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IPF diagnosis: flexibility is a virtue

IPF diagnosis: flexibility is a virtue. Athol Wells Royal Brompton Hospital. AUW has received consultancy or lecturing fees from Actelion, Bayer, Boehringer Ingelheim, Intermune /Roche. The only utility of a diagnostic guideline is to reduce confusion. Adapted from the maxim of EJ Potchen.

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IPF diagnosis: flexibility is a virtue

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  1. IPF diagnosis: flexibility is a virtue Athol Wells Royal Brompton Hospital

  2. AUW has received consultancy or lecturing fees from Actelion, Bayer, Boehringer Ingelheim, Intermune/Roche

  3. The only utility of a diagnostic guideline is to reduce confusion Adapted from the maxim of EJ Potchen

  4. The broken 2011 guideline …….. Suspected IPF Yes Identifiable causes for ILD? No Not UIP HRCT UIP Possible UIPInconsistent with UIP Surgical LungBiopsy Not UIP UIPProbable UIP / Possible UIP Non-classifiable fibrosis MDD IPF IPF / Not IPF Not IPF Adapted from: Raghu G, Collard HR, Egan JJ, et al. Am J RespirCrit Care Med 2011;183:788-824.

  5. IPF diagnosis:in ERS 2018 • IPF revised diagnostic guideline published • Efforts to reconcile the guideline with the Fleischner white paper on IPF diagnosis • IPF management profoundly influenced by diagnostic algorithms • Diagnostic thresholds critical in increasing or decreasing access to anti-fibrotic therapy

  6. Differences between the 2018 guideline and the Fleischner statement:When the guideline was presented at ATS 2018, initial perception that the two statements are contradictory with opposing views on diagnostic testsIn reality, views on BAL (conditional support), cryobiopsy (a “work in progress”) and MD discussion are broadly similarThe only apparently major difference relates to biopsy recommendations in probable UIP (previously “possible UIP”) on HRCT

  7. Fleischner: SLB often superfluous in patients with probable UIP (formerly “possible UIP”) on HRCTGuideline: Conditional positive for SLB in patients with probable UIP on HRCT i.e. SLB should be undertaken in the majority

  8. The difference between views on SLBx in “probable UIP” lies in a key question… What exactly are we trying to achieve in the diagnosis of IPF: certain diagnosis or certain management?

  9. Source material • Ryerson CJ et al. A standardized diagnostic ontology for fibrotic interstitial lung disease. An international working group perspective. Am J RespirCrit Care Med 2017; 196:1249-54. • Lynch DA et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med 2018; 6:138-53 • Raghu G et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J RespirCrit Care Med 2018; 198:e44-e68 • Wells AU. IPF diagnosis: flexibility is a virtue. Lancet Respir Med 2018; 6:735-7

  10. The clinical value of making a diagnosis lies in information on the likely natural history and treated courseAn IPF diagnosis justifies anti-fibrotic therapyIn specifying rigorous “guideline” criteria for a definite diagnosis of IPF, we risk losing sight of a key question……… What level of IPF diagnostic likelihood justifies the introduction of an anti-fibrotic drug?

  11. A diagnosis can be….. • Established >90% • Provisional - high confidence 70–90% - low confidence 50–70% • Unclassifiable <50% Ryerson CJ, et al. Am J RespirCrit Care Med. 2017;196(10):1249-54

  12. “If you don’t know where you are going, any road will get you there”Lewis Carroll

  13. An established diagnosis

  14. A provisional diagnosis

  15. Unclassifiable disease

  16. The Fleischner Society view of diagnosis “If diagnostic tissue is not available, a working diagnosis of IPF may be made after careful multidisciplinary evaluation.” A working IPF diagnosis is a provisional diagnosis made with high confidence such that IPF-specific therapy is the only logical approach In effect, the Fleischner Society endorses the use of IPF-specific treatment in selected patients with probable UIP on HRCT and no biopsy data. This includes patients with a provisional IPF diagnosis, made with high confidence (wrt Ryerson et al) Lynch DA, et al. Lancet Respir Med. 2018;6(2):138-153; Ryerson CJ, et al. Am J RespirCrit Care Med. 2017;196(10):1249-54

  17. Is this a strong negative for biopsy? “The diagnosis of IPF may be confidently made in a patient with a typical clinical context of IPF, with a CT pattern of definite or probable UIP. In all other circumstances, multidisciplinary diagnosis is appropriate to inform……” Many patients with suspected IPF have a compatible clinical picture which is not typical Younger age, features of IPAF, probably non-significant HP exposure ……… to name just a few examples Using GRADE-speak, the Fleischner view equates to a conditional negative view of surgical biopsy in patients with suspected IPF and probable UIP on HRCT It is absolutely NOT a strong negative statement Lancet Respir Med 2018; 6:138-53

  18. “Possible UIP” (= “probable UIP”) in the INPULSIS studies • In the two INPULSIS nintedanib studies, the majority of patients met formal ATS/ERS IPF diagnostic criteria • Classical UIP on HRCT in the correct clinical context (50%) • “Possible UIP” (now “probable UIP”) on HRCT, biopsy confirmation of UIP (15%) • However in large minority (35%), there was possible UIP on HRCT + traction bronchiectasis, with no biopsy performed • These patients had a “working diagnosis” of IPF. Outcomes evaluated in a post hoc analysis Raghu G, et al. Am J Respir Crit Care Med. 2017;195:78–85

  19. Annual rate of decline in FVC inthe INPULSIS studies Probable UIP on HRCTand no biopsy Meet 2011 guideline criteria n=213 n=425 n=125 n=298 Placebo Nintedanib Raghu G, et al. Am J Respir Crit Care Med. 2017;195:78–85

  20. The conditional positive SLB statement in the 2018 joint guideline • SLB and BAL are both suggestedand not mandated in patients with suspected IPF and probable UIP on HRCT • It seems likely that most USA clinicians will not take up the BAL suggestion • It seems similarly likely that many clinicians will not take up the SLB suggestion if anti-fibrotic therapy can be used when a confident provisional diagnosis of IPF can be made Raghu G, et al. Am J RespirCrit Care Med. 2018;198(5):e44-e68

  21. What is common to the two statements……… Probable UIP Indeterminate on HRCT CT: alternative diagnosis MDD Integrate clinical and HRCT data SLB performed MDD Not IPF IPF

  22. A conditional positive recommendation for SLB in probable UIP i.e. the majority • The nature of the population is crucial • In younger referral centre populations, a conditional positive recommendation may be more difficult to sustain. This may also be true, to a lesser extent, of clinical trial cohorts • But how does the recommendation read with regard to real world populations outside referral centres?

  23. A conditional positive for SLB in the “IPF clinical syndrome”: you must be joking….. • Median age in several series 68–69 years • But many patients aged less than 69 years have major comorbidities, severe pulmonary function impairment at presentation or decline to undergo SLB • Therefore, a majority can be achieved only by biopsying many patients aged 70–75 years

  24. The problem is GRADE “The decision to do surgical lung biopsy to make a diagnosis of UIP-IPF must be individualised based on risk factors and discussion with the patient.” No such statement is possible in GRADE. A so-called average statement is made specifying SLB in a minority or majority of patients The trouble is that the decision is SO conditional….. Lancet Respir Med 2018;6:138-153

  25. Wells AU. Lancet Respir Med. 2018;6(10):735-737

  26. Where does this leave us? • The guideline defines how to reach a definite diagnosis of IPF • But clinicians are not required to have absolute diagnostic uncertainty in order to treat • The difference between the two statements on surgical biopsy is simply that difference. • As clinicians, we can and should do as we see fit in diagnosing IPF. A diagnostic likelihood >70% is quite sufficient to drive management

  27. The reality is that patients will decide whether a majority of those with suspected IPF and probable UIP on HRCT undergo SLB For informed discussion there are at least three required pieces of information

  28. The patient needs to know whether the decision is a close call

  29. Risk must be unsparingly stated

  30. Mortality 1.7% for elective procedures, 16% for non-elective procedures • Risk factors: age, increasing comorbidity, open surgery and provisional diagnoses of IPF or CTD-ILD (severity not analysed) Hutchinson JP, et al. Am J Respir Crit Care Med. 2016;193:1161-7

  31. If the baseline mortality risk is 1.7%, and age>65 years and a plausible diagnosis of IPF are independent risk factors….. what is the risk associated with SLB in a 70 year-old patient with suspected IPF? 3-4%? 5%? 5-10%?

  32. The patient needs to know whether anti-fibrotic therapy will, in any case, be used if a SLB is not performed

  33. Conditional positive vs negative recommendations (guideline vs Fleischner) = the difference between diagnostic certainty and diagnostic likelihood providingconfident IPF management It is surely doubtful that the majority of patients will accept the risks of SLB if it is unlikely to influence management of the disease

  34. Summary • IPF diagnosis can be definite or a confident “working diagnosis” • The necessary level of information differs, but management is the same • Patients with a non-definite but provisional diagnosis of IPF made with high confidence will mostly decline to undergo SLB • Therefore, we can avoid acrimony on the statements

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