Disclosures Timely Topics in I have nothing to disclose! Pulmonary Medicine Lorriana Leard, MD Associate Professor of Clinical Medicine Chief of Clinical Operations UCSF Pulmonary, Critical Care, Allergy & Sleep Medicine Lorriana.Leard@ucsf.edu Overview Ø Cases with new management strategies that you might face in practice….or just want to Case of Shortness of Breath know about…. 1
Case of Shortness of Breath Case of Shortness of Breath PE: 114/73 HR 70 RR 16 57 year old man presents with mild O2 Sat 96% RA (93% walking) dyspnea on exertion x 2 month, no cough Inspiratory crackles at both bases Normal cardiac exam, no JVD, no edema Ø PMH: GERD No clubbing, joint deformities, rashes Ø Meds: Omeprazole 40mg daily Ø SH: lifetime non-smoker, pharmacist Ø FH: no family history of lung disease What is next best step in Case of Shortness of Breath management? Lasix A. Levofloxacin B. PPD C. HRCT scan D. Echocardiogram E. 2
CXR is Not Useful for Case of Shortness of Breath Differentiating ILD’s FVC 5.10 (83%) FEV1 4.42 (90%) HP FEV1 / FVC 0.87 IPF TLC 7.40 (88%) DLCO 23.41 (57%) CTD- NSIP ILD HRCT Scan Specific HRCT Findings Ø ILD protocol Ø Honeycombing ◆ Inspiratory plus expiratory images Ø Reticulation ◆ Prone as well as supine Ø Ground Glass Opacities Ø Traction Bronchiectasis Ø Air trapping Ø Nodules Ø Emphysema 3
HRCTs are essential in ILD Case of Shortness of Breath • Pattern of abnormality on HRCT scan may suggest a specific ILD • HRCT findings guide subsequent diagnostic tests • HRCT findings may be sufficient for diagnosis Case of Shortness of Breath Case of Shortness of Breath 4
Case of Shortness of Breath Case of Shortness of Breath What is the best thing to tell a Case of Shortness of Breath patient at this point? Prednisone at 1 mg/kg should be started to A. try to reverse this disease. There is no available treatment. Most B. patients live 3-5 years from time of diagnosis. You should be seen by a specialist and your C. case discussed with a multidisciplinary team before any treatment is started. You should have a lung biopsy to establish D. the diagnosis. 5
ILD Classification Multidisciplinary Approach to Diagnosis Pulmonary Fibrosis Assessment Information 1.0 Step Method Provided 0.9 Exposure-related: Idiopathic Connective Other: 1 Individual HRCT - Occupational interstitial tissue disease: - Sarcoidosis 0.8 - Environmental pneumonia (IIP) - Scleroderma - Vasculitis/Diffuse alveolar 0.7 HRCT, clinical - Avocational - Rheum arthritis hemorrhage 2 Individual 0.6 data Idiopathic - Medication - Sjogrens - Langherhans cell pulmonary 0.5 - MCTD histiocytosis Discussion HRCT, clinical fibrosis - Dermatomyositis - Lymphagioleiomyomatosis (clinician & 0.4 3 data (IPF) - Pulmonary alveolar radiologist) 0.3 proteinosis 0.2 Individual Desquamative interstitial Respiratory bronchiolitis - Eosinophilic pneumonias (clinician, pneumonia (DIP) interstitial lung dis. (RBILD) - Neurofibromatosis HRCT, clinical 0.1 4 radiologist & data, SLB 0 Acute interstitial Cryptogenic organizing pathologist) 1 2 3 4 5 pneumonia (AIP) pneumonia (COP) HRCT, clinical 5 Discussion data, SLB Nonspecific interstitial Lymphocytic interstitial pneumonia (NSIP) pneumonia (LIP) Modified from: Flaherty KR, et al. AJRCCM. 2004;170:904 -9 10. Differentiating Diseases Don’t stop with a diagnosis of Predicts Prognosis “Pulmonary Fibrosis” Ø Reasons for a specific diagnosis: 1950-90’s: Lumpers 2000: Splitters DIP ◆ Many forms are treatable ◆ Treatment depends on the diagnosis ◆ Prognosis varies /IPF ◆ Eligibility for clinical trials Bjoraker et al, AJRCCM ‘98 6
Case of Shortness of Breath Idiopathic Pulmonary Fibrosis Ø Average survival from diagnosis: 2.5-3 years Ø Afflicts men more than women Ø No apparent race or ethnic predilection Ø HRCT: subpleural, basila r predominant reticulation, Ø Path: UIP pattern honeycombing, and traction bronchiectasis Systematic Review / Meta-Analysis What do you recommend? Prednisone, Azathioprine and N- A. Acetylcysteine (NAC) Nintenadib B. Pirfenidone C. Palliative care consultation as there is no D. treatment for this disease B or C E. Canestaro WJ, et. al. CHEST 2016; 149(3):756-766 7
Systematic Review / Meta- Analysis Conclusions Ø Pirfenidone and Nintedanib ASCEND ◆ are first treatments shown to slow rate of disease progression (FVC decline) ◆ Long term mortality impact not clear King et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. NEJM 2014;370:2083 ASCEND ASCEND: Study design Ø Enrolled 555 highly-selected patients with IPF As sessment of Pirfenidone to C onfirm E fficacy a nd Safety in Idiopathic Pulmonary Fibrosis Ø Randomized to pirfenidone or placebo x 52 wks ◆ Performed in response to an FDA request for an additional trial to support approval 1°: Pirfenidone ◆ Designed to enrich subjects for disease FVC n = 278 progression (as measured by change in FVC) IPF 52 wks 2°: n = 555 6MWT distance; Placebo PFS; n = 277 dyspnea; death King. NEJM 2014;370:2083 King. NEJM 2014;370:2083 8
ASCEND: Subjects ASCEND: 1° Endpoint Relative difference = 45% Baseline Pirfenidone Placebo P value < 0.001 (n=278) (n=277) Age, years 68 68 Male sex 80% 77% FVC 68% 69% DLCO 44% 44% 6MWT distance 415 421 Dyspnea (UCSD) 34 37 Definite UIP HRCT 96% 95% King. NEJM 2014;370:2083 King. NEJM 2014;370:2083 INPULSIS: Study design Ø Enrolled 1066 patients with IPF/likely IPF INPULSIS Ø Randomized (3:2) to nintedanib/placebo for 52 wks nintedanib 1°: FVC n = 638 Richeldi et al. Efficacy and safety of nintedanib in idiopathic pulmonary IPF 2°: 52 wks n = 1066 acute fibrosis. NEJM 2014;370:2071 exacerbation; Placebo QOL; n = 423 death Richeldi NEJM 2014;370:2071 9
INPULSIS: Subjects INPULSIS: 1° Endpoint Baseline INPULSIS 1 INPULSIS II Nintedanib Placebo Nintedani Placebo b Age, years 67 67 66 67 Male sex 81% 80% 78% 78% FVC 80% 81% 80% 82% Mean difference 109.9 (71.3, 148.6) DLCO 48% 48% 47% 46% P value < 0.001 Oxygen sat 96% 96% 96% 96% SGRQ score 40 40 40 39 Richeldi NEJM 2014;370:2071 Richeldi NEJM 2014;370:2071 But what about when the ILD Summary disease still does progress.. Ø Don’t stop at “pulmonary fibrosis” Ø And now a word about Lung Transplant… Ø History is essential Ø HRCT scans are a key diagnostic tool Ø The diagnosis of ILD should be made using a multidisciplinary approach Ø Treatment depends on the specific type of ILD ◆ there are now 2 treatments available for IPF 10
Lung Transplant for IPF Lung Transplant § Should be Ø ECLS / ECMO supports patients considered in all to LT patients < 70 years Ø Ex vivo perfusion systems support donor lungs to LT § 50-60% 5 year survival after transplant Bjoraker et al, AJRCCM ‘98, Neurohr et al, Transplant International, ‘10 Case of Recurrent Pneumonia Ø 31 year old man originally from Mexico Case of Recurrent prevents for evaluation. Pneumonia ◆ history of recurrent pneumonias from a young age. ◆ hospitalized 4 times in the past 3 years Ø His chief complaint is dyspnea and cough productive of brown mucous, and chest pain. He can walk about 3 blocks. He's limited by dyspnea, fatigue and palpations. 11
Case of Recurrent Pneumonia CXR Ø VS: BP 129/79 HR 90 T 36.7°C RR 20 SpO2 97% BMI 18.6 kg/m2 Ø Chronically ill appearing, cachectic, and frail Ø No sinus tenderness, No LAD Ø RRR, S1 and S2 present Ø Lungs with rhonchi bilaterally, prolonged expiratory phase, reduced air movement Ø Digital clubbing What is next best step to Spirometry establish the diagnosis? 11/19/14 Sweat Chloride Test A. Sputum : CF PCR for common mutations BMI 18.6 B. -AFB Culture negative x 3 A1AT genotype C. FVC 1.69 Bronchoscopy D. (36%) Echocardiogram FEV1 0.98 E. (25%) FEV1/FVC 57.76 12
Mortality Rates in Case Diagnostic testing Hispanic and Non-Hispanic CF Patients Ø Sweat Chloride = 79 [Normal <40 mmol/L] Ø CF PCR for common mutations ◆ Heterozygous for the delF508 mutation Ø CFTR Full Gene Sequence Analysis ◆ One copy F508del ◆ One copy G551S Buu et. al. CHEST 2016; 149(2):380-389 He is wondering if there is any Modulation of CFTR defects CFTR specific therapy. What do you tell him? Ivacaftor is likely to improve lung function A. and quality of life. No genotype specific therapy is available B. outside of a clinical trial. Sorry, nothing is available. Gene therapy has C. not panned out as we had hoped. Pittman J et. al. CHEST 2015; 148 ( 2 ): 533 - 542 13
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