IPF Diagnostic Methods and Differential Diagnosis

Content Importance of early diagnosis IPF diagnosis based on HRCT Initial clues to suspect IPF Risks and benefits of surgical lung biopsy Guidelines for Diagnosis Histopathologic criteria for UIP pattern Diagnostic algorithm for IPF Combining patterns in the diagnosis of IPF Exclusion of other known causes Patient population in clinical trials: ASCEND Other tests and tools Patient population in clini cal trials: INPULSIS® HRCT criteria for UIP pattern References

Importance of early diagnosis Diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and is often delayed1,2 On average, diagnosis is delayed 1-2 years from onset of symptoms1,2 About 50% of IPF patients are initially misdiagnosed for aging, cardiac disease, emphysema, bronchitis, asthma or COPD2,3 Early and accurate diagnosis is necessary to help ensure timely access to appropriate interventions4 A delay in diagnosis and proper treatments results in higher risk of death independent of the severity of the disease.4 Survival from the time of evaluation adjusted for age and FVC across quartiles of delay4 1. Schoenheit G, et al. Chron Respir Dis 2011;8:225–231. 2. Collard HR, et al. Respir Med 2007;101:1350–1354. 3. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 4. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842–847.

Initial clues to suspect IPF Patients with IPF may present the following symptoms: Non-productive, dry and hacking cough1,2 Unexplained dyspnoea on exertion1-3 Finger clubbing1,2 Bibasilar inspiratory velcro crackles2 Restrictive pattern on pulmonary function tests5 1. Schoenheit G, et al. Chron Respir Dis 2011;8:225–231. 2. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 3. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842–847. 4. Kim DS, et al. Proc Am Thorac Soc 2006;3:285–292.

Guidelines for Diagnosis According to current guidelines (ATS/ERS/JRS/ALAT 2011) a diagnosis of IPF requires the following diagnostic criteria:1 The presence of a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) in patients not subjected to surgical lung biopsy   Exclusion of other known interstitial lung diseases (ILDs) (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity) Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.

Diagnostic algorithm for IPF Suspected IPF Identifiable causes for ILD? HRCT Surgical Lung Biopsy MDD IPF/Not IPF per Table 6 Not IPF IPF No? Yes Possible UIP* Inconsistent w/ UIP* UIP† Probable UIP†/Possible UIP† Non-classifiable † UIP* Not UIP† Based on these criteria, the 2011 guidelines (ATS/ERS/JRS/ALAT) provide a diagnostic algorithm for clinicians to follow for the best possible standard in diagnosing IPF.1 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.

Exclusion of other known causes The medical history and examination should focus on: Medical history Physical examination Medication use Previous or concurrent illness Environmental or occupational exposures Smoking history Family history of respiratory diseases Auscultation Finger clubbing Extrapulmonary signs Given the fact that early symptoms of IPF are often non-specific and can also occur in other ILDs or respiratory diseases, it is of particular importance to exclude known causes of ILD, due to differences in prognosis and treatment responses . This is done by obtaining a careful medical history and physical examination.1-4 1. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 2. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 3. Ryu JH, et al. Mayo Clin Proc 2007;82:976–986. 4. American Thoracic Society. Am J Respir Crit Care Med 2000;161:646–664.

Other tests and tools Bronchoalveolar lavage (BAL) cellular analysis The 2011 guidelines recommend, however, that BAL cellular analysis should not be performed in the diagnostic evaluation of IPF in the majority of individuals, but may be appropriate for a minority.1 BAL cellular analysis may be useful in excluding other conditions, especially chronic hypersensitivity pneumonitis which may mimic IPF.2 The evidence regarding whether or not BAL generally increases accuracy of IPF diagnosis is currently still unclear.1 Serologic testing for connective tissue disease Serologic testing is valuable to rule out connective tissue disease, as this may present with UIP pattern.2 Tests should include rheumatoid factor, anti- cyclic citrullinated peptide, and anti-nuclear antibody titer and pattern.1,2 Serologic evaluation should be performed even in the absence of signs or symptoms of connective tissue disease.1,2 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 2. Du Bois RM. Eur Respir Rev 2012;21:141–146.

HRCT criteria for UIP pattern Possible UIP pattern1 Inconsistent with UIP1 All 4 features Subpleural, basal predominance Reticular abnormality Absence of features listed in the “not UIP pattern” section Honeycombing with or without traction bronchiectasis All 3 features Any of the 7 features Upper or mid-lung predominance Peribronchovascular predominance Extensive ground-glass abnormality (extent > reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation/air- trapping (bilateral, in ≥3 lobes) Consolidation in bronchopulmonary segment(s)/lobe(s) Since the past years, HRCT has become central to the diagnostic pathway of IPF.1 HRCT provides critical data needed to determine whether surgical lung biopsy or further tests are required to achieve a specific diagnosis of IPF.2 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 2. Ryu JH, et al. Mayo Clin Proc 2007;82:976–986.

IPF diagnosis based on HRCT UIP pattern: In conjunction with the exclusion of other known causes of ILDs, the evidence of a UIP pattern on HRCT is considered sufficient for a definitive diagnosis of IPF.1 Possible UIP pattern: According with 2011 guidelines, if HRCT findings yield a possible UIP pattern, lung biopsy may be necessary to confirm the diagnosis of IPF.1 If patients with a possible UIP pattern on HRCT are assessed by experienced experts, HRCT could be used for the diagnosis of IPF and histological confirmation might not be essential to obtain this diagnosis.2 Inconsistent with UIP pattern: HRCT results that are inconsistent with a UIP pattern necessitate lung biopsy to make a diagnosis.1 In about two thirds of the cases IPF can be diagnosed by clinical and radiological criteria. Thus, surgical lung biopsy is needed in about one third of cases to achieve the ultimate diagnosis, which requires multidisciplinary cooperation.3 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 2. Raghu G, et al. Lancet Respir Med 2014;2:277–284. 3. Kaarteenaho R. Respir Res 2013;14:43.

Risks and benefits of surgical lung biopsy Confirm a diagnosis if HRCT is unclear or atypical1,2 Determination of cellular characteristics of affected lung tissue for prognosis2 Prolonged air leak (6-12%)3-5 Mortality (3-5%)3-5 Pneumonia3-5 Need for mechanical ventilation4 Pneumothorax5 Haemothorax5 Increased risk of exacerbation in patients diagnosed with IPF3-5 Before deciding to perform a lung biopsy the potential benefits must be weighed against the potential risks.1 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824. 2. Kaarteenaho R. Respir Res 2013;14:43. 3. Park JH, et al. Eur J Cardiothorac Surg 2007;31:1115–11193. 4. Sigurdsson MI, et al. Ann Thorac Surg 2009;88:227–232. 5. Fibla JJ, et al. Interact Cardiovasc Thorac Surg 2012;15:276–279.

Histopathological criteria for UIP pattern In order to narrow the diagnosis, biopsy results must meet certain criteria:1 Definite UIP Probable UIP Possible UIP Not UIP All 4 features Evidence of marked fibrosis/architectural distortion, ± honeycombing in a predominantly subpleural/paraseptal distribution Presence of patchy involvement of lung parenchyma by fibrosis Presence of fibroblast foci Absence of features against a diagnosis of UIP suggesting an alternate diagnosis Evidence of marked fibrosis/architectural distortion, ± honeycombing Absence of either patchy involvement or fibroblastic foci, but not both Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see “Not UIP” tab) OR Honeycomb changes only All 3 criteria Patchy or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation Absence of other criteria for UIP (see “Definite UIP” tab) Any of the 6 criteria Hyaline membranes Organizing pneumonia Granulomas Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway- centered changes Other features suggestive of an alternate diagnosis 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.

Combining patterns in the diagnosis of IPF Combination of HRCT and surgical lung biopsy for the diagnosis of IPF1 (requires multidisciplinary discussion) HRCT pattern Surgical lung biopsy pattern Diagnosis of IPF? UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP Yes No Probable Inconsistent with UIP Possible Bold type indicates combinations of HRCT and surgical lung biopsy patterns that correspond with a diagnosis of IPF. Particularly in cases of discordant radiologic and histopathologic patterns a multidisciplinary discussion among experienced clinicians, radiologists and pathologists may lead to a greater diagnostic clarification and improve the accuracy of diagnosis.1 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788–824.

Patient population in clinical trials – ASCEND trial Recent clinical trials that served as a basis for the approval of two new medications for IPF differed regarding their inclusion criteria. The ASCEND study enrolled patients without a surgical biopsy only if they showed a definite UIP pattern on HRCT. The following table of eligibility criteria shows that lack of definite pathologic or surgical evidence automatically led to exclusion from the study in spite of a possible UIP pattern on HRCT:1 Surgical lung biopsy not available Pathology panel: definite UIP Pathology panel: probable UIP Pathology panel: possible UIP Pathology panel: Inconsistent w/ UIP or not classifiable Radiology panel: Definite UIP Eligible NOT Eligible Possible UIP Inconsistent with UIP An inclusion also required the extent of fibrotic changes on HRCT scan (honeycombing, reticular changes) to be greater than the extent of emphysema. Features supporting an alternative diagnosis led to exclusion from the trial.15 1. King TE Jr, et al. N Engl J Med 2014;370:2083-92.

Patient population in clinical trials – INPULSIS® trials Eligibility criteria based on chest HRCT if surgical lung biopsy was not available To qualify to enter the INPULSIS® trials if a surgical lung biopsy was not available, the criteria A and B and C; or criteria A and C; or criteria B and C had to be met. A Definite honeycomb lung destruction with basal peripheral predominance B Presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal and peripheral predominance C Atypical features are absent, specifically nodules consolidation. Ground glass opacity, if present, is less extensive than reticular opacity pattern The INPULSIS® trials included patients with a HRCT based definite and possible UIP diagnosis where a surgical biopsy was not available (see table).1 This way, a broader patient population was eligible for enrolment in INPULSIS® compared to ASCEND. In cases where a surgical biopsy was necessary and radiological and pathological results were contradictory, two field experts would discuss and reach a consensus as to whether the patient should be included.16 1. Richeldi L, et al. N Engl J Med 2014:2071–82.

References Schoenheit G., et al. Living with idiopathic pulmonary fibrosis: an in- depth qualitative survey of European patients. Chron Respir Dis 2011;8:225–231. Du Bois RM. An earlier and more confident diagnosis of idiopathic pulmonary fibrosis. Eur Respir Rev 2012;21:141–146. Raghu G., et al. Diagnosis of idiopathic pulmonary fibrosis with high- resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med 2014;2:277–284. Collard HR., et al. Patient experiences with pulmonary fibrosis. Respir Med 2007;101:1350–1354. Meltzer EB., et al. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis 2008;3:8. Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013;14:43. Lamas DJ., et al. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med 2011;184:842–847. Park JH., et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg 2007;31:1115–1119. Kim DS., et al. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006;3:285–292. Raghu G., et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824. Sigurdsson MI., et al. Diagnostic surgical lung biopsies for suspected interstitial lung diseases: a retrospective study. Ann Thorac Surg 2009;88:227–232. Ryu JH., et al. Diagnosis of interstitial lung diseases. Mayo Clin Proc 2007;82:976–986. Fibla JJ., et al. Aggregate risk score for predicting mortality after surgical biopsy for interstitial lung disease. Interact Cardiovasc Thorac Surg 2012;15:276–279. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646–664. King Talmadge E. Jr, et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med 2014. Richeldi L, et al. Supplement to: Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014:2071–8.

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