Challenges in Pulmonary and Critical Care: 2018 Interstitial Lung Disease: Evolving Our Understanding of a Deadly Disease 1 Faculty Kevin Flaherty, MD, MS Professor in Pulmonary and Critical Care Medicine University of Michigan Ann Arbor, MI 2 Disclosures Kevin Flaherty, MD, MS serves as a consultant for Boehringer Ingelheim, Veracyte, Roche/Genentech, FibroGen, and Sanofi Genzyme. 3 1
Learning Objectives 1. Explain the importance of early identification and differentiation of interstitial lung disease (ILDs). 2. Describe the diagnostic approach for ILD, and when to refer patients to ILD centers. 3. Discuss the management of idiopathic pulmonary fibrosis (IPF), including its risk factors and comorbidities. 4. Recognize the role of patient education for effective management of ILD. 4 PRE-TEST QUESTIONS 5 Pre-I1: On average how much time is estimated to elapse between onset of symptoms and correct diagnosis: 1. 6 months 2. 1-2 years 3. 3-4 years Pre-test ARS Question 1 4. More than 5 years 6 2
Pre-test ARS Question 2 Pre-I2: Each of the following diagnostic tests should typically be performed in the evaluation of patients with suspected ILD except: 1. Complete history and physical exam 2. Complete pulmonary function testing including pulmonary mechanics and diffusion capacity for carbon monoxide 3. High resolution CT of the chest 4. Video assisted surgical lung biopsy 7 Pre-test ARS Question 3 Pre-I3: A 64 year old male with newly diagnosed IPF returns to clinic to discuss possible therapy. Which of the following choices would be most likely to slow the decline in his lung function (FVC)? 1. Prednisone/azathioprine/N-acetyl cysteine 2. Pirfenidone or nintedanib 3. Warfarin 4. N-acetyl cysteine 5. Imatanib 8 Pre-test ARS Question 4 Pre-I4: Each of the following co-morbidities are common with IPF except: 1. Cardiovascular disease 2. Gastroesophageal reflux disease 3. Obstructive sleep apnea/sleep disorders 4. Asthma 5. Pulmonary hypertension 9 3
Pre-test ARS Question 5 Pre-I5: How confident are you in your ability to educate patients with ILD on the most effective strategies to improve their outcomes? 1. Not at all confident 2. Not very confident 3. Somewhat confident 4. Pretty much confident 5. Very confident 10 Interstitial Lung Diseases - Difficulties Diverse group of disorders (130+) Similar symptoms, physiology, radiology Difficult nomenclature Limited, often toxic, treatments 11 Interstitial Lung Diseases - Difficulties Diverse group of disorders (130+) Similar symptoms, physiology, radiology Difficult nomenclature Limited, often toxic, treatments 12 4
Path to Diagnosis is Often Long and Tortuous Symptom Onset Often 1-2 years Diagnosis Patients are often misdiagnosed with bronchitis, asthma, COPD, emphysema, or heart disease as symptoms are common manifestations of many diseases Early and accurate diagnosis allows timely initiation of appropriate therapy 13 Distinguishing Dyspnea: IPF Prevalence COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis. 1. Raghu G et al. Resp Crit Care Med. 2006;174:810-816. 2. Go AS et al. Circulation. 2013;127:e6-e245. 3. Wheaton AG et al. MMWR Morb Mortal Wkly Rep. 2015;64:289-295. 14 When to Suspect ILD History Chronic exertional dyspnea Chronic cough without purulence Fatigue Physical Examination Bilateral velcro-like crackles Clubbing/acrocyanosis Physiologic Findings Low DLCO Resting/exertional desaturation Normal/Reduced FVC Chest Radiograph Nonspecific changes/bilateral basal reticular infiltrates 15 Lederer & Martinez N Engl J Med 2018:378:1811-23 5
Diffuse Parenchymal Lung Disease (DPLD) DPLD of known cause, eg, Idiopathic Granulomatous Other forms of drugs or association, eg, Interstitial DPLD, eg, DPLD, eg, LAM, HX, collagen vascular disease Pneumonias sarcoidosis etc Major Rare Unclassifiable Idiopathic Pulmonary Fibrosis Lymphoid Interstitial Pneumonia Nonspecific interstitial pneumonia (idiopathic) Pleuroparenchymal Fibroelastosis Acute Interstitial Pneumonia Respiratory bronchiolitis interstitial lung disease Desquamative Interstitial Pneumonia Cryptogenic Organizing Pneumonia ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304 Travis et al., Am J Resp Crit Care Med 2013; 188(6):733-48 16 Idiopathic Pulmonary Fibrosis IPF is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause. It occurs primarily in older adults, is limited to the lungs, and is defined by the histopathologic and/or radiologic pattern of Usual Interstitial Pneumonia 17 Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 IPF - Pathobiology 18 Aryal & Nathen Expert Opinion Emerging Drugs 2018;23:159-72 6
Interstitial Lung Disease Diagnostic Team Clinician Radiologist Pathologist Communication among multidisciplinary team members is essential for an accurate diagnosis 19 Putting the Pattern in Context Usual Interstitial Pneumonia (UIP) Idiopathic Pulmonary Fibrosis (IPF) Nonspecific Interstitial Pneumonia (NSIP) Idiopathic Organizing Pneumonia Idiopathic COP/BOOP Rheumatoid Lung Chronic Exposures -Hypersensitivity pneumonia -Occupational -Connective Tissue Disease - Hypersensitivity Pneumonia OP due to: - a very long list. 20 2018 ATS/ERS/JRS/ALAT Diagnostic Criteria for IPF Exclusion of known causes of Interstitial Lung Disease (ILD)* AND Pattern of UIP on HRCT and/or histopathology *Environmental exposures Connective tissue disease Drug toxicity etc. Diagnosis of IPF can be made in MDT setting after considering clinical, HRCT and histopathology 21 Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 7
HRCT Patterns of UIP 2018 Guidelines 22 Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 HRCT Patterns of UIP 2018 Guidelines UIP Subpleural & basal predominant; distribution often heterogeneous Honeycombing +/-peripheral traction bronchiectasis or bronchiolectasis Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 23 HRCT Patterns of UIP 2018 Guidelines Probable UIP Subpleural & basal predominant; distribution often heterogeneous Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis May have mild ground glass opacification Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 24 8
HRCT Patterns of UIP 2018 Guidelines Indeterminate for UIP Subpleural & basal predominant Subtle reticulation May have mild GGO or distortion (early UIP pattern) CT features and/or distribution of lung fibrosis that do not suggest any specific etiology (truly indeterminate) Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 25 HRCT Patterns of UIP 2018 Guidelines Alternative Diagnosis Features suggest another diagnosis CT Features: Cysts Marked mosaic attenuation Predominant GGO Profuse micronodules Centrilobular nodules Nodules Consolidation Predominant distribution: Peribronchovascular Perilymphatic Upper or mid-lung Other: Pleural plaques (consider asbestosis) Dilated esophagus (consider CTD) Distal clavicular erosions (consider RA) Extensive lymph node enlargement Pleural effusions, pleural thickening (consider CTD/drugs) Raghu et al., ATS/ERSJ/RS/ALAT Consensus Statement. Am J Respir Crit Care Med. 2018: 198:5 26 HRCT Machine Learning Deep learning algorithm to classify HRCT into UIP, possible UIP or inconsistent with UIP 1157 HRCT scans (929 training set, 89 validation, 139 Test A) 150 HRCT scans from separate study Test B with 91 thoracic radiologist interpretations RESULTS Test A 76 % accuracy with 93% within one category Test B Thoracic radiologist 71% accurate Test B Machine 73% accurate (better than 60/91, 66% radiologists) Weighted kappa Radiologist 0.67, Machine/Radiologist 0.69 Similar results using Fleischner HRCT criteria 27 Walsh et al, Lancet Resp Med Sept 2018 9
HRCT Machine Learning Similar prognostic separation for UIP pattern assigned by majority radiology opinion or machine Algorithm 28 Walsh et al, Lancet Resp Med Sept 2018 Probability of IPF Increases with Advancing Age and Increased Fibrosis on HRCT OR per 5-year age increment 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Odds Ratio per 5-year increase in age 60 65 70 75 80 Age (Yrs) IPF Probability at least 80% (specificity 96%) when: - Age over 60 and - Reticulation on HRCT at least ~30% 29 Salisbury ML, et al. Respir Med. 2016;118:88-95. Brownell R, et al. Thorax. 2017;1 72: 424-9. Diagnostic Process for IPF 30 Martinez, et al. Nature Reviews. 2017:3; article 17074 10
Non-pharmacologic Care for Patients with IPF Components of Care Educate patients Refer to reliable sources Treatment of comorbid illness GERD, OSA, CAD Prescribe O2 Screen for resting/ nocturnal/exertional requirement Close monitoring of symptoms and pulmonary function Exercise Pulmonary rehabilitation 31 Comorbidities are Common in IPF Contribute to decreased quality of life May be related to the pathobiology of ILD/IPF May be more common in IPF Common comorbidities include: Cardiovascular disease (3%-68%) Gastroesophageal reflux disease (0%-94%) Obstructive sleep apnea/sleep disorders (6%-91%) Pulmonary hypertension (3%-86%) COPD (6%-67%) Lung cancer (3%-48%) 32 Raghu G. Eur Respir J. 2015;46(4). 2015 Treatment Recommendations for IPF Strong Recommendation Against Use: Anticoagulation (warfarin), Pred/Aza/NAC, ambrisentan, Imatinib Conditional Recommendation for Use: Nintedanib, pirfenidone, GERD Conditional Recommendation Against Use: NAC, macitentan, bosentan, sildenafil Raghu, et al. Am J Respir Crit Care Med 2015;192:e3-19 33 11
High Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis Mortality NAC = 9% Placebo = 11% p=0.69 Demedts et al; NEJM 2005;353:2229-42 34 PANTHER Prednisone-Azathioprine-Nacetyl cysteine: A Trial THat Evaluates Responses in IPF Diagnosis of IPF with FVC > 50%, DLCO > 30% predicted Three arms Placebo N-acetyl cysteine Pred/aza/NAC Primary Endpoint Change in FVC over 60wk Raghu et al. N Engl J Med 2012; 366:1968-71 35 Interim Analysis with 50% data Combination n = 77, Placebo n= 78 Increased Death 8 vs 1, p=0.01 Increased Hosp 23 v 7, p<0.001 No physio/clinical benefit Termination of combination therapy at mean of 32 weeks Recommendation against use of pred/azthioprine/n-acetyl cysteine Raghu et al. N Engl J Med 2012; 366:1968-71 36 12
NAC Does Not Reduce FVC Decline 37 Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101. Tollip (rs3750920) Genotype Associated with Response to N-acetyl Cysteine CC genotype HR 3.23 (95% CI 0.79, 13.16) p=0.10 CT genotype HR 0.76 (95% CI 0.27, 2.19) p=0.62 TT genotype HR 0.14 (95% CI 0.02, 0.83) p=0.03 38 Oldham et al. Am J Resp Crit Care Med 2015;192:1475-82 Pharmacologic Management of IPF FDA approved October 15, 2014 39 Lederer and Martinez N Eng J Med. 2018;378:1811-23 13
Pirfenidone and Nintedanib Attenuate Loss of FVC Across Multiple Patient Subgroups Pirfenidone Nintedanib 40 Noble PW et al. Eur Respir J. 2016;47:243-253. Costabel U et al. Am J Respir Crit Care Med. 2016;193(2):178-185. RECAP Open Label Extension Study of Pirfenidone Enrolled 1,058 of the 1,334 patients from the phase 3 studies Followed September 2008 à June 2015 Common Adverse events Nausea (28%) Diarrhea (23%) Fatigue 20%) Dizziness (17%) Costabel et al. Respiration 2017;94:408-15 41 INPULSIS-ON Open Label Extension of Nintedanib 807 completed INPULSIS 734 enrolled INPUULSIS-ON 304 (41%) new nintedanib 31 month median exposure Crestaniet al. Lancet Resp Med 2017;94:408-15 Events/100 exposure years Prior/New nintedanib Diarrhea 60.1 / 71.2 Vomiting 7.2 / 10.8 Bleeding 8.4 / 6.7 Major Cardiovascular 3.4 / 2.4 Acute Exacerbation 5.8 / 5.2 42 14
Engaging in a Shared Decision-making Process Physician provides Treatment options Risks and benefits Mutually acceptable decision Patient provides Personal preferences Values and concerns Discuss the efficacy and safety of FDA-approved therapies Listen to patient s preferences and concerns Focus on symptom control and management of comorbidities Set treatment expectations Look at the option of lung transplantation 43 INJOURNEY Nintedanib with add on Pirfenidone Safety 12 week open label, 4-5 weeks run in on nintedanib 150mg/BID with randomization to placebo or pirfenidone Primary endpoint was GI adverse events 44 Vancheri C, et al. Am J Respir Crit Care Med. 2017:197 INJOURNEY Nintedanib with add on Pirfenidone Change in FVC at 12 weeks 45 Vancheri C, et al. Am J Respir Crit Care Med. 2017:197 15
Safety of Nintedanib added to Pirfenidone 24 week, single arm, open label study of patients on stable pirfenidone for > 16 weeks with add-on nintedanib Primary endpoint was remaining in study for 24 weeks 89 patients enrolled 69 (78%) completed 13 withdrew from AE 4 completed at lower dose 2 withdrew other reason 1 listed for lung transplant Flaherty KR, et al. Eur Resp J. 2018;52 At least 1 TEAE > 1 TEAE 88 (99%) Diarrhea 44 (49%) Nausea 41 (46%) Vomiting 21 (24%) Decreased appetite 14 (16%) Fatigue 11 (12%) Dyspepsia 8 (9%) Headache 8 (9%) Photosensitivity/Rash 7 (8%) Abdominal pain 5 (6%) 46 Dizziness 5 (6%) Gastroesophageal Reflux (GERD) in IPF GER is highly prevalent in patients with IPF Observational study (n = 204); 47% received GER medical therapy, and 5% surgical 47 Lee JS, et al. Am J Respir Crit Care Med. 2011;184:1390-1394. WRAP-IPF Evaluation of Laproscopic Anti-reflux Surgery in Patients with IPF and GERD Surgery favored in: Rate of FVC decline (primary) -0.05 vs 0.13 Liters (p=0.28) Time to death or 10% drop FVC (p=0.038) Time to death, 10% drop FVC or Acute Exacerbation (p=0.048) Worst rank FVC analysis (p=0.017) Fewer acute exacerbations, respiratory hospitalizations, lung transplant, non-respiratory hospitalization (p=ns) 58 subjects with IPF, FVC >50% & DeMeester score of >14.7 48 Raghu et al. Lancet Respir Med 2018;6 16
Presence of Streptococcus or Staphylococcus is Associated with IPF Disease Progression 55 subjects enrolled in the COMET study Microbiome analysis of BAL fluid Disease progression = Death, Transplant, Acute Exacerbation, drop of FVC of 10% or DLCO of 15% Streptococcus p=0.009 Han, et al. Lancet Resp Med 2014:2;548-56 Staphylococcus p=0.01 49 Co-Trimoxazole Treatment in IPF 181 subjects with IPF randomized to co-trimoxazole vs placebo for 12 months No difference in FVC, DLCO, 6MWT, MRC dyspnea score Survival Fewer respiratory tract infections Increased nausea and rash Improved mortality in perprotocol patients (not ITT) 3/53 vs 14/65; HR 0.21 (0.06, 0.78; p=0.02) 50 Sulgina, et al. Thorax 2013:68;155-62 CLEAN-UP IPF Study Randomized trial of subjects with IPF Trimethoprim/sulfamethoxazole or doxycycline vs placebo Followed up to 36 months Primary endpoint First non-elective hospitalization or death Secondary endpoints Lung function, Patient reported outcomes NCT 02759120 51 17
IPF Pathobiology Lederer and Martinez N Eng J Med. 2018;378:1811-23 52 IPF Emerging Therapeutic Targets Pentraxin 2 analogs Anti-Connective Tissue Growth Factor Anti-integrin antibodies Leukotreine antagonists Anti-LOX antibodies Protein kinase inhibitors Autotaxin-LPA pathway inhibitors PI3-kinase-mTOR pathway inhibitors Anti B-lymphocyte agents Antimicrobial agents Stem cell transplant 53 Aryal & Nathen Expert Opinion Emerging Drugs 2018;23:159-72 Members of the IPF Care Team Multidisciplinary Team of Physicians Pulmonary, Radiology, Pathology, Rheumatology, Cardiology, Thoracic Surgery, Lung Transplant Social Work Clinical Nurse Specialist Palliative Care Students/Residents/Fellows Research Coordinator Support Group 54 18
Impact of Delays in Evaluation at Tertiary Center on Survival in Patients with IPF 1.0 0.8 <1 year 1-2 years 2-4 years >4 years Survival 0.6 0.4 0.2 Lamas DJ et al. Am J Respir Crit Care Med. 2011;184(7):842-847. 0.0 P for trend =.03 0 1 2 3 4 5 Years 55 www.pulmonaryfibrosis.org 56 POST-TEST QUESTIONS 57 19
Pre-I1: On average how much time is estimated to elapse between onset of symptoms and correct diagnosis: 1. 6 months 2. 1-2 years 3. 3-4 years Post-test ARS Question 1 4. More than 5 years 58 Post-test ARS Question 2 Pre-I2: Each of the following diagnostic tests should typically be performed in the evaluation of patients with suspected ILD except: 1. Complete history and physical exam 2. Complete pulmonary function testing including pulmonary mechanics and diffusion capacity for carbon monoxide 3. High resolution CT of the chest 4. Video assisted surgical lung biopsy 59 Post-test ARS Question 3 Pre-I3: A 64 year old male with newly diagnosed IPF returns to clinic to discuss possible therapy. Which of the following choices would be most likely to slow the decline in his lung function (FVC)? 1. Prednisone/azathioprine/N-acetyl cysteine 2. Pirfenidone or nintedanib 3. Warfarin 4. N-acetyl cysteine 5. Imatanib 60 20
Post-test ARS Question 4 Pre-I4: Each of the following co-morbidities are common with IPF except: 1. Cardiovascular disease 2. Gastroesophageal reflux disease 3. Obstructive sleep apnea/sleep disorders 4. Asthma 5. Pulmonary hypertension 61 Post-I5: After participating in this program, how confident are you now in your ability to educate patients with ILD on the most effective strategies to improve their outcomes? 1. Not at all confident 2. Not very confident 3. Somewhat confident 4. Pretty much confident 5. Very confident Post-test ARS Question 5 62 21