Title: Department of Pharmacology and Therapeutics 4th Medical lectures
1Department of Pharmacology and Therapeutics
4th Medical lectures
2Suspicion 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
3aetiology
- Incidence
- Males 31.5/100,000
- Females 26.1/100,000
- Pathogenesis
- Injury to the lung coupled with attempts to heal
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5Classification
- 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
6Inhaled 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 Scleroderma Polymyositi
s/dermatomyositis Systemic lupus
erythematosus Rheumatoid arthritis Mixed
connective tissue disease Ankylosing
spondylitis Primary Sjögren's syndrome Behçet's
syndrome Infectious Atypical
pneumonias Pneumocystis carinii
pneumonia Tuberculosis
7Idiopathic Sarcoidosis Eosinophilic
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
carcinomatosis Bronchoalveolar cell
carcinoma Miscellaneous Lymphangioleiomyomatosis
Histiocytosis X Adapted from Flaherty and
Martinez.
8Diagnostic 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
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11Clinical 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
12Symptoms
- 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
13Occupational/ 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
14Medications
15Smoking history
- RBILD, DIP, and eosinophilic granuloma
- Almost exclusively in smokers
- HP/EAA
- Less common in smokers
- If occurs in smokers more severe and chronic
16Examination
- 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.
17Physiology
- Restrictive pattern
- Laboratory features
- FBC
- Electrolytes
- Autoantibody screen
- Inflammatory markers
18Radiology
- Chest X-Ray (20 Normal)
- HRCT
19HRCT Findings in IPF
- Bibasal subpleural distribution
- Reticular shadowing
- Honeycombing
- Lack of ground glass opacification
- Widened interlobular septae
- Tractional bronchiectasis
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21HRCT NSIP/ Path NSIP HRCT NSIP/ Path UIP HRCT
UIP/ Path UIP
22BAL/TBBX/Lung biopsy
- Depends on clinical suspicion
- Risk v benefit
- Presence of classical clinical and radiological
features
23Concordant UIP Discordant UIP NSIP
24IPF Survival
Daniil ZD et al. Am J Respir Crit Care Med. 1999
160899 Bjoraker JA et al. Am J Respir Crit Care
Med. 1998 157 199
25- 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 patientswho possess
features consistent with a more likely favourable
outcome
26Interferon Gamma (INF-? 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
27Interferon Gamma
Raghu G, et al N Eng J Med, 2004 350 125-33
28Interferon Gamma
INSPIRE International Study of Survival Outcomes
in Idiopathic Pulmonary Fibrosis with Interferon
Gamma 1-b 2 years, 600 pts, 75 centres, Less
severe disease FVC gt55 DLCO gt35
29Pirfenidone Rationale for Therapy
- Antifibrotic agent
- Decreases fibroblast proliferation
- Decreases ECM production
- Inhibits TGF-ß 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
30Pirfenidone
- 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
31Pirfenidone
- 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
32N-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
33N-Acetyl Cysteine
- IFIGENIA trial
- 155 patients NAC Pred AZA
- NAC titrated to 600mg t.i.d
- 1º endpoint at 12 months
- 15 ? VC
- 20 ? DLCO
- Trend toward improved mortality
34Endothelin 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
35Bosentan
- 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 62.5?125 bid
36The Evolution of IPF therapy
- Steroids Azathioprine anti-oxidants
anti-fibrotic ERAs,anti-TNF ?????? -
-
- 1950s 2004
37Summary 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