Prof. Mona Mansour Professor of Pulmonary Medicine Ain Shams University

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

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

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

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 pneumoniaDiffuse alveolar damage Respiratory bronchiolitis interstitial lung diseaseRespiratory bronchiolitis Desquamative 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

Clinical, radiologic, and histologic features, treatment and prognosis of the idiopathic interstitial pneumonias LIPDIP,RB-ILDAIPCOPNSIPIPFClinical Radiographic Pathologic Diagnosis Chronic (>12mo), women Subacute (weeks to months), smoker Abrupt (1-2 wk) Subacute (<3mo) Subacute to chronic (months to years Chronic (>12mo)Duration of illness Rare10-17%Rare (<2%)4-12%14-36%47-64%Frequency of diagnosis DiffuseDIP: 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

Clinical, radiologic, and histologic features, treatment and prognosis of the idiopathic interstitial pneumonias (Conti.) LIPDIP RB-ILD Smoking cessation Diffuse alveolar damage Organizing pneumonia NSIPUsual 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 5%mortality in 5 yr 66% mortality in <6mo Deaths rareUnclear, <10% mortality in 5 yr 50-80% mortality in 5yr Prognosis Septal and bronchovascula r thickening Thin-walled cysts Lower lobe Volume loss Subpleural sparing may be seen Traction Bronchiectasis/bronch iolectasis Architectural distortion Focal ground glass (rare)

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.

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.

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

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.

Idiopathic Pulmonary fibrosis : (IPF) IPF affects the interstitial and the alveolar spaces showing a light microscopic appearance of usual interstitial pneumonia Definition:

Slide no13 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.

 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%) Clinical features and natural history

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 FEV 1 /FVC ratio and impaired gas exchange : increased Po 2 [A–a]- decreased Pao 2 with rest or exercise or decreased DL CO 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 > 50 yr Insidious onset of otherwise unexplained dyspnea on exertion Duration of illness > 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(A– a)O2 = alveolar-arterial pressure difference for oxygen; VC = vital capacity.

Prevalence 7-20 individuals per population Predominates in old age-more common in males with history of smoking

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.

Blood markers:  Rheumatoid factor or antinuclear antibody for connective tissue diseases.  Angiotensin-converting enzyme for sarcoidosis  ANCA for Wegner’s granulomatosis

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.

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

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.

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

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.

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)

Drug treatment in IPF  Prednisolone  Arathioprine or cyclophosphamide  Pirfenidone  Interferon y-1b  Warfarin  Bosentan  Etanercept  Imatinib mesylate

Management Current Recommendations for treatment of IPF 1.Prednisolone 0.5 mg/Kg/day orally for 4 weeks 0.25 mg/Kg/day for 8 weeks mg/Kg/day 2.Azathioprine 2 to 3 mg/Kg/day to maximum dose 150 mg/day Dosing should be give at 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 3.N-acetyl cysteine due to oxidant antioxidant imbalance, as it is a precursor for glutathione synthesis 4.Oxygen 5.Preventive therapy for osteoporosls

Future Therapies 1.Pirfenidone: oral antifibrotic agent improvement in vital capacity at 9 months and decrease episodes of acute exacerbations of IPF. 2.Interferon Y-1b 3.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 4.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.

Future Therapies(cont.) 5.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.

Future Therapies(cont.) 6.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.

Lung transplantation In severe disease :  Gas transfer <39% predicted  Limited disease gas transfer >40% but FVC falls >10% over 6 months  Saturation <88% during 6 minutes walk test.

Slide no31 Prognosis Some parameters can predict mortality Fall in FVC > 10% Fall in gas transfer > 15% Fall in oxygen saturation <88% during 6 minute walk test. Typical HRCT Within high mortality pulmonary hypertension is associated with systolic SPAP > 50 mmHg