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INTERSTITIAL PULMONARY FIBROSIS

By: Dr.Bidhi ChandJunior Resident

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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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

INFLAMMATORY HYPOTHESIS

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Injury

Epithelial cells

Progression of Lung Fibrosis

Capillary

Endothelialcells

?

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Epithelial cells

Collagen

Myofibroblast

Cell death

Growth factors and other products of epithelial cell Injury

Tissue Model of Lung Fibrosis

Capillary

Endothelialcells

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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

NON INFLAMMATORY (MULTIPLE HIT) HYPOTHESIS

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NONINFLAMMATORY (MULTIPLE HIT) HYPOTHESIS

Recurrent pulmonary

injury

Epithelial/endothelial injury and apoptosis

Loss of basement membrane

Failure of re-epithelialization/ re-endothelialization

ECM deposition

Fibroblast proliferation

Release of profibrotic growth factors (TGF-b, PDGF, IGF-1)

Progressive fibrosis with loss of lung architecture

TGF- b = transforming growth factor-betaPDGF = platelet derived growth factorIGF-1 = insulin-like growth factor-1

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• 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

Chemokine imbalance

Increased angiogenesis

Fibrosis

VASCULAR REMODELING HYPOTHESIS

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

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

USUAL INTERSTITIAL PNEUMONIA PATTERN

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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 2-

4 weeks (500-1800mg) – tried in open trial result were un-

impressive. 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 N-acetyl 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 :

74% at 1 year

58% at 3 years

47% at 5 years

and 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……………..