Overarching Principles IPF Pulmonary Hypertension Asthma COPD • Patient education regarding their illness and appropriate treatment expectations • Patients are partners in therapy • Importance of multidisciplinary teams
ILD: A Pragmatic Pneumonic Diseases Sub-categories/examples Category Idiopathic Interstitial Pneumonias (IIPs) Sarcoidosis IPF, NSIP, Unclassifiable, COP, Amyloidosis Idiopathic Lymphangioleiomyomatosis RB-ILD, DIP, AIP, LIP, PPFE PLCH, Eosinophilic pneumonia. Neurofibromatosis, DAH Immunologic Connective tissue disorders Inorganic Asbestosis, silicosis Inhalational Bird fanciers disease, Organic: Chronic hypersensitivity pneumonitis farmer ’ s lung Antiarrhythmics, antimicrobials, chemotherapy agents, biologics Iatrogenic Radiation Viral CMV, influenza Infectious Fungal Pneumocystis carinii Chronic CHF Lymphangitic carcinomatosis Neoplastic Bronchoalveolar carcinoma Adapted from Guide to Clinical Management of IPF. Nathan, Brown and King. Springer 2016.
Fibrotic Lung Disease: Sorting Out the Alphabet Soup Interstitial lung disease CTD-ILD Fibrotic lung disease Early interstitial NSIP lung abnormalities Chronic IPF HP Unclassifiable Idiopathic interstitial pneumonias Brown AW. Annals ATS . 2018;15:806-807.
Where does IPF fit in the context of the ILDs? • IPF is the most common of the idiopathic interstitial pneumonias (IIPs) • Definition of IPF: – Chronic, progressive fibrosing interstitial pneumonia of unknown cause – Older adults – Limited to the lungs – Histopathologic and/or radiologic pattern of UIP Raghu G, et al. Am J Respir Crit Care Med . 2018;198(5):e44-e68.
Key Clinical Features of IPF • Increasing breathlessness on exertion • Non-productive cough • Patient age > 50 years • Bibasilar inspiratory crackles • Digital clubbing in many cases Raghu G, et al. Am J Respir Crit Care Med . 2018;198(5):e44-e68.
IPF Diagnosis: Flow Diagram-ATS Guidelines, 2018 HRCT is critical in the diagnostic process IPF Raghu G et al. Am J Respir Crit Care Med . 2018;198(5):e44-e68.
2018 Diagnosis of IPF: An Official ATS-ERS-JRS-ALAT Practice Guideline • Usual Interstitial Pneumonia (UIP) is the hallmark pattern of IPF – Refined radiological AND histopathological patterns of UIP to 4 diagnostic categories • UIP • Probable UIP • Indeterminate • Alternate diagnosis Raghu G et al. Am J Respir Crit Care Med . 2018 Sep 1;198(5):e44-e68.
UIP Pattern on HRCT Subpleural reticulation Honeycomb cysts No atypical features = UIP pattern
Making the Diagnosis of IPF: Placing HRCT in Context of Lung Biopsy Histopathology Pattern IPF Suspected Indeterminate for UIP Probable UIP Alternate Diagnosis UIP UIP IPF IPF IPF Non-IPF dx Probable UIP IPF IPF IPF (likely) Non-IPF dx HRCT Pattern Indeterminate IPF IPF (likely) Indeterminate Non-IPF dx IPF Alternate Diagnosis Non-IPF dx Non-IPF dx Non-IPF dx (likely) Raghu G et al. Am J Respir Crit Care Med . 2018;198(5):e44-e68.
Threshold for IPF Diagnosis “ Clinomics ” “ IPF-ometer ” HRCT Alternate diagnosis Indeterminate UIP pattern Increasing PFTS:restriction age CXR:?ILD No exposures Probable UIP pattern No CTD “Velcro” crackles at lung bases ILD UIP pattern SOB +/- cough Concept slide (from the mind of a Bayesian)
ILD: Developing an Index of Suspicion for IPF vs. Other • What is the pretest likelihood for IPF? – Depends on how old – Depends on exposure history • Smoking ( increases likelihood of IPF) • Birds, molds (increases likelihood of Chronic HP) – Depends on gender – Depends on presence or absence of CTD features • Exclusion of other known causes of ILD is important given differences in clinical course, management and outcomes
“Look, Listen and Walk” • LOOK at the skin and fingers • LISTEN carefully for crackles – Both lung bases – Laterally in mid-axillary line – Anteriorly • WALK the patient in the hallway (or on a staircase) – Try to elicit exertional dyspnea if possible – Measure SpO 2 before and after walking – A 3% drop in SpO 2 indicates exertional desaturation
Attempt to Identify the Cause of ILD Perform a Detailed History and Physical Disease Questions/Findings Chemotherapy, amiodarone, nitrofurantoin, other drugs; check Drug/Radiation-induced ILD PneumoTox.com, radiation therapy to the chest Connective Tissue Disease-related Joints, skin, Raynaud’s reflex, dry eyes/mouth, muscle weakness or pain ILD Vasculitis Sinus disease, hoarseness, hematuria, hemoptysis Chronic Hypersensitivity Exposure to mold sources, birds, down bedding, farming or agriculture Pneumonitis Pneumoconioses Occupational history Familial ILD Family history of ILD, sarcoidosis, home oxygen use, autoimmune disease PFF Pocket Card, kindly provided by PFF
Attempt to Identify the Cause of ILD Continued Order Relevant Blood Tests Disease Blood Tests Eosinophilic pneumonia CBC with differential Sarcoidosis Serum calcium Scleroderma/MCTD ANA, Scl70, centromere, U1RNP Rheumatoid arthritis RF, CCP Sjogren’s ANA, Ro/SSA, La/SSB ANA, Jo-1, CK, myoglobin, aldolase, consider Idiopathic inflammatory myositis myositis panel Vasculitis Anti-PR3 and MPO (ANCA), creatinine Chronic hypersensitivity pneumonitis HP panel (controversial) CTD-ILD ESR, CRP PFF Pocket Card, kindly provided by PFF
Impact of Multidisciplinary Team Discussion on IPF Diagnosis at Referral Center Management Recommendations No change Referral MDM in diagnosis diagnosis diagnosis of IPF of IPF of IPF (n=17) (n=27) (n=25) Pre-referral Post referral/multidisciplinary team discussion * P < 0.05 using McNemar’s test Jo HE. Respirology . 2016;21:1482-1444.
Importance of Early Diagnosis and Referral Delayed Access to Subspecialty Care and Survival < 1 year 1-2 years 2-4 years > 4 years Survival p for trend = 0.04 Years Lamas DJ, et al. Am J Respir Crit Care Med. 2011 ; 184:842-847.
Management of Patients with IPF
IPF Has an Unpredictable Disease Course Disease Variable onset of symptoms Progression Diagnosis Unpredictable patterns of progression Demise Time
IPF: Survival in the Pre-antifibrotic Era 2000-2009 (N=521) 100 IPF no LTx from evaluation IPF no LTx from PFTs 80 Percent survival Median survival: 36 and 42 months 60 40 20 0 0 12 24 36 48 60 72 84 96 108 120 Months Nathan SD, et al. Chest . 2011;140:221-229.
Decline in FVC Associated with Decreased Probable Survival Analysis of 1132 placebo-treated subjects from six studies of the clinical development for nintedanib and pirfenidone Study Time (Days) Paterniti MO, et al. Ann ATS . 2017;14:1395-1402.
Registry Data: The Impact of Antifibrotic Therapy on Survival Australia Europe Kaplan Meier plot of cumulative survival antifibrotic treatment no antifibrotic treatment Transplant-free survival (%) p = 0.001 No antifibrotics (n=501) Antifibrotics (n=146) Timespan (months) first diagnosis-last visit or death Time years Jo HE, et al. Eur Respir J . 2017;49:1601592. Guenther A, et al. Resp Res . 2018;19:141.
Approved Antifibrotic Therapies for Patients with IPF Pirfenidone Nintedanib • FDA approval 2014 • FDA approval 2014 • Anti-fibrotic properties; • Tyrosine kinase inhibitor; exact mechanism of action targets FGFR, PDGFR, unknown VEGFR, FLT3 • Orally administered, • Orally administered, 801 mg, three times daily 150 mg, two times daily • Nausea, rash/sun sensitivity, • Diarrhea, nausea dyspepsia/GERD Pirfenidone. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022535s005lbl.pdf Nintedanib. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205832s004lbl.pdf Galli JA, et al. Respirology . 2017;22:1171-1178.
Pirfenidone: Significant Improvement in FVC Decline Primary Endpoint Patients with ≥ 10% FVC Decline or Death (%) 48% Relative Reduction Week King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Pirfenidone Associated with Reduction in Relative Risk of Mortality vs. Placebo (120 Weeks) 8% HR = 0.61, 0.37-0.99 P = 0.042 HR = 0.55, 0.33-0.93 7% P = 0.024 HR = 0.47, 0.25-0.87 6.9% P = 0.013 6% 6.3% 5% 5.1% Deaths 4% 4.2% 3% 3.5% 2% 2.4% 1% 0% Treatment-Emergent All- IPF-Related Mortality Treatment-Emergent IPF- Cause Mortality Related Mortality Pirfenidone (n = 623) Placebo (n = 624) Nathan SD, et al. Lancet Respir Med . 2017;5:33-41.
Nintedanib: Significant Improvement in FVC Decline INPULSIS-1 INPULSIS-2 52% 45% Relative Relative Reduction Reduction Nintedanib Placebo Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
Mortality Data from TOMORROW and INPULSIS Trials (Nintedanib vs Placebo, 52 Weeks) HR = 0.70, 0.46-1.08 9% P = 0.095 8% 8.3% HR = 0.57, 0.34-0.97 P = 0.027 7% HR = 0.62, 0.37-1.06 P = 0.078 6.7% 6% 5.8% Deaths 5.7% 5% 4% 3% 3.6% 3.5% 2% 1% 0% All-Cause Mortality On-Treatment Mortality Respiratory Mortality Nintedanib (n = 723) Placebo (n = 508) Richeldi L, et al. Respir Med . 2016;113:74-79.
Time to First Acute Exacerbation (Investigator-reported): INPULSIS Pooled Nintedanib 150 mg bid Placebo HR 0.64 (95% CI; 0.39, 1.05) P =.0823 Nintedanib 150 mg bid Placebo (n=423) (n=638) Patients with ≥1 acute exacerbation, n (%) 31 (4.9) 32 (7.6) Adapted from Richeldi L, et al. N Engl J Med . 2014;370:2071-2082.
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