arrows).
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42-year-old woman with biopsy-proven idiopathic pulmonary fibrosis. Highresolution CT shows patchy bilateral ground-glass opacities and mild
predominantly subpleural reticulation.
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57-year-old man with biopsy-proven idiopathic pulmonary fibrosis. Highresolution CT (HRCT) shows patchy bilateral areas of ground-glass
opacity. Fine reticulation is observed in subpleural regions.
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BRONCHOALVEOLAR LAVAGE
Increase in Polymorphonuclear leucocytes, neutrophil
products, eosinophils, activated alveolar macrophage,
alveolar macrophages products, cytokines, growth factors.
• BAL-useful research tool but its diagnostic usefulness
is limited.
• Increase in neutrophils/ eosinophils in BAL fluid –
worse prgonosis.
• BAL lymphocytosis – less honey combing and greater
responsiveness to treatment.
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TBLB (Transbronchial Lung Biopsy)
Not helpful in making a diagnosis of IPF as limited Lung
tissue is obtained. But can exclude by identifying an
alternative specific diagnosis.
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Surgical Lung Biopsy
By open or video assisted thoracoscopic methods –
gold standard for diagnosis of IPF. Large piece of Lung
parenchyma is required, optimally from several sites.
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USUAL INTERSTITIAL PNEUMONIA PATTERN
Mason: Murray & Nadel's Textbook of
Respiratory Medicine, 4th ed.
Idiopathic Pulmonary Fibrosis, Gross
and Huninghake, NEJM, 2001.
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HONEYCOMB PATTERN
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COMPLICATIONS OF IPF
Interstitial lung disease can lead to series of life-
threatening complications, including :Pulmonary Hypertension
Unlike systemic high Blood Pressure, this condition
affects only the artries in Lungs. It begins when scar tissue
retricts the smaller blood vessels, limiting blood flow in
Lungs. This in turn raises pressure within the Pulmonary
arteries. Pulmonary hypertension is a serious illness that
becomes progressively worse.
Cont…..
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• Right sided heart failure (cor-pulmonale) :
This is
serious condition occur when heart’s lower chamber
(right ventricle) : which is less muscular than the left- has
to pump harder than usual to move blood through
obstructed pulmonary arteries Eventually the right
ventricle fails from the extra strain.
• Respiratory failure : In the end stage of chronic
interstitial lung disease, respiratory failure occurs when
severely low blood oxygen levels along with rising
pressure in the pulmonary arteries and right ventricle
causes heart failure.
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The Course of IPF
Although the course of idiopathic pulmonary fibrosis
varies greatly from person to person, the disease usually
develops slowly, sometimes over years.
The early stages are marked by alveolitis, an
inflammation of the air sacs called alveoli, in the lungs.
The job of the air sacs is to allow the transfer of O2 from
Lungs into the blood and elimination of CO2 from Lungs
and out of the body.
Contd…
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As IPF progresses, the alveoli become damaged and
scarred, the stiffening of the lungs, makes breathing difficult
and bring on a feeling of breathlessness, especially during
activities that require extra effort.
In addition, scarring of the alveoli reduces the ability of
lungs to transfer oxygen. The resulting lack of O2 in to the
blood (hypoxemia) may cause increase in the blood vessels
of the lungs, a situation known as pulmonary hypertension.
The high blood pressure in the lungs then puts a strain on
right ventricle the lower right side of the heart, which pumps
the oxygen – poor blood into the lungs.
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TREATMENT AND DRUGS
• The Lung Scarring that occurs in pulmonary fibrosis
cannot be reversed, and no current treatment has
proved effective in stopping the ultimate progression of
the disease. Some treatments, may improve symptoms
temporarily or slow the disease’s progress. Other
improve quality of life.
Cont…..
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Specific Treatment Options are:
• Medications
• Oxygen Therapy
• Pulmonary Rehabilitation
• Lung Transplantation
Cont…..
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Medications :
• Corticosteroids
• Immunosupressant/ Cytotoxic agents
• Antifibrotic agents in along or combination
• Anti-oxidant agents
Cont…..
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Corticosteroids:
The main stay of treatment for idiopathic pulmonary
fibrosis is medication that help to reduce inflammation.
Inflammation is thought to play a role in the injury and
fibrosis of Lung tissue. So corticosteroids that stop the
inflammation are thought to have an effect on the
resulting damage.
• Despite their widespread use only 10-30% of pateint with
IPF improve on quantitative assessment when treated
with corticosteroids.
Cont…..
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• If response is to occur, it is usually noted with three months.
• Prolonged treatment for a minimum of 1-2 years and
sometimes indefinitely is reasonable for patient exhibiting
unequivocal response to therapy.
• High dose IV pulse methylprednisolone has no proven
advantage over oral corticosteriods.
• Now,
treatment
with
steroid
alone
is
considered
in
appropriate, corticosteroids, should be used in conjuction with
cytotoxic agents.
• Favorable response to combination is seen in 15-50% of
cases.
Cont…..
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CYTOTOXIC / IMMUNOSUPPRESSANT
1) Azothioprine
2) Cyclophosphamide
Azothioprine : is a medicine that effects the immune
system. Because it can cause serious side effects, it may be
prescribed with corticosteroids – is associated with improvement
and enhanced survival in some patient.
Cyclophosphamide : High dose IV administered every 24 weeks (500-1800mg) – tried in open trial result were unimpressive. A recent study suggested that combined corticosteroid
and cyclophosphamide therapy has no impact on the survival of
patient with IPF.
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AGENTS THAT AFFECT COLLAGEN SYNTHESIS
OR FIBROSIS
1) Colchicine
2) D-Pencillamine
3) Interferon Gamma
4) Pirfenidone
Interferon gamma : inhibits proliferation of lung fibroblasts in dose
dependent manner and a reduce protein synthesis in fibroblasts.
-
In an open randomized study with 18 patients who had not
respondend to glucocorticoids and other immunosupressive agents –
200mg interferon gamma 1b , 3 times/wk for 12 month along with
predinsolone resulted in improvement in TLC and partial pressure of O2.
Cont…..
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- Subsequent studies dampened hopes, when Honore et al
reported 4 cases of IPF who developed irreversible
respiratory
failure
following
treatment
with
Interferon
Gamma.
- Increased level of IL-18 in induced sputum of patient with
IPF have been found to decrease after treatment with
interferon gamma.
- A recent meta analysis showed interferon therapy – reduced
mortality.
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Pirfenidone – Anti Fibrotic Agents
A larged well controlled multinational clinical trial
programme has been demonstrated the effectiveness and
safety of pirfenidone in the treatment of IPF. Study present in
American Thoracic Society International Conference, Tronoto.
Daily consumption of pirfenidone can slow down the
progression of IPF by improving the lung capacity. Study
conducted on 275 patient by Takashi Ogura in Japanese
patients with mild-moderate IPF patient was randomly divided
into three groups were administered 1800mg/ day (High dose)
or 1200mg/day (low dose) of pirfenidone or placebo for 52
weeks.
Cont…..
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Then vital capacity assessed at week 52, the researchers
found that the loss of vital capacity in high dose regimen group
was significantly lower when compared with the low dose
regime and with the placebo group.
The rate of deterioration IPF was reduced in patients taking
pirfenidone. The drug was relatively well tolerated. The only
side effect of the drug to be noticed was photosensitivity, which
as mild severity.
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Anti Oxidant Agents
- Glutathione , taurine, niacin, inhibit development of fibrosis in
animal models.
- Acetyle cysteine – a precurser of glutathione, can replenish
pulmonary glutathione levels.
- In study with 18 patients with IPF treated with 600mg Nacetyl cysteine TID for 12 weeks in addition to their latest
immunosupressant therapy – significant improvement PFT.
- A recent double blind, randomized, placebo controlled
multicenter study assessed the effectiveness over 1 year of
high dose oral acetyl cysteine added to standard therapy with
prednisolone and azothioprine – show acetyl cysteine slowed
deterioration of vital capacity at the end of 1 year.
Cont…..
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Pulmonary Rehabilitation / General Supportive
measures :
The aim of the pulmonary rehabilitation is not only to
improve daily functioning, but also to help people with
interstitial lung disease to live fully satisfying life. Pulmonary
rehabilitation program focus on:
1) Physical exercise, to improve your endurance.
2) Breathing techniques that improve lung efficiency.
3) Emotional Support
4) Nutritional Counselling
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General Supportive measures :
- Smoking cessation
- Avoidance
of
any
other
environmental
(including
occupational) causes.
- Stopping
any
medication
thought
to
be
causing
or
contributing to pulmonary fibrosis.
- Treating any respiratory tract infections promptly.
- Patients should be encouraged to receive influenza or
vaccination and pneumococal vaccine.
- Good pulmonary hygiene is important.
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Lung Transplantation :
Lung transplantation is a treatment option for selected
patients with advanced disease refractory to medical therapy.
Lung transplant improves long term survival. Survival rates
worldwide after single lung transplantation are approximately :
and
74%
at 1 year
58%
at 3 years
47%
at 5 years
42%
at 10 years
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PROGNOSIS :
The prognosis variable and depends on the specific diagnosis and
severity. Some disease are insidious in onset and gradual progression,
while other disease are acute in onset but responsive to therapy. Idiopathic
pulmonary fibrosis is progressive illness, producing increasingly severe
symptoms, and generally has a poor prognosis.
Mortality data for 3 year and 5 year mortality rate are approximately 50%
and 80% respectively. Although IPF occurs in older patients with co-morbid
diseases, most patients with IPF die as direct consequence of the Lung
fibrosis. However, some patients with IPF remain stable for a number of
years. The median survival rate of biopsy – proven IPF is less than three
years. Most will die as a result of respiratory failure, but other will develop
infections secondary to steroid therapy or right heart failure.
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Poor outcome is associated with:
• Older age
• Male gender
• Severe dyspnoea
• History of Cigarette Smoking
• Severe loss of Lung function
• Appearance and severity of fibrosis on radiological studies
• Lack of response to therapy.
• Prominent Fibroblastic foci on histopathological evaluation.
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CONCLUSION
IPF is a severe condition with a worse prognosis
than all other ILDs.
 The accuracy and timeliness of IPF diagnosis
must be improved in order to improve
treatment opportunities and outcomes.
 However, there is often a long delay before a
diagnosis is made and today the diagnosis is
too often insufficiently secure or accurate.

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ISSUES NEED TO BE ADDRESSED

The guidelines (exclusion of alternate
diagnosis, optimal interpretation of CT,
combination CT and histopathological
evaluation with a multidisciplinary discussion
implying a pulmonologist, a radiologist and a
pathologist expert on ILD) have to be strictly
applied.
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Thanks……………..
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