Sarcoidosis
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Dr. Vinay Mohan Bhagat Dept. of Chest And Tbc, G.M.C. Amritsar November,1, 2007
Definition •
• • •
Chronic Non-infectious Multisystemic noncaseating epitheliod granulomatous disorder of unknown cause, Which involves eyes, brain, heart, lungs, bones and kidneys, skin, liver and spleen. In advanced lung disease fibrotic changes are seen. Oral corticosteroids is first line of treatment
History • • • • • • •
1877- Jonathan Hutchison in skin lession Carl Boeck &Caesar Boeck.. epitheliod and giant cell, sarcoid 1889…Mortimer Malady 1889..Besnier .. Lupus Pernio 1909.. Heerfordt.. Uveoparotid fever 1915-kuznitsky & bittorf… systemic involvement 1919- Schaumann..systemic involvement 1917..Lymphogranuloma benigna
History • •
• • • • •
1940.. Universally “sarcoidosis” term 1941-Ansger Kveim &Louis Siltzbach… skin reaction test after innoculation…”Kveim Test” 1946-Lofgren ..lofgren So erythema,LN,polyarthr. 1951-52..Corticosteriod first time 1958.. Wurm proposed radio classification 1975.. First international meet on sarcoidosis 1987… “ WASOG “
Epidemiology •
• • • • •
Increased prevalence found in N. Europe (especially Scandinavia, Ireland, Great Britain), N. America, Japan and African American women Low incidence: China, India, Africa, Russia 0.2 in poland to 64 / lakh in sweden Course worse in African Americans than whites Worldwide: 80% of affected patients are white Unlike many others ds. In lung it favours non smokers
Genetic factors • • • • • •
Prevalence in certain race Familial clustering HLA -B1, -B8, and -DR3 ..good prognosis HLA-B22 in Italians HLA-Cw7 in Caucasians ..good prognosis HLA DR-17 good prognosis in Scandinavians; protracted course with DR 15 and 16
Genetic factors • •
-DRw52,-DR5j Japanese patients have poor prognosis Negative association: HLA B12 and -DR4
Pathology •
•
•
Non- caseating epitheliod granuloma composed of histiocytes, giant cells and lymphocytes. Multinucleated giant cell among histiocyte (epitheliod) & Lymphocyte at periphery . Inclusion bodies ( nonspecific end product) • Schaumann bodies • Crystalline incl bodies • Asteroid bodies
Non-caseating granulomas in Sarcoidosis
Pathologic DDx Lungs • •
• •
TB, atypical mycobacteriosis Fungal : aspergillosis, crytptococcosis, histoplasmosis, blastomycosis, coccidiodomycosis Mycoplasma Pneumoconioses: berrylium, titanium, aluminum
• • • • • •
Leprosy , tertiary syphillis Drug reactions Hypersensitivity pneumonitis Aspiration of foreign materials Wegener’s granulomatosis NSG (necrotizing sarcoid granulomatosis
Etiology • •
Unknown, likely immunological basis. An exaggerated cellular immune response • ? Aquired • ? Inherited • ? Both
Immunopathology •
•
Sarcoid granulomas consist of focal accumulations of epitheloid cells, macrophages, lymphocytes, mainly T cells! T lymphocytes…slightly B cells in the circulatory system.
Granulomatous reaction • T cells predominantly CD4 accumulate • •
• •
Releases IFN-gamma, IL-2 and other cytokines Macrophages are recruited and release its own inflammatory soup (TNF, IL12, IL15, growth factors) CD45RO + Th1 type lymphocyte is activated Granuloma formation
T-Lymphocyte CD4
macrophage lymphokines
Interleukin-1 Interleukin-2
B lymphocyte Polyclonal Antibody production
activated
T
lymphocytes Macrophage migration Inhibitory factor
Monocyte chemocytic factor
capillary
Activated macrophage
Granuloma formation
Presentation • • • • • • •
Present with pulmonary symptoms or found on x-ray! Fatigue Malaise Fever Night sweats Weight loss Cough
Presentation • • • •
Shortness of breath Skin (new lesions) Pain or irritation of eyes Bell's palsy
Presentation • • • • •
Bilateral symmetrical hilar lymphadenopathy Pulmonary infiltrates Skin lesions Eye lesions(uveitis) Other organs may be involved,
Organ involved •
Respiratory
•
Liver
•
Larynx
•
Spleen
•
Sino-nasal
•
Lymph nodes
•
Ocular
•
Heart
•
Salivary glands
•
•
Skin
Central nervous system.
•
Bone
Plain films Widening of right paratracheal stripe
Obliteration of AP window Multiple small pulmonary nodules Bilateral hilar prominence
“1,2,3 sign”
Differential Diagnosis •
• • •
•
Sarcoidosis (74% of cases with bilateral hilar adenopathy) Lymphoma (20%) Primary tuberculosis Fungal infections • Histoplasmosis • Coccidioidomycosis Bronchogenic carcinoma
• •
• •
Metastatic lymph node enlargement Silicosis and coal workers' pneumoconioses Lymphangitic spread of carcinoma: Interstitial pulmonary fibrosis
Role of Imaging in the Diagnosis of Sarcoidosis •
• • • •
The first indication that a patient has sarcoidosis is often an abnormal chest radiograph 90% of patients have characteristic hilar lymphadenopathy “Egg shell” calcification of HLN 50% have parenchymal lung disease Chest radiography can be used to stage sarcoidosis
CXR staging • • • • • •
Routine chest roentgenograms are staged using Scadding's classification: Stage 0 = normal Stage 1 = hilar adenopathy alone Stage 2 = hilar adenopathy plus parenchymal infiltrates Stage 3 = parenchymal infiltrates alone Stage 4 = pulmonary fibrosis
Staging of Sarcoidosis
•
Stage 0 - Normal findings on chest radiograph
Stage I (bilateral hilar adenopathy)
Staging of Sarcoidosis
•
Stage I - Bilateral hilar lymphadenopathy, which may be accompanied by paratracheal adenopathy
Bilateral hilar lymph adenopathy • •
Characteristic feature of sarcoid Often symptom less but may have associated dull ache in chest, malaise & fever
B/L Hilar Nodes • • • • • • • • •
D/D
Sarcoidosis Tuberculosis (ussually unilateral) Lymphoma (pain, systemic upsets ) Leukaemia (blood count diagnostic) Coccidiomycosis (USA) Histioplasmosis (USA) Berrylium disease (occupational) Hypogammaglobulinaemia (reccu. infec) Enlarged pulm. Arteries (CT Scan)
Stage II Reticular nodules and BHL
•
Stage II - Bilateral hilar adenopathy with pulmonary infiltrates
Pulmonary Infiltration • • •
More progressive & leads to dyspnea… cor pulmonale…death Honeycomb appearance on chest x-ray! PFT’s restrictive pattern
HRCT – subpleural nodules
Staging of Sarcoidosis
•
Stage III - Parenchymal infiltrates without hilar adenopathy
Staging of Sarcoidosis
•
Stage IV - Advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts, and emphysema
Skin • • • • • • • • •
21% approx. Women > Men Erythema nodosum (anterior legs) Plaque (face, buttocks) Papule Nodule Lupus pernio Infilteration of old scar Bilateral symmetrical hilar lymphadenopathy + erythema nodosum = sarcoidosis!!!
Pathologic DDX Skin • • •
TB, atypical mycobacteriosis Fungal infections Reaction to foreign bodies: • • • •
•
Beryllium , Zirconium , Tattooing , Paraffin , etc.
Rheumatoid nodules
Bone & Joint • • • • •
3% Poly- Arthralgias Bone cysts (especially in the digits) Subcutaneous Swelling Unaffected by steroids
Acute Sarcoid Arthritis • • • • •
Migratory, Additive, Symmetric Polyarthritis (usu. Ankles & knees) Monoarthritis very rare Minimal effusion Minimal Inflammation Synovial Bx- Mild inflammation
LN involvement • • • •
Most common : cervical, epitrochlear, axillary, and inguinal nodes Seen in 1/3 of patients Glands are discrete, movable and nontender Do not ulcerate and form draining sinuses
Cardiac • • • •
5-27% Ventricular dysrhythmias ..45% Conduction defects Cardiomyopathy with CHF
Cardiac • • • • •
Hypercalcemia Extrinsic pulm.fibrosis… cor pulmonale Rx.. corticosteroids (cyclophosphamide in unresponsive), Implantable pacemakers Lung heart transplatation
Liver • • • •
~ 60-90% 20-30% hepatomegaly Alk. Phosphate Jaundice rare
Diagnosis • • •
Diagnosis by exclussion Non-caseating granulomas in biopsy Increase in lymphoctes and a high CD4/CD8 cell ratio • Laboratory tests may indicate leukopenia, hypercalcemia (5%), hypercalciuria (20%), elevated ACE levels
History , physical examination Sarcoidosis ? Rule out other Major diag. test
Ancillary diag test
• HIV • Neoplastic • Mycobacterium • Fungal • Other interstitial Lung ds
•Skin test for •anergy •ACE •Gallium -67 scan •BAL •24 hour urine calcium
•Routine blood test •Chest x-ray •Organ function •Biopsy
Labs • •
•
X-ray CBC normochromic, normocytic anemia, Lymphopenia, leukopenia Uric acid
•
• • • •
Chem calcium & hypergammaglob ulinemia Bronchial Biopsy ACE in 75% PFT restrictive pattern ESR
Special Tests • Abnormal liver function, especially increased alkaline phosphatase is frequently encountered • Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent • Kveim-Siltzbach skin test can be performed. This test is fairly sensitive (approximately 80%) and highly specific (> 95%)
Diagnostics • •
• • •
Kveim-Stiltzbach test Intradermal injection 0.1-0.2ml of homogonized tissue of organs involved with sarcoidosis causes delayed cutaneous reaction in 4-6 weeks Low false positivity 1-2% No more available, now a history Within granulomas are multi-nucleated giant cells with stellate inclusions , asteroid bodies and laminated calcifications called Schaumann’s bodies
Serum ACE •
•
Serum ACE activity elevated in 40- 90% due to macrophage activity, but nonspecific since histoplasmosis, acute miliary TB, hepatitis, and lymphomas also have this finding (5% false +) Lacks diagnostic specificity and poor prognostic value in identifying patients with progressive disease
Serum ACE •
• •
Tissue ACE activity is highest in sarcoid lymph nodes rather than in pulmonary tissues Prednisone will lower serum-angiotensin converting enzyme Hyperthyroidism and diabetes will increase serum angiotensin converting enzyme level
Gallium scanning • •
11*107 bq intravenous ..ant post thorax scan 3 days later Whole-body gallium scanning is sensitive, but not specific • Symmetric uptake in mediastinal and hilar nodes (lambda sign) • In lacrimal, parotid, and salviary glands (panda sign) • Pathognomonic for sarcoidosis
BAL • • • •
First 20 cc should be discarded Increased lymphocytes CD4 : CD8 .. 10:1 CD4/CD8 ratio is elevated in sarcoidosis on bronchoalverolar lavage, but reduced in hypersensitivity pneuomonitis
Biopsy •
Tissue biopsy is essential • Biopsy almost always positive if skin, lymph nodes, conjunctiva involved
•
•
Transbronchial biopsy is best initial procedure for securing histologic evidence since granulomas can be seen regardless of chest xray findings Diagnosis of pulmonary sarcoidosis relies on : a) tight, well-formed granulomas and a rim of lymphcoytes and fibroblasts b) perilymphatic distribution of granulomas c) exclusion of an alternative cause
High-resolution CT imaging
•
•
Multiple areas of consolidation and small nodular opacities, predominantly limited to the bronchovascular interstitium Appearance consistent with sarcoidosis
High-resolution CT imaging •
Indications for CT
• atypical clinical and/or chest radiograph findings • detection of complications of the lung disease (e.g. bronchiectasis, pulmonary fibrosis, etc.) • normal chest radiograph but a clinical suspicion of the disease.
•
Classic findings on lung CT scans • widespread small nodules with a bronchovascular and subpleural distribution • thickened interlobular septae • architectural distortion • conglomerate masses
To treat or not to treat... • •
• • •
Spontaneous resolution Hilar lymphadenopathy alone with no evidence of lung parenchymal involvement…NO treatment! Variable course Side effects of medications Bottomline: there is a need for serial reevaluation
When to treat? Criteria for institution of glucocorticoid therapy
Disabling symptoms Fever Arhtralgias Cough Dyspnea Chest discomfort Exercise limitation
Organ dysfunction Lung Eye Heart CNS Liver
Organ derangeme nt Enlarged LN Enlarged spleen Parotitis Cutaneous lesions
Abnormal tests
Ancillary criteria
Hypercalcem ia Progressively elevated liver enzymes
Elevated #s of BAL lymphocyte s Elevated ACE Abnormal gallium-67 scan
Use of steroids Acutely suppress the manifestions of the disease; QUESTIONABLE IMPACT ON LONG-TERM NATURAL HISTORY • Prednisone 0.5 to 1 mg/kg/day for 4-6 weeks and then taper over 2-3 months. Treat for a minimum of 1 year using the lowest possible suppressive dose. • Repeat if the disease reactivates. • Consider alternative modalities if steroids fail • Prevent osteoporosis
Response to steroids • • •
•
Generally used for skin lesions, iritis, uveitis, nasal polyps, or airway disease Inhaled corticosteroids (?) Systemic therapy: remission of granuloma, relief of respiratory symptoms, and improvement in CXR and lung function studies Relapse after steroid withdrawal: > 1/3 within 2 years
Alternative Drugs • • • •
Methotrexate 5-15 mg/wk single dose Hydroxychloroquine (Plaquenil) 100-200 mg per day Azathioprine 50-100 mg per day Chlorambucil 0.1-0.2 mg/kg. (Lymphoproliferative ds. Ln)
•
Thalidomide 50-100 mg/day
•
NSAID’s
Treatment with Cytotoxic Drugs
•
• •
Methotrexate 5-15 mg/week; can be used solely for cutaneous and musculoskeletal symptoms. Systemic sarcoidosis refractory to steroids: Cutaneous sarcoidosis: reinstitution after relapse
Treatment with Cytotoxic Drugs •
Methotrexate toxicity: Hypersensitivity pneumonitis and hepatotoxicity
•
Appear to be limited with the use of folic or folinic acid
•
Avoid in patients with significant renal failure
Treatment with Cytotoxic Drugs
•
Azathioprine +/- prednisone Chlorambucil +/- prednisone Cyclophosphamide +/- prednisone
•
Efficacy appear similar to methotrexate
• •
Prognosis • • • •
If bilateral hilar lymphadenopathy…80% remission rate 80% of patients will have spontaneous resolution within two years 10% will have significant fibrosis but no further worsening of disease after 2 yrs 10% (higher in some populations, including African Americans) will have chronic dz.
Prognosis • •
About 10% will have serious disability such as ocular or respiratory Mortality < 3%-10% • Pulm fibrosis leading to cpr failure is most common cause of death • Also pulmonary hemorrhage from asperigilloma
Treatment of Complciations •
• •
Bronchiectasis and its complications : - antibiotics, antifungal (aspergilloma) - surgical resection and embolization for hemoptysis Osteoporosis prevention: vitamin D, calcium, nasal calcitonin, bisphosphonate Pulmonary rehab, O2, lung transplantation
PFT’s •
•
•
Pulm fxn tests show restriction, decreased compliance, and impaired diffusing capacity Co2 retention is uncommon, but airway obstruction is common in endobronchial disease and late stages with pulm fibrosis or bullae Serial pfts are important for guiding treatment
• •
•
•
•
Pulmonary Function No impairment occurs in stages 0 and 1. In stages 2 and 3 restrictive changes are seen. Treatment and Prognosis 85% of these patients improve spontaneously, but 15% may develop progressive fibrosis and respiratory failure. Treatment is oftenr observation, but in symptomatic patients or deteriorating PFT’s – treatment recommended. Prednisone 0.5- 1 mg/kg initially, then tapered and continued for 6 months to 1 year.
Definition •
• • •
Chronic Non-infectious Multisystemic noncaseating epitheliod granulomatous disorder of unknown cause, Which involves eyes, brain, heart, lungs, bones and kidneys, skin, liver and spleen. In advanced lung disease fibrotic changes are seen. Oral corticosteroids is first line of treatment
History • • • • • • •
1877- Jonathan Hutchison in skin lession Carl Boeck &Caesar Boeck.. epitheliod and giant cell, sarcoid 1889…Mortimer Malady 1889..Besnier .. Lupus Pernio 1909.. Heerfordt.. Uveoparotid fever 1915-kuznitsky & bittorf… systemic involvement 1919- Schaumann..systemic involvement 1917..Lymphogranuloma benigna
History • •
• • • • •
1940.. Universally “sarcoidosis” term 1941-Ansger Kveim &Louis Siltzbach… skin reaction test after innoculation…”Kveim Test” 1946-Lofgren ..lofgren So erythema,LN,polyarthr. 1951-52..Corticosteriod first time 1958.. Wurm proposed radio classification 1975.. First international meet on sarcoidosis 1987… “ WASOG “
Epidemiology •
• • • • •
Increased prevalence found in N. Europe (especially Scandinavia, Ireland, Great Britain), N. America, Japan and African American women Low incidence: China, India, Africa, Russia 0.2 in poland to 64 / lakh in sweden Course worse in African Americans than whites Worldwide: 80% of affected patients are white Unlike many others ds. In lung it favours non smokers
Genetic factors • • • • • •
Prevalence in certain race Familial clustering HLA -B1, -B8, and -DR3 ..good prognosis HLA-B22 in Italians HLA-Cw7 in Caucasians ..good prognosis HLA DR-17 good prognosis in Scandinavians; protracted course with DR 15 and 16
Genetic factors • •
-DRw52,-DR5j Japanese patients have poor prognosis Negative association: HLA B12 and -DR4
Pathology •
•
•
Non- caseating epitheliod granuloma composed of histiocytes, giant cells and lymphocytes. Multinucleated giant cell among histiocyte (epitheliod) & Lymphocyte at periphery . Inclusion bodies ( nonspecific end product) • Schaumann bodies • Crystalline incl bodies • Asteroid bodies
Non-caseating granulomas in Sarcoidosis
Pathologic DDx Lungs • •
• •
TB, atypical mycobacteriosis Fungal : aspergillosis, crytptococcosis, histoplasmosis, blastomycosis, coccidiodomycosis Mycoplasma Pneumoconioses: berrylium, titanium, aluminum
• • • • • •
Leprosy , tertiary syphillis Drug reactions Hypersensitivity pneumonitis Aspiration of foreign materials Wegener’s granulomatosis NSG (necrotizing sarcoid granulomatosis
Etiology • •
Unknown, likely immunological basis. An exaggerated cellular immune response • ? Aquired • ? Inherited • ? Both
Immunopathology •
•
Sarcoid granulomas consist of focal accumulations of epitheloid cells, macrophages, lymphocytes, mainly T cells! T lymphocytes…slightly B cells in the circulatory system.
Granulomatous reaction • T cells predominantly CD4 accumulate • •
• •
Releases IFN-gamma, IL-2 and other cytokines Macrophages are recruited and release its own inflammatory soup (TNF, IL12, IL15, growth factors) CD45RO + Th1 type lymphocyte is activated Granuloma formation
T-Lymphocyte CD4
macrophage lymphokines
Interleukin-1 Interleukin-2
B lymphocyte Polyclonal Antibody production
activated
T
lymphocytes Macrophage migration Inhibitory factor
Monocyte chemocytic factor
capillary
Activated macrophage
Granuloma formation
Presentation • • • • • • •
Present with pulmonary symptoms or found on x-ray! Fatigue Malaise Fever Night sweats Weight loss Cough
Presentation • • • •
Shortness of breath Skin (new lesions) Pain or irritation of eyes Bell's palsy
Presentation • • • • •
Bilateral symmetrical hilar lymphadenopathy Pulmonary infiltrates Skin lesions Eye lesions(uveitis) Other organs may be involved,
Organ involved •
Respiratory
•
Liver
•
Larynx
•
Spleen
•
Sino-nasal
•
Lymph nodes
•
Ocular
•
Heart
•
Salivary glands
•
•
Skin
Central nervous system.
•
Bone
Plain films Widening of right paratracheal stripe
Obliteration of AP window Multiple small pulmonary nodules Bilateral hilar prominence
“1,2,3 sign”
Differential Diagnosis •
• • •
•
Sarcoidosis (74% of cases with bilateral hilar adenopathy) Lymphoma (20%) Primary tuberculosis Fungal infections • Histoplasmosis • Coccidioidomycosis Bronchogenic carcinoma
• •
• •
Metastatic lymph node enlargement Silicosis and coal workers' pneumoconioses Lymphangitic spread of carcinoma: Interstitial pulmonary fibrosis
Role of Imaging in the Diagnosis of Sarcoidosis •
• • • •
The first indication that a patient has sarcoidosis is often an abnormal chest radiograph 90% of patients have characteristic hilar lymphadenopathy “Egg shell” calcification of HLN 50% have parenchymal lung disease Chest radiography can be used to stage sarcoidosis
CXR staging • • • • • •
Routine chest roentgenograms are staged using Scadding's classification: Stage 0 = normal Stage 1 = hilar adenopathy alone Stage 2 = hilar adenopathy plus parenchymal infiltrates Stage 3 = parenchymal infiltrates alone Stage 4 = pulmonary fibrosis
Staging of Sarcoidosis
•
Stage 0 - Normal findings on chest radiograph
Stage I (bilateral hilar adenopathy)
Staging of Sarcoidosis
•
Stage I - Bilateral hilar lymphadenopathy, which may be accompanied by paratracheal adenopathy
Bilateral hilar lymph adenopathy • •
Characteristic feature of sarcoid Often symptom less but may have associated dull ache in chest, malaise & fever
B/L Hilar Nodes • • • • • • • • •
D/D
Sarcoidosis Tuberculosis (ussually unilateral) Lymphoma (pain, systemic upsets ) Leukaemia (blood count diagnostic) Coccidiomycosis (USA) Histioplasmosis (USA) Berrylium disease (occupational) Hypogammaglobulinaemia (reccu. infec) Enlarged pulm. Arteries (CT Scan)
Stage II Reticular nodules and BHL
•
Stage II - Bilateral hilar adenopathy with pulmonary infiltrates
Pulmonary Infiltration • • •
More progressive & leads to dyspnea… cor pulmonale…death Honeycomb appearance on chest x-ray! PFT’s restrictive pattern
HRCT – subpleural nodules
Staging of Sarcoidosis
•
Stage III - Parenchymal infiltrates without hilar adenopathy
Staging of Sarcoidosis
•
Stage IV - Advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts, and emphysema
Skin • • • • • • • • •
21% approx. Women > Men Erythema nodosum (anterior legs) Plaque (face, buttocks) Papule Nodule Lupus pernio Infilteration of old scar Bilateral symmetrical hilar lymphadenopathy + erythema nodosum = sarcoidosis!!!
Pathologic DDX Skin • • •
TB, atypical mycobacteriosis Fungal infections Reaction to foreign bodies: • • • •
•
Beryllium , Zirconium , Tattooing , Paraffin , etc.
Rheumatoid nodules
Bone & Joint • • • • •
3% Poly- Arthralgias Bone cysts (especially in the digits) Subcutaneous Swelling Unaffected by steroids
Acute Sarcoid Arthritis • • • • •
Migratory, Additive, Symmetric Polyarthritis (usu. Ankles & knees) Monoarthritis very rare Minimal effusion Minimal Inflammation Synovial Bx- Mild inflammation
LN involvement • • • •
Most common : cervical, epitrochlear, axillary, and inguinal nodes Seen in 1/3 of patients Glands are discrete, movable and nontender Do not ulcerate and form draining sinuses
Cardiac • • • •
5-27% Ventricular dysrhythmias ..45% Conduction defects Cardiomyopathy with CHF
Cardiac • • • • •
Hypercalcemia Extrinsic pulm.fibrosis… cor pulmonale Rx.. corticosteroids (cyclophosphamide in unresponsive), Implantable pacemakers Lung heart transplatation
Liver • • • •
~ 60-90% 20-30% hepatomegaly Alk. Phosphate Jaundice rare
Diagnosis • • •
Diagnosis by exclussion Non-caseating granulomas in biopsy Increase in lymphoctes and a high CD4/CD8 cell ratio • Laboratory tests may indicate leukopenia, hypercalcemia (5%), hypercalciuria (20%), elevated ACE levels
History , physical examination Sarcoidosis ? Rule out other Major diag. test
Ancillary diag test
• HIV • Neoplastic • Mycobacterium • Fungal • Other interstitial Lung ds
•Skin test for •anergy •ACE •Gallium -67 scan •BAL •24 hour urine calcium
•Routine blood test •Chest x-ray •Organ function •Biopsy
Labs • •
•
X-ray CBC normochromic, normocytic anemia, Lymphopenia, leukopenia Uric acid
•
• • • •
Chem calcium & hypergammaglob ulinemia Bronchial Biopsy ACE in 75% PFT restrictive pattern ESR
Special Tests • Abnormal liver function, especially increased alkaline phosphatase is frequently encountered • Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent • Kveim-Siltzbach skin test can be performed. This test is fairly sensitive (approximately 80%) and highly specific (> 95%)
Diagnostics • •
• • •
Kveim-Stiltzbach test Intradermal injection 0.1-0.2ml of homogonized tissue of organs involved with sarcoidosis causes delayed cutaneous reaction in 4-6 weeks Low false positivity 1-2% No more available, now a history Within granulomas are multi-nucleated giant cells with stellate inclusions , asteroid bodies and laminated calcifications called Schaumann’s bodies
Serum ACE •
•
Serum ACE activity elevated in 40- 90% due to macrophage activity, but nonspecific since histoplasmosis, acute miliary TB, hepatitis, and lymphomas also have this finding (5% false +) Lacks diagnostic specificity and poor prognostic value in identifying patients with progressive disease
Serum ACE •
• •
Tissue ACE activity is highest in sarcoid lymph nodes rather than in pulmonary tissues Prednisone will lower serum-angiotensin converting enzyme Hyperthyroidism and diabetes will increase serum angiotensin converting enzyme level
Gallium scanning • •
11*107 bq intravenous ..ant post thorax scan 3 days later Whole-body gallium scanning is sensitive, but not specific • Symmetric uptake in mediastinal and hilar nodes (lambda sign) • In lacrimal, parotid, and salviary glands (panda sign) • Pathognomonic for sarcoidosis
BAL • • • •
First 20 cc should be discarded Increased lymphocytes CD4 : CD8 .. 10:1 CD4/CD8 ratio is elevated in sarcoidosis on bronchoalverolar lavage, but reduced in hypersensitivity pneuomonitis
Biopsy •
Tissue biopsy is essential • Biopsy almost always positive if skin, lymph nodes, conjunctiva involved
•
•
Transbronchial biopsy is best initial procedure for securing histologic evidence since granulomas can be seen regardless of chest xray findings Diagnosis of pulmonary sarcoidosis relies on : a) tight, well-formed granulomas and a rim of lymphcoytes and fibroblasts b) perilymphatic distribution of granulomas c) exclusion of an alternative cause
High-resolution CT imaging
•
•
Multiple areas of consolidation and small nodular opacities, predominantly limited to the bronchovascular interstitium Appearance consistent with sarcoidosis
High-resolution CT imaging •
Indications for CT
• atypical clinical and/or chest radiograph findings • detection of complications of the lung disease (e.g. bronchiectasis, pulmonary fibrosis, etc.) • normal chest radiograph but a clinical suspicion of the disease.
•
Classic findings on lung CT scans • widespread small nodules with a bronchovascular and subpleural distribution • thickened interlobular septae • architectural distortion • conglomerate masses
To treat or not to treat... • •
• • •
Spontaneous resolution Hilar lymphadenopathy alone with no evidence of lung parenchymal involvement…NO treatment! Variable course Side effects of medications Bottomline: there is a need for serial reevaluation
When to treat? Criteria for institution of glucocorticoid therapy
Disabling symptoms Fever Arhtralgias Cough Dyspnea Chest discomfort Exercise limitation
Organ dysfunction Lung Eye Heart CNS Liver
Organ derangeme nt Enlarged LN Enlarged spleen Parotitis Cutaneous lesions
Abnormal tests
Ancillary criteria
Hypercalcem ia Progressively elevated liver enzymes
Elevated #s of BAL lymphocyte s Elevated ACE Abnormal gallium-67 scan
Use of steroids Acutely suppress the manifestions of the disease; QUESTIONABLE IMPACT ON LONG-TERM NATURAL HISTORY • Prednisone 0.5 to 1 mg/kg/day for 4-6 weeks and then taper over 2-3 months. Treat for a minimum of 1 year using the lowest possible suppressive dose. • Repeat if the disease reactivates. • Consider alternative modalities if steroids fail • Prevent osteoporosis
Response to steroids • • •
•
Generally used for skin lesions, iritis, uveitis, nasal polyps, or airway disease Inhaled corticosteroids (?) Systemic therapy: remission of granuloma, relief of respiratory symptoms, and improvement in CXR and lung function studies Relapse after steroid withdrawal: > 1/3 within 2 years
Alternative Drugs • • • •
Methotrexate 5-15 mg/wk single dose Hydroxychloroquine (Plaquenil) 100-200 mg per day Azathioprine 50-100 mg per day Chlorambucil 0.1-0.2 mg/kg. (Lymphoproliferative ds. Ln)
•
Thalidomide 50-100 mg/day
•
NSAID’s
Treatment with Cytotoxic Drugs
•
• •
Methotrexate 5-15 mg/week; can be used solely for cutaneous and musculoskeletal symptoms. Systemic sarcoidosis refractory to steroids: Cutaneous sarcoidosis: reinstitution after relapse
Treatment with Cytotoxic Drugs •
Methotrexate toxicity: Hypersensitivity pneumonitis and hepatotoxicity
•
Appear to be limited with the use of folic or folinic acid
•
Avoid in patients with significant renal failure
Treatment with Cytotoxic Drugs
•
Azathioprine +/- prednisone Chlorambucil +/- prednisone Cyclophosphamide +/- prednisone
•
Efficacy appear similar to methotrexate
• •
Prognosis • • • •
If bilateral hilar lymphadenopathy…80% remission rate 80% of patients will have spontaneous resolution within two years 10% will have significant fibrosis but no further worsening of disease after 2 yrs 10% (higher in some populations, including African Americans) will have chronic dz.
Prognosis • •
About 10% will have serious disability such as ocular or respiratory Mortality < 3%-10% • Pulm fibrosis leading to cpr failure is most common cause of death • Also pulmonary hemorrhage from asperigilloma
Treatment of Complciations •
• •
Bronchiectasis and its complications : - antibiotics, antifungal (aspergilloma) - surgical resection and embolization for hemoptysis Osteoporosis prevention: vitamin D, calcium, nasal calcitonin, bisphosphonate Pulmonary rehab, O2, lung transplantation
PFT’s •
•
•
Pulm fxn tests show restriction, decreased compliance, and impaired diffusing capacity Co2 retention is uncommon, but airway obstruction is common in endobronchial disease and late stages with pulm fibrosis or bullae Serial pfts are important for guiding treatment
• •
•
•
•
Pulmonary Function No impairment occurs in stages 0 and 1. In stages 2 and 3 restrictive changes are seen. Treatment and Prognosis 85% of these patients improve spontaneously, but 15% may develop progressive fibrosis and respiratory failure. Treatment is oftenr observation, but in symptomatic patients or deteriorating PFT’s – treatment recommended. Prednisone 0.5- 1 mg/kg initially, then tapered and continued for 6 months to 1 year.
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