Sarcoidosis: Classification & Diagnosis. Christophe von Garnier Universitätsklinik für Pneumologie Inselspital und Tiefenauspital
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1 Sarcoidosis: Classification & Diagnosis Christophe von Garnier Universitätsklinik für Pneumologie Inselspital und Tiefenauspital
2 EPIDEMIOLOGY SARCOIDOSIS Prevalence / Incidence of 1 36 / / year Prevalence and incidence linked to age, sex, ethnic origin, and geographical location Highest rates: Northern Europeans and African Americans Lowest rates: Japan 70% of patients aged years Europe and Japan: second incidence peak women >50 years Rare <15 years or >70 years Female to male ratio 1.2 : 1.8 Hillerdal G et al. Am Rev Respir Dis 1984; 130: Morimoto T, et al. Eur Respir J 2008; 31:
3 RISK FACTORS SARCOIDOSIS Exposure to musty/mouldy odours, insecticides, metal-processing industries, 9/11 firefighters; risk decreased in smokers Deubelbeiss U et al. Eur Respir J 2010; 35: Newman LS et al. Am J Respir Crit Care Med 2004; 170: Crowley LE et al. Am J Ind Med 2011; 54: Perlman SE et al. Lancet 2011; 378: Genetic factors (?2/3) familial % cases siblings and monozygotic twins (80x) Rybicki BA et al. Am J Respir Crit Care Med 2001; 164: Sverrild A et al. Thorax 2008; 63:
4 SARCOIDOSIS CAUSE? Genetic susceptibility and environmental factors Exaggerated immune response to unidentified antigens - Organic / anorganic dusts - Mycobacterial antigens (mycobacterial catalase-peroxidase) - Propionibacteria Autoimmunity Chen ES et al. Clin Chest Med 2008;29: Ishige I et al. Lancet 1999; 354: McCaskill JG et al. Am J Respir Cell Mol Biol 2006; 35:
5 PATHOPHYSIOLOGY Inappropiate immune response(s) to unidentified antigen(s) Antigen-presenting cell activation by PAMPs (pathogen-associated molecular patterns) TH1 related inflammation Granuloma formation Antigen elimination resolution Profibrotic (CCL18) fibrosis Iannuzzi MC et al. N Engl J Med Nov 22;357(21):
6 GENES AND SARCOIDOSIS Sarcoidosis associated with genetic risk profile constituted by multitude of variant genes MHC II genes (HLA-DRB1) Susceptibility Phenotype Prognosis Schupp JC, et al. Pneumologie Apr;70(4):
7 INITIAL EVALUATION SARCOIDOSIS History (environmental/occupational exposure, family history) Physical Examination CXR Pulmonary functions tests (plethysmography + diffusion capacity) ECG (24h ECG) Laboratory: Complete blood count + differential cell count Creatinine Liver function tests Serum protein electrophoresis Serum and 24h Urine Calcium Ophthalmologic evaluation (slit lamp, tonometry, fundoscopy) Valeyre D et al. Lancet 2014; 383: ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15: 52 58
8 INITIAL EVALUATION SARCOIDOSIS Thoracic CT (difficult diagnosis and/or complications) Criado E et al. Radiographics 2010;30: Cardio-pulmonary exercise testing - dyspnoea with normal lung function / DLCO Marcellis RG et al. Lung 2013; 191: Wallaert B et al. Respiration 2011; 826: monitoring of disease course ± immune-suppression Lopes AJ et al. Braz J Med Biol Res 2012; 45: Kollert F et al. Respir Med 2011; 105: Echocardiography, right heart catheter (pulmonary hypertension) Nunes H et al. Presse Med 2012; 41: e Baughman RP et al. Chest 2010; 138: Interferon gamma release assay (immune-suppression)
9 DIAGNOSTIC ALGORITHM Clinical & Radiographic Presentation History, Physical, Imaging, Baseline Evaluation Typical symptoms: persistent cough fever arthralgias visual changes skin lesions fatigue (70%) Specific Clinical Presentation Tissue biopsy may not be required Löfgren Syndrome Heerfordt Syndrome Asymptomatic hilar adenopathy (CXR) Lambda and Panda sign (Gallium 67) Judson MA. F1000Prime Rep 2014;6:89 Govender P et al. Clin Chest Med 36 (2015)
10 LÖFGREN SYNDROME Bilateral hilar lymphadenopathy Arthritis Erythema Nodosum
11 HEERFORDT SYNDROME Uveitis Parotitis Facial Palsy
12 DIAGNOSTIC ALGORITHM Clinical & Radiographic Presentation History, Physical, Imaging, Baseline Evaluation Typical symptoms: persistent cough fever arthralgias visual changes skin lesions fatigue (70%) Specific Clinical Presentation Tissue biopsy may not be required Löfgren Syndrome Heerfordt Syndrome Asymptomatic hilar adenopathy (CXR) Lambda and Panda sign (Gallium 67) Non-Specific Clinical Presentation Tissue biopsy is required Biopsy suspicious lesion Biopsy pulmonary tissue and/or adenopathy Blind biopsy accessible site Exclude other Granulomatous Disease Document Systemic Involvement Judson MA. F1000Prime Rep 2014;6:89 Govender P et al. Clin Chest Med 36 (2015)
13 ORGAN INVOLVEMENT SARCOIDOSIS 50% asymptomatic Baughman RP et al. Am J Respir Crit Care Med 2001;164(10 Pt l):1886 Govender P et al. Clin Chest Med 36 (2015)
14 LEVELS OF CONFIDENCE IN DIAGNOSIS Clinical and radiological presentation Non-caseating granulomas No alternative diagnosis Govender P et al. Clin Chest Med 36 (2015) Judson MA. Semin Respir Crit Care Med 2007; 28: ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp
15 PULMONARY SARCOIDOSIS RADIOGRAPHIC STAGES STAGE I STAGE II STAGE III STAGE IV Lymphadenopathy Lymphadenopathy + Infiltrates Infiltrates Frequency 50% 25-30% 10-12% 5% Resolution 60-90% 40-70% 10-20% 0% Fibrosis Keijsers RG et al. Clin Chest Med 36 (2015) Scadding JG. BMJ 1961;2:
16 HRCT FINDINGS Classic findings (potentially reversible) Lymphadenopathy: bilateral hilar, mediastinal, right paratracheal, subcarinal, aortopulm. Reticulonodular pattern: micronodules (2 4 mm, well defined, bilateral distribution) Perilymphatic distribution of nodules (peribronchovascular, subpleural, interlobular septal) Upper and middle zones predominance parenchymal abnormalities Keijsers RG et al. Clin Chest Med 36 (2015) Criado E et al. Radiographics 2010; 30:
17 HRCT FINDINGS Classic findings (potentially reversible) Lymphadenopathy: bilateral hilar, mediastinal, right paratracheal, subcarinal, aortopulm. Reticulonodular pattern: micronodules (2 4 mm, well defined, bilateral distribution) Perilymphatic distribution of nodules (peribronchovascular, subpleural, interlobular septal) Upper and middle zones predominance parenchymal abnormalities Uncommon findings (potentially reversible) Lymphadenopathy: unilateral, isolated, anterior and posterior mediastinal, paracardiac Reticular pattern Isolated cavitations Isolated ground glass opacities without micronodules Mosaic attenuation pattern Pleural disease (effusion, pleural thickening, chylothorax, pneumothorax) Mycetoma Macronodules (>5 mm, coalescing); galaxy sign and cluster sign Keijsers RG et al. Clin Chest Med 36 (2015) Criado E et al. Radiographics 2010; 30:
18 HRCT FINDINGS Classic findings reflecting irreversible fibrosis or chronic disease Reticular opacities, predominantly middle and upper zones Architectural distortion Traction bronchiectasis Volume loss, predominantly upper lobes Calcified lymphnodes Fibrocystic changes Uncommon findings reflecting irreversible fibrosis or chronic disease Honeycomb-like changes Reticular opacities in predominantly lower lobes Keijsers RG et al. Clin Chest Med 36 (2015) Criado E et al. Radiographics 2010; 30:
19 SELECTION OF BIOPSY SITE DIAGNOSTIC OPTIONS FOR SAMPLING 1. Easily accessible site first (skin, nose, conjunctiva, peripheral lymph node) 2. Intra-thoracic disease 3. Diagnostic dilemma no easily accessible diagnostic site Govender P et al. Clin Chest Med 36 (2015)
20 SELECTION OF BIOPSY SITE DIAGNOSTIC OPTIONS FOR SAMPLING 1. Easily accessible site first (skin, nose, conjunctiva, peripheral lymph node) 2. Intra-thoracic disease 3. Diagnostic dilemma no easily accessible diagnostic site Sample Diagnostic yield TBB 40-90% EBB 40-60% EBUS-TBNA 54-93% Gilman MJ et al. Chest 1983;83:159 Shorr AF et al. Chest 2001;120: Drent M et al. Semin Respir Crit Care Med 2007;28: von Bartheld MB et al. JAMA 2013;309: Plit M et al. Intern Med J 2012;42:434 8
21 BRONCHOALVEOLAR LAVAGE IN SARCOIDOSIS Lymphocytes 20-50% in 80% of patients Degree of lymphocytosis correlates with disease activity CD4/CD8 Ratio Sensitivity Specificity > % 92% > % 94-96% Kantrow SP et al. Eur Respir J 1997;10: Drent M et al. Semin Respir Crit Care Med 2007;28:
22 SELECTION OF BIOPSY SITE DIAGNOSTIC OPTIONS FOR SAMPLING 1. Easily accessible site first (skin, nose, conjunctiva, peripheral lymph node) 2. Intra-thoracic disease 3. Diagnostic dilemma no easily accessible diagnostic site Blind Biopsy Site Diagnostic yield Conjunctiva 55% Minor salivary glands 20-58% Scalene lymph nodes 74-80% Liver 50-60% Gastrocnemius (Erythema nodosum) 90% Bonfioli AA et al. Semin Ophthalmol 2005;20: Nessan VJ et al. N Engl J Med 1979;301:922 4 Harvey J et al. Sarcoidosis 1989;6:47 50 Stjernberg N et al. Acta Med Scand 1980;207:111 3 Truedson H et al. Acta Chir Scand 1985;151:121 3 Karagiannidis A et al. Ann Hepatol 2006;5:251 6 Andonopoulos et al. Clin Exp Rheumatol 2001;19:569 72
23 PET/CT IN PATIENTS WITH SARCOIDOSIS Localisation occult sites for biopsy Assessment of inflammatory activity Identification myocardial lesions Routine use not recommended Mostard RL et al. Respir Med 2011; 105: Mostard RL et al. BMC Pulm Med 2012; 12: 57 Youssef G et al. J Nucl Med 2012;53: Teirstein AS et al. Chest 2007;132: Soussan M et al. J Nucl Cardiol 2013;20: Sobic-Saranovic D et al. J Nucl Med 2012; 53:
24 DIFFERENTIAL DIAGNOSES SARCOIDOSIS ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Govender P et al. Clin Chest Med 36 (2015)
25 PROGNOSIS SARCOIDOSIS Acute ( 2 yrs): - White ethnicitiy - Acute onset: - Löfgren, erythema nodosum, - acute arthritis, acute uveitis - CXR Stage 0, I - HLA DRB1*03 Chronic ( 3 5 yrs) - Black ethnicity - Disease onset >40years - multisystem: CNS, Bone, ENT, Lupus pernio, nephrocalcinosis, post. uveitis - CXR Stage IV - low income, socio-economic barriers Valeyre D et al. Lancet 2014; 383: ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15:
26 PROGNOSIS SARCOIDOSIS Variable clinical course: 50% spontaneous resolution <2 years remission unlikely > 5years Refractory: progressing despite treatment Main complications chronic sarcoidosis: fibrosis pulmonary hypertension persistent disabling symptoms impaired quality of life Valeyre D et al. Lancet 2014; 383: ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15:
27 MONITORING SARCOIDOSIS Every 3-6 months: clinical examination and CXR Every 6 months: pulmonary function tests, ECG and blood tests (serum creatinine and calcium concentrations) Relapse in patients with spontaneous remission rare (8%) 37 74% exacerbation / relapse when corticosteroids reduced/discontinued Relapses peak 2 6 months after corticosteroid withdrawal Relapses rare after 3 years without symptoms Follow-up: Minimum 3 years after end of treatment before confirming recovery Valeyre D et al. Lancet 2014; 383: ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15:
28 SUMMARY SARCOIDOSIS Diagnosis of exclusion: History and physical examination footprints of sarcoidosis or alternative diagnoses? Classic presentations (asymptomatic bilateral hilar adenopathy, Heerfordt / Löfgren sy.) may not require tissue confirmation Uncertainty: Tissue biopsy easily accessible site with least morbidity Sampling pulmonary disease by bronchoscopy (BAL, TBB, EBUS- TBNA) high diagnostic yield with low complication rates Despite tissue confirmation: Diagnosis never secure follow-up over a number of years required for diagnostic certainty ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp Govender P et al. Clin Chest Med 36 (2015)
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