Download - Sarcoidosis & orphan lung disease

Sarcoidosis & Sarcoidosis &

Orphan Lung Orphan Lung

DiseasesDiseases

Iman Galal , MDIman Galal , MDPulmonary Medicine DepartmentPulmonary Medicine Department

Ain Shams UniversityAin Shams University

At The End Of This Lecture You Should Know

Who discovered Sarcoidosis?

Epidemiology of Sarcoidosis

Epidemiology of Sarcoidosis

Pathology of Sarcoidosis

Pathophysiology of Sarcoidosis

Organ involvement in Sarcoidosis

Staging of Sarcoidosis

How to diagnose Sarcoidosis?

How to treat Sarcoidosis?

Recommended clinical evaluation of Sarcoidosis

How to assess the activity of Sarcoidosis?

Historical Perspective

In 1887, Sir Jonathan Hutchinson was the first to describe a case of cutaneous sarcoid disease. He named the condition "Mortimer's Malady" after the patient.

In 1899, Caesar Boeck called this condition 'sarcoid' as he thought it resembles sarcoma. It was called "Boeck's Sarcoid" in his honour.

Sir Jonathan Sir Jonathan HutchinsonHutchinson Caesar BoeckCaesar Boeck

Epidemiology

Non-infectious multisystem granulomatous disorder of unknown origin.

Female > Male.

Black > White.

3rd & 4th decade with 2nd peak at 6th decade.

Prevalence rate: 10-40 cases per 100,000.

Mortality rate: 1-5 %.

Etiology

Disease of unknown cause.

Possible infectious & transmissible cause in

genetically susceptible individuals.

Possible environmental exposure cause.

Possible genetic-environmental interactions.

Possible autoimmune cause.


T-helper cells to T-suppressor cells ratio is increased in BAL but decreased in peripheral blood.

Exaggerated T-cell activity indicates an altered immune response.

Hyper globulinemia (Ig A & Ig G).

Mass effect of granulomas damages the tissues.


Non-caseating epithelioid cell granuloma is the characteristic lesion of sarcoidosis.

It occurs along perivascular, peribronchial & septal region areas rich in lymphatic vessels.

Granuloma consists of a central collection of modified mononuclear phagocytes called epithelioid cells.

Epithelioid cells are mature macrophages that gain secretory & bactericidal capabilities but lose some phagocytic capability.


Epithelioid cells are large, polygonal and have an elliptical nucleus which contains fine chromatin & 1-2 nucleoli.

Conglomeration of epithelioid cells with multiple peripherally arranged nuclei forms giant cells in the central part of the granuloma.

The central epithelioid & giant cells are surrounded by a rim of small, oval, basophilic T-lymphocytes.

Inclusion Bodies in Sarcoidosis

Schaumann’s Bodies (Conchoidal Bodies) &

Birefringent Crystals:

Large, concentrically lamellated, calcified structures that are present within the cytoplasm of giant cells in 88% of cases of sarcoidosis.

The majority of Schaumann’s bodies have birefringent crystals composed of calcium oxalate.

Birefringent crystals may serve as a nidus for their formation.


Asteroid Bodies:

Intracytoplasmic stellate inclusions within giant cells exhibiting 30 or more rays radiating from a central core.

They probably represent functionally obsolescent cell organelles.

Reported in 2 – 9 % of sarcoidosis.


Hamazaki-Wesenberg Bodies:

Also known as yellow-brown bodies, yellow bodies, spindle bodies & chromogenic bodies & giant extracellular & intracellular lysosomes.

Seen in lymph nodes.

They are 0.5 - 0.8 mm oval or spindle shaped, and often exhibit a yellow-brown color.

Because they may exhibit an appearance similar to yeast like budding they may be mistaken for fungal organisms.

Organ Involvement in Sarcoidosis

Organ System % of affection

Pulmonary > 90 %

Psychosocial 30-60 %

Ocular 20-30 %

Skin 20-30 %

Hematologic 20-30 %

Endocrine 10-30 %

Hepatic/Abdominal 10-20 %

Joints & Musculoskeletal

10-20 %

Exocrine gland 10-20 %

URT & Oral cavity 5-10 %

Cardiac 5-10 %

Neurological 5-10 %

Renal <5 %

Genitourinary <5 %

Classification of Sarcoidosis

Asymptomatic (2/3 of patients).

Acute sarcoidosis ± erythema nodosum.

Intermediate sarcoidosis with symptoms or

signs of pulmonary disease for < 2 years.

Chronic pulmonary sarcoidosis of > 2 years.

Dominant extrapulmonary sarcoidosis.

Pulmonary Sarcoidosis

Scadding's Classification

Stage 0=normal (5-15%)

Stage 1=Hilar LDN alone (45-65%)

Stage 2=Hilar LDN + parenchymal

infiltrates (30-40%)

Stage 3=Parenchymal infiltrates

alone (10-15%)

Stage 4=Pulmonary fibrosis (5%)

Endobronchial Sarcoidosis

Cutaneous Sarcoidosis

Erythema Erythema NodosumNodosum

Lofgren's Syndrome

Bilateral hilar lymphadenopathy.

Fever.

Arthritis.

± Erythema nodosum.


Lupus PernioLupus Pernio

http://dermatology.cdlib.org/133/case_reports/pernio/3.jpg


RAISED PLAQUESRAISED PLAQUES NODULAR LESIONSNODULAR LESIONS

Ocular Sarcoidosis

Unilateral or bilateral anterior & posterior uveitis

(commonest).

Conjunctival Granuloma.

Iris Granuloma.

Optic neuritis.

Chorioretinitis.

Ocular Sarcoidosis

Iris GranulomaIris Granuloma

Conjunctival GranulomaConjunctival Granuloma

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Anterior Anterior UveitisUveitis

URT & Oral Cavity Sarcoidosis

Sinusitis.

Nasal congestion.

Intermittent epistaxis.

Destruction of nasal septum & Saddle Nose.

Upper airway obstruction, stridor & acute

respiratory failure.

Hoarseness.

URT & Oral Cavity Sarcoidosis

Saddle NoseSaddle Nose

Exocrine Glands

Panda SignPanda Sign

Bilateral symmetrical gallium uptake by the lacrimal, parotid,

and submandibular glands with Sicca syndrome

Exocrine Glands

Heerfordt SyndromeHeerfordt Syndrome

Bilateral hilar lymphadenopathy.

Fever.

Facial palsy.

Parotid enlargement.

Uveitis.

Joint & Musculoskeletal Sarcoidosis

Phalanges in the hands & feet are most frequently

affected.

Multiple.

Punched out lytic lesions, lacelike honeycomb

appearance, or extensive bone erosion with

pathologic fractures.

The articular spaces are usually intact

Arthralgia & polyarthritis.

Subcutaneous soft-tissue mass or tenosynovitis.

Myopathy.

Skeletal Sarcoidosis

PUNCHED OUT LYTIC LESIONS PUNCHED OUT LYTIC LESIONS Focal osteolytic lesions in the fingers are Focal osteolytic lesions in the fingers are

most common abnormality.most common abnormality.

LACY TRABECULAR PATTERNLACY TRABECULAR PATTERN Osteolysis has left a lacy trabecular Osteolysis has left a lacy trabecular

pattern in this phalanx (arrow)pattern in this phalanx (arrow)

Muscle Sarcoidosis

Endocrine Sarcoidosis

Involvement of the

hypothalamus Diabetes

Insipidus

Hyperintensity of the

posterior pituitary lobe

caused by intracellular

nerosecretory granules.

Vitamin D in Sarcoidosis

Extrarenal source of calcitriol in Sarcoidosis is

Alveolar Macrophage & Epithelioid cells that

contains 1,α-hydroxylase, which converts 25(OH)

D3 to 1,25(OH)2 D3.

PTH gene expression is up-regulated by TNF-α &

IL-6 produced by sarcoid macrophages.

Absence of feedback for hypercalcemia no

down-regulation of 1,α-hydroxylase in response to

high level of calcitriol & PTH.

Renal Sarcoidosis

Calcium metabolism in Calcium metabolism in Sarcoidosis First described by Harrel in 1939

Clinical manifestations:

- Hypercalciuria 40-62% (>400 mg/24hr)

- Hypercalcemia – asymptomatic, 5%

- Nephrocalcinosis from chronic hypercalciuria +/- hypercalcemia

- Nephrolithiais 10%

- Main cause of chronic renal failure

Renal Sarcoidosis

Neurosarcoidosis

Unilateral or bilateral

Bell’s palsy.

Optic neuritis.

Multiple or solitary

parenchymal mass.

May have a ring-like

appearance.

Mimic glioblastoma or

metastases.

Neurosarcoidosis

Hematologic Sarcoidosis

Lymphadenopathy: cervical, axillary,

epitrochlear & supraclavicular.

Splenomegly & hypersplenism.

Peripheral blood lymphopenia.

Hepatic Sarcoidosis

Dysfunction of these organ is

uncommon.

Hepatosplenic Sarcodosis: minimal

organomegaly & coalescing granulomas.

Liver & Spleen Sarcoidosis

GIT Sarcoidosis

Most common site: stomach dyspepsia

& abdominal pain.

Gastric sarcoidosis has predilection for the

antrum.

Diagnosis requires endoscopic biopsy

Genital Sarcoidosis

Testicular involvement can be associated with Epididymitis and is typically Bilateral & Multiple.

Does not affect fertility & does not increase the incidence of fetal or obsterical complications.

Cardiac Sarcoidosis

Clinically evident cardiac sarcoidosis is uncommon, Clinically evident cardiac sarcoidosis is uncommon, affecting 2-7% of patients with sarcoidosis. However, affecting 2-7% of patients with sarcoidosis. However, occult involvement is much higher (> 20%).occult involvement is much higher (> 20%).

Cardiac involvement may occur at any point during Cardiac involvement may occur at any point during the course of sarcoidosis, may occur in the absence the course of sarcoidosis, may occur in the absence of pulmonary or systemic involvement & may be a of pulmonary or systemic involvement & may be a presenting feature.presenting feature.

Sarcoidosis can involve any part of the heart, Sarcoidosis can involve any part of the heart, including myocardium, endocardium & pericardium.including myocardium, endocardium & pericardium.

Although the disease is often clinically silent, cardiac Although the disease is often clinically silent, cardiac sarcoidosis is a leading cause of death among sarcoidosis is a leading cause of death among patients with sarcoidosis, with mortality rate of 50-patients with sarcoidosis, with mortality rate of 50-85%.85%.

Clinical Manifestations of Cardiac Sarcoidosis

Asymptomatic granulomata.

Conduction defects (e.g., bundle branch blocks; complete heart block).

Atrial arrhythmias.

Mitral insufficiency.

Ventricular aneurysms.

Pericardial effusions; fibrosis.

Tachyarrhythmias (ventricular > atrial).

Congestive heart failure.

Cardiac Sarcoidosis

Guidelines for Diagnosis of Cardiac Sarcoidosis from Japanese Ministry of Health & Welfare:

Cardiac sarcoidosis is diagnosed when histologic analysis of operative or endomyocardial biopsy specimens demonstrates epithelioid granuloma without caseating granuloma

Clinical diagnosis group:

In patients with histologic diagnosis of extracardiac sarcoidosis, cardiac sarcoidosis is diagnosed when (a) and 1 or more of (b–e) are present.

(a) Complete right bundle branch block, left-axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contraction (>grade 2 in Lown’s classification), or abnormal Q or ST–T change on electrocardiogram or Holter electrocardiogram

(b) Abnormal wall motion, regional wall thinning or thickening, or dilatation of LV on echocardiogram

(c) Perfusion defect in 201Tl myocardial scintigram or abnormal accumulation in 67Ga-citrate or 99mTc-pyrophosphate myocardial scintigram

(d) Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed ejection fraction of LV

(e) Interstitial fibrosis or cellular infiltration over moderate grade in endomyocardial biopsy even if findings are nonspecific

Diagnosis

Clinical.

Radiological (Chest radiograph & Gallium scan).

Functional (Spirometry, DLCO & Lung Volumes).

Laboratory (CBC with differential count & SACE).

Skin tests.

Biopsy.

ECG.

Opthalmological examination.

Organ-specific investigations.

Radiological Staging of Sarcoidosis

Scadding's

Classification

Stage 0=normal

Stage 1=Hilar LDN alone

Stage 2=Hilar

LDN+parenchymal

infiltrates

Stage 3=Parenchymal infiltrates

alone

Stage 4=Pulmonary fibrosis

Strong predilection for the Strong predilection for the

Upper LungUpper Lung

Gallium 67 Scan

Lung gallium scan is a type of nuclear scan involving radioactive gallium (Ga.).

The test helps determine whether a patient has inflammation in the lungs.

Gallium is injected IV.

The scan will be taken 6-24 hrs after the gallium is injected. (time depends on whether the condition is acute or chronic ).

During the test, you lie on a table that moves underneath a scanner called a gamma camera. The camera detects the rays emitted by the gallium.

Gallium 67 Scan

Serum Angiotensin Converting Enzyme (SACE)

SACE is the most widely used test in the follow-up of sarcoidosis patients.

It is a membrane bound glycoprotein found in Activated Alveolar Macrophages & at the surface of Epithelioid cells & consequently may reflect development & extent of granulomas.

It may be normal in early & acute disease reflecting the small number of granulomas present at this stage.

It is poorly correlated with pulmonary function & variably related with radiographic stage.

It correlates with the degree of extrapulmonary lesions.

Serum Angiotensin Converting Enzyme (SACE)

ACE is secreted by granulomas and may be present in serum, CSF & BAL washings.

Steroids decrease SACE with a delay after onset of treatment. A minimum dose of prednisone is required to normalized SACE. After discontinuing steroids, a transient increase in SACE may occur before final normalization.

In spontaneous recovery of sarcoidosis without steroids, even previously persistently elevated SACE levels may normalize.

It is positive in 60% of sarcoidosis patients. SACE is neither sensitive nor specific in

diagnosing sarcoidosis.

Causes of Positive ACE

Sarcoidosis Pulmonary Berylliosis Asbestosis

Gaucher's Disease Hypersensitivity Pneumonitis Miliary Tuberculosis Coccidioidomycosis Lymphoma Silicosis

Non-Pulmonary Primary Biliary Cirrhosis Diabetes Mellitus Leprosy Crohn's Disease Hyperthyroidism .

The Kveim-Siltzbach Test

The test is based upon studies conducted by Dr. Morten

Ansgar Kveim, a Norwegian dermatologist in 1941 & was

later studied by Dr. Louis Siltzbach in New York.

It is the only test that, if positive, is considered to be

diagnostic of sarcoidosis.

It is both sensitive & specific.

The test involves intradermal injection of a suspension of

granuloma-containing spleen or lymph node from a patient

with sarcoidosis.

A positive test is characterized by the formation of a papule

at the site of injection within 4-6 wks which, on microscopic

examination, exhibits non-necrotizing granulomas.


Because of the difficulties involved in preparation,

standardization & validation of the test material as

well as significant variation in the sensitivity &

specificity of test suspensions obtained from

different sources, the need for a biopsy procedure

& the wait of 4-6 weeks for a diagnosis, the Kveim

test has been largely replaced by TBLB for the

diagnosis of sarcoidosis.

It may have a role in atypical cases where tissue is

difficult or impossible to obtain, such as in

neurosarcoidosis.


http://granuloma.homestead.com/Kveim3_NCSP_27.jpg

http://granuloma.homestead.com/Kveim_NCSP_27.JPG

http://granuloma.homestead.com/Kveim2_NCSP_27.JPG

Lung Volumes & Capacities

Obstructive impairment is as common as restrictive impairment

Biopsy

Palpable lymph nodes

Subcutaneous nodule

Cutaneous lesion

Enlarged parotid

Lacrimal gland

Transbronchial lung biopsy (TBLB)

Cardiac Sarcoidosis

Diagnostic test Clinical feature

ECGNon-specific ST & T wave changes; conduction disturbances; arrhythmias

24-Holter monitor Arrhythmias (rest or exercise)

2-D echocardiography Focal hypokinesis; ventricular thinning or hypertrophy; wall motion abnormalities; depressed ejection fraction; papillary muscle dysfunction; bright echos

Adenosine thallium201 radionuclide scan

Segmental defects; improve with exercise or adenosine

Gallium67 & Technetium99 scans

Increased myocardial uptake

Positron emission tomography (PET)

Increased myocardial uptake

MRI High-intensity lesions; thinning ventricular wall

Endomyocardial biopsies Nonnecrotizing granulomata;

mononuclear cell infiltrates; fibrosis

Treatment of Sarcoidosis

Corticosteroids: Glucocorticoids are very potent & effective drugs

in preventing & suppressing inflammation caused by mechanical, chemical, infectious & immunological stimuli.

They act mainly by repression of inflammatory genes, e.g. interleukin (IL)-1 & tumour necrosis factor (TNF), adhesion molecules & receptors & partly by induction of anti-inflammatory genes e.g.,IL-1 receptor antagonist.

In Sarcoidosis, corticosteroids have been shown to restore the balance between locally produced type-1 & type-2 T-helper cell cytokines.

When To Treat?

Progressive or persistent symptomatic pulmonary disease

Threatened organ failure e.g., severe cardiac, neurological.

Asymptomatic pulmonary disease with persistent infiltrates

or progressive loss of lung function

Palpable splenomegly or hypersplenism

Severe myopathy, fatigue & weight loss.

Disfiguring skin lesion.

Uveitis unresponsive to topical corticosteroids.

Persistent hypercalcaemia, renal or hepatic dysfunction.

Painful lymphadenopathy.

Treatment of Sarcoidosis

Decision to Treat with CORTICOSTEROIDS:

Patient Subgroup Decision:

1. Asymptomatic Pts → No treatment

2. Mild Pulmonary Dysfunction → Observation

3. Mild-Mod. Pulmonary Dysfunction → Observation →

Treat if no improvement after 6 months.

4. Severe Pulmonary Dysfunction → Treatment

Corticosteroids in Systemic Sarcoidosis

DrugDrug DoseDose

CorticosteroidsCorticosteroids

Prednisone 20-40 mg/d for 2 wk, 5 mg/2 wks till Prednisone 20-40 mg/d for 2 wk, 5 mg/2 wks till 10-15 mg, then maintain for 8-12 ms, then taper 10-15 mg, then maintain for 8-12 ms, then taper 2.5 mg/2-4 wks.2.5 mg/2-4 wks.

Reinstitute if relapse Reinstitute if relapse

Alternative Drug Therapy

Methotrexate 10-20 mg/wk + folate 1 mg/d

Hydroxychloroquine 200 mg once or twice/day

Chloroquine 500 mg/other day for 6 ms then 6 ms drug holiday

Azathioprine 100-200 mg/day

Doxycyclin, Minocyclin 100 mg twice/day


Corticosteroid resistance, however, has also

been described in Sarcoidosis patients & is

characterised by exaggerated TNF-release by

alveolar macrophages compared to that found

in patients showing favourable responses to

steroids.

Thus, steroid-refractory disease might benefit

from treatment with anti-TNF-antibody, i.e.

infliximab.


Infliximab & Etanercept: Infliximab is a “monoclonal antibody” that

blocks the action of TNFα by binding to it & preventing it from signaling the receptors for TNFα on the surface of cells.

TNFα is one of the key cytokines that triggers & sustains the inflammation response.

Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble & transmembrane forms of TNFα & inhibits or prevents the effective binding of TNFα with its receptors.


Infliximab & Etanercept: Treatment with infliximab has recently proved

effective in the treatment of refractory sarcoidosis.

Etanercept, a soluble TNF receptor construct, was found ineffective against pulmonary & chronic ocular sarcoidosis.

Etanercept binds soluble TNF alone, whereas infliximab also binds to the membrane-bound form.

Potential Role for Antioxidants in Sarcoidosis

Enhanced production of reactive oxygen species

(ROS), capable of reducing endogenous defense

levels & enhancing inflammation, is suggested to

play a role in sarcoidosis.

Antioxidant supplementation offers protection not

only against ROS-mediated damage but also by

reducing inflammation.

A promising candidate for antioxidant

supplementation is the flavonoid quercetin.

Recommended Clinical Evaluation In Sarcoidosis

Baseline:•History taking, with emphasis on occupational & environmental exposure•Physical examination, with emphasis on lung, skin, eye, liver, heart•Biopsy to obtain histologic confirmation of non-caseating granulomas•Chest radiography•Pulmonary-function testing — spirometry + measurement of gas exchange (e.g., DLCO (or) ABGs)•Electrocardiography•Ophthalmologic evaluation with slit-lamp examination•Biochemical evaluation for hepatic & renal function+ measurement of s. Ca•Tuberculin skin test•Other tests depending on clinical presentation & suspicion of extrathoracic disease; assessment of extent and severity of organ involvement

Follow-up:•Monitoring for resolution or disease progression & for new organ involvement.•Referral to subspecialists if there is evidence of disease progression or new organ involvement.

Take Home Messages

Therapy need not be given to all patients. Once initiated, at least 1 yr of treatment is required. Monitoring is mandatory if steriods discontinued. Steroid sparing agents useful for chronic patients. No long term benefit from corticosteroid therapy in

asymptomatic pts., regardless of CXR stage. Asymptomatic pts. with normal PFT should not be

treated because of radiographic abnormality alone. Neurologic, cardiac & ocular involvement warrants

early therapy.

Orphan Lung Orphan Lung

DiseasesDiseases

Definition

An ‘Orphan' disease is the name given

to a disease that is not widely

researched and/or for which there is no

specific treatment, thus making patients

feel 'orphan' in the world of healthcare.

Orphan Lung Diseases

Lymphangioleiomyomatosis (LAM).

Pulmonary Langerhans’ Cell histiocytosis.

Pulmonary Alveolar Proteinosis (PAP).

Amyloidosis.

Scleroderma.

Idiopathic chronic eosinophilic pneumonia.

Lymphangioleiomyomatosi

s

Lymphangioleiomyomatosis (LAM) is a rare

disorder of unknown etiology characterized by

proliferation of atypical smooth muscle cell (LAM

cell) in pulmonary lymphatics, venules & small

airways.

The dominant clinical features are: ILD, chylous

pleural effusion & recurrent pneumothorax.

It occurs in females during the childbearing

period.

Diagnosis of LAM

Clinical.

Radiological: chest radiograph.

PFTs (combined obstructive & restrictive).

Biopsy: TBLB.

Treatment of LAM

Hormonal therapy e.g., progesterone &

tamoxifen.

Hormonal manipulations e.g.,

oophorectomy.

Lung transplantation.

New experimental therapies e.g.,

Rapamycin, Doxycycline & Octreotide.

Pulmonary Langerhans’ Cell

Histiocytosis

Langerhans’ cell histiocytosis or Eosinophilic

granuloma of the lung.

Clinical: dry cough, dyspnea, chest pain rhinitis,

fatigue, fever, pneumothorax, hemoptysis, diabetes

insipidus & skeletal involvement with cystic bony

lesions .

Examination: clubbing, cor pulmonale & crackles.

Langerhans’ cells are differentiated cells of

monocyte–macrophage lineage that function as

APCs.

Common in young smokers.

Diagnosis of Langerhans’ Cell

Histiocytosis

Clinical.


PFTs (normal, obstructive, restrictive or

mixed).

Biopsy: BAL & TBLB.

Diagnosis of Langerhans’ Cell

Histiocytosis

Corticosteroids & cytotoxic drugs no

value.

New experimental therapies e.g., gene

therapy.

Treatment of Langerhans’ Cell

Histiocytosis

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a

syndrome of unknown etiology characterized by

excessive accumulation of surfactant

phospholipids & apoproteins within alveolar

spaces.

It can be primary (classic) or secondary

(pseudoproteinosis) due to environmental

exposure, drugs, infections & hematologic

malignancies.

More common in males between 30 & 50 yrs.

Diagnosis of PAP

Clinical: dyspnea, dry cough, clubbing,

cyanosis & widespread crackles.


PFTs restrictive pattern.

ABGs.

Laboratory LDH.

Biopsy: FOB, BAL, TBLB & open lung

biopsy lipid laden

macrophages.

Diagnosis of PAP

Treatment of PAP

Therapeutic whole lung lavage under

general anesthesia using double lumen

ETT (10-20 L saline for every lung).