Practical approach to Idiopathic Pulmonary Fibrosis.
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Transcript of Practical approach to Idiopathic Pulmonary Fibrosis.
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