Diagnostic challenges in IPF

Transcription

1 Medicine, Nursing and Health Sciences Diagnostic challenges in IPF Dr Ian Glaspole Central and Eastern Clinical School, Alfred Hospital and Monash University March 2015 Disclosures Consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Intermune Unrestricted educational grant from Boehringer- Ingelheim 1

2 Summary 1. Current diagnostic guidelines 2. The role of HRCT and pathology 3. Importance and role of multi-disciplinary discussion Diagnostic challenges in IPF 1. Easy: Current diagnostic guidelines 2. Trickier: The role of HRCT and pathology 3. Difficult: Importance and role of MDTs 2

3 BACKGROUND Accurate diagnosis matters! Clear distinction in therapies for ILD now exists Anti-fibrotic therapies for IPF Immuno-modulatory therapies for CTD-ILD, etc Lung transplantation Other Antigen avoidance Best supportive care Palliative care Accurate diagnosis appropriate management 3

4 Effective therapies for IPF will soon be available: anti-fibrotics Annual rate of FVC change (ml/yr) Pirfenidone (N = 278) Placebo (N = 277) Adjusted annual rate of decline in FVC (ml/year) King TE. N Engl J Med. 2014;370: Richeldi L. N Engl J Med. 2014;370: Nintedanib 150 mg bid (n=638) Placebo (n=423) EASY 4

5 CURRENT DIAGNOSTIC GUIDELINES Raghu G. Am J Respir Crit Care Med 2011;188: Idiopathic pulmonary fibrosis Chronic, progressive, fibrosing interstitial pneumonia of unknown cause Incidence of approximately 5-15 per per year Prevalence of approximately per in US Median survival of 33 months Clinical features: Progressive Dyspnoea, cough and exercise limitation Impaired quality of life Death via progression, acute exacerbation Raghu G. Am J Respir Crit Care Med 2011;188:

6 IPF can be hard to distinguish from other ILD s clinically Similarities Differences Dyspnea Progressive Exertional Cough Non-productive Velcro-like crackles, clubbing Restrictive PFT defect Hypoxia Reticular change on CXR/HRCT Prior/current exposures Occupation/Environmental Medication Smoking Extra-pulmonary findings Sarcoidosis Connective tissue disease Vasculitis LAM Serology Rheumatologic, vasculitic Others if indicated: eg, precipitins Bronchoscopy Characteristic BAL or TBBx 2011 ATS/ERS Diagnostic Criteria for IPF UIP pattern on HRCT without surgical biopsy Exclusion of known causes of ILD AND OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

7 TRICKIER THE ROLE OF HRCT 7

8 HRCT criteria for UIP UIP Pattern Possible UIP Pattern Subpleural, basal predominance + + Reticular abnormality + + Honeycombing (+/- traction bronchiectasis) + - Absence of inconsistent features + + Raghu G, et al. Am J Respir Crit Care Med. 2011;183: UIP pattern Misumi S. Proc Am Thorac Soc 2006; 3:

9 Possible UIP pattern traction bronchiectasis Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188: The differential diagnoses for a possible UIP pattern is broad DIP Smoking related IF CTD-ILD NSIP Chronic HP Asbestosis 9

10 Our ability to confidently distinguish UIP from NSIP in the absence of HC is low Elliot et al 25 patients with NSIP and 22 with UIP the presence of honeycombing as a predominant feature had a specificity of 96% and positive predictive value of 90% for UIP a predominant pattern of ground-glass attenuation and/or reticular opacity, with minimal to no honeycombing was demonstrated in 48 (96%) of 50 readings in patients with NSIP, and in 26 (59%) of 44 readings of patients with UIP It is possible to confidently identify UIP when substantial honeycombing is present, but a substantial proportion of patients with UIP have CT findings similar to those of NSIP, and can be distinguished only by biopsy Elliot TL et al. J Comput Assist Tomogr 2005;29: Misumi S. Proc Am Thorac Soc 2006;3.: , HRCT features inconsistent with IPF Inconsistent Features Upper lobe predominant Peribronchovascular predominance Ground-glass > extent of reticular abnormality Profuse micronodules Discrete cysts Diffuse mosaic attenuation/gas-trapping Consolidation Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

11 Inconsistent With UIP Hodnett PA, et al. Am J Respir Crit Care Med. 2013;188: EVEN TRICKIER 11

12 THE ROLE OF PATHOLOGY Histopathological criteria for UIP pattern Marked architectural distortion, ±honeycombing UIP Pattern Probable Possible + subpleural/ parasepstal distribution Patchy fibrosis + Fibroblastic foci + Absence of features suggesting alternate diagnosis + (or HC changes alone) 1 of fibrosis ± inflammation Raghu G, et al. Am J Respir Crit Care Med. 2011;183:

13 Idiopathic Pulmonary Fibrosis Normal Lung Usual Interstitial Pneumonia Lederer D. Idiopathic Pulmonary Fibrosis Normal Lung Fibroblastic focus in Usual Interstitial Pneumonia Lederer D. 13

14 Histopathological features inconsistent with IPF Inconsistent Features Hyaline membranes (except in exacerbation) Organizing pneumonia* Granulomas* Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway centered changes Other features suggestive of an alternate diagnosis Raghu G, et al. Am J Respir Crit Care Med. 2011;183: UIP occurs in other conditions as well CTD-ILD Chronic hypersensitivity pneumonitis Asbestosis Familial IPF 14

15 Surgical lung biopsy can be risky Mortality Utz P et al: Retrospective analysis of lung biopsy specimens demonstrating UIP from at Mayo Clinic; 30 day mortality of 10/60 biopsied patients; 3/53 of stable patients (5.7%) Plönes T et al: Retrospective analysis of VATS lung biopsy specimens demonstrating UIP from at University Medical Center Freiburg: 30 day mortality of 0% Acute exacerbations Ghatol P et al: Literature review of 7 case series: incidence of AE between 2-7 %. Mortality rate for AEs high (>60 %). 1 case where non-pulmonary surgery performed. Utz P. Eur Respir J 2001; 17: Plönes T. Respir Med : Ghatol A et al Lung 2012;190: Pre-biopsy considerations Is it necessary? Is it safe? Extensive honeycombing Pulmonary hypertension High oxygen requirements Low DLCO or FVC Progressive disease/acute exacerbation What about cryobiopsy? 15

16 HRCT Pattern 8/04/2015 Diagnosis of IPF: influence of lung biopsy findings Surgical Lung Biopsy Pattern UIP Probable UIP Possible UIP Nonclassifiable Not UIP UIP IPF IPF IPF IPF Not IPF Possible UIP IPF IPF +/- IPF (probable) +/- IPF (probable) Not IPF Inconsistent with UIP +/- IPF (possible) Not IPF Not IPF Not IPF Not IPF Raghu G, et al. Am J Respir Crit Care Med. 2011;183: QUITE DIFFICULT 16

17 IMPORTANCE AND ROLE OF MULTIDISCIPLINARY DISCUSSION Recommendation: We recommend that a multidisciplinary discussion should be used in the evaluation of IPF (strong recommendation, low-quality evidence). 17

18 Current guidelines for diagnosis: MDT The process of achieving a multidisciplinary diagnosis in a patient [via] dynamic, close communication between clinician, radiologist, and when appropriate, pathologist Integrated presentation of: Clinical data: presentation, exposures, smoking status, associated diseases, lung function, laboratory findings Radiologic findings Lung biopsy: where more informative than HRCT Key benefits: Improve interobserver agreement in diagnosis Recognise a broader range of ILD Travis W. Am J Respir Crit Care Med 2013;188: Raghu G. Am J Respir Crit Care Med 2011;188: Marked heterogeneity in MDT governance Wide range of clinical information presentation methods: 36 18

19 Commonest diagnostic dilemmas reported in expert MDTs Dilemma type Total First listed dilemma Diagnostic material: quality, sufficiency, interpretation 9 2 IPF diagnosis 8 6 Chronic HP diagnosis 7 4 Appropriateness of immune suppression 5 0 Non IPF/HP diagnosis (NSIP, cystic lung disease, CPFE, unclassifiable) 5 2 CTD diagnosis 2 0 Appropriateness of anti-fibrotic therapy 2 0 NEARLY IMPOSSIBLE 19

20 Anti-fibrotics indicated Anti-fibrotics not indicated 8/04/2015 HOW DO WE ADDRESS OUR CONFLICTING INFLUENCES WHEN DIAGNOSIS IS UNCERTAIN? A potential diagnostic and treatment algorithm for IPF in an era of anti-fibrotic therapy Definite IPF Presentation: Clinical features HRCT chest PFT Serology Biopsy Definitely not IPF Difficult to classify ILD Lung function Non progressive Progressive Probably is IPF MDT discussion Probably isn t IPF Unclassifiable ILD Choose approach least likely to harm patient, consider anti-fibrotics. 20

21 Caveats Model suggests treatment of those with probable IPF PBS funding criteria unestablished: may only fund for definite disease of mild to moderate severity Study interpretation: benefit only shown within definite IPF of mild to moderate severity Frequent monitoring is required of those not treated as may acquire more diagnostic features of IPF at follow up Influences on diagnosis Physician specific Clinicians prefer to diagnose treatable disorders Clinicians value EBM Clinicians prefer to use medications with low SE profile Clinicians have low threshold to treatment of fatal disorders Clinicians prefer to deliver good news Disease specific Diagnostic confidence is often limited Two diagnoses may have equal likelihood Absence of evidence vs evidence of absence with regards efficacy in other fibrotic disorders 21

22 Anti-fibrotics indicated Anti-fibrotics not indicated 8/04/2015 Controversial hypothesis: Could the availability of anti-fibrotic agents skew clinicians diagnoses towards disorders that meet treatment indications for their prescription? Fibrotic NSIP? IPF Treatment available Evidence based medicine Low SE profile Otherwise fatal Real world ILD diagnosis is frequently uncertain Definite IPF Presentation: Clinical features HRCT chest PFT Serology Biopsy Definitely not IPF Difficult to classify Lung function Non progressive Progressive Probably is IPF MDT discussion Probably isn t IPF Unclassifiable ILD Choose approach least likely to harm patient, consider anti-fibrotics. 22

23 Can we handle the truth ( that diagnosis is uncertain)? After thorough evaluation, we will have (many) patients: Whose diagnosis is uncertain, but: Whose disease is progressive and likely fatal Can we be brave enough to make distinct treatment choices for uncertain diagnoses? Importance and role of multi-disciplinary discussion If ILD is difficult, or impossible, to classify, management should be based on the most probable diagnosis after MDD and consideration of the expected disease behaviour. Travis W. Am J Respir Crit Care Med 2013;188:

24 Summary Diagnosis is often uncertain in real world management of IPF and other ILD The availability of anti-fibrotic and other efficacious therapies for ILD has made accurate diagnosis of IPF and other specific ILD s of vital importance The use of an expert MDT minimises the risk of inaccurate diagnosis and maximises the chance of appropriate therapeutic decisions being applied A famous sufferer of IPF Evel Knievel, RIP 2007 Robert Craig Knievel multiple jumps between 1965 and 1977 Quote: If someone says to you, that guy should have never jumped the canyon... Do me a favour. Tell him that you saw me here and regardless of what I was, that you knew me, and that I kept my word. 24