Department of Pharmacology and Therapeutics4th Medical lectures20/Oct/2005

Suspicion of DPLDDyspnoea/CoughSymptoms often subtle, non specific and slowly progressiveLong period before diagnosis confirmedSome patients are asymptomatic Diagnosed on the basis of abnormal radiology /PFTsNeed to maintain an index of suspicionEsp if environmental/occupational exposures/ concomitant medical conditions

aetiologyIncidenceMales 31.5/100,000Females 26.1/100,000PathogenesisInjury to the lung coupled with attempts to heal

Classification

ATS/ERS consensus statementDPLD secondary to identificable causesEnvironmentalOccupationalDrugsCTD/IBDDPLD secondary to granulomatous diseasesRare DPLD with well defined clinicopathological featuresLAMHistiocytosis XEosinophilic pneumoniaPulmonary alveolar proteinosisIIP

Connective Tissue Disease

SclerodermaPolymyositis/dermatomyositisSystemic lupus erythematosusRheumatoid arthritisMixed connective tissue diseaseAnkylosing spondylitisPrimary Sjgren's syndromeBehet's syndrome

Infectious

Atypical pneumoniasPneumocystis carinii pneumoniaTuberculosis

Inhaled AgentsInorganic:Silica AsbestosBerylliumOrganic:Animal/bird antigensFarm antigens

Drug-InducedAntibioticsAntiarrhythmicsAnti-inflammatory agentsChemotherapeutic agentsAntidepressantsRadiationOxygen

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.

Diagnostic approachATS/ERS Integrated clinical, radiological and pathological approachEssential to diagnosis UIP/IPF HistoryExaminatonSelected lab studiesImaging studies In selected patients TBBX/Surgical Biopsy

Clinical HistorySexLAM, Tuberosis Sclerosis premenopausal womenWomen with IPF have a better prognosisAge sarcoidosis, Familial IPF, Eosinophilic GranulomaCo morbidity CTD, IBDDrug exposure - BPMANAssessment of living and work conditionsOccupation/ social/leisureRisks for HIV

Symptoms DyspnoeaCoughOther symptomsHaemoptysisalveolar hemorrhage syndromes, pulmonary vascular diseases, lymphangioleiomyomatosis, tuberous sclerosis, and chronic mitral valve disease.Pleuritic chest paincollagen vascular illness, or a pneumothorax in patients with lymphangioleiomyomatosis, tuberous sclerosis, or eosinophilic granuloma.Onset of symptoms can give cluesAcute 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 historyDiagnostic importanceTherapeutic importanceOccupational exposureOften long latent periodavian, animal, fish proteins, fungal spores, asbestos, silica, cobalt, beryllium, aluminum, isocyanates, and copper sulfate. HomeThe presence or absence of pets, especially birds

Medications:http://www.pneumotox.com

Smoking historyRBILD, DIP, and eosinophilic granuloma Almost exclusively in smokersHP/EAALess common in smokersIf 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.

PhysiologyRestrictive patternLaboratory featuresFBCElectrolytesAutoantibody screenInflammatory markers

Radiology

Chest X-Ray (20% Normal)HRCT

HRCT Findings in IPFBibasal subpleural distributionReticular shadowingHoneycombingLack of ground glass opacificationWidened interlobular septaeTractional bronchiectasis

HRCT NSIP/ Path NSIPHRCT NSIP/ Path UIPHRCT UIP/ Path UIP

BAL/TBBX/Lung biopsyDepends on clinical suspicionRisk v benefitPresence of classical clinical and radiological features

Concordant UIPDiscordant UIPNSIP

IPF SurvivalDaniil 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 approachesImprove survival orQuality of life for patientsUntil 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

Interferon Gamma (INF- 1b)Rationale for use Pilot study, 1999Raghu 2004: R, MC, PC, DB; 330 patients48 week follow upSC TIWFailed to reach primary efficacy endpoint

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

Interferon GammaINSPIREInternational 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 TherapyAntifibrotic agentDecreases fibroblast proliferationDecreases ECM productionInhibits TGF- collagen synthesisInhibits mitogenic effect of PDGFAmeliorated fibrosis in a hamster model of bleomycin lungBeneficial effect in Hermansky-Pudlak syndromeOrally activeSafe

PirfenidoneInitial trial Raghu et al, 1999Osaka et al, 2004: R, PC, DB, MC trial 107 ptsDose titrated to 600 t.i.d.1 endpoint lowest O2 saturation at 6MWT2 endpoints: Change in baseline pulmonary functionEvents of acute exacerbation of IPFQOL scoreDisease progression by HRCT pattern

PirfenidoneStudy aborted by DSMBInterim analysis of endpointsAcute exacerbations of IPF: 5 vs. 0p =0.0032ADR: photosensitivity & nauseaINTERMUNE sponsored larger RCT

N-Acetyl Cysteine Rationale for useOxidative stressGlutathioneNAC propertiesRestoration of glutathioneReduction of fibroblastsDecreases ECM componentsInhibition of proinflammatory & profibrotic cytokines and signal transducersImproves lung functionSafe

N-Acetyl CysteineIFIGENIA trial155 patients: NAC + Pred + AZANAC titrated to 600mg t.i.d1 endpoint at 12 months15% VC20% DLCO Trend toward improved mortality

Endothelin Receptor AntagonistsRationale for useEndothelin promotes expression of smooth muscle, fibrboblasts and ECM protein Animal modelsEndothelin levels elevated in IPF Efficacy in pulmonary arterial hypertension3 drugs currently under evaluationBosentanSitaxsentan & Ambrisentan

BosentanBUIILD 1 (IPF)132 patients, 32 centres, 9 countries1 endpoint at 12 months: 6 MWT2 endpoint: mortality, lung function, QOLOngoingSimilar dose titration to PAH trials: 62.5125 bid

The Evolution of IPF therapy

Steroids Azathioprine anti-oxidants anti-fibrotic ERAs,anti-TNF ??????

1950s 2004

Summary: What should we do now?No FDA therapy approved for IPFMultimodality therapy ?Supplementary oxygenPulmonary rehabilitationPatient with EARLY diseaseCombination therapyPrednisolone and Azathioprine (or Cyclophosphamide)Experimental therapy in a RCTPatient with LATE diseaseLung transplantationExperimental therapy in a RCT