Hamlet’s Delight New Guidelines for IPF CRC 2011 Ted Marras, MD FRCPC Toronto Western Hospital / University Health Network

Declarations Potential conflicts of interest Financial Study participation: Actelion, Boehringer- Ingelheim, Gilead, Intermune Grant support: CPFF, CIHR Other Clinical and academic interest in ILD Off label use of therapies None of the medications mentioned have a formal indication for treating IPF

Objectives Considering revised guidelines for idiopathic pulmonary fibrosis (IPF): 1. Consider appropriate investigations and diagnostic algorithm for IPF 2. Select a management strategy that is most appropriate for a given IPF patient 3. Select an appropriate strategy of clinical follow-up for a given IPF patient What’s presented here will undoubtedly have omissions, possibly small deviations from document to come

IPF What is it? Chronic, progressive fibrosis of the lung Unknown cause Why is it bad? Stiff lung  dyspnea Scarred lung  poor gas exchange Poor prognosis (difficult to quantify) What’s presented here will undoubtedly have omissions, possibly small deviations from document to come

IPF - HRCT Peripheral, basal predominant: Reticulations, interlobular septal thickening, intralobular reticulations Honeycombing Woman, 70s, longstanding dry cough and dyspnea

IPF - Histology = UIP A) Heterogeneity, traction emphysema B) Subpleural fibrosis, fibroblast foci C) Fibroblast focus D) Microscopic honeycombing Raghu. Clin Chest Med 2004. 25(4)621-36.

IPF - Natural history Raghu AJRCCM 183.788-824. 2011

ATS / ERS / JRS / ALAT Provide evidence- based recommendations on diagnosis and management of IPF Joint Taskforce 22 Pulmonary physicians 4 Chest radiologists 4 Lung pathologists 3 Health care librarians 1 Expert methodologist (respirologist) Raghu et al. AJRCCM 2011, 183:788-824

Recommendations Reviewed published data Recommendations on questions Direction – yes / no Strength – strong / weak Evidence quality Voted on by committee members

Recommendations Raghu et al. AJRCCM 2011, 183:788-824

Recommendations Raghu et al. AJRCCM 2011, 183:788-824

Objectives Considering revised guidelines for idiopathic pulmonary fibrosis (IPF): 1. Consider appropriate investigations and diagnostic algorithm for IPF 2. Select a management strategy that is most appropriate for a given IPF patient 3. Select an appropriate strategy of clinical follow-up for a given IPF patient What’s presented here will undoubtedly have omissions, possibly small deviations from document to come

Diagnosis Excluding Connective Tissue Disease Should a CTD serologic evaluation be performed in all people with suspected IPF? No reliable data UIP may occure in any CTD and may present before overt CTD

Diagnosis Excluding Connective Tissue Disease Should a CTD serologic evaluation be performed in all people with suspected IPF? No reliable data Question Recommendation Vote Yes/No/Abs Direction Strength Evidence quality CTD serology? Yes Weak Very low 23/0/0 Even in absence of overt CTD: RF, anti-CCP, ANA (ENA – Jo-1, Scl-70, etc. may be helpful)

Diagnosis Utility of BAL / TBBx BAL may help differentiate HP TBBx may help with granulomatous disorders Should BAL / TBBx be performed in all people with suspected IPF?

Diagnosis Utility of BAL / TBBx BAL may help differentiate HP TBBx may help with granulomatous disorders Should BAL / TBBx be performed in all people with suspected IPF? Question Recommendation Vote Yes/No/Abs Direction Strength Evidence quality BAL? No Weak Low 4/18/1 TBBx? 0/23/0

Diagnosis Multi-disciplinary discussion (MDD) IPF diagnosis usually requires expertise from clinicians, radiologists, pathologists Proper communication increases inter-observer agreement Should MDD be used in evaluating suspected IPF? Operationalizing this outside of highly specialized centres is a challenge

Diagnosis Multi-disciplinary discussion (MDD) IPF diagnosis usually requires expertise from clinicians, radiologists, pathologists Proper communication increases inter-observer agreement Should MDD be used in evaluating suspected IPF? Question Recommendation Vote Yes/No/Abs Direction Strength Evidence quality MDD? Yes Strong Low 0/23/0 Operationalizing this outside of highly specialized centres is a challenge Not possible for many practitioners Efforts to promote verbal communication should be made

Diagnosis Consider: Clinical Radiology - HRCT Histology - surgical lung biopsy

Diagnosis HRCT Relevant features Distribution subpleural / basal predominant Reticulation Honeycombing + traction bronchiectasis Absence of inconsistent features: Upper lobe predominant Peribronchial predominant GGO > reticulation Profuse micronodules Discrete cysts – multiple, bilateral, away from HC Diffuse mosaicism Consolidation

Diagnosis HRCT HRCT classification for suspected IPF UIP pattern (1,2,3,4) Possible UIP pattern (1,2,4) Inconsistent with UIP (4 not fulfilled) Subpleural / basal Reticulation Honeycombing + traction bronchiectasis Absence of inconsistent features

Diagnosis Histology Relevant features Fibrosis + subpleural / paraseptal HC Patchy Fibroblast foci Absence of inconsistent features: Hyaline membranes Organizing pneumonia Granulomas Marked inflammation away from HC Predominantly airway centred

Diagnosis Histology Histologic classification for suspected IPF UIP pattern (1,2,3,4) Probable UIP pattern (1 and [2 or 3] and 4) or HC only Possible UIP pattern (1,4) Not UIP pattern (4 not fulfilled) Fibrosis + subpleural / paraseptal HC Patchy Fibroblast foci Absence of inconsistent features

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Probable* Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) Not UIP Yes No Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Probable* Inconsistent with UIP (inconsistent features) All others Possible* Subpleural / basal, Reticulation, Honeycombing + traction bronchiectasis, Absence of inconsistent features * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Probable* No Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Consistent with UIP (lack HC / traction bronchiectasis) UIP / Probable Possible UIP Probable* Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* May lack patchiness or HC * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* Fibrosis only * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* * Multidisciplinary discussion recommended

Diagnosis HRCT / Histology Surgical biopsy IPF? UIP Not done (clinically typical) UIP / Probable / Possible Not UIP Yes No Possible UIP (lack HC) UIP / Probable Probable* Inconsistent with UIP (inconsistent features) All others Possible* Large proportion will have “possible” HRCT (no HC) and “possible” SLBx (fibrosis w/o alternate cause); Lots of MDDs! * Multidisciplinary discussion recommended

Diagnosis Suspected IPF yes Identifiable cause? Not IPF

Diagnosis Suspected IPF Identifiable cause? Not IPF HRCT IPF yes no UIP IPF

Diagnosis Suspected IPF Identifiable cause? Not IPF HRCT yes Identifiable cause? Not IPF no HRCT possible UIP or inconsistent with UIP UIP Surgical Biopsy IPF

Diagnosis Suspected IPF Identifiable cause? Not IPF HRCT yes Identifiable cause? Not IPF no HRCT possible UIP or inconsistent with UIP Not UIP UIP Surgical Biopsy IPF

Diagnosis Suspected IPF Identifiable cause? Not IPF HRCT yes Identifiable cause? Not IPF no HRCT possible UIP or inconsistent with UIP Not UIP UIP Surgical Biopsy UIP, probable, possible IPF See table

Objectives Considering revised guidelines for idiopathic pulmonary fibrosis (IPF): 1. Consider appropriate investigations and diagnostic algorithm for IPF 2. Select a management strategy that is most appropriate for a given IPF patient 3. Select an appropriate strategy of clinical follow-up for a given IPF patient Early treatment refers to medical therapy meant to modify IPF disease course

IPF Treatment Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 Maybe should look carefully at the ones for which there is a weak recommendation against

IPF Treatment Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 Maybe should look carefully at the ones for which there is a weak recommendation against

IPF Treatment Steroid + Aza + NAC* Weak 3 / 17 / 3 Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC* Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 IFIGENIA - No diff in mortality or dyspnea, HRQL, radiology; 30% drop-out; unclear significance of the observed effect; no placebo * Small physiologic benefit, may have significant toxicities

IPF Treatment NAC alone* 5 / 15 / 3 Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone* 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 IFIGENIA, some supportive uncontrolled data, safe; BUT preparation not standardized * Limited data, safe, maybe cheap; preparation not standardized

IPF Treatment Anticoagulation* 1 / 20 / 2 Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation* 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 Supportive study; not blinded, differential drop-outs; failure to exclude PE * Supportive study, several limitations

IPF Treatment Pirfenidone Low-mod 4 / 10 / 17 Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17

IPF Treatment Pirfenidone Low-mod 4 / 10 / 17 Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 But incomplete data set

IPF Treatment Pirfenidone Low-mod 4 / 10 / 17 Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 But highly selective enrollment (desat on unvalidated ex test), primary endpoint changed part-way through

IPF Treatment Pirfenidone Low-mod 4 / 10 / 17 Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids alone No Strong Very low 0 / 21 / 2 Colchicine Cyclosporine 0 / 18 / 4 Steroid + Aza / CY Low Steroid + Aza + NAC Weak 3 / 17 / 3 NAC alone 5 / 15 / 3 IFN gamma High 0 / 17 / 6 Bosentan Moderate 0 / 10 / 13 Etanercept Anticoagulation 1 / 20 / 2 Pirfenidone Low-mod 4 / 10 / 17 Voting by subsequent electronic polling to included the 2 latter studies: to be reviewed in Dr. Fell’s presentation

“Nonpharmacologic” Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Pulmonary rehabilitation Yes Weak Low 19 / 0 / 3 Oxygen Strong Very low 18 / 0 / 4 Transplantation 21 / 0 / 1 Rehab – long-term benefit unclear; O2 – for resting hypoxemia, leaving exertional up for debate; Tx – timing critical; discuss at Dx and detailed eval at 1st sign of objective deterioration

Transplant Who to consider? Discuss at diagnosis Detailed evaluation: Advanced at diagnosis With objective deterioration Fairly liberal criteria to consider for assessment / transplant

Transplant Who to consider? Discuss at diagnosis Detailed evaluation: Advanced at diagnosis With objective deterioration Baseline Severe dyspnea DLCO<40% 6MW SaO2 < 88% Extensive HC on HRCT Longitudinal Increasing dyspnea FVC decrease >10%* DLCO decrease >15%* Progression on HRCT Fairly liberal criteria to consider for assessment / transplant * Absolute measure

Additional Treatment - Acute exacerbations AEIPF - Definition “Acute, clinically significant deterioration of unidentifiable cause in a patient with underlying IPF” Diagnostic Criteria IPF with unexplained worsening < 30 days HRCT new bilateral GGO and/or consolidation superimposed on typical IPF pattern No infection by tracheal aspirate or BAL Exclude: CHF, PE, identifiable acute lung injury cause Median mortality among series

Additional Treatment Treatment Recommendation Vote Yes/No/Abs Direction Strength Evidence quality Steroids in AEIPF Yes Weak Very Low 14 / 5 / 1 Mechanical ventilation No Low 2 / 19 / 1 Pulmonary hypertension Very low 8 / 14 / 1 Asymptomatic GERD 15 / 8 / 0

Objectives Considering revised guidelines for idiopathic pulmonary fibrosis (IPF): 1. Consider appropriate investigations and diagnostic algorithm for IPF 2. Select a management strategy that is most appropriate for a given IPF patient 3. Select an appropriate strategy of clinical follow-up for a given IPF patient What’s presented here will undoubtedly have omissions, possibly small deviations from document to come

Monitoring for progression Routine PFT Sustained change in absolute: FVC of 10% (e.g. 2L1.8L)* DLCO of 15% (Both associated with mortality, suggestive of progression) *Smaller progressive, sustained changes MAY be relevant (e.g. 5-10% FVC decline)

Sunset George Lake, Killarney Provincial Park, Aug 2005

Monitoring for progression Routine PFT Sustained change in absolute: FVC of 10% (e.g. 2L1.8L) DLCO of 15% (Both associated with mortality, suggestive of progression) 6MW distance / oximetry too variable over long time periods (good discriminative test, not a good evaluative test) Discriminative test – accurately distinguishes the sick from the well; or discriminates by illness severity Evaluative test – accurately evaluates changes over time (natural history or interventions)