Practical approach

to

Idiopathic

Pulmonary Fibrosis

Dr .Heba Ashebani

General practitioner

Abusetta hospital.

What is the Pulmonary Interstitium ?

•The interstitial space is defined as continuum of loose

connective tissue throughout the lung .

•composed of three subdivisions:

othe Broncho vascular (axial), surrounding the bronchi,

arteries, and veins from the lung root to the level of the

respiratory bronchiole.

othe parenchymal ( acinar ), situated between the alveolar and

capillary membranes.

othe subpleural , situated beneath the pleura, as well as in the

interlobular spate .

•NOTE :

The interstitium of the lung is not normally visible radiographically;

it becomes visible only when disease (e.g., edema, fibrosis, tumor).

Subdivisions of interstitiumSubdivisions of interstitium

IDIOPATHIC PULMONARY

FIBROSIS ( IPF)

OR

CRYPTOGENIC FIBROSIN

ALVEOLITIS ( CFA)

IDIOPATHIC PULMONARY

FIBROSIS ( IPF)

OR

CRYPTOGENIC FIBROSIN

ALVEOLITIS ( CFA)

IPF25-35%

Drugs

Autoimmune disease

Occupation

NSIP

Sarcoid

Cause of IPF is UNKNOWN

• Incidence : 10 – 15 / 100,000 .

Male > Female (2 : 1) .

5000 new cases IPF per year in UK .

Number of cases are increasing worldwide .

• Onset: Usually between 70 and 80 years .

• Etiology : Uncertain , but a single cause appears unlikely ,

even in patients with biopsy-proven IPF .

•Risk factors for developing IPF:

oSmoking (2.8 fold increased risk).

oOccupational exposures.

-Hard woods, metals, asbestos.

oFamily history of pulmonary fibrosis.

oPossibly gastro-oesophageal reflux disease (GORD).

All major criteria and at least 3 of the 4 minor criteria are requirED

•Major criteria :

a) Absence of other known causes of interstitial lung disease.

b) A restrictive lung function profile .

c) HRCT appearance of predominantly basal reticular abnormalities

with honeycombing and little or no ground-glass appearance.

Diagnostic criteria

D) No features of an alternative diagnosis in transbronchial lung

biopsy ( granulomas ) Or Broncho alveolar lavage ( in lymphocytes ).

•Minor criteria :

a) Age > 50 years .

b) Insidious unexplained exertional dyspnea .

c) duration of illness > 3 months .

d) Predominantly basal or widespread crackles on auscultation .

Multiple microscopic foci of injury occurring over many years

Pathogenesis

Focal fibroblast proliferation (fibroblastic foci)

Collagen deposition

Progressive clinical course

Death

Histological pattern underlying IPF is USUAL INTERSTITIAL

PNEUMONIA (UIP).

-Temporal heterogonous areas of end stage fibrosis and

honeycombing , with areas of active proliferation of fibroblast

(suggesting diffuse ongoing microscopic alveolar epithelial injury).

-Fibroblastic foci: subepethelial foci of proliferating fibroblasts.

Histological features

- A patchy chronic inflammatory cells infiltrate is variably present .

-Honey combing (common) cystic space is lined by bronchial

epithelium.

Temporalheterogeneity

Peripheral accentuation of fibrosis

Interstitial inflammation and fibrosis

with alveolar wall

thickening

• Clinical assessment :

oEvaluate symptoms.

oOccupational exposures.

oMedications.

oFamily history.

• Examination:

oOxygen saturation

oClubbing of finger nails

oListen to chest for “crackles”

Establishing Diagnosis

Clinical features

• Progressive exertional dyspnea without wheeze .

•A nonproductive cough , although sputum production is present in

few patients.

• Chest discomfort , fatigue, and weight loss are occasional features .

• Digital clubbing is present in over 50% of patients and has been

Presentation and Features of IPF

An adverse prognostic determinant in some series .

•On auscultation : very fine end-inspiratory crackles are typically

heard bilaterally at the lung bases and become widespread in

advanced disease .

• Central cyanosis and clinical evidence of pulmonary

hypertension , with or without right ventricular failure , are late

features .

Chest radiography :

•Typically shows small lung volumes and predominantly peripheral

and basal reticulonodular shadowing .

•Obscuration of the hart borders and diaphragms in advanced disease

•Overt honeycombing in 10 % of cases .

•The heart may appear to be enlarged in the absence of

cardiovascular disease .

•This profile is very nonspecific , occurring in many other fibrotic

processes .

•Normal CXR does not exclude IPF .

High-resolution CT

•HRCT are pathognomonic in up to 70% of patients.

•The disease is predominantly postero-basal and peripheral ,

becoming widespread in advanced disease .

• Reticular pattern , with or without honey-combing .

•A minor component of ground glass attenuation .

•Traction bronchiectasis in lower lobes .

•Reactive mediastinal lymphadenopathy is usual on HRCT and is not

indecative of coexisting disease process unless also present CXR.

•Prone HRCT sections maybe required in early disease .

Lung function tests

•Restrictive ventilatory defect in VC , TLC , RV , sometimes appears

normal in early disease.

• in DLco levels even in early disease

• . ABG could be normal in early disease .

•Mild arterial hypoxia with widening of the alveolar-arterial gradient.

• Sever hypoxia is a late feature .

• Increased Paco2 levels occur in terminal disease .

•6 minutes walk test + oximetry easier ,better for disease

progression and regression.

Blood tests

•Blood tests contribute little to management of IPF .

• Secondary polycythemia my occur in sever disease.

IF diagnosis is uncertain…..• Some circumstances the CT scan has unusual features which are not

typical for IPF.

•May need a bronchoscopy.

•May need a surgical lung biopsy.

Broncho-alveolar lavage

•BAL is useful diagnostic test when a surgical biopsy is not performed

• In IPF , Typically there is an increase in total cell counts with an

excess of neutrophils and/or eosinophils .

•A mild lymphocytosis is infrequent , but striking rises lymphocyte

counts suggest an alternative disorder such as NSIP .

•Useful in excluding infections.

Surgical lung biopsy

•A surgical lung biopsy is the histological diagnostic procedure of

choice .

•Video-assisted thoracoscopic biopsy is the most widely advanced

procedure .

• Strongly recommended that at least two sites are biopsied .

• Larger biopsies are required to determine whether abnormalities

Are heterogeneous or homogenous .

Echocardiography

Routine echocardiography is warranted at presentation and in

patients subsequently developing disproportionate hypoxia or a

selective serial reduction in Dlco .

Prognosis

The 5 years survival is approximately 10 to 15 % in IPF .

IPF is a progressive disease.

Median survival is 3 years from diagnosis

Features are associated with a worse outcome

Grade of evidence

Increasing age. ++

Resting hypoxia. ++

Major desaturation on during 6-min walk test <88%.

++

Serial decline in in FVC or Dlco. ++

Prominent honeycombing on HRCT. ++

Presence of pulmonary hypertension. ++

Increasing dyspnea +

Major desaturation on maximal exercise testing

+

Moderate impairment of lung function +

High profusion of fibroblastic foci +

Establish Diagnosis

Clinical

• Symptoms• Smoking

history• Exposures• Features of

CTD• Examination

Investigations

• CXR• CT Thorax• Blood tests• Lung

Function

Pathology

• Broncho-alveolar lavage

• Surgical lung biopsy

Multi-Disciplinary Team (MDT)Discussion

•Prednisolone and azathioprine +/- N-acetylcysteine :

o Prednisolone : low dose (such as 10 mg daily) +

o Azathioprine :During the first month a test dose (50 mg /day) is usual ,with

weekly full blood count monitoring .

then a change to full dosage is made at four weeks (2.5mg/kg per day up to

maximum dose of 150mg/kg)

Treatment of IPF

Full blood count and liver function tests performed 6 to 8 weeks there

after .

oN-acetylcystine : ( 600mg three times a day ).

PANTHER IPF CLINICAL TRIAL

•Phase III trial , double blind placebo controlled trial.

•Enrolled 238 out of 390 patients with mild to moderate IPF .

Pred / Aza / NAC Placebo

Mortality 11 % 1 %

Hospitalizations 29 % 8%

side effects 31 % 9%

• British Thoracic Society recommended not used for newly

diagnosed IPF .

• Discussion with consultant should be obtained .

American thoracic society conference

MAY2014•Outcome on Acetylcystine

•Original study ( PANTHER trial ) interrupted due to safety concerns

about the triple therapy ( Prednisone ,Azathioprine ,N-acetylcystine)

Group .

• study completed with placebo and Acetylcystine alone groups.

•Enrolled 264 patients (131 placebo 133 acetycystine 600mg three

times daily)

•Mild to moderate IPF (FVC> 50% , Dlco > 30%).

•60 weeks of treatment with either placebo or acetylcystiene 600 mg

three times daily .

•NO difference in change in FVC.

•NO difference in acute exacerbations of IPF .

•NO survival advantage.

•The study only assessed acetylcysteine in mild and moderate IPF.

• It is not known if acetylcysteine is of benefit in people with more

sever IPF (FVC < 50%).

Published by IPF clinical research network , NEJM 2014.

Outcome on Pirfenidone (antifibrotic) :

•Pirfenidone is antifibrotic therapy , but how it works Unknown.

•3 previous clinical trials had let to the treatment being approve in 30

Countries in Europe in including UK , and Canada .

•ASCEND study 555 patients with IPF ( FVC 50-90 % , Dlco 30-90%)

277 placebo , 278 Pirfenidone .

KEY FINDINGS OF STUDY

•Pirfinedone reduced progression of IPF by almost 50%.

•Perfinidone reduced risk of death from IPF at 1 year by 68%.

•Pirfenedone does not affect symptoms of breathlessness .

• S/E : skin rash ( 28 %) , GIT symptoms such as acid reflux ( 11.9 %)

And loss of appetite (15%).

NEW TREATMENT : Ninetdanib

Inhibits growth factors ( tyrosine kinase inhibitor )that have been

implicated in the development of pulmonary fibrosis .

• INPULSIS trial were 2 studies conducted, simultaneously ,enrolled

1066 patients ,(placebo 423 ,Nintedanib 638 ).

•Mild to moderate IPF ( FVC > 50% , dlCO 30-79% ).

Key findings of the study

•The drug slowed decline in FVC over 52 weeks .

•Trend towards a reduced rate of death .

•The effect on acute exacerbations of IPF was not consisted across the

studies .

•Diarrhea is the most common side effect .

•Approved by the U.S FDA in OCTOBER 2014.

Lung transplantation

• suitable for those patients physically eligible to undergo a major

transplant operation.

• lung transplant has been shown to reduce the risk of death by 75%

as compared with patients who remain on the waiting list.

• Symptomatic patients with IPF younger than 65 years of age and with

a body mass index (BMI) ≤26 kg/m2 should be referred for lung

transplantation.

• the most recent data suggest that bilateral lung transplantation is

superior to single lung transplantation in patients with IPF.

• Five-year survival rates after lung transplantation in IPF are estimated

at between 50 to 56%.

Supportive Treatments

• Smoking cessation

•Pulmonary Rehab and exercise

-Improves strength and walk distance

•Palliative Care Services

Oxygen therapy

•Not for everyone with IPF.

•People who are limited by low blood oxygen:

-walking outside / gardening

-around the house

-at night

-all or most of the time

•Different types of oxygen

-Long term oxygen therapy (LTOT).

-Oxygen for exercise (ambulatory).

-Short burst.

Preventing chest infections

•Vaccination:

Annual flu vaccine.

Pneumonia vaccine.

•Prompt treatment of infections with antibiotics.

Supportive

• Breathlessness management

• Oxygen

Symptoms

• Cough

Disease specific

• Medication

• Lung transplant