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

Identifiable causes for ILD? The broken 2011 guideline …….. Suspected IPF Yes Identifiable causes for ILD? No Not UIP HRCT UIP Possible UIP Inconsistent with UIP Surgical Lung Biopsy Not UIP UIP Probable 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 Respir Crit Care Med 2011;183:788-824.

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

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 tests In reality, views on BAL (conditional support), cryobiopsy (a “work in progress”) and MD discussion are broadly similar The only apparently major difference relates to biopsy recommendations in probable UIP (previously “possible UIP”) on HRCT

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

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?

Source material Ryerson CJ et al. A standardized diagnostic ontology for fibrotic interstitial lung disease. An international working group perspective. Am J Respir Crit 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 Respir Crit Care Med 2018; 198:e44-e68 Wells AU. IPF diagnosis: flexibility is a virtue. Lancet Respir Med 2018; 6:735-7

The clinical value of making a diagnosis lies in information on the likely natural history and treated course An IPF diagnosis justifies anti-fibrotic therapy In 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?

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

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

An established diagnosis

A provisional diagnosis

Unclassifiable disease

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 Respir Crit Care Med. 2017;196(10):1249-54

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

“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

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

The conditional positive SLB statement in the 2018 joint guideline SLB and BAL are both suggested and 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 Respir Crit Care Med. 2018;198(5):e44-e68

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

A conditional positive recommendation for SLB in probable UIP i. e 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?

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

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

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

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

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

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

Risk must be unsparingly stated

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

If the baseline mortality risk is 1 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%?

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

Conditional positive vs negative recommendations (guideline vs Fleischner) = the difference between diagnostic certainty and diagnostic likelihood providing confident 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

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