Dr.

Vinay Mohan Bhagat

Dept. of Chest And Tbc,
G.M.C. Amritsar
November,1, 2007
 Definition
• Chronic Non-infectious Multisystemic non-
caseating 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 • Leprosy , tertiary
mycobacteriosis syphillis
• Fungal : • Drug reactions
aspergillosis, • Hypersensitivity
crytptococcosis, pneumonitis
histoplasmosis,
blastomycosis,
• Aspiration of
coccidiodomycosis foreign materials
• Mycoplasma
• Wegener’s
granulomatosis
• Pneumoconioses:
berrylium, titanium,
• NSG (necrotizing
aluminum 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
macrophage CD4

lymphokines
Interleukin-1 Interleukin-2
B lymphocyte

Polyclonal
Antibody
production activated T lymphocytes

Macrophage migration
Inhibitory factor
Monocyte chemocytic factor

Activated Granuloma formation

capillary macrophage
 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 • Central nervous
system.
• Skin
• 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 • Metastatic lymph
cases with bilateral node enlargement
hilar adenopathy) • Silicosis and coal
• Lymphoma (20%) workers'
• Primary tuberculosis pneumoconioses
• Fungal infections • Lymphangitic spread
• Histoplasmosis of carcinoma:
• Coccidioidomycosis
• Interstitial pulmonary
fibrosis
• Bronchogenic
carcinoma
 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 non-
tender
• 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 •Routine blood test •Skin test for
• Neoplastic •Chest x-ray •anergy
• Mycobacterium •Organ function •ACE
• Fungal •Biopsy •Gallium -67 scan
• Other interstitial •BAL
Lung ds •24 hour urine calcium
 Labs
• X-ray • Chem - calcium
• CBC - &
hypergammaglob
normochromic, ulinemia
normocytic • Bronchial Biopsy
anemia,
Lymphopenia,
• ACE in 75%
leukopenia • PFT restrictive
pattern
• Uric acid • 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 x-
ray 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 Abnormal Ancillary

Organ Organ
symptoms tests criteria
derangeme
dysfunction nt
Fever Hypercalcem Elevated #s
Arhtralgias ia of BAL
Lung Enlarged
Cough Progressively lymphocyte
Eye LN
Dyspnea elevated s
Heart Enlarged
Chest liver Elevated
CNS spleen
discomfort enzymes ACE
Liver Parotitis
Exercise Abnormal
Cutaneous
limitation gallium-67
lesions
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.