IPF DIAGNOSTIC METHODS AND DIFFERENTIAL DIAGNOSIS CONTENT Importance Importance of of early early diagnosis diagnosis IPF IPF diagnosis diagnosis based based on on HRCT HRCT Initial Initial clues clues to to suspect suspect IPF IPF Risks Risks and and benefits benefits of of surgical surgical lung lung biopsy biopsy Guidelines Guidelines for for Diagnosis Diagnosis Histopathologic Histopathologic criteria criteria for for UIP UIP pattern pattern
Diagnostic Diagnostic algorithm algorithm for for IPF IPF Combining Combining patterns patterns in in the the diagnosis diagnosis of of IPF IPF Exclusion Exclusion of of other other known known causes causes Patient Patient population population in in clinical clinical trials: trials: ASCEND ASCEND Other Other tests tests and and tools tools Patient Patient population population in in clini clinical cal trials: trials: INPULSIS
INPULSIS HRCT HRCT criteria criteria for for UIP UIP pattern pattern References References IMPORTANCE OF EARLY DIAGNOSIS Diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and is often delayed 1,2 Survival from the time of evaluation adjusted for age and FVC across quartiles of delay4 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 1. Schoenheit G, et al. Chron Respir Dis 2011;8:225231. 2. Collard HR, et al. Respir Med 2007;101:13501354. 3. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 4. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842847. 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
Bibasilar inspiratory velcro crackles2 Finger clubbing1,2 Restrictive pattern on pulmonary function tests5 1. Schoenheit G, et al. Chron Respir Dis 2011;8:225231. 2. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 3. Lamas DJ, et al. Am J Respir Crit Care Med 2011;184:842847. 4. Kim DS, et al. Proc Am Thorac Soc 2006;3:285292. 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;183:788824. DIAGNOSTIC ALGORITHM FOR IPF 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 Suspected Suspected IPF IPF Yes Identifiable
Identifiable causes causes for for ILD? ILD? No? HRCT HRCT UIP* Possible UIP* Inconsistent w/ UIP* Surgical Surgical Lung Lung Biopsy Biopsy Not UIP UIP Probable UIP/Possible UIP Non-classifiable MDD MDD IPF IPF IPF/Not IPF/Not IPF IPF per per Table Table 66 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. Not Not IPF IPF EXCLUSION OF OTHER KNOWN CAUSES 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 The medical history and examination should focus on: Medical history Medication use Previous or concurrent illness Environmental or occupational exposures Smoking history Family history of respiratory diseases Physical examination Auscultation Finger clubbing Extrapulmonary signs 1. Meltzer EB, et al. Orphanet J Rare Dis 2008;3:8. 2. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 3. Ryu JH, et al. Mayo Clin Proc 2007;82:976986. 4. American Thoracic Society. Am J Respir Crit Care Med 2000;161:646664. OTHER TESTS AND TOOLS Bronchoalveolar lavage (BAL) cellular analysis Serologic testing for connective tissue disease 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
Serologic testing is valuable to rule out connective tissue disease, as this may present with UIP pattern.2 BAL cellular analysis may be useful in excluding other conditions, especially chronic hypersensitivity pneumonitis which may mimic IPF.2 Tests should include rheumatoid factor, anticyclic 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 The evidence regarding whether or not BAL generally increases accuracy of IPF diagnosis is currently still unclear.1 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 2. Du Bois RM. Eur Respir Rev 2012;21:141146. HRCT CRITERIA FOR UIP PATTERN 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 UIP pattern1 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 Subpleural, basal predominance Reticular abnormality Absence of features listed in the not UIP pattern section 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/airtrapping (bilateral, in 3 lobes) Consolidation in bronchopulmonary segment(s)/lobe(s) 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 2. Ryu JH, et al. Mayo Clin Proc 2007;82:976986. 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 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 Surgical lung biopsy needed for diagnosis ; 33.33% Diagnosis based on radiological and clinical findings; 66.67% Inconsistent with UIP pattern: HRCT results that are inconsistent with a UIP pattern necessitate lung biopsy to make a diagnosis. 1 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 2. Raghu G, et al. Lancet Respir Med 2014;2:277284. 3. Kaarteenaho R. Respir Res 2013;14:43. RISKS AND BENEFITS OF SURGICAL LUNG BIOPSY Before deciding to perform a lung biopsy the potential benefits must be weighed against the potential risks.1 Benefits Confirm a diagnosis if HRCT is unclear or atypical1,2 Determination of cellular characteristics of affected lung tissue for prognosis2 Risks 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 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 2. Kaarteenaho R. Respir Res 2013;14:43. 3. Park JH, et al. Eur J Cardiothorac Surg 2007;31:111511193. 4. Sigurdsson MI, et al. Ann Thorac Surg 2009;88:227232. 5. Fibla JJ, et al. Interact Cardiovasc Thorac Surg 2012;15:276279. HISTOPATHOLOGICAL CRITERIA FOR UIP PATTERN In order to narrow the diagnosis, biopsy results must meet certain criteria: 1 Definite 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 Probable UIP 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 Possible UIP 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) Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see Not UIP tab) 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. Not UIP Any of the 6 criteria Hyaline membranes Organizing pneumonia Granulomas Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airwaycentered changes Other features suggestive of an alternate diagnosis COMBINING PATTERNS IN THE 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 Combination of HRCT and surgical lung biopsy for the diagnosis of IPF 1 (requires multidisciplinary discussion) HRCT pattern Surgical lung biopsy pattern Diagnosis of IPF? UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP Yes Yes Yes Yes No Possible UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP Yes Yes Probable Probable
No Inconsistent with UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP Possible No No No No Bold type indicates combinations of HRCT and surgical lung biopsy patterns that correspond with a diagnosis of IPF. 1. Raghu G, et al. Am J Respir Crit Care Med 2011;183:788824. 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 Eligible Eligible Eligible NOT Eligible Radiology panel: Possible UIP NOT Eligible Eligible Eligible NOT Eligible NOT Eligible Radiology panel: Inconsistent with UIP NOT Eligible NOT Eligible NOT Eligible NOT Eligible NOT Eligible 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 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 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 1. Richeldi L, et al. N Engl J Med 2014:207182. REFERENCES
Schoenheit G., et al. Living with idiopathic pulmonary fibrosis: an indepth qualitative survey of European patients. Chron Respir Dis 2011;8:225231. Collard HR., et al. Patient experiences with pulmonary fibrosis. Respir Med 2007;101:13501354. Meltzer EB., et al. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis 2008;3:8. Lamas DJ., et al. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med 2011;184:842847. Kim DS., et al. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006;3:285292. 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;183:788824. Ryu JH., et al. Diagnosis of interstitial lung diseases. Mayo Clin Proc 2007;82:976986. 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;161:646664. Du Bois RM. An earlier and more confident diagnosis of idiopathic pulmonary fibrosis. Eur Respir Rev 2012;21:141146.
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;2:277284. Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013;14:43. Park JH., et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg 2007;31:11151119. Sigurdsson MI., et al. Diagnostic surgical lung biopsies for suspected interstitial lung diseases: a retrospective study. Ann Thorac Surg 2009;88:227232. Fibla JJ., et al. Aggregate risk score for predicting mortality after surgical biopsy for interstitial lung disease. Interact Cardiovasc Thorac Surg 2012;15:276279. 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 2014:20718. MORE SLIDE KITS CAN BE FOUND ON WWW.INIPF.COM
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