Case Presentation. Case Presentation (continued) PHYSICAL EXAMINATION. 60 year old college professor dyspnea with exertion dry cough, throat clearing

Transcription

1 Primary Care Medicine: Concepts and Controversies Thursday, February 18, 21 Fiesta Americana Puerto Vallarta, Mexico Interstitial Lung Disease: A Clinician s Approach to Diagnosis and Management Talmadge E. King, Jr., M.D. Krevins Distinguished Professor of Medicine Chair, Department of Medicine University of California San Francisco (UCSF) San Francisco, CA Case Presentation 6 year old college professor dyspnea with exertion dry cough, throat clearing Occupational/Environmental Exposures: shipyard worker (in his 2 s) home remodeled (within last 5 yrs.) Case Presentation (continued) PAST MEDICAL HISTORY: former smoker (2 pack-yrs; quit 1 yrs) coronary artery disease systemic arterial hypertension chronic nasal congestion GERD FAMILY & SOCIAL HISTORY Negative for lung disease MEDICATIONS: lisinopril (ACE inhibitor) lortadine (antihistamine) omeprazole (proton pump inhibitor) albuterol/ atrovent Case Presentation (continued) PHYSICAL EXAMINATION RR 14 Bibasilar crackles O 2 sat 98% at rest 9% after walking 2 meters 1

2 Case Presentation (continued) HRCT Scan of Lungs Baseline 1 yr 2 yr FEV1 2.8 (87) 2.7 (86) 2.5 (8) FVC 3.2 (72) 3.2 (72) 3. (68) FEV1/FVC 87% 85% 84% TLC 4. (59) 4.1 (61) 3.4 (5) DLCO 16.1 (6) 16.6 (62) 13.5 (51) Questions What is the diagnosis? Are additional studies needed to determine diagnosis? What is the prognosis? What treatment should be instituted? Diffuse Parenchymal Lung Diseases or Interstitial Lung Diseases (ILD) Heterogeneous group of noninfectious, nonmalignant processes of the lower respiratory tract (interstitial pneumonias) that commonly result Symptoms: dyspnea and cough Signs: crackles on chest exam; (clubbing) PFTs: restrictive ventilatory impairment Chest imaging: diffuse interstitial opacities Lung biopsy: granulomatous or interstitial inflammation and fibrosis Outcome: often progressive and often fatal 2

3 Lung Fibrosis Follows Many Different Forms of Lung Injury What are the Causes of ILD? Granulomatous reaction Drugs (chemotherapy) Radiation Inorganic dusts (asbestos, fumes, gases) Collagen vascular diseases Pulmonary hemorrhage syndromes (vasculitides) Lymphocytic infiltrative disorders Eosinophilic pneumonias Idiopathic interstitial pneumonias (UIP, DIP, NSIP, BOOP) Inherited diseases (tuberous sclerosis, familial PF) Endstage Fibrosis ( Honeycomb lung ) Major Histopathological Patterns Granulomatous Processes Granulomatous Reaction Inflammatory and fibrotic Sarcoidosis Organic dusts Hypersensitivity pneumonitis Inorganic dusts beryllium silica Granulomatous vasculitides Wegener s granulomatosis Churg-Strauss 3

4 Interstitial Inflammation and Fibrosis Diffuse Parenchymal Lung Diseases Idiopathic interstitial pneumonias (UIP, DIP, NSIP, OP, DAD, LIP) Collagen vascular diseases Inorganic dusts (asbestos, fumes, gases) Drugs (chemotherapy) Radiation Pulmonary hemorrhage syndromes Lymphocytic infiltrative disorders Eosinophilic pneumonias Inherited diseases (tuberous sclerosis) Other Systemic Disorders Occupational and Environmental Exposures Idiopathic Interstitial Pneumonias Connective Tissue Diseases Drug-Induced Lung Injury These conditions are uncommon and few physicians have substantial experience with their diagnosis and management. How Common is ILD? Diagnosis Prevalence Incidence Men Women Men Women Pulmonary fibrosis Occupational and environmental Connective tissue diseases Sarcoidosis Drug and radiation Pulmonary hemorrhage syndromes Other Total Coultas et al. Am.J.Respir.Crit.Care Med. 1994; 15:

5 Clinical Manifestations and Approach to the Diagnosis of ILD Approach to the Diagnosis of ILD: It Often Takes A Village! Clinical History Physical Laboratory PFTs Radiology Chest X-ray HRCT Pathology Surgical lung biopsy Primary Care Pulmonologists Radiologists Pathologists Multidimensional and multidisciplinary ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 22;165: Clinical Presentations of DPLD Most common: DOE, cough, abnormal CXR, physiological impairment. Some: symptoms/signs, normal CXR & PFTs. (HRCT, BAL or exercise usually abnormal) Rarely, asymptomatic with abnormal CXR or physiological impairment (abnormal spirometry or low DLCO) Associated with another disease, esp, CTD Positive exposure history ILD Presentation: Symptoms and Signs Breathlessness (dyspnea) during or after physical activity Spasmodic, dry cough Gradual, unintended weight loss Fatigue or malaise Rapid shallow breathing Crackles on chest examination Clubbing, or enlargement of the ends of the fingers (or sometimes the toes) 5

6 PATIENT WITH SUSPECTED DPLD PATIENT WITH SUSPECTED DPLD Age Duration of illness Family history Exposures (patient & spouse, at work, home, hobbies) Drugs Careful History & Physical Exam Rapid shallow breathing Crackles on chest examination Clubbing Pulmonary Function Testing Chest X-ray and CT Scans Bronchoscopy (TBBx) Bronchoalveolar Lavage Open Lung Biopsy Exercise Testing Careful History & Physical Exam Routine Studies PFTs = Restrictive Impairment Measurements of Gas Exchange Expiratory flow (l/s) Flow is increased at all lung volumes IPF Pred Volume (Liters from TLC) Elastic recoil is increased Emphysema TLC (% PRED) 1 5 Normal range IPF Transpulmonary Pressure (cm H 2 O) Hypoxemia worsens Excessive ventilatory and heart rate response Correlates with disease severity Exercise Testing Predicted max VO 2 (%) 6

7 Hx and HRCT confident for IPF STOP UIP Approach to the ILD Patient Patient with Suspected ILD Hx and HRCT Dx of other ILD NSIP STOP Hx, PE, CXR, PFT, Labs RBILD HRCT Atypical clinical or CT features of IPF No DIP VATS DAD Yes - OP Not IIP (e.g. associated collagen vascular disease, environmental, drugrelated, etc.) Suspected other ILD Dx likely by bronch? LIP STOP Is bronch diagnostic? + STOP Non IIP Importance of Early Diagnosis of ILD Provide an explanation of the patients symptoms Identify treatable diseases Allow early initiation of treatment Allow for earlier referral and enrollment in clinical trials Generally limited to patients with mild to moderate disease Begin evaluation for lung transplant earlier Diffuse Parenchymal Lung Diseases Drug-Induced Lung Injury Drug-induced Lung Disease Common but NOT easy to prove Clinical-radiologic-pathologic pattern unreliable Diagnosis of exclusion (vs. infection, heart failure) Occurs usually during the treatment or shortly after the drug is withdrawn Can have long latent period (months to years, e.g., carmustine) 7

8 Diffuse Parenchymal Lung Diseases Occupational and Environmental Exposures Occupational and Environmental Exposures Occupational and Environmental Exposures Inorganic dusts asbestosis silicosis Organic dusts Fungal spores Animal proteins Gases, fumes, vapors, aerosols 8

9 Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis) NOT a single, uniform disease Complex syndrome of varying: clinical presentation intensity natural history An immunologic reaction to an inhaled agent, particularly an organic antigen. King, TE, Jr. UpToDate EPIDEMIOLOGY Largely unknown. Few population-based studies Prevalence and incidence vary considerably depending upon case definitions intensity of exposure to inciting antigens season geographical conditions local practices and customs proximity to certain industries host risk factors King, TE, Jr. UpToDate Prevalence - Farmer's lung Number of cases in the population at risk at a given time Affects.4 to 7 percent of the farming population Varies by Region and climate farming practices ~ 9% at risk in humid zones to 2% in drier zones United States 42 to 3 (per 1,) United Kingdom 12 to 23 France 437 King, TE, Jr. UpToDate Incidence - Farmer's lung Number of new cases in the population at risk in a given year 8 to 54 per 1, per year Varies considerably and is influenced by several factors. In Finland, significant variation according to season Most cases occur in April near the end of the indoor feeding season for cattle Lowest in October, when outdoor feeding is norm. The incidence correlates positively with the King, TE, Jr. UpToDate 9

10 Prevalence -- Bird Fanciers Prevalence -- Bird Fanciers Highly variable 2 to 2, per 1, persons at risk Likely higher among bird fanciers than among farmers because contact with antigens is more prolonged Species of birds and the handling practices employed may affect prevalence Pigeon breeders: 6, to 21, per 1, per year (6 to 21 percent per year) King, TE, Jr. UpToDate King, TE, Jr. UpToDate Incidence Other Exposures High attack rates during sporadic outbreaks 52% office workers with humidifier lung (Ganier M, et al. Chest 198; 77:183) 37% lifeguards at public swimming pool (Rose CS, et al. Am J Public Health 1998; 88:795) 27% workers at an injection molding plant manufacturing polyurethane foam parts for automobiles (Simpson C, et al. Am J Ind Med 1996; 3:48) 15% office workers with contaminated forced air system (Banaszak EF, N Engl J Med 197; 283:271) King, TE, Jr. UpToDate ETIOLOGIC AGENTS Wide range of occupations and avocations Over 3 etiologies reported. Some are single or small number of cases and require further study. King, TE, Jr. UpToDate 1

11 Ceiling Tiles in Office of Owner Water on the Roof Damage To HVAC Unit 11

12 Swimming Pool and Water Units Hot Tub Lung Mycobacterium-avium Complex CHEST 1997; 111: Treatment Modify or avoid the culprit environment in order to minimize ongoing exposure. Corticosteroid treatment with.5 to 1. mg of prednisone per kg of ideal body weight per day (up to 6 mg/day) should be considered for severely symptomatic patients. The initial dose is maintained for one to two weeks and is then tapered over the next two to four weeks. Maintenance therapy is rarely required. Diffuse Parenchymal Lung Diseases Systemic Disorders King, TE, Jr. UpToDate 12

13 Other Systemic Diseases Sarcoidosis Vasculitides Wegener's granulomatosis Churg-Strauss syndrome Hemorrhagic syndromes Goodpasture's syndrome Pulmonary capillaritis Pulmonary Histiocytosis X Chronic gastric aspiration Lymphangitic carcinomatosis Alveolar proteinosis Chronic pulmonary edema Sarcoidosis: Definition A multisystem granulomatous disease of unknown cause(s) that primarily affects the lung and lymphatic systems of the body. Sven Löfgren: we cannot adequately define sarcoidosis because we do not know its etiology Sarcoidosis: Epidemiology Incidence (rate per 1,) Sarcoidosis: Epidemiology Estimated Prevalence/1, Number of new cases occurring during a given time, usually 1 yr. Lifetime risk for U.S. blacks is 2.4 percent, and that for U.S. whites.85 percent U.S. Blacks U.S. Whites Finland Great Britain Japan Blacks Puerto Ricans Hispanics Whites James, D.G. and Y. Hosoda, Epidemiology, in Sarcoidosis and other granulomatous disorders., D.G. James, Editor. 1994, Marcel Dekker, Inc.: New York. p

14 Sarcoidosis: Epidemiology Estimated Prevalence: Comparisons >5/1, Denmark: 53/1, Sweden: 55-64/1, 4-5/1, Germany: 43/1, 3-4/1, NYC: 39/1, 2-3/1, Norway: 27/1, Great Britain: 2/1, 1-2/1, Canada: ~1/1, France: 1/1, Under 1/1, Japan: <5/1, Australia: 8/1, Brazil: <3/1, Spain:.5/1, Sarcoidosis: Epidemiology Age at Presentation Seen at all ages Peak incidence: age Blacks are (?) younger No relation to clinical presentation, prognosis, or geographic location Scandinavian countries and Japan have a second peak incidence in women > 5 yr Neville E, Walker AN, James DG. Prognostic factors predicting outcome of sarcoidosis: analysis of 818 patients. QJMed 1983;52: Percent of cases (n = 818) Age at Onset CRITERIA FOR DIAGNOSIS Compatible clinical illness Histologic confirmation Exclusion of other illnesses Sarcoidosis: Initial Evaluation Exclude Critical Organ Involvement Determine Extent and Severity of Disease Exclude Other Diseases Thomas KW, Hunninghake GW: Sarcoidosis. JAMA 23; 289(24):

15 Sarcoidosis: Initial Evaluation Exclude Critical Organ Involvement Complete neurological examination Electrocardiogram Complete ophthalmologic examination Sarcoidosis: Initial Evaluation Determine Extent and Severity of Disease Chest radiographs Pulmonary function testing: spirometry, DLCO Hepatic enzyme measurements Renal assessments: electrolyte, blood urea nitrogen, creatinine levels Urine analysis Complete blood cell count Serum calcium levels Thomas KW, Hunninghake GW: Sarcoidosis. JAMA 23; 289(24): Thomas KW, Hunninghake GW: Sarcoidosis. JAMA 23; 289(24): Sarcoidosis: Initial Evaluation Exclude Other Diseases Occupational and environmental exposure history Tuberculin skin test What are the signs and symptoms of sarcoidosis? Thomas KW, Hunninghake GW: Sarcoidosis. JAMA 23; 289(24):

16 Symptoms at Presentation 4 to 6% are asymptomatic Commonly discovered on routine chest x-ray 1 to 15% begin acutely with Lofgren s syndrome 9% have intrathoracic disease Chest x-ray useful anatomical guide for lung involvement, cannot be used to: Stage activity of disease Assess functional defects SARCOIDOSIS Lofgren s Syndrome Acute presentation o Women, esp. Swedish, Irish, Puerto Rican o Erythema nodosum o Acute arthralgia o Bilateral hilar lymphadenopathy Only 1-28% of cases at presentation Invariably improves within 1 to 2 yrs. SARCOIDOSIS: Lofgren s Syndrome Radiographic Stages of Sarcoidosis Classification is based on the PA chest radiogram only. Sometimes the CT scan or 67Ga lung scan gives information suggesting a different stage Hunninghake GW, Costabel U, Ando M, et al. ATS Statement on sarcoidosis. AMJ Respir Crit Care Med. 1999;16:

17 Estimated Frequency of Extrathoracic Involvement Peripheral lymph nodes 73% Skin 32% Liver 21% Eye 21% Spleen 18% Bone 14% Treatment of Sarcoidosis Corticosteroids Cytotoxic Agents Methotrexate Azathioprine. Cyclophosphamide Chlorambucil Other Agents Hydroxychloroquine (Chloroquine) Ketoconazole Infliximab Absolute and Relative Indications for Corticosteroids Diffuse Parenchymal Lung Diseases Absolute Ocular Myocardial Central Nervous System Relative Hypercalcemia Skin Lesions Connective Tissue Disorders 17

18 Systemic Sclerosis Polymyositis-Dermatomyositis Pulmonary Manifestations CTD Rheumatoid Arthritis ILD complicating CTDs accounts for ~ 25 percent of all ILD mortality and 2 percent of all respiratory deaths in U.S.A. Usually the CTD is clinically evident. CTDs affect all areas of the lung, i.e., the airways, alveoli, vascular system and pleura, and does so in various degrees and combinations Pulmonary Manifestations CTDs Often the ILD is mild, but may be progressive and dominate the clinical picture Pathogenesis unclear but thought to be part of the systemic process. Diffuse Parenchymal Lung Diseases Idiopathic Interstitial Pneumonias 18

19 Diffuse Parenchymal Lung Diseases Idiopathic Pulmonary Fibrosis (UIP) Idiopathic interstitial pneumonias How Common Are the Different Histopathological Patterns of IIP? HISTOPATHOLOGICAL SUBGROUPS Relative Frequency SURVIVAL FOR UIP vs. NSIP 1 1 UIP = 47-62% NSIP = 14-36% DIP/RBILD = 1-17% AIP = 2% Other = 12-26% % Alive NSIP UIP Others NSIP UIP * other = bronchiolitis (4), BOOP (4), CEP (1), HSP (1), honeycomb changes only (1), hemorrhage (1), scarring/pneumonia (1) Years Daniil ZD et al. Am J Respir Crit Care Med. 1999;16:899. Years Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157:

20 Idiopathic Pulmonary Fibrosis Overview - IPF Onset: Usually between 5 and 7 years Clinical presentation Males, current or former smokers Progressive dyspnea on exertion Paroxysmal cough, usually non-productive Abnormal breath sounds on chest auscultation Abnormal chest x-ray or HRCT Restrictive pulmonary physiology with reduced lung volumes and DLCO, and widened AaPO2 Epidemiology of IPF Incidence 1.7 cases per 1, per year for males 7.4 cases per 1, per year for females. 6.8 and 16.3 per 1, pe Prevalence (approximately 35,-55, cases) 2 cases per 1, for males 13 cases per 1, for females. Nationwide prevalence of IPF in Finland (as defined by the new ATS/ERS criteria) was estimated to be 16 to 18 per 1,. Incidence and prevalence of IPF increases markedly with age Per Hundred Thousand Incidence Male Female Estimated 31, New Patients per Year in the United States Estimated 83, Current Patients in the United States Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary Fibrosis. Paper presented at: CHEST 22 San Diego, CA. Per Hundred Thousand Prevalence Male Female

21 IPF/UIP: Radiographic Findings HRCT Pattern Consistent With UIP-IPF Pattern Chest Radiograph HRCT Bibasilar, peripheral reticular opacities ( ± traction bronchiectasis) Lower lobe honeycombing Irregular lines in the upper lobes. One present: sensitivity = 91%, specificity = 64%, positive predictive value =79%, negative predictive value = 82% Both present: sensitivity = 74%, specificity = 81%, positive predictive value = 85%, negative predictive value = 67%. Absence of alveolar opacities, peribronchovascular nodules, micronodules, mediastinal adenopathy Chest. 23;124: Idiopathic Pulmonary Fibrosis Usual Interstitial Pneumonia Healthy Lung Idiopathic Pulmonary Fibrosis Peripheral acinar distribution Subpleural and adjacent to the septa and bronchovascular bundles Fibroblastic foci = organizing acute lung injury and sites of active collagen synthesis in a badly distorted lung 21

22 No Effective Treatment for IPF/UIP and Survival Rate is Very Poor 1 1 IPF/UIP Natural history % Alive UIP UIP Years Years Daniil ZD et al. Am J Respir Crit Care Med. 1999;16:899. Bjoraker JA et al. Am J Respir Crit Care Med. 1998;157:199. IPF: As bad as lung cancer! Disease 5-year survival (%) Lung cancer 14 IPF-UIP 2-3 CHF <5 Colorectal cancer 62 Median survival of patients with biopsy-proven IPF is less than 3 years after diagnosis (n = 238) Median survival from onset of symptoms = 8.8 mo; 95% CI: Median survival from diagnosis = 35.2 mo; 95% CI: Breast cancer 86 Prostate cancer 9 King TE Jr, et al Am J Respir Crit Care Med 21; 164:

23 Forced vital capacity (FVC) declines ~2 ml per year Slow decline, rapidly progressive vs acute exacerbation.5 Baseline Pirfenidone= Slowly progressive Respiratory function/symptoms Acute exacerbations Rapidly progressive IFNγ = Etanercept= -.2 Bosentan = Time (weeks) >5 Years // NAC = -.19 Placebo Percent alive Change from baseline (liters).1 In IPF there are several patterns of progression (5-year survival = 2-3%) 6 Radiographic Changes of Acute Exacerbation Smoking status has profound impact on the disease pattern and clinical course Pathologic Changes of Acute Exacerbation UIP Progressive bilateral shadowing of lung parenchyma Do not usually resolve, even after treatment OP DAD Ambrosini, V., A. Cancellieri, M. Chilosi, M. Zompatori, R. Trisolini, L. Saragoni, and V. Poletti. 23. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 22(5):

24 Where we re going Anti-inflammatory Immunomodulation Anti-fibrotic IPF: Treatment Immunosuppression Corticosteroids Colchicine D-penicillamine Azathioprine Cyclophosphamide Anti-oxidant NAC Glutathione IFN-γ 1b Etanercept Pirfenidone Imatinib Bosentan Anti-proliferative FG-319? GC-18? Statins? LO Inhibitors? Combo Tx? 195s 199s 29 Future Thank you for your attention. 24