Sarcoidosis: Classification & Diagnosis...2016/06/16 · Sarcoidosis: Classification & Diagnosis...
Transcript of Sarcoidosis: Classification & Diagnosis...2016/06/16 · Sarcoidosis: Classification & Diagnosis...
SGP 2016
Sarcoidosis:
Classification & Diagnosis
Christophe von Garnier
Universitätsklinik für Pneumologie
Inselspital und Tiefenauspital
SGP 2016
EPIDEMIOLOGY SARCOIDOSIS
Hillerdal G et al. Am Rev Respir Dis 1984; 130: 29–32.
Morimoto T, et al. Eur Respir J 2008; 31: 372–79.
• Prevalence 4.7 – 64 / 100 000
• Incidence of 1 – 36 / 100 000 / 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 25–45 years
• Europe and Japan: second incidence peak women >50 years
• Rare <15 years or >70 years
• Female to male ratio 1.2 : 1.8
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RISK FACTORS SARCOIDOSIS
•Genetic factors (?2/3)
familial 3.6-9.6% cases
siblings and monozygotic twins (80x)
Rybicki BA et al. Am J Respir Crit Care Med 2001; 164: 2085–91.
Sverrild A et al. Thorax 2008; 63: 894–96.
•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: 1088–97
Newman LS et al. Am J Respir Crit Care Med 2004; 170: 1324–30
Crowley LE et al. Am J Ind Med 2011; 54: 175–84
Perlman SE et al. Lancet 2011; 378: 925–34
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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: 365–77
Ishige I et al. Lancet 1999; 354: 120–23
McCaskill JG et al. Am J Respir Cell Mol Biol 2006; 35: 347–56www.clevelandclinicmeded.com
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PATHOPHYSIOLOGYInappropiate 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. 2007 Nov 22;357(21):2153-65.
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GENES AND SARCOIDOSIS
Schupp JC, et al. Pneumologie. 2016 Apr;70(4):231-40.
MHC II genes
(HLA-DRB1)
Susceptibility
Phenotype
Prognosis
Sarcoidosis associated with
genetic risk profile constituted
by multitude of variant genes
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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: 1155–67
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15: 52–58
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INITIAL EVALUATION SARCOIDOSIS
• Thoracic CT (difficult diagnosis and/or complications)
Criado E et al. Radiographics 2010;30: 1567-1586
• Cardio-pulmonary exercise testing
- dyspnoea with normal lung function / DLCO
Marcellis RG et al. Lung 2013; 191: 43–52
Wallaert B et al. Respiration 2011; 826: 501–08
- monitoring of disease course ± immune-suppression
Lopes AJ et al. Braz J Med Biol Res 2012; 45: 256–63
Kollert F et al. Respir Med 2011; 105: 122–29
• Echocardiography, right heart catheter (pulmonary hypertension)
Nunes H et al. Presse Med 2012; 41: e303–16
Baughman RP et al. Chest 2010; 138: 1078–85.
• Interferon gamma release assay (immune-suppression)
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DIAGNOSTIC ALGORITHM
Judson MA. F1000Prime Rep 2014;6:89
Govender P et al. Clin Chest Med 36 (2015) 585–602
Clinical & Radiographic PresentationHistory, Physical, Imaging, Baseline Evaluation
Specific Clinical PresentationTissue biopsy may not be required
•Löfgren Syndrome
•Heerfordt Syndrome
•Asymptomatic hilar adenopathy (CXR)
•“Lambda and Panda” sign (Gallium 67)
Typical symptoms:
•persistent cough
•fever
•arthralgias
•visual changes
•skin lesions
•fatigue (70%)
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LÖFGREN SYNDROME
Bilateral hilar
lymphadenopathy
Arthritis Erythema
Nodosum
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HEERFORDT SYNDROME
Uveitis Parotitis Facial Palsy
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DIAGNOSTIC ALGORITHM
Judson MA. F1000Prime Rep 2014;6:89
Govender P et al. Clin Chest Med 36 (2015) 585–602
Clinical & Radiographic PresentationHistory, Physical, Imaging, Baseline Evaluation
Specific Clinical PresentationTissue biopsy may not be required
•Löfgren Syndrome
•Heerfordt Syndrome
•Asymptomatic hilar adenopathy (CXR)
•“Lambda and Panda” sign (Gallium 67)
“Non-Specific” Clinical PresentationTissue biopsy is required
•Biopsy suspicious lesion
•Biopsy pulmonary tissue and/or adenopathy
•Blind biopsy accessible site
Exclude other Granulomatous Disease
Document Systemic Involvement
Typical symptoms:
•persistent cough
•fever
•arthralgias
•visual changes
•skin lesions
•fatigue (70%)
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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) 585–602
ORGAN INVOLVEMENT SARCOIDOSIS
50% asymptomatic
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LEVELS OF CONFIDENCE IN DIAGNOSIS
Clinical and radiological
presentation
Non-caseating
granulomas
No alternative
diagnosis
Govender P et al. Clin Chest Med 36 (2015) 585–602
Judson MA. Semin Respir Crit Care Med 2007; 28: 83–101
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
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Keijsers RG et al. Clin Chest Med 36 (2015) 603–619
Scadding JG. BMJ 1961;2:1165-72.
PULMONARY SARCOIDOSIS
RADIOGRAPHIC STAGES
STAGE I STAGE II STAGE III STAGE IV
Lymphadenopathy Lymphadenopathy
+ Infiltrates
Infiltrates Fibrosis
Frequency 50% 25-30% 10-12% 5%
Resolution 60-90% 40-70% 10-20% 0%
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Keijsers RG et al. Clin Chest Med 36 (2015) 603–619
Criado E et al. Radiographics 2010; 30: 1567–86
HRCT FINDINGSClassic 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
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HRCT FINDINGSClassic 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) 603–619
Criado E et al. Radiographics 2010; 30: 1567–86
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HRCT FINDINGS
Uncommon findings reflecting irreversible fibrosis or chronic disease
• Honeycomb-like changes
• Reticular opacities in predominantly lower lobes
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
Keijsers RG et al. Clin Chest Med 36 (2015) 603–619
Criado E et al. Radiographics 2010; 30: 1567–86
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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) 585–602
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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
Gilman MJ et al. Chest 1983;83:159
Shorr AF et al. Chest 2001;120:109–14
Drent M et al. Semin Respir Crit Care Med 2007;28:486–95
von Bartheld MB et al. JAMA 2013;309:2457–64
Plit M et al. Intern Med J 2012;42:434–8
Sample Diagnostic yield
TBB 40-90%
EBB 40-60%
EBUS-TBNA 54-93%
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BRONCHOALVEOLAR LAVAGE IN SARCOIDOSIS
Lymphocytes 20-50% in 80% of patients
Degree of lymphocytosis correlateswith disease activity
CD4/CD8 Ratio Sensitivity Specificity
> 3.5 59% 92%
> 4.0 59% 94-96%
Kantrow SP et al. Eur Respir J 1997;10:2716–21.
Drent M et al. Semin Respir Crit Care Med 2007;28:486–95.
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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
Bonfioli AA et al. Semin Ophthalmol 2005;20:177–82
Nessan VJ et al. N Engl J Med 1979;301:922–4
Harvey J et al. Sarcoidosis 1989;6:47–50
Blind Biopsy Site Diagnostic yield
Conjunctiva 55%
Minor salivary glands 20-58%
Scalene lymph nodes 74-80%
Liver 50-60%
Gastrocnemius (Erythema nodosum) 90%
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
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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: 1917-1924 Mostard RL et al. BMC Pulm Med 2012; 12: 57
Youssef G et al. J Nucl Med 2012;53: 241–48 Teirstein AS et al. Chest 2007;132:1949–53
Soussan M et al. J Nucl Cardiol 2013;20: 120–27 Sobic-Saranovic D et al. J Nucl Med 2012; 53: 1543-1549
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DIFFERENTIAL DIAGNOSES SARCOIDOSIS
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
Govender P et al. Clin Chest Med 36 (2015) 585–602
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PROGNOSIS SARCOIDOSISAcute (≤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: 1155–67
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15: 52–58.
SGP 2016
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: 1155–67
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15: 52–58.
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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: 1155–67
ATS Statement on Sarcoidosis. Am J Respir Crit Care Med 1999 Vol 160. pp 736-755
Rizzato G et al. Sarcoidosis Vasc Diff use Lung Dis 1998; 15: 52–58.
SGP 2016
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 736-755
Govender P et al. Clin Chest Med 36 (2015) 585–602