ACUTE SEVERE ASTHMA

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Interstitial Pulmonary Fibrosis (Update)
BY
Prof. Mona MansourProfessor of Pulmonary
Medicine Ain Shams University
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Update classification

• In 1998, katrenslein and Myres put a
  classification to include histopathologically
  distinct subgroups

• UIP-DIP-RB-ILD, acute interstitial pneumonia
  (Hamman-Rich) and NSIP

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• In 2001, ATS/Eur. Consensus emphasized the
  importance of an integrated clinical,
  radiological and pathological approach to the
  diagnosis of IIP, and considered this the new
  gold standard.
• They recommended reserving the term (IPF) to UIP
  as a histological pattern with the worst
  prognosis.
• UIP is a distinct pathophysiologic entity
  characterized by minimal inflammation and chronic
  fibroproliferation caused by abnormal
  parenchymatous wound healing for diagnosis of
  idiopathic pulmonary fibrosis

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• On the other hand, the theory of generalized
  inflammation leading to wridespread parenchymal
  fibrosis is true for many corticosteroid
  responsive ILDs
• DIP - Eosinophilic pneumonia
• RB-ILD - Sarcoidosis
• NSIP - Organizing pneumonia
• HP

• The most common pathological pattern in
  connective tissue disease is NSIP

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Histological and clinical classification of
idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis Usual interstitial pneumonia
Nonspecific interstitial pneumonia (provisional) Nonspecific interstitial pneumonia
Cryptogenic organizing pneumonia Organizing pneumonia
Acute interstitial pneumonia Diffuse alveolar damage
Respiratory bronchiolitis interstitial lung disease Respiratory bronchiolitis
Desquamative interstitial pneumonia Desquamative interstitial pneumonia
Lymphocytic interstitial pneumonia Lymphocytic interstitial pneumonia
Unclassifiable interstitial pneumonia some
cases are unclassifiable for a variety of reasons
his group represents a heterogeneous group
with poorly characterized clinical and
radiological features that need further study
COP is the preferred term, but is synonymous with
idiopathic bronchiolitis obliterans organizing
pneumonia
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Clinical, radiologic, and histologic features,
treatment and prognosis of the idiopathic
interstitial pneumonias
LIP DIP,RB-ILD AIP COP NSIP IPF Clinical Radiographic Pathologic Diagnosis
Chronic (gt12mo), women Subacute (weeks to months), smoker Abrupt (1-2 wk) Subacute (lt3mo) Subacute to chronic (months to years Chronic (gt12mo) Duration of illness
Rare 10-17 Rare (lt2) 4-12 14-36 47-64 Frequency of diagnosis
Diffuse DIP Diffuse ground-glass opacity in the middle and lower lung zones Diffuse, bilateral Subpleural or peribronchial Peripheral, subpleural, basal, symmetric Peripheral, subpleural, basal predominance HRCT
Centrilobular nodules ground-glass attenuation RB-ILD Bronchial wall thickening, centrilobular nodules, patchy ground-glass opacity Ground-glass opacities, often with lobular sparing Patchy consolidation Ground-glass attenuation Reticular opacities
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Clinical, radiologic, and histologic features,
treatment and prognosis of the idiopathic
interstitial pneumonias (Conti.)
Septal and bronchovascular thickening Thin-walled cysts Lower lobe Volume loss Subpleural sparing may be seen Traction Bronchiectasis/bronchiolectasis Architectural distortion Focal ground glass (rare)
LIP DIP RB-ILD Smoking cessation Diffuse alveolar damage Organizing pneumonia NSIP Usual interstitial pneumonia Histologic patterns
Corticosteroid Responsiveness Corticosteroid Responsiveness Effectiveness of Corticosteroid Unknown Corticosteroid Responsiveness Corticosteroid Responsiveness Poor response to corticosteroid Or cytotoxic agents Treatment
Not well defined 5mortality in 5 yr 66 mortality in lt6mo Deaths rare Unclear, lt10 mortality in 5 yr 50-80 mortality in 5yr Prognosis
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Figure 1. Historical progression of the
classification of the idiopathic interstitial
pneumonias (see text for details). Adapted by
permission from References 87 and 88. AIP acute
interstitial pneumonia BOOP bronchiolitis
obliterans organizing pneumonia DAD diffuse
alveolar damage DIP desquamative interstitial
pneumonia GIP giant cell interstitial
pneumonia IPF idiopathic pulmonary fibrosis
LIP lymphocytic interstitial pneumonia NSIP
nonspecific interstitial pneumonia OP
organizing pneumonia RB-ILD respiratory
bronchiolitis interstitial lung disease UIP
usual interstitial pneumonia.


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Diagnosis

• Restrictive pattern and impaired gas exchange
• Many ILDs are associated with obstructive pattern
  due to bronchiolocentric pattern.
• As Sarcoidosis, hypersensitivity pneumonitis
  (HP)
• Hypoxia
• - alveolo-capillary block during exercise
• - ventilation perfusion mismatch is the major
  factor
• PFT has limited role in disease progression or
  response to therapy.

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Open lung biopsy

• Open lung biopsy via thoracotomy and
  video-assisted thoracoscopic surgery give the
  greatest overall diagnostic sensitivity.
• Transbronchial biopsy is not recommended
• BAL diagnostic in
• Sarcoidosis lymphocytosis with increased
  T-helper
• cells and a high CD4/CD8 ratio
• HP lymphocytosis suppressor CD8
• IPF increase in neutrophils and eosinophils

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HRCT

• Introduction in 1980s
• Identification of the presence of the disease
• Extent of the disease
• Patterns
• Guide to site of biopsy
• Assess clinical course and response to therapy
• HRCT lacks diagnostic specificity in ILDs
• It correlates poorly with the histologic pattern.

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Idiopathic Pulmonary fibrosis (IPF)
Definition

• IPF affects the interstitial and the alveolar
  spaces showing a light microscopic appearance of
  usual interstitial pneumonia

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Chest radiograph from a patient with
biopsy-proven IPF, showing bibasal pulmonary
reticulonodular shadowing with volume loss. b
High-resolution CT scan from the same patient
showing characteristic interlobular and
intralobular septal thickening, ground glass
attenuation, loss of volume, traction
bronchiectasis and honeycombing with a subpleural
bibasal predominance.
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Clinical features and natural history

• chronic progressive exertional breathlessness
• non productive cough
• Inspiratory crackles
• 50 finger clubbing
• Cor pulmonale
• Misdiagnosis as left ventricular failure or low
  respiratory tract infection
• Acute clinical deterioration precedes death in
  half of the patients.
• Mortality due to RF (39), heart failure (14),
  lung cancer (10), ischemic heart disease (10)
  infection (6) and PE (30)

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American thoracic society/european respiratory
society criteria for diagnosis of idiopathic
pulmonary fibrosis in absence of surgical lung
biopsy
Major criteria
Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases
Abnormal pulmonary function studies that include evidence of restriction reduced VC, often with an increased FEV1/FVC ratio and impaired gas exchange increased Po2 Aa- decreased Pao2 with rest or exercise or decreased DLCO
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans
Transbronchial lung biopsy or BAL showing no features to support an alternative diagnosis
Minor criteria
Age gt 50 yr
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness gt 3 mo
Bibasilar, inspiratory crackles
Definition of abbreviations BAL
bronchoalveolar lavage DLCO diffusing capacity
of the lung for carbon monoxide HRCT
high-resolution computed tomography ILD
interstitial lung disease P(Aa)O2
alveolar-arterial pressure difference for oxygen
VC vital capacity.
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Prevalence

• 7-20 individuals per 100.000 population

• Predominates in old age-more common in males with
  history of smoking

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Diagnosis
It is important to distinguish between IPF (UIP)
and non IPF for prognosis and response to
treatment. Idiopathic pulmonary fibrosis (Known)
as cryptogenic fibrosing alveolitis has a
survival rate comparable to many cancers.
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Blood markers

• Rheumatoid factor or antinuclear antibody for
  connective tissue diseases.
• Angiotensin-converting enzyme for sarcoidosis
• ANCA for Wegners granulomatosis

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Pathology

• IPF and usual interstitial fibrosis are used
  interchangeably.
• Interstitial inflammation and fibrosis (UIP) is
  distinguishable from UIP in asbestosis,
  connective tissue diseases, chronic
  hypersensitivity pneumonitis and drug induced
  lung diseases.
• Patchy alveolar and capillary damage
• Alveolar epithelial injury as patchy necrosis and
  loss of type I pneumocytes
• Regenerative hyperplasia of type II pneumocytes.
• Alveolar capillary injury as cytoplasmic swelling
  and basement membrane thickening with
  fibroblastic foci and honey comb fibrosis.

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Figure 2. Gross pathological specimen showing
lung fibrosis and honeycombing in an individual
who had advanced IPF.
View larger version (130K)
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Pathogenesis of IPF

• The cause of IPF is unknown
• Original inflammation/alveolitis hypothesis
  suggested that IPF is a chronic inflammatory
  disease. Oral steroids and cytotoxic agents are
  suggested as anti-inflammatory therapy.
• The current epithelial /mesenchymal hypothesis
  IPF results from repeated and unidentified
  exogenous and endogenous stimuli leading to
  sequential microscopic lung injury with
  disruption of alveolar epithelium failure of
  re-epithelialization on going injury with
  proliferation of interstitial fibroblasts
  fibroblast myofibroflast foci and ultimately
  fibrosis.

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Pathogenesis of IPF (Cont.)

• Aberrant angiogenesis imbalance in the
  expression of angiogenic (IL-8) versus
  angiostatic (IFN gamma inducible protein IP-10)
  CXC chemokines favouring net angiogenesis
• IFN-y is suggested as a potential therapy leading
  to marked increase in CXC chemokines (CXC11) as a
  potent inhibitor of angiogenesis esp. in
  bleomycin induced pulmonary fibrosis.
• Various environmental stimuli
• Cigarete smoking Chronic aspiration
• Metal and wood dusts Infection as Epstein Barr
  virus

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Pathogenesis of IPF (Cont.)

• Genotype phenotype interaction
• Familial IPF rare present in younger age some are
  associated with surfactant protein C genes
  mutations resulting in protein misfolding causing
  type II cell injury
• Tsakiri and his colleagues located the disease
  gene for IPF in chromosome 5 and identified
  telomere shortening
• In alveolar microlithiasis mutations in SL C34,
  A2.
• Susceptibility to IPF probably involves a
  combination of genetic polymorphisms related to
  epithelial injury and abnormal wound healing.

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The shift from considering IPF as a disease
characterized by inflammation to a disease with
aberrant wound healing has led to the development
of designer (antifibrotic therapies)
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Drug treatment in IPF

• Prednisolone
• Arathioprine or cyclophosphamide
• Pirfenidone
• Interferon y-1b
• Warfarin
• Bosentan
• Etanercept
• Imatinib mesylate

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ManagementCurrent Recommendations for treatment
of IPF

• Prednisolone
• 0.5 mg/Kg/day orally for 4 weeks
• 0.25 mg/Kg/day for 8 weeks
• 0.125 mg/Kg/day

• Azathioprine
• 2 to 3 mg/Kg/day to maximum dose 150 mg/day
• Dosing should be give at 25-50 mg /day and
  increase gradually by 25 mg increments every 7 to
  10 days until the maximum dose is reached.
• It may be substituted by cyclophosphamide

1. N-acetyl cysteine due to oxidant antioxidant
   imbalance, as it is a precursor for glutathione
   synthesis
2. Oxygen
3. Preventive therapy for osteoporosls

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Future Therapies

• Pirfenidone oral antifibrotic agent
• improvement in vital capacity at 9 months and
  decrease episodes of acute exacerbations of IPF.

1. Interferon Y-1b

1. Warfarin

1. Pulmonary embolism is implicated to be a common
   cause of death
2. Microvascular injury and abnormal vascular
   phenotypes in IPF
3. Pulmonary hypertension
4. Plasma D-dimer was high in patients dying from
   acute excerbations of IPF

• Endothelin antagonism (Bosentan)
• - Endothelins are a family of 21 amino-acid
  peptides with profibrotic effects.
• - Endothelin I is expressed in a variety of
  pulmonary diseases as
• pulmonary vascular diseases and
  pulmonary fibrosis.

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Future Therapies(cont.)

1. Tumour necrosis factors antagonism (Etanercept)

• TNF? is a proinflammatory cytokine and a critical
  mediator in the pathogenesis of pulmonary
  fibrosis.
• It stimulates fibroblast proliferation and
  collagen gene up regulation.
• In IPF macrophages release of TNF? localized to
  hyperplastic type II alveolar epithelial cells.
• Cytokine gene polymorphisms in TNF? gene on
  chromosome 6.
• Etanercept is a recombinant soluble TNF? receptor
  blockers.

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Future Therapies(cont.)

1. Imatinib mesylate, a phenyl aminopyrimidine
   derivative

• A specific tyrosine kinase inhibitor.
• Inhibits platelet derived growth factor PDGE
  receptor tyrosine kinase leading to pulmonary
  fibrosis.
• Inhibits proliferation of mesenchymal cells in
  bleomycin induced pulmonary fibrosis.

• Why imatinib is not so effective . It induces ?1
  acid glycoprotein (AGP) a major drug binding
  protein, it binds imatinib during fibrosis and
  prevents its antifibrotic effects.

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Lung transplantation

• In severe disease
• Gas transfer lt39 predicted
• Limited disease gas transfer gt40 but FVC falls
  gt10 over 6 months
• Saturation lt88 during 6 minutes walk test.

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Prognosis

• Some parameters can predict mortality
• Fall in FVC gt 10
• Fall in gas transfer gt 15
• Fall in oxygen saturation lt88 during 6 minute
  walk test.
• Typical HRCT
• Within high mortality pulmonary hypertension is
  associated with systolic SPAP gt 50 mmHg

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Thank You