6/22/2018

Disclosures • Nothing to Disclose Interstitial Lung Disease: Decoding the Alphabet Soup Rupal J. Shah, MD MS Director, Interstitial Lung Disease Clinic University of California, San Francisco

Outline • What is ILD? • Diagnostic Approach • Specific types of ILD • Available therapies • Cases

1 6/22/2018

What is the pulmonary interstitium? Not Just Interstitial

• Anatomic space that is lined by • Misnomer because many ILD’s affect the epithelial and endothelial cells airways, parenchyma, blood vessels and • Contains collagen, elastin, reticulin, pleura ECM • Also in the connective tissue of the • More accurately described as diffuse lung (interlobular septa, visceral parenchymal lung disease pleura, peribronchovascular sheaths) • Over 100 types of ILD’s

Epidemiology

Farrand, E et al The hospitalized patient with interstitial lung disease: A hospitalist primer J Hosp Med 2017 Lederer DJ, et al Idiopathic pulmonary fibrosis NEJM 2018

2 6/22/2018

Diagnosis Outline • Challenge: Presentation is usually nonspecific • What is ILD? • Average time from symptom onset to • Diagnostic Approach diagnosis: 1-2 years • Specific types of ILD • Early recognition is important! • Available therapies • Cases

67 yo M with progressive dyspnea and cough. Treated with abx for bronchitis. Clinical Evaluation: History 40 pack year smoker, quit 6 years ago. 85% On exam, late inspiratory crackles, Elements Examples +clubbing. Demographics Age, IPF > 50 CXR shows increased basilar reticulation. Time course Acute, sub-acute, chronic What additional historical information is Extra-pulmonary symptoms of CTD Raynauds, rash, inflammatory arthritis, proximal muscle most likely to assist in establishing a weakness, dry eyes/mouth DIP, RB-ILD, LCH, AEP diagnosis? 15% Smoking history Medications/Radiation Nitrofurantoin, Amiodarone, methotrexate, chemotherapy, radiation 0% 0% 77 medications (pneumotox.com) A. Allergy History HP exposures (home, work, hobbies) Avian (birds, down), molds (water damage, swamp cooler), mycobacteria (indoor hot tub, metal working fluid) B. Family History ry ry ry ry to to to to Asbestos, beryllium, metal dusts C. Occupational History is is is is Occupational exposures H H l H l H y ly a e g i n v r m o a Early graying, cryptogenic cirrhosis, bone marrow disorders D. Travel History lle a i r Family history of ILD F at T A p u Travis, WD et al An official ATS/ERS statement: Update of the cc 12 O international multidisciplinary classification of IIP AJRCCM 2013

3 6/22/2018

Clinical Evaluation: Physical Exam Clinical Evaluation: Physical Exam (images) Elements Examples Face and mucus membranes Scleritis, saliva pool & dentition, oral ulcers, leukoplakia, mouth opening, squared off telangectasias, fibrofolliculomas, malar rash Lungs Dry crackles (listen at bases or may miss early disease!) Inspiratory squeaks (bronchiolitis) Cardiac Signs of pulmonary hypertension Hands Clubbing, mechanics hands, sclerodactyly, nail bed capillaries, palmar telangectasias, Gottrons papules, synovitis and deformities, dystrophic nails Neuro Proximal muscle weakness

Travis, WD et al An official ATS/ERS statement: Update of the 13 14 international multidisciplinary classification of IIP AJRCCM 2013

Diagnosis CXR • Imaging • Pulmonary Function Tests • Laboratory • Bronchoscopy • Surgical lung biopsy

4 6/22/2018

CT chest • High resolution CT scan with inspiratory and expiratory images

Reticulation Nodular Pattern

5 6/22/2018

Bronchiectasis Air Trapping

Consolidation Ground Glass Cysts

6 6/22/2018

HRCT guides differential PFT Interpretation

Fibrotic Cystic Nodular • IPF • LAM • Perilymphatic Order • CTD-ILDs • LCH • Sarcoidosis full • cHP • LIP • LIP PFT’s • Others • BHD • Amyloidosis • Pneumoconioses Consolidation/GGO • Lymphangitic • NSIP carcinomatosis • OP • Centrilobular • AEP/CEP • HP, RB, FB, LCH • Infection

25

Pulmonary Function Test Flow Volume Loop

Spirometry Predicted Observed %Pred FVC 3.72 2.24 60% FEV1 3.06 1.78 58% FEV1/FVC 82 79 96%

Plethysmography TLC 5.26 3.38 64%

Diffusion Diffusing Capacity 29.01 8.01 28%

7 6/22/2018

Clinical Evaluation: Laboratory Analysis Elements Comment CBC with differential Macrocytosis (telomeropathy) Eosinophilia (CEP) Autoimmune serologies Next slide HP precipitans Poor sensitivity and specificity, limited range of antigens tested Genetic testing Selected cases (e.g. BHD), emerging for FPF Telomere length measurement Emerging VEGF-D Lymphangioleiomyomatosis

Travis, WD et al An official ATS/ERS statement: Update of the 29 Respir. Med. 2016;113:80-92 30 international multidisciplinary classification of IIP AJRCCM 2013

Bronchoscopy Surgical Lung Biopsy • Mortality – 1.7% (elective) – 16% (non-elective)

Meyer KC, Raghu G. Bronchoalveolar lavage for the evaluation of interstitial lung Hutchinson,JP et al In-Hospital Mortality after SLB for ILD in 32 disease: is it clinically useful? Eur Respir J. 2011;38:761-769. the US 2000-2011 AJRCCM 2015

8 6/22/2018

History, Physical Exam, Procedures CT scan, labs are unsafe Diagnosis of highest Multi Disciplinary Conference probability Diagnosis! Is bronchoscopy safe IPF Non and indicated? diagnostic HP (some) No LCH, AP, LAM Sarcoid Surgical Lung Biopsy Some occupational lung Malignancy Non diseases Eosinophilic pneumonia diagnostic COP

Bronchoscopy Diagnostic • Agreement is best when there is a consensus discussion between clinicians, radiology, and pathology Confident diagnosis Adapted from Wells, AU ILD guideline: the BTS with Thoracic society of Australia and New Zealand and Irish Flaherty KR, King TE, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach Thoracic Society Thorax 2008 to diagnosis? Am J Respir Crit Care Med. 2004;170:904-910.

Outline Focus on fibrotic lung disease • What is ILD? • Diagnostic Approach Idiopathic Connective Hyper- • Specific types of ILD Pulmonary Tissue sensitivity Fibrosis Disease Pneumonitis Other • Available therapies Antifibrotics Immunomodulation • Cases Extrapulmonary dz / antigen avoidance

36

9 6/22/2018

73 yo F with IPF presents to ER with increased dyspnea. SaO2 Idiopathic Pulmonary Fibrosis 90% on 10LPM. Dry crackles at 58% lung bases. Sputum gram stain • IPF is a specific form of chronic, is negative. CT shows new progressive fibrotic interstitial lung areas of alveolar consolidation disease that occurs in older adults and 26% is characterized by radiographic or superimposed on reticulation. pathologic usual interstitial pneumonia Which is the most appropriate 11% without a secondary cause next test? 5% • UIP pattern: peripheral basilar A. Bronchoscopy with BAL reticulation, traction bronchiectasis and honeycombing without other features B. Fungal serologies L s . y A ie .. d B g ri tu (i.e. ground glass, air trapping, etc) th lo e s i o et C. Right heart catheterization w r h w – y e t lo CTD, asbestosis, chronic HP, XRT p s a l o l c a c ga t w D. Swallow study s n ar S o u e ch F h n t o h r ig 6/22/2018Official ATS/ERS/JRS/ALAT Guidelines on Idiopathic Pulmonary Fibrosis. AJRCCM 2011;183:788 38 B R

IPF: Why is diagnosis important? IPF: Treatment Options • Median survival • IPF

~4 years Pirfenidone Nintedanib • Acute exacerbation rate 5-10% per year

Ryerson CJ et al Predicting survival across interstitial lung disease: the ILD-GAP model Chest 2014 39 King, TE et al A phase 3 trial of pirfenidone in patients with IPF NEJM 2014 40 Richeldi, LR Efficacy and safety of nintedanib in IPF NEJM, 2014

10 6/22/2018

IPF Medications IPF exacerbation Nintedanib Pirfenidone Main Benefit • About half the decline in FVC over 1 • About half the decline in FVC over 1 year, on average, compared to no year, on average, compared to no • Definition: IPF+acute worsening (within 1 treatment treatment Other Possible Benefits • Probably reduces risk of acute • Probably reduces 1-year mortality month), CT with new GGO/consolidation, exacerbations and risk of respiratory hospitalization exclusion of other causes (i.e. heart Administration • 1 pill twice daily with food • 3 tablets thee times daily with food Tolerance/side effects • Loose stools/diarrhea (~2/3) • Nausea/vomiting (~1/3) failure/infection) • Nausea (~1/4) • Weight loss (~1/8) • Weight loss (~1/10) • Photosensitivity/Rash (~1/4) • • Fatigue (~1/5) Treatment: supportive care, steroids (mixed Safety • Possible increased risk of myocardial • Abnormal liver tests (4%) evidence), antibiotics, lung transplant infarction (~1% increase) • Abnormal liver tests (5%) • Median survival 3-4 months Discontinuation • ~20% • ~15% (1 year) Presentation Title and/or Sub Brand Name 6/22/2018 41 Cost per year • $96,000 Here • $94,000

• 64-year-old woman is evaluated for a 6-week history of dyspnea, dry cough, fever, chills, night sweats, and fatigue, which have not Which is the most likely diagnosis? responded to treatment with antibiotics; she has lost 2.2 kg (5 lb) during that time. The 38% patient had a thorough examination 6 A. Cryptogenic organizing months ago while she was asymptomatic that included routine laboratory studies, age- pneumonia 25% and sex-appropriate cancer screening, and a chest radiograph; all results were normal. B. Idiopathic pulmonary 19%19% Nonsmoker, no known environmental exposures, no recent travel or sick contacts. fibrosis Meds: aspirin and a multivitamin. • Exam: temperature is 37.8°C (100.0°F); C. Nonspecific interstitial other vital signs are normal. Cardiac pneumonitis examination is normal. There are scattered ...... i. crackles in the mid-lung zones with i . ti it D. Lymphocytic interstitial iz y ti t n ar s s associated rare expiratory wheezes. There is a n r er rg o te t o in in no digital clubbing. Musculoskeletal and skin pneumonitis c lm c i u ic ti n p if y ge c c c examinations are normal. Chest radiograph o i e o t th sp h p a n p is shown. ry p o m C io N y Id L

11 6/22/2018

Cryptogenic Organizing Pneumonia Nonspecific interstitial pneumonia • Presentation: subacute-chronic • Organizing pneumonia is a common • pattern of lung injury in multiple Can see this pattern with: processes (infection, CTD, HP, etc) – Autoimmune disease • Essential to rule out secondary causes – Hypersensitivity pneumonitis Overlap with NSIP suggests – Medication toxicity autoimmune disease, especially – Can be idiopathic myositis-related • Spectrum from pure cellular (inflammatory) to pure fibrotic • Presentation subacute • Majority resolves with steroids (6-12 • Clinical course is variable from reversible (cellular) to stable to months), relapses common, rare cases progressive progressive/refractory • Treatment: Immunomodulation Travis, WD et al An official ATS/ERS statement: Update of the 45 Travis, WD et al An official ATS/ERS statement: Update of the international multidisciplinary classification of IIP AJRCCM 2013 international multidisciplinary classification of IIP AJRCCM 2013

Hypersensitivity Pneumonitis Connective Tissue Disease

• Mixed Dermatomyositis/ No consensus diagnostic criteria Systemic Rheumatoid Sjogren’s Connective Polymyositis/ SLE Sclerosis Arthritis Syndrome – Classic imaging + good exposure Tissue Disease Antisynthetase – Lung biopsy • Described as acute, sub-acute, and chronic ILD Occurrence Likely Common Possible Common Likely Unusual • Over 200 exposures identified: NSIP (80-90%), UIP (50-60%), NSIP (28-60%), NSIP, OP, NSIP/OP NSIP, OP – Avian: feathers and droppings ILD Type NSIP, OP – Molds, mycobacteria, thermophilic actinomycetes UIP (10-20%) NSIP, OP, DIP LIP (20%) overlap, UIP, DAD DAH – Some chemicals – Hot TUB Esophgeal Consider Drug-induced Anti-Ssa/SSb Disease Pearl dysfunction PH screening Anti-Jo1, MDA-5 overlap, anti- (anti-TNF, MTX) Cysts • Treatment PH screening RNP – Remove exposure – Prednisone +/- mycophenolate or azathioprine 47 48

12 6/22/2018

Immunosuppression Smoking Related Lung Disease • Respiratory Bronchiolitis related ILD • Desquamative Interstitial Pneumonitis • Langerhans Cell Histiocytosis (EG) • Treatment: smoking cessation & avoidance of second-hand smoke. Rarely require immunosuppression

Travis, WD et al An official ATS/ERS statement: Update of the international multidisciplinary classification of IIP AJRCCM 2013 50

Sarcoid Sarcoid • Diagnosis: Tbbx (unless • Granulomatous disorder: Non caseating granulomas peripheral involvement) – Hilar adenopathy • Treatment: Corticosteroids – Centrilobular nodules • Lofgren syndrome: – Skin, joint, eye lesions – Fever, EN, polyathralgias, hilar • 4x more common in AA lymphadenopathy • 20-60 years – NSAID’s – 80% resolve without tx • Mimics: TB, fungal infections, malignancy, berylliosis • Heerfordt syndrome: uveitis, parotid enlargement, fever, facial palsy

13 6/22/2018

Eosinophilic Pneumonia Eosinophilic Pneumonia • Acute: symptoms <4 weeks, cough, SOB, fever • Chronic: Gradual onset (4-5 • Bibasilar crackles months), cough, fever, SOB • Often do NOT have peripheral eosinophilia • Peripheral eosinophilia, imaging • Imaging: diffuse, patchy ground glass with peripheral opacities, BAL • Diagnosis: BAL eosinophilia>25%, febrile illness, pulmonary eos>25% opacities, exclude other causes – Differential: EGPA (usually peripheral eos), fungus, parasite, • Differential: drugs, fungal drug reaction infection, EGPA, COP • Treatment: steroids • Tx: prolonged steroids

Occupational Lung Disease Occupational Lung Disease • Asbestos is one of the most common • Silica: Progressive massive fibrosis (PMF), – Insulation, brakes, shipbuilding, construction, pulmonary alveolar proteinosis – Acute silicosis: massive exposure to silica (denim textiles, mining/milling of asbestos sandblasters) – Asbestosis – Stone, rock, concrete, brick, block, and mortar – Pleural Plaques • Coal workers pneumoconiosis: – BAPE – Upper lobe predominant nodules->PMF – Mesothelioma – Caplan’s syndrome: lung nodules+joint sx like RA

14 6/22/2018

Interstitial Lung Abnormalities Lung Transplant • Increased lung density on CT • Only effective therapy for progressive fibrotic disease scans in patients with no history of ILD • Considered up to age 75 (at UCSF) • 2-10% of the population • Major contraindications are: active tobacco use, • Association with reduction in PFT, recent malignancy, and significant coronary disease exercise capacity, development of • Early referral is critical ILD, and mortality • http://lungtransplanteducation.ucsf.edu/ • Refer to pulmonary

Putman, RK et al Association between ILA and All-cause mortality JAMA 2016

Conclusions Refer to us! • Multiple types of ILD • UCSF ILD Program • Consider in older patient with cough or subacute • https://www.ucsfhealth.org/clinic/in shortness of breath terstitial_lung_disease_program/# • Evaluation starts with high resolution CT, may need surgical lung biopsy • 415.353.2577 • Important to distinguish IPF from other types of • [email protected] ILD as treatment differs

15