Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis Terrence Coulter, MD Ferrell-Duncan Clinic Cox Health System Springfield, MO Objectives What do the lungs do? ⧫ Review basic lung function ⧫ Define the interstitium ⧫ Primary function is ⧫ Define interstitial lung disease (ILD) gas exchange ⧫ Clinical presentation ⧫ Let oxygen move in ⧫ Causes ⧫ Let carbon dioxide ⧫ Diagnosis move out ⧫ Therapy for IPF How do the lungs do this? Restrictive diseases Neuromuscular weakness ⧫ First, air has to move to the region ⧫ Spinal cord where gas exchange occurs. ⧫ Trauma, MS, tumor ⧫ Motor nerves ⧫ ALS, GBS, phrenic nerve ⧫ For this, you need ⧫ Neuromuscular junction ⧫ MG, Lambert Eaton a normal ribcage ⧫ Botulism, organophosphate and respiratory ⧫ Muscles ⧫ Muscular/myotonic dystrophy muscles that work ⧫ Mitochondrial myopathy properly Restrictive diseases Restrictive diseases Loss of lung elasticity Diseases of the chest wall ⧫ Parenchymal lung ⧫ Ankylosing spondylitis disease ⧫ Congenital deformities, ⧫ Interstitial lung disease including pectus excavatum ⧫ ⧫ Flail chest Pulmonary fibrosis ⧫ Kyphoscoliosis ⧫ Thoracoplasty ⧫ Fibrothorax ⧫ Abdominal processes, including morbid obesity and ascites ⧫ Chest wall tumors What happens when there is ILD? ⧫ Interstitial structures become thickened / inflamed. Expansion of the interstitial compartment (portion of lung parenchyma sandwiched b/w the epithelial and endothelial basement membranes) Nomenclature Epidemiology ⧫ ILD is more frequent than previously recognized ⧫ More than 200 diseases can result in interstitial lung disease (ILD) ⧫ Incidence ranges from 7 to 16 cases per 100,000 in ⧫ The term interstitial is misleading since US most of these disorders are also associated with extensive alterations of ⧫ The prevalence of preclinical and undiagnosed ILD is alveolar and airway architecture 10 times that of clinically recognized ⧫ Among these, IPF is the most common, representing at least 30% of incident cases Clinical conundrum ⧫ At least 150 clinical entities associated with ILD ⧫ Difficult to determine the best specific diagnostic approach ⧫ A conclusive cause (even after lung bx) cannot always be ascertained in a significant number of patients ⧫ Even when a specific diagnosis is made, an effective therapeutic regimen is not available for many patients Scar = bad prognosis I Inflammation N F L A M M S A T C I O N A R Fibrosis Nicholson et al. Am J Respir Crit Care Med 2000;162:2213-2217 BOOP DAD DIP OB BO UIP NSIP HP COP LIP Hamman-Rich AIP IPF RB-ILD UIP CFA OP What type of fibrosis is the PCP most likely to see? Making the diagnosis ⧫ History ⧫ ++++ Idiopathic pulmonary fibrosis (IPF) ⧫ Aging population ⧫ Exam ⧫ ++++ Connective tissue disease-related ⧫ Pulmonary physiology ⧫ RA, SLE, Sjogren’s syndrome ⧫ Radiography ⧫ + Chronic hypersensitivity pneumonitis ⧫ Organic exposure ⧫ +/- lung biopsy History: chief complaint History ⧫ Symptoms/existence of concurrent disease ⧫ Typically, ILD presents with: ⧫ Patients may… ⧫ 1. Have known CTD ⧫ Dyspnea—subacute, insidious onset ⧫ 2. Dyspnea from occult CTD-related ILD ⧫ “I thought I was just…” ⧫ Getting older ⧫ Family history ⧫ 5# heavier ⧫ ⧫ Out of shape Pulmonary fibrosis ⧫ Less than 5% of pts with IPF ⧫ +/- dry cough ⧫ Auto dominant pattern with variable penetrance ⧫ Fatigue ⧫ Mutation of surfactant protiens ⧫ No wheeze, no chest pain ⧫ Rheumatologic disease History: exposures History: exposures ⧫ Current or previous medications ⧫ Smoking ⧫ www.pneumotox.com ⧫ ⧫ Chemotherapy IPF ⧫ Amiodarone ⧫ DIP ⧫ Nitrofurantoin ⧫ Amino acid supplements ⧫ RB-ILD ⧫ Oily nose drops ⧫ Langerhans cell histiocytosis ⧫ External beam radiation ⧫ Anti-GBM disease ⧫ Current or previous recreational drug use (Goodpasture’s) ⧫ Occupational, environmental, avocational History: exposures History: connective tissue diseases ⧫ Birds (proteins) ⧫ Bloom on feathers ⧫ RA ⧫ Mucin in excrement ⧫ Symmetric arthritis/small joints ⧫ Feather pillow/down comforter ⧫ Morning stiffness ⧫ Fumes, dusts, gases ⧫ Subcutaneous nodules ⧫ Asbestos ⧫ Smoker ⧫ Beryllium ⧫ SSc ⧫ Microbial agents ⧫ ⧫ Hot tubs (indoor/enclosed) Raynauds ⧫ Basement shower ⧫ After 40 y.o. in FEMALE ⧫ Free-standing humidifiers ⧫ After 30 y.o. in MALE ⧫ Water damage to home ⧫ Esophageal dysmotility ⧫ Cooling systems (swamp cooler) ⧫ Skin tightening History: connective tissue diseases ⧫ PM/DM ⧫ Proximal muscle weakness ⧫ Rashes Physical Exam ⧫ Rough skin on the hands ⧫ Sjögren’s Syndrome ⧫ Dry eyes/mouth ⧫ Dental caries Physical examination ⧫ Skin ⧫ Rash ⧫ Purupura ⧫ Telangiectasia ⧫ Nodules ⧫ Calcinosis Physical examination Physical examination Clubbing ⧫ Chest 25-50% with IPF ⧫ Velcro crackles are NEVER normal 50% with DIP 75% with ILD-RA Rare in sarcoid, EG COPD no clubbing !! Must listen here Laboratory Laboratory ⧫ ANA—the pattern matters ⧫ Isolated high MCV ⧫ Nucleolar ANA any titer – TO RHEUM ⧫ Methotrexate ⧫ Azathioprine ⧫ SSA is a myositis associated ab (ANA -) ⧫ ??? Telomerase abnormality ⧫ ACE level non-specific ⧫ Elevated MCV ⧫ Don’t order it ⧫ History of bone marrow irregularities ⧫ Premature graying ⧫ HP panels unhelpful ⧫ Cryptogenic cirrhosis ⧫ ⧫ Precipitating IgG to organic antigens Pulmonary fibrosis ⧫ Don’t order them Pulmonary function testing Restrictive Pattern ⧫ Lung volumes ▪ Decreased ⧫ Spirometry FEV1 ⧫ DLCO ▪ Decreased FVC ⧫ ABG ▪ FEV1/FVC normal or increased Suspect restriction? Check diffusing capacity ⧫ ⧫ Obtain lung volumes and diffusing capacity Restriction with normal DLCO ⧫ Extrapulmonary: ⧫ TLC less than 80% or below LLN? obesity, ⧫ TLC 80-65% mild NM weakness, ⧫ TLC 65-50% moderate pleural effusion ⧫ TLC <50% severe ⧫ Restriction with reduced DLCO ⧫ Interstitial lung disease Volumes may be normal if… Impaired Gas Exchange ⧫ SpO2 at rest is unhelpful ⧫ Exercise oximetry + ⧫ Never normal to desaturate ⧫ 6-minute walk test …but the DLCO will be very low What does ILD look like? ⧫ Abnormal opacities: ⧫ Linear ⧫ Reticular ⧫ Nodular ⧫ Reticulonodular ⧫ Honeycombing ⧫ A good place to look for ILD is between rib spaces; close to the chest wall, there should normally be very few lung markings, and certainly no nodules or fine lines Idiopathic Pulmonary Idiopathic Pulmonary Fibrosis Fibrosis Reticulonoduar shadowing Irregular heart border Idiopathic Pulmonary Fibrosis This patient also has lung cancer (a complication of pulmonary fibrosis) Radiology: diagnosing ILD ⧫ A normal CXR does not rule out the presence of ILD ⧫ “ILD protocol” HRCT ⧫ Can be normal in up to 10% of ⧫ No IV contrast cases ⧫ Supine and prone ⧫ More so hypersensitivity ⧫ Inspiratory and expiratory images pneumonitis ⧫ Reconstruction algorithm — 1-1.5mm thick HRCT Terminology ⧫ Opacities ⧫ Lines (reticular) ⧫ Dots or Circles (nodules) ⧫ Patches ⧫ Attenuation (shade of gray) ⧫ Consolidation – obscures underlying vessels ⧫ Ground glass – does not obscure underlying vessels Interlobular septal thickening Traction bronchiectasis Reticular opacities Honeycombing Peripheral/ subpleural Lower zone Ground glass opacities Putting it all Together ⧫ History ⧫ Exam ⧫ Labs ⧫ ANA, RF, anti-CCP ⧫ Physiology Integrate to get ⧫ Full PFTs “summary diagnosis” ⧫ Gas exchange ⧫ 6MWT ⧫ Radiology ⧫ HRCT ⧫ Pathology IPF/UIP Therapy for ILD • Age: usually greater than 50 ⧫ Not all patients require therapy • Male to female ratio: between 1:1 and 2:1 ⧫ General: treat clinically significant, progressive dz • 75% have a smoking history ⧫ All therapeutic regimens require monitoring • Insidious exertional dyspnea which is disabling over time • Nonproductive cough - refractory to antitussive ⧫ Glucocorticoids no longer the mainstay medication • Fever, malaise and arthralgia reported in 50% ⧫ Steroid-sparing / immune-suppressing / immunomodulatory / cytotoxic agents 2012: Triple Therapy Harmful for IPF Patients Time to Death or Hospitalization The PANTHER-IPF trial examined the safety and efficacy of a triple therapy with prednisone, azathioprine and N- acetylcysteine.1 -Randomized, double-blind, placebo- controlled -Stopped after 50% of the data had been collected (n=155, 32 weeks) because of increased mortality and hospitalization in the triple therapy group 1.The IPF Clinical Research Network. NEJM 2012;366:1968-77. 2014/2015: Two Medications Available for the Treatment of IPF Change from Baseline in FVC The PANTHER-IPF trial was partially continued to examine the safety and efficacy of N-acetylcysteine (NAC) • In October 2014, the US Food and treatment versus placebo.1 In the past two Drug Administration (FDA) approved Randomized, double-blind, placebo- years, the first two new drugs, nintedanib and controlled, n=264 pirfenidone, for the treatment of medications for patients with IPF in the United States Endpoints: FVC, mortality and acute the treatment of exacerbations • In January 2015, the European IPF have been At the end of the trial (60 weeks), no Commission (EC) approved significant benefits in favor of N- approved in the nintedanib for the European Union acetylcysteine treatment could be shown United States (pirfenidone has been approved since 2011) 1.The IPF Clinical Research Network. NEJM 2014:370:2093-101. 2.Oldham J. M, et al. AJRCCM 191;2015:A2162. Overview Nintedanib Overview Pirfenidone Annual rate of lung function decline in 1 • FDA and EMA approvals were based on FVC • Approved since 2011 by European Proportion of patients with ≥10% ® 0 decline in FVC or death (%)2 the phase 3 INPULSIS 1 & 2 trials and Commission based on evidence from data from the Phase 2 TOMORROW trial -75 the CAPACITY trials (Phase 3; n = • The randomized, double-blind and 779)1

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