sarcoidosis: classification & diagnosis...2016/06/16  · sarcoidosis: classification &...

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%)

SGP 2016

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%

SGP 2016

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

SGP 2016

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

SGP 2016

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

SGP 2016

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

SGP 2016

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.

SGP 2016

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

SGP 2016

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.

SGP 2016

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