Department of Pharmacology and Therapeutics

4th Medical lectures

20/Oct/2005

Suspicion of DPLD

• Dyspnoea/Cough• Symptoms often subtle, non specific and slowly

progressive• Long period before diagnosis confirmed• Some patients are asymptomatic

– Diagnosed on the basis of abnormal radiology /PFTs

• Need to maintain an index of suspicion– Esp if environmental/occupational exposures/

concomitant medical conditions

aetiology

• Incidence– Males 31.5/100,000– Females 26.1/100,000

• Pathogenesis– Injury to the lung coupled with attempts to

heal

Classification

• ATS/ERS consensus statement– DPLD secondary to identificable causes

• Environmental• Occupational• Drugs• CTD/IBD

– DPLD secondary to granulomatous diseases– Rare DPLD with well defined clinicopathological features

• LAM• Histiocytosis X• Eosinophilic pneumonia• Pulmonary alveolar proteinosis

– IIP

Inhaled Agents

Inorganic:

   Silica

   Asbestos

   Beryllium

Organic:

   Animal/bird antigens

   Farm antigens

Drug-Induced

Antibiotics

Antiarrhythmics

Anti-inflammatory agents

Chemotherapeutic agents

Antidepressants

Radiation

Oxygen

Connective Tissue Disease

SclerodermaPolymyositis/dermatomyositisSystemic lupus erythematosusRheumatoid arthritisMixed connective tissue diseaseAnkylosing spondylitisPrimary Sjögren's syndromeBehçet's syndrome

Infectious

Atypical pneumoniasPneumocystis carinii pneumoniaTuberculosis

Idiopathic

SarcoidosisEosinophilic granuloma

Idiopathic Interstitial Pneumonia (IIP)

Bronchiolitis obliterans organizing pneumonia (OP)Lymphocytic interstitial pneumonia (LIP)Usual interstitial pneumonia (UIP)Nonspecific interstitial pneumonia (NSIP)Desquamative interstitial pneumonia (DIP)Respiratory bronchiolitis with interstitial lung disease (RB-ILD)Acute interstitial pneumonia (AIP).

Malignant

Lymphangitic carcinomatosisBronchoalveolar cell carcinoma

Miscellaneous

LymphangioleiomyomatosisHistiocytosis X

Adapted from Flaherty and Martinez. Adapted from Flaherty and Martinez.

Diagnostic approach

• ATS/ERS – Integrated clinical, radiological and

pathological approach– Essential to diagnosis UIP/IPF

• History• Examinaton• Selected lab studies• Imaging studies • In selected patients

– TBBX/Surgical Biopsy

Clinical History

• Sex– LAM, Tuberosis Sclerosis – premenopausal women– Women with IPF have a better prognosis

• Age – sarcoidosis, Familial IPF, Eosinophilic Granuloma

• Co morbidity – CTD, IBD• Drug exposure - BPMAN• Assessment of living and work conditions• Occupation/ social/leisure• Risks for HIV

Symptoms • Dyspnoea• Cough• Other symptoms

– Haemoptysis• alveolar hemorrhage syndromes, pulmonary vascular diseases,

lymphangioleiomyomatosis, tuberous sclerosis, and chronic mitral valve disease.

– Pleuritic chest pain• collagen vascular illness, or a pneumothorax in patients with

lymphangioleiomyomatosis, tuberous sclerosis, or eosinophilic granuloma.

– Onset of symptoms can give clues• Acute process:

– atypical infections, eosinophilic pneumonia, pulmonary hemorrhage, Wegener's granulomatosis, AIP, initial hypersensitivity reactions, or bronchiolitis obliterans organizing pneumonia (BOOP).

• Sub-Acute/Chronic process:– IPF, silica- or asbestos-related lung disease, long-standing

hypersensitivity pneumonitis (HP), drug-induced lung diseases

Occupational/ Environmental history

• Diagnostic importance

• Therapeutic importance

• Occupational exposure– Often long latent period

• avian, animal, fish proteins, fungal spores, asbestos, silica, cobalt, beryllium, aluminum, isocyanates, and copper sulfate.

• Home• The presence or absence of pets, especially birds

Medications:

• http://www.pneumotox.com

Smoking history

• RBILD, DIP, and eosinophilic granuloma – Almost exclusively in smokers

• HP/EAA– Less common in smokers– If occurs in smokers – more severe and

chronic

Examination

• The physical examination are generally nonspecific.

• Dry bibasilar crackles, although inspiratory high-pitched rhonchi (“squeaks”) can be seen with bronchiolar disorders.

• Clubbing (most common in IPF) • Right heart failure • Signs of underlying connective tissue

disorders.

Physiology

• Restrictive pattern

• Laboratory features– FBC– Electrolytes– Autoantibody screen– Inflammatory markers

Radiology

• Chest X-Ray (20% Normal)

• HRCT

HRCT Findings in IPF

• Bibasal subpleural distribution

• Reticular shadowing

• Honeycombing

• Lack of ground glass opacification

• Widened interlobular septae

• Tractional bronchiectasis

HRCT NSIP/ Path NSIP

HRCT NSIP/ Path UIP

HRCT UIP/ Path UIP

BAL/TBBX/Lung biopsy

• Depends on clinical suspicion

• Risk v benefit

• Presence of classical clinical and radiological features

Concordant UIP

Discordant UIP

NSIP

IPF Survival

Daniil ZD et al. Am J Respir Crit Care Med. 1999; 160:899Bjoraker JA et al. Am J Respir Crit Care Med. 1998; 157: 199

• No data exist that adequately documents that any of the

current treatment approaches– Improve survival or

– Quality of life for patients

• “Until adequate studies are conducted that define the

best treatment for patients with IPF, this committee

suggests… combined therapy (corticosteroid and either

azathioprine or cyclophosphamide) for patients…who

possess features consistent with a more likely favourable

outcome”

Interferon Gamma (INF-γ 1b)

• Rationale for use

• Pilot study, 1999

• Raghu 2004: R, MC, PC, DB; 330 patients

• 48 week follow up

• SC TIW

• Failed to reach primary efficacy endpoint

Interferon Gamma

Raghu G, et al N Eng J Med, 2004; 350: 125-33

Interferon GammaINSPIRE

International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis with Interferon Gamma 1-b

2 years, 600 pts, 75 centres,

Less severe diseaseFVC >55%DLCO >35%

Pirfenidone: Rationale for Therapy

• Antifibrotic agent• Decreases fibroblast proliferation• Decreases ECM production• Inhibits TGF-β collagen synthesis• Inhibits mitogenic effect of PDGF• Ameliorated fibrosis in a hamster model of bleomycin

lung• Beneficial effect in Hermansky-Pudlak syndrome• Orally active• Safe

Pirfenidone

• Initial trial Raghu et al, 1999• Osaka et al, 2004: R, PC, DB, MC trial 107 pts• Dose titrated to 600 t.i.d.• 1º endpoint lowest O2 saturation at 6MWT• 2º endpoints:

– Change in baseline pulmonary function– Events of acute exacerbation of IPF– QOL score– Disease progression by HRCT pattern

Pirfenidone

• Study aborted by DSMB– Interim analysis of endpoints

• Acute exacerbations of IPF: 5 vs. 0• p =0.0032

• ADR: photosensitivity & nausea

• INTERMUNE sponsored larger RCT

N-Acetyl Cysteine

• Rationale for use– Oxidative stress– Glutathione

• NAC properties– Restoration of glutathione– Reduction of fibroblasts– Decreases ECM components– Inhibition of proinflammatory & profibrotic cytokines

and signal transducers– Improves lung function– Safe

N-Acetyl Cysteine

• IFIGENIA trial• 155 patients: NAC + Pred + AZA• NAC titrated to 600mg t.i.d• 1º endpoint at 12 months

– 15% Δ VC– 20% Δ DLCO

• Trend toward improved mortality

Endothelin Receptor Antagonists

• Rationale for use– Endothelin promotes expression of smooth muscle,

fibrboblasts and ECM protein – Animal models

• Endothelin levels elevated in IPF • Efficacy in pulmonary arterial hypertension• 3 drugs currently under evaluation

– Bosentan– Sitaxsentan & Ambrisentan

Bosentan

• BUIILD 1 (IPF)– 132 patients, 32 centres, 9 countries– 1º endpoint at 12 months: 6 MWT– 2 º endpoint: mortality, lung function, QOL– Ongoing– Similar dose titration to PAH trials: 62.5125

bid

The Evolution of IPF therapy

• Steroids Azathioprine anti-oxidants anti-fibrotic ERA’s,anti-TNF ??????

1950s 2004

Summary: What should we do now?

• No FDA therapy approved for IPF– Multimodality therapy ?

• Supplementary oxygen• Pulmonary rehabilitation• Patient with EARLY disease

– Combination therapy• Prednisolone and Azathioprine (or Cyclophosphamide)

– Experimental therapy in a RCT

• Patient with LATE disease– Lung transplantation– Experimental therapy in a RCT