Sarcoidosis & orphan lung disease
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  • Propionibacterium acnes, borrelia burgdorferi, chlamydia pneumonia, rickettsia helvetica, DNA viruses, mycobacterial catalase-peroxidase protein (mKatG) <br />
  • antigen(s) enter the host and are phagocytosed by antigen-presenting cells (APCs), predominantly macrophages or dendritic cells. The <br /> APCs process the antigen and subsequently present it via human leukocyte antigen (HLA) class II molecules to a restricted set <br /> of T-cell receptors on naive T lymphocytes, primarily of the CD41 class. Induction of the immune response depends on intact cell-mediated immunity The immune reaction begets polarization of the T lymphocytes to a Th1 phenotype, followed by cellular recruitment, proliferation, and differentiation leading to formation of the sarcoid granuloma. A panoply of cytokines and chemokines has been reported in association with sarcoidosis. <br /> Over time, the granuloma can either resolve or go on to form fibrosis. Fibrosis is associated with TNF, IL-8 and ET-1. Resolution is associated by IL-10 <br />
  • Non-caseating epithelioid cell granuloma in lung and giant cells <br />
  • LANGHANS&apos; GIANT CELL Langhans&apos; giant cell in center of granuloma containing cytoplasmic inclusion bodies as ca and iron-laden Schaumann bodies , stellate asteroid bodies, birefringent crystals, and small oval brown Hamasaki-Weseberg bodies. These inclusion bodies are common in sarcoidosis but are nonspecific. Langhans&apos; giant cell is surrounded by epithelioid cells . <br />
  • Schaumann’s Bodies can occur to a lesser extent, in chronic beryllium disease, tuberculosis, hypersensitivity pneumonitis, and other granulomatous conditions <br />
  • (A) Schaumann’s body within giant cell. (B) Calcium oxalate crystal within giant cell; polarized light (at arrow). (C) Early <br /> Schaumann’s body forming around calcium oxalate crystals within giant cell; polarized light. (D) Asteroid bodies within giant cell. (E) <br /> Hamazaki-Wesenberg bodies in lymph node; oil immersion (at arrows). (F) Hamazaki-Wesenberg bodies in lymph node. <br />
  • the percentages of patients in each stage at the time of presentation <br />
  • This MRI (axial, T1 with gadolinium) shows a frontal intracerebral mass that was proven by biopsy to be neurosarcoidosis. <br />
  • Kveim test - skin biopsyNon-necrotizing granulomas <br />
  • A rare disease is a disease that affects less than one person in every 2,000 <br />
  • The primary event in the pathogenesis of pulmonary Langerhans’-cell histiocytosis probably involves cigarette-smoke–induced recruitment <br /> and activation of Langerhans’ cells to the lung, a process that may result from a variety of potential mechanisms. Cigarette <br /> smoke may activate alveolar macrophages through bombesin-like peptides (BLP) released from airway neuroendocrine cells. <br /> Other antigens in cigarette smoke, including tobacco glycoprotein (TGP), may stimulate alveolar macrophages to produce cytokines <br /> (such as tumor necrosis factor <br /> a[TNFa] or granulocyte–macrophage colony-stimulating factor [GM-CSF]) or other factors that enhance <br /> recruitment and activation of Langerhans’ cells. Cigarette smoke may also directly activate Langerhans’ cells to secrete cytokines <br /> (such as tumor necrosis factor <br /> a <br /> or <br /> granulocyte–macrophage colony-stimulating factor) that mediate local accumulation of <br /> inflammatory cells, with resultant formation of nodules. Uptake of cigarette-smoke antigens by alveolar macrophages or Langerhans’ <br /> cells may also promote local expansion of T lymphocytes and further inflammation. Through the action of tobacco glycoprotein, <br /> reduced interleukin-2 secretion by lymphocytes may occur, thereby enhancing local survival and proliferation of Langerhans’ <br /> cells. T lymphocytes may further stimulate B-lymphocyte activation, promoting secretion of antibodies and immune-complex formation. <br /> Fibroblast activation and fibrosis may result from the local synthesis of tumor growth factor <br /> b <br /> (TGFb <br /> ) and tumor necrosis <br /> factor <br /> a <br /> by alveolar macrophages. <br />
  • confluent nodules with a mid and upper zone predominance. <br />
  • Langerhans’ Cells with the Typical Delicate and Folded Nuclei (Straight Arrow) and Scattered Interspersed Eosinophils (Curved Arrow) <br />
  • environmental exposure: silica , aluminum, fiberglass, volcanic ashes <br /> Drugs: chlorpheneramine, amiodarone <br /> Hematologic malignancy: leukemia, lymphoma <br /> Infections: PCCP, MB TB <br />
  • Posterior-anterior (PA) view of a chest radiograph revealing perihilar infiltrates with a classic &quot;butterfly&quot; distribution. <br />
  • Computed tomography of the chest reveals a branching pattern of white linear areas forming geometric shapes over-lying consolidated areas. This pattern is described as &quot;crazy paving: Ground-glass opacity superimposed with interlobular septal thickening and intralobular lines <br />

Sarcoidosis & orphan lung disease Sarcoidosis & orphan lung disease Presentation Transcript

  • Sarcoidosis & OrphanSarcoidosis & Orphan Lung DiseasesLung Diseases Iman Galal , MDIman Galal , MD Pulmonary Medicine DepartmentPulmonary Medicine Department Ain Shams UniversityAin Shams University
  •  Page 2 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?
  •  Page 3 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 HutchinsonSir Jonathan Hutchinson Caesar BoeckCaesar Boeck
  •  Page 4 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 %.
  •  Page 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.
  •  Page 6 Pathophysiology of Sarcoidosis
  •  Page 7 Pathophysiology of Sarcoidosis  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.
  •  Page 8 Pathology of Sarcoidosis
  •  Page 9 Pathophysiology of Sarcoidosis  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.
  •  Page 10 Pathophysiology of Sarcoidosis  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.
  •  Page 11 Pathology of Sarcoidosis
  •  Page 12 Pathology of Sarcoidosis
  •  Page 13 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.
  •  Page 14 Pathology of Sarcoidosis
  •  Page 15 Inclusion Bodies in Sarcoidosis 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.
  •  Page 16 Inclusion Bodies in 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.
  •  Page 17 Pathology of Sarcoidosis
  •  Page 18 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 %
  •  Page 19 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.
  •  Page 20 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%)
  •  Page 22 Endobronchial Sarcoidosis
  •  Page 23 Cutaneous Sarcoidosis Erythema NodosumErythema Nodosum
  •  Page 24 Lofgren's Syndrome  Bilateral hilar lymphadenopathy.  Fever.  Arthritis.  ± Erythema nodosum.
  •  Page 25 Cutaneous Sarcoidosis Lupus PernioLupus Pernio
  •  Page 27 Ocular Sarcoidosis  Unilateral or bilateral anterior & posterior uveitis (commonest).  Conjunctival Granuloma.  Iris Granuloma.  Optic neuritis.  Chorioretinitis.
  •  Page 28 Ocular Sarcoidosis Iris GranulomaIris Granuloma Conjunctival GranulomaConjunctival Granuloma Punched-outchoroidoretinallesionsPunched-outchoroidoretinallesions Anterior UveitisAnterior Uveitis
  •  Page 29 URT & Oral Cavity Sarcoidosis  Sinusitis.  Nasal congestion.  Intermittent epistaxis.  Destruction of nasal septum & Saddle Nose.  Upper airway obstruction, stridor & acute respiratory failure.  Hoarseness.
  •  Page 30 URT & Oral Cavity Sarcoidosis Saddle NoseSaddle Nose
  •  Page 31 Exocrine Glands Panda SignPanda Sign Bilateral symmetrical gallium uptake by the lacrimal, parotid, and submandibular glands with Sicca syndrome
  •  Page 32 Exocrine Glands Heerfordt SyndromeHeerfordt Syndrome  Bilateral hilar lymphadenopathy.  Fever.  Facial palsy.  Parotid enlargement.  Uveitis.
  •  Page 33 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.
  •  Page 34 Skeletal Sarcoidosis PUNCHED OUT LYTIC LESIONSPUNCHED OUT LYTIC LESIONS Focal osteolytic lesions in the fingers are mostFocal osteolytic lesions in the fingers are most common abnormality.common abnormality. LACY TRABECULAR PATTERNLACY TRABECULAR PATTERN Osteolysis has left a lacy trabecular pattern inOsteolysis has left a lacy trabecular pattern in this phalanx (arrow)this phalanx (arrow)
  •  Page 36 Muscle Sarcoidosis
  •  Page 37 Endocrine Sarcoidosis  Involvement of the hypothalamus  Diabetes Insipidus  Hyperintensity of the posterior pituitary lobe caused by intracellular nerosecretory granules.
  •  Page 39 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.
  •  Page 40 Renal Sarcoidosis Calcium metabolism inCalcium 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
  •  Page 41 Renal Sarcoidosis
  •  Page 42 Neurosarcoidosis  Unilateral or bilateral Bell’s palsy.  Optic neuritis.  Multiple or solitary parenchymal mass.  May have a ring-like appearance.  Mimic glioblastoma or metastases.
  •  Page 43 Neurosarcoidosis
  •  Page 44 Hematologic Sarcoidosis  Lymphadenopathy: cervical, axillary, epitrochlear & supraclavicular.  Splenomegly & hypersplenism.  Peripheral blood lymphopenia.
  •  Page 45 Hepatic Sarcoidosis  Dysfunction of these organ is uncommon.  Hepatosplenic Sarcodosis: minimal organomegaly & coalescing granulomas.
  •  Page 46 Liver & Spleen Sarcoidosis
  •  Page 47 GIT Sarcoidosis  Most common site: stomach dyspepsia & abdominal pain.  Gastric sarcoidosis has predilection for the antrum.  Diagnosis requires endoscopic biopsy
  •  Page 48 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.
  •  Page 49 Cardiac Sarcoidosis  Clinically evident cardiac sarcoidosis is uncommon, affectingClinically evident cardiac sarcoidosis is uncommon, affecting 2-7% of patients with sarcoidosis. However, occult2-7% of patients with sarcoidosis. However, occult involvement is much higher (> 20%).involvement is much higher (> 20%).  Cardiac involvement may occur at any point during the courseCardiac involvement may occur at any point during the course of sarcoidosis, may occur in the absence of pulmonary orof sarcoidosis, may occur in the absence of pulmonary or systemic involvement & may be a presenting feature.systemic involvement & may be a presenting feature.  Sarcoidosis can involve any part of the heart, includingSarcoidosis can involve any part of the heart, including myocardium, endocardium & pericardium.myocardium, endocardium & pericardium.  Although the disease is often clinically silent, cardiacAlthough the disease is often clinically silent, cardiac sarcoidosis is a leading cause of death among patients withsarcoidosis is a leading cause of death among patients with sarcoidosis, with mortality rate of 50-85%.sarcoidosis, with mortality rate of 50-85%.
  •  Page 50 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.
  •  Page 51 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
  •  Page 52 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.
  •  Page 53 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 theStrong predilection for the Upper LungUpper Lung
  •  Page 54 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.
  •  Page 55 Gallium 67 Scan
  •  Page 56 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.
  •  Page 57 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.
  •  Page 58 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 .
  •  Page 59 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.
  •  Page 60 The Kveim-Siltzbach Test  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.
  •  Page 61 The Kveim-Siltzbach Test
  •  Page 62 Lung Volumes & Capacities Obstructive impairment is as common as restrictive impairment
  •  Page 63 DLCO
  •  Page 64 Biopsy  Palpable lymph nodes  Subcutaneous nodule  Cutaneous lesion  Enlarged parotid  Lacrimal gland  Transbronchial lung biopsy (TBLB)
  •  Page 65 Cardiac Sarcoidosis Diagnostic test Clinical feature ECG Non-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
  •  Page 66 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.
  •  Page 67 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.
  •  Page 68 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
  •  Page 69 Corticosteroids in Systemic Sarcoidosis DrugDrug DoseDose CorticosteroidsCorticosteroids  Prednisone 20-40 mg/d for 2 wk, 5 mg/2 wks tillPrednisone 20-40 mg/d for 2 wk, 5 mg/2 wks till 10-15 mg, then maintain for 8-12 ms, then taper10-15 mg, then maintain for 8-12 ms, then taper 2.5 mg/2-4 wks.2.5 mg/2-4 wks.  Reinstitute if relapseReinstitute if relapse
  •  Page 70 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
  •  Page 71 Alternative Drug Therapy  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.
  •  Page 72 Alternative Drug Therapy 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.
  •  Page 73 Alternative Drug Therapy 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.
  •  Page 74 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.
  •  Page 75 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.
  •  Page 76 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 LungOrphan Lung DiseasesDiseases
  •  Page 78 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.
  •  Page 79 Orphan Lung Diseases  Lymphangioleiomyomatosis (LAM).  Pulmonary Langerhans’ Cell histiocytosis.  Pulmonary Alveolar Proteinosis (PAP).  Amyloidosis.  Scleroderma.  Idiopathic chronic eosinophilic pneumonia.
  •  Page 80 Lymphangioleiomyomatosis  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.
  •  Page 81 Diagnosis of LAM  Clinical.  Radiological: chest radiograph.  PFTs (combined obstructive & restrictive).  Biopsy: TBLB.
  •  Page 82 Treatment of LAM  Hormonal therapy e.g., progesterone & tamoxifen.  Hormonal manipulations e.g., oophorectomy.  Lung transplantation.  New experimental therapies e.g., Rapamycin, Doxycycline & Octreotide.
  •  Page 83 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.
  •  Page 84 Diagnosis of Langerhans’ Cell Histiocytosis  Clinical.  Radiological: chest radiograph.  PFTs (normal, obstructive, restrictive or mixed).  Biopsy: BAL & TBLB.
  •  Page 85 Diagnosis of Langerhans’ Cell Histiocytosis
  •  Page 86 Diagnosis of Langerhans’ Cell Histiocytosis
  •  Page 87  Corticosteroids & cytotoxic drugs no value.  New experimental therapies e.g., gene therapy. Treatment of Langerhans’ Cell Histiocytosis
  •  Page 88 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.
  •  Page 89 Diagnosis of PAP  Clinical: dyspnea, dry cough, clubbing, cyanosis & widespread crackles.  Radiological: chest radiograph.  PFTs restrictive pattern.  ABGs.  Laboratory LDH.  Biopsy: FOB, BAL, TBLB & open lung biopsy lipid laden macrophages.
  •  Page 90 Diagnosis of PAP
  •  Page 91 Diagnosis of PAP
  •  Page 92 Treatment of PAP  Therapeutic whole lung lavage under general anesthesia using double lumen ETT (10-20 L saline for every lung).
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