Immunology of the Lung Immune - Mediated Lung Diseases Interstitial Lung Diseases Dr. Hristina Andreeva, MD Department of ...
Disposition <ul><li>Classification and Epidemiology </li></ul><ul><li>Pulmonary Immunobiology and Inflammation </li></ul><...
2
Epidemiology of Interstitial Lung Diseases   <ul><li>Idiopathic pulmonary fibrosis </li></ul><ul><li>Occupational/environm...
Pulmonary Immunobiology and Inflammation  Consensus 2000   “adopted” pathways  of  immune control in processing  foreign a...
Pulmonary Immunobiology and Inflammation  Consensus 2000 <ul><li>Neutrophils   - under  normal conditions the lung is desi...
Pulmonary Immunobiology and Inflammation    Consensus 2000 <ul><li>type II alveolar cells   –  secreting and dividing cell...
Immunologic Methods for Diagnosis  in  Lung Diseases <ul><li>blood ( serology )  – C3, C4, C1-IHN,  Ig (G, A, M), IgE, CRP...
BALF normal respiratory cells profile 8
Pleural Fluid normal respiratory cells profile 9
SARCOIDOSIS <ul><li>Definition  -  a multisystem disorder of unknown origin </li></ul><ul><li>It commonly affects young an...
SARCOIDOSIS <ul><li>age  - < 40, peak 20 - 29, second peak  in  women  over 50 </li></ul><ul><li>rate  - 5.9 - men, 6.3-wo...
SARCOIDOSIS <ul><li>infectious  -  viruses (EBV, HHV, CMV, CoxBV), B. burg-dorferi, M. tuberculosis (50-80% of cases +), M...
SARCOIDOSIS <ul><li>T-cell-mediated anergy  -  negative skin tests for CMI </li></ul><ul><li>Th1 activated lymphocytes   -...
SARCOIDOSIS <ul><li>morphology  -  noncaseating epitheloid cell granuloma consisting of Mo-Ma (epitheloid & giant cells), ...
SARCOIDOSIS   Clinical presentation and organ involvement <ul><li>Lungs   - 90%, larynx, trachea, bronchi, pleural effusio...
SARCOIDOSIS Markers of  Activity <ul><li>recent   progressive dry cough </li></ul><ul><li>progressive dyspnea </li></ul><u...
SARCOIDOSIS   Immunologic  Diagnosis <ul><li>skin test for CMI </li></ul><ul><li>peripheral blood immunophenotyping </li><...
Active & Non Active  Sarcoidosis <ul><li>    Monocyte like Macrophages   </li></ul><ul><li>CD14 bright /CD11b bright  ...
Flowcytometric BALF analysis  Active Sarcoidosis CD14 bright /CD11b bright  HLA-DR  dim  /CD16  dim CD 4+ lymphocytic alve...
Hypersensitivity Pneumonitis   (HP) <ul><li>Allergic disease of the lung parenchyma with inflammation </li></ul><ul><li>in...
Hypersensitivity Pneumonitis <ul><li>cases  - reported worldwide </li></ul><ul><li>association  - with occupational allerg...
Hypersensitivity Pneumonitis     Etiology <ul><li>bacteria  - contaminated hay, grains, fertilizer mushroom compost  </li>...
Hypersensitivity Pneumonitis <ul><li>primary pathogenetic mechanism involves the effectors T-ly </li></ul><ul><li>accumula...
Hypersensitivity Pneumonitis     Immunopathogenesis <ul><li>Acute phase  -  Arthus-like reaction  ( 4 h - 24 h), high seru...
Hypersensitive Pneumonitis Clinical Features <ul><li>acute  -  single or multiple episodes of dyspnea, cough, fever, chill...
<ul><li>serum  -  precipitating antibodies: Ouchterlony analysis, increased serum levels of Complement </li></ul><ul><li>s...
Hypersensitive Pneumonitis respiratory cells profile   27
Flowcytometric BALF analysis   HP CD 8+ lymphocytic alveolitis CD4/CD8 Ratio = 0.36 28
Hypersensitive Pneumonitis   in conclusion <ul><li>differential diagnosis  -  other interstitial lung diseases, sarcoidosi...
Interstitial Lung Disease with    BALF  Lymphocytosis Hypersensitivity pneumonitis  (60-80%) Sarcoidosis  (Acute - 40-60%)...
Autoimmune - Mediated Lung Disease <ul><li>Connective tissue disease   -  SLE, RA, SS, PSS, DM </li></ul><ul><li>Antiphosp...
Connective Tissue Diseases   <ul><li>clinical features  –  polyserositis  </li></ul><ul><li>SLE  - pleuritis 30%; chest pa...
Antiphospholipid Syndrome   <ul><li>Pulmonary Embolism  & Infarction  -  recurrent deep venous thrombosis  in  1/3 of APS ...
Diffuse Alveolar Hemorrhage  <ul><li>etiology  -  SLE, APS, Behcet, Goodpasture, Henoch-Schonlein,  IgA nephropathy, micro...
Diffuse Alveolar Hemorrhage <ul><li>association   WG - 43% capillaritis, 7% DAH </li></ul><ul><li>Microscopic polyarteriti...
Flowcytometric BALF analysis   DAH  erythrocytes are lysed elevated activated neutrophils  Additional findings: hemoptysis...
Autoimmune - Mediated Lung Disease   in conclusion   <ul><li>serology -   autoantibodies </li></ul><ul><li>immunologic dia...
Interstitial Lung Disease with    BALF  Neutrophilia <ul><li>Idiopathic pulmonary fibrosis  (15-40 %) </li></ul><ul><li>Cr...
Idiopathic  Pulmonary Fibrosis Consensus 2000 <ul><li>definition  -  a specific form of  fibrosing interstitial pneumonia ...
<ul><li>major  immunologic  features </li></ul><ul><li>- immune complexes are present  in serum and in the lungs in the ea...
Idiopathic  Pulmonary Fibrosis Immune Pathogenesis 41
Idiopathic  Pulmonary Fibrosis <ul><li>clinical  picture  -   insidious onset, dyspnea, nonproductive cough, dry bibasilar...
<ul><li>Chronic aspiration </li></ul><ul><li>Rheumatic diseases, collagen vascular disease </li></ul><ul><li>APS  - fibros...
Idiopathic  Pulmonary Fibrosis General BALF Results   <ul><li>lymphocytosis  -  god GK response </li></ul><ul><li>low Neu,...
Flowcytometric BALF analysis  Pulmonary fibrosis elevated neutrophils - 61%  phenotypicaly activated patterns  CD62L- / CD...
Pulmonary Eosinophilic  Syndromes   Classification <ul><li>Idiopathic Acute Eosinophilic Pneumonia </li></ul><ul><li>Idiop...
Pulmonary Eosinophilic  Syndromes Main Diagnostic Criteria <ul><li>Peripheral blood eosinophilia ( >500 Eos/mm 3 ) </li></...
Interstitial lung disease associated with    BALF Eosinophilia <ul><li>High count (>30%) </li></ul><ul><li>Tropical pulmon...
Flowcytometric analysis  Peripheral Eosinophilia Discrimination of ACTIVATED Eos High sideward scatter High degree of auto...
References  <ul><li>Demedts M et al. Eur Respir J Suppl.2001, 32, 2-16. </li></ul><ul><li>Crapo JD et al. Am J Respir Crit...
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  • Immunology of the Lung Immune - Mediated Lung Diseases

    1. 1. Immunology of the Lung Immune - Mediated Lung Diseases Interstitial Lung Diseases Dr. Hristina Andreeva, MD Department of Immunology and Transfusion Medicine, Haukeland Hospital -Bergen
    2. 2. Disposition <ul><li>Classification and Epidemiology </li></ul><ul><li>Pulmonary Immunobiology and Inflammation </li></ul><ul><li>Main Immunological Methods </li></ul><ul><li>serology, cell mediated immunity, Flowcytometry – blod, BALF </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>Hypersensitivity Pneumonitis </li></ul><ul><li>Autoimmune Mediated Lang Diseases </li></ul><ul><li>Idiopathic Pulmonary Fibrosis </li></ul><ul><li>Pulmonary Eosinophilic Syndromes </li></ul>1
    3. 3. 2
    4. 4. Epidemiology of Interstitial Lung Diseases <ul><li>Idiopathic pulmonary fibrosis </li></ul><ul><li>Occupational/environmental </li></ul><ul><li>Post inflammatory pulmonary fibrosis </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>Connective tissue disease </li></ul><ul><li>Hypersensitivity pneumonitis </li></ul><ul><li>Drugs and radiation </li></ul>3
    5. 5. Pulmonary Immunobiology and Inflammation Consensus 2000 “adopted” pathways of immune control in processing foreign antigens <ul><li>mucociliary clearance </li></ul><ul><li>10 10 particles per day </li></ul><ul><li>5x10 8 alveoli / 100m 2 area </li></ul><ul><li>upper & lower respiratory </li></ul><ul><li>tracts - ciliated epithelium </li></ul><ul><li>lymphatic tissues - NALT, BALT, draining lymph nodes </li></ul><ul><li>secretory IgA - immobilizes Ag </li></ul><ul><li>AM - poor APC , but “excellent cleaners” without initiating an inflammation - preventing the alveolar capil. membrane </li></ul><ul><li>T-cells - residual  T - cells </li></ul><ul><li>CD4 - /CD8 -  T cells </li></ul><ul><li>CD4+ & CD8+ - hyporesponsive </li></ul><ul><li>B- cells - high % in interstitium </li></ul>4
    6. 6. Pulmonary Immunobiology and Inflammation Consensus 2000 <ul><li>Neutrophils - under normal conditions the lung is designed to exclude Neu from alveolar capillary membrane; </li></ul><ul><li>- transendothelium trafficking via CAM </li></ul><ul><li>- phagocytic defence - ingesting and clearing damaged epithelium </li></ul><ul><li>Eos, Ba, Mast cells – transvessels migration, role in Asthma, Eosinophilic Pneumonia, Lung Fibrosis, Lung parasitic diseases </li></ul><ul><li>Oxidative stress - reactive oxygen and NO intermediates  tissue injury; antioxidants - glutathione (100x) higher than in other tissues, extracellular superoxide dismutase (alveolar type II cells) </li></ul>pulmonary inflammatory events 5
    7. 7. Pulmonary Immunobiology and Inflammation Consensus 2000 <ul><li>type II alveolar cells – secreting and dividing cells </li></ul><ul><li>(Surfactant, SOD3, IL-8, MCP-1, MIP12, RANTES) </li></ul><ul><li>bronchiolar epithelial serous cells (Clara cells) - secreting and dividing cells (stem cells for ciliated/not ciliated bronch. epith.) </li></ul><ul><li>(lactoferrin,  - defensin, cathelicidins, SP, cyt-p450) </li></ul><ul><li>type II alveolar cells and Clara cells - a potent source of cytokines and variety peptide/protein antibiotics - LL37/ hCAP18, PhosphoLipase - A2, Clara Cell 26kDa protein </li></ul>unique immune characteristics 6
    8. 8. Immunologic Methods for Diagnosis in Lung Diseases <ul><li>blood ( serology ) – C3, C4, C1-IHN, Ig (G, A, M), IgE, CRP,  1-AT , autoantibodies, infections diseases </li></ul><ul><li>blood ( cells ) - CMI -  CD3, CD4, CD8, CD19, NK, adhesion molecules CD62L, CD11b, CD54, CD25, CD86 </li></ul><ul><li>cutaneous tests – test for type 1 allergic reaction; MULTITEST® CMI ( Skin Test Antigens for Cell-Mediated Immunity) ; Mantu test </li></ul><ul><li>invasive methods - bronchoscopy, pleural punction - respiratory cells profile in BALF and PF </li></ul><ul><li>biopsy - histological examination, immunohistochemial staining </li></ul>7
    9. 9. BALF normal respiratory cells profile 8
    10. 10. Pleural Fluid normal respiratory cells profile 9
    11. 11. SARCOIDOSIS <ul><li>Definition - a multisystem disorder of unknown origin </li></ul><ul><li>It commonly affects young and middle-aged adults and frequently presents with bilateral hilar lymphadenopathy, pulmonary infiltration, ocular and skin lesions. The liver, spleen, salivary glands, nervous system, muscles, bones also may be involved. </li></ul><ul><li>The diagnosis is established when clinical, radiological findings are supported by histological evidence of noncaseating epitheloid cell granulomas. </li></ul><ul><li>1877 Jonathon Hutchinson - first described erythema nodosum </li></ul><ul><li>1899 Caesar Boeck - used the term “sarcoid”- benign sarcoma </li></ul><ul><li>1941 Morten Ansgar Kveim - intra-cutaneous Kveim’ test </li></ul>Statement of Sarcoidosis 2000 10
    12. 12. SARCOIDOSIS <ul><li>age - < 40, peak 20 - 29, second peak in women over 50 </li></ul><ul><li>rate - 5.9 - men, 6.3-women - 100 000/ year </li></ul><ul><li>race - 0.85% whites - asymptomatic; 2.4% blacks - severe </li></ul><ul><li>overall mortality - 1% - 5% </li></ul><ul><li>transmission - 40% contact way (person to person) exposure to an environmental agents; occupational risk (beryllium, metal dusts, organic Ag); familial 5% </li></ul><ul><li>seasons - winter and early spring </li></ul><ul><li>smoking - more commonly in nonsmokers </li></ul><ul><li>genetic factors - class I-HLA-A1, B8, B22 - Italy, class II-DR3, 17, 15, 16 </li></ul>Epidemiology 11
    13. 13. SARCOIDOSIS <ul><li>infectious - viruses (EBV, HHV, CMV, CoxBV), B. burg-dorferi, M. tuberculosis (50-80% of cases +), Mycoplasma </li></ul><ul><li>inorganic - aluminum, zirconium, talc, Ro-radiation </li></ul><ul><li>organic - pine tree pollen </li></ul><ul><li>T- Cell Receptor features - existence of T cells with restricted TCR usage, these TCR have highly restricted TCR - V segment, with special antigen recognition </li></ul>Etiology 12
    14. 14. SARCOIDOSIS <ul><li>T-cell-mediated anergy - negative skin tests for CMI </li></ul><ul><li>Th1 activated lymphocytes - cytokine release at foci of disease </li></ul><ul><li>Proliferation - of local lymphocytes (CD4+), activation of blood T-cells and Mo-Ma </li></ul><ul><li>Granuloma formation - T-cells, Mo-Ma, epitheloid cells, multinucleated giant cells type Langhans </li></ul><ul><li>Peripheral blood - T-lymphopenia, immune complexes, hypergammaglobulinemi </li></ul><ul><li>Pulmonary manifestation - CD4+ lymphocytic alveolitis </li></ul>Major Immunologic Features 13
    15. 15. SARCOIDOSIS <ul><li>morphology - noncaseating epitheloid cell granuloma consisting of Mo-Ma (epitheloid & giant cells), lymphocytes - CD4 central, CD8 in peripheral zone; fibrosis - from periphery to center </li></ul><ul><li>location - lymph node (intrathoracic); lung, liver, spleen, skin; CNS, in the lung 75% - close to bronchioles, subpleural, perilobular; 50% - lung vascular involvement </li></ul><ul><li>course of granulomas - either resolve or spontaneous remission; parenchymal fibrosis </li></ul><ul><li>tumor-related sarcoid reactions - regional lymph nodes with noncaseating epitheloid cell granulomas with frequency of 4.4% - NHML, H’s D, seminoma </li></ul><ul><li>granulomatous lesions of unknown significance (the GLUS syndrome) - 15 - 20% of biopsy samples </li></ul>Histopathology 14
    16. 16. SARCOIDOSIS Clinical presentation and organ involvement <ul><li>Lungs - 90%, larynx, trachea, bronchi, pleural effusion </li></ul><ul><li>Lymph nodes -1/3 </li></ul><ul><li>Heart - 5%, arrhythmias, block </li></ul><ul><li>Liver - 20% palp., 80% - biopsy </li></ul><ul><li>Skin - 25%, erythema nodosum, lupus pernio </li></ul><ul><li>Ocular - 11-83%, uveitis, KC - sicca, dacryocystitis, ret. vasculitis </li></ul><ul><li>NS - 10%, CNS-cranial nerve 7, hypothalamus, pituitary regions </li></ul><ul><li>Muscular-skeletal - 25-39% </li></ul><ul><li>GI tract - 1%, mimic Crohn’s D </li></ul><ul><li>Blood - anemia - 4 - 20% leucopenia - 40% </li></ul><ul><li>Parotid glands - 6% </li></ul><ul><li>hyper Ca - emia / uria - 10% </li></ul><ul><li>Reproductive organs - uterus, breast, testis -1/3 orchiectomies </li></ul>15
    17. 17. SARCOIDOSIS Markers of Activity <ul><li>recent progressive dry cough </li></ul><ul><li>progressive dyspnea </li></ul><ul><li>systemic: fatigue, fever, polyathralgia, erythema nodosum, lymphadenopathy </li></ul><ul><li>progressive changes on chest Ro-graphs or lung CT scans </li></ul><ul><li>BALF - CD4+ alveolitis with activated Mo-Ma </li></ul><ul><li>hypercalceuria > hypercalcemia </li></ul><ul><li>high serum levels of ACE </li></ul>16
    18. 18. SARCOIDOSIS Immunologic Diagnosis <ul><li>skin test for CMI </li></ul><ul><li>peripheral blood immunophenotyping </li></ul><ul><li>immunophenotyping of BALF cells profile !!! </li></ul><ul><li>high CD4/ CD8 Ratio </li></ul><ul><li>lymphocyte > 16% </li></ul><ul><li>noncaseating granulomas </li></ul><ul><li>serum levels of immunoglobulin subclasses </li></ul>17
    19. 19. Active & Non Active Sarcoidosis <ul><li>  Monocyte like Macrophages </li></ul><ul><li>CD14 bright /CD11b bright </li></ul><ul><li>HLA-DR dim /CD16 dim </li></ul><ul><li>intermediary phenotype in NS </li></ul><ul><li>correlation -  % CD4+/CD25+ </li></ul><ul><li>and  CD14 on Mo ~ Ma in BALF from patients with AS </li></ul><ul><li>(r=0.94, p=0.001) </li></ul>* p<0.05, ** p<0.01 18
    20. 20. Flowcytometric BALF analysis Active Sarcoidosis CD14 bright /CD11b bright HLA-DR dim /CD16 dim CD 4+ lymphocytic alveolitis CD4/CD8 Ratio = 3.22  Monocyte like Macrophages 19
    21. 21. Hypersensitivity Pneumonitis (HP) <ul><li>Allergic disease of the lung parenchyma with inflammation </li></ul><ul><li>in the alveoli and interstitial spaces induced by acute or chronic inhalation of wide variety of inhaled materials. </li></ul>Definition 20
    22. 22. Hypersensitivity Pneumonitis <ul><li>cases - reported worldwide </li></ul><ul><li>association - with occupational allergens </li></ul><ul><li>age - males 30-50 are usually affected </li></ul><ul><li>rate - 3 per 1000, 50% of individuals exposed to environmental antigens don’t develop HP </li></ul><ul><li>smokers have a low incidence </li></ul><ul><li>cofactors - viral infection or endotoxin in the last 6m. </li></ul><ul><li>elimination of the allergen eliminates the disease </li></ul>Epidemiology 21
    23. 23. Hypersensitivity Pneumonitis Etiology <ul><li>bacteria - contaminated hay, grains, fertilizer mushroom compost </li></ul><ul><li>fungi - moldy barley tobacco, compost, redwood bark, sauna water, moldy cheese, moldy walls, grass </li></ul><ul><li>insects - wheat weevil (wood pulp, dust, infected flour) </li></ul><ul><li>organic chemicals - anhydride, isocyanates </li></ul><ul><li>other - coffee bean protein, rat urine protein, animal fur protein </li></ul><ul><li>Important condition - the allergen must be inhaled in aerosol or particle form to reaching the alveoli during normal respiration - </li></ul><ul><li>1 min. / 750 000 fungi spores </li></ul>22
    24. 24. Hypersensitivity Pneumonitis <ul><li>primary pathogenetic mechanism involves the effectors T-ly </li></ul><ul><li>accumulation of T-ly in the lung </li></ul><ul><li>type III allergic reactions are involved in the pathogenesis </li></ul><ul><li>development of T - suppressor alveolitis </li></ul><ul><li>allergens are frequently components of biologic organisms or their products </li></ul><ul><li>sensitization probably occurs only after repeated exposures </li></ul><ul><ul><ul><li>Major Immunologic Features </li></ul></ul></ul>23
    25. 25. Hypersensitivity Pneumonitis Immunopathogenesis <ul><li>Acute phase - Arthus-like reaction ( 4 h - 24 h), high serum levels of Ig A to inhaled allergen in BALF; vasculitis of alveolar capillaries due to Immune Complexes - acute pneumonitis, remaining asymptomatic </li></ul><ul><li>Subacute phase - CMI (within 3 weeks of exposure), local proliferation of T (CD8+) lymphocytes , local secretion of Th2 lymphokines (IL-4, 5, 10), activated Ma - noncaseating granulomatous inflammation of interstitial spaces </li></ul><ul><li>Onset of the disease - function of the local lung - mucosal cell </li></ul><ul><li>mediated immunity </li></ul>24
    26. 26. Hypersensitive Pneumonitis Clinical Features <ul><li>acute - single or multiple episodes of dyspnea, cough, fever, chills, malaise, chest pain, onset 4h-8h after high dose allergen exposure, decline within 24h. Acute phase seldom is diagnosed at time. </li></ul><ul><li>subacute - over a period of weeks, without typical clinical patterns, fatigue, weight loss, cough, dyspnea </li></ul><ul><li>chronic disease - fatigue, weight loss, gradual progressive dyspnea. A low-dose continuous exposure to allergen is presented. </li></ul>25
    27. 27. <ul><li>serum - precipitating antibodies: Ouchterlony analysis, increased serum levels of Complement </li></ul><ul><li>skin tests - in the acute phase, intradermal application of the allergen elicits edema & erithema at 4-6h, subsiding completely by 24h </li></ul><ul><li>bronchial provocation testing - inhalation of allergen extract and 24h following up the pulmonary function </li></ul><ul><li>BALF - lymphocytic alveolitis </li></ul><ul><li>↑ CD8+ , ↑ Ma (CD80+/86+), mast cells >1% </li></ul><ul><li>BALF - ↑ Neu or/and ↑ Eos in advanced forms </li></ul><ul><li>BALF - ↑ Plasma cells + ↑ IgG/Albumin Ratio in acute phase </li></ul>Hypersensitive Pneumonitis Immunologic Diagnosis 26
    28. 28. Hypersensitive Pneumonitis respiratory cells profile 27
    29. 29. Flowcytometric BALF analysis HP CD 8+ lymphocytic alveolitis CD4/CD8 Ratio = 0.36 28
    30. 30. Hypersensitive Pneumonitis in conclusion <ul><li>differential diagnosis - other interstitial lung diseases, sarcoidosis, atypical pneumonitis, ABPA, asthma, pneumoconiosis </li></ul><ul><li>treatment - systemic corticosteroid therapy, elimination of the environmental allergen </li></ul><ul><li>complications - bronchiolitis obliterans, IBF, progressive pulmonary insufficiency and cor pulmonale </li></ul><ul><li>prognosis - good for the acute and subacute stages once the cause has been identified and avoided, together with adequate therapy and prevention </li></ul>29
    31. 31. Interstitial Lung Disease with BALF Lymphocytosis Hypersensitivity pneumonitis (60-80%) Sarcoidosis (Acute - 40-60%) Idiopathic pulmonary fibrosis (15-30%) Berylliosis Granite workers Amiodarone pneumonitis Lymphoma/Pseudolymphoma Pulmonary Langerhans cell histiocytosis 30
    32. 32. Autoimmune - Mediated Lung Disease <ul><li>Connective tissue disease - SLE, RA, SS, PSS, DM </li></ul><ul><li>Antiphospholipid Syndrome (APS) </li></ul><ul><li>Pulmonary Vasculitis Syndromes </li></ul><ul><li>systemic necrotizing vasculitis ( Polyarteritis Nodosa, Allergic granulomatosis of Churg & Strauss ) </li></ul><ul><li>Wegener’s Granulomatosis, Henoch-Schonlein Purpura, </li></ul><ul><li>Behcet’s Disease </li></ul><ul><li>Goodpasture’s Syndrome - pulmonary-renal involvement </li></ul><ul><li>Post inflammatory Pulmonary Fibrosis </li></ul>31
    33. 33. Connective Tissue Diseases <ul><li>clinical features – polyserositis </li></ul><ul><li>SLE - pleuritis 30%; chest pain 50%; atypical pneumonia - lupus pneumonitis - 71% ; pulmonary hypertension.; DAH; pneumothorax, hemothorax, vasculitis </li></ul><ul><li>RA - interstitial lupus pneumonitis </li></ul><ul><li>P SS - dyspnea, chr. cough, pleuritis, fibrosis, pulm. hypertension </li></ul><ul><li>immunologic diagnosis - serology </li></ul><ul><li>immunologic diagnosis - cytology –BALF, PF </li></ul><ul><li>Neu - 41%, Eos - 24% </li></ul><ul><li>with clinical picture - worse baseline fibrosis </li></ul><ul><li>Ly - 24% asymptomatic </li></ul><ul><li>in 56% of the cases- BALF cytology is the once way for the right diagnosis and for monitoring the treatment response </li></ul>32
    34. 34. Antiphospholipid Syndrome <ul><li>Pulmonary Embolism & Infarction - recurrent deep venous thrombosis in 1/3 of APS cases </li></ul><ul><li>cough, dyspnea, pleuritic chest pain, embolic pneumonia , last stage - Pulmonary Hypertension </li></ul><ul><li>Pulmonary Hypertension </li></ul><ul><li>Major Pulmonary Arterial Thrombosis - main right pulmonary artery ; embolic pneumonia </li></ul><ul><li>Pulmonary microthrombosis - often is a histopathology diagnosis, in situ microthrombosis with capillaritis and DAH -> ARDS </li></ul><ul><li>Immunologic diagnosis - ACA,  GPI, lupus anticoagulant, ANA positive in 30%-40%, platelet activation status </li></ul>33
    35. 35. Diffuse Alveolar Hemorrhage <ul><li>etiology - SLE, APS, Behcet, Goodpasture, Henoch-Schonlein, IgA nephropathy, microscopic polyarteritis, WG, Churg-Strauss </li></ul><ul><li>clinical features - nose hemorrhage, hemoptysis, mucosal hemorrhagic ulcerations, diffuse alveolar infiltrates on X-ray, anemia , adequate platelets number & function </li></ul><ul><li>immunologic pathogenesis - immune complexes </li></ul><ul><li>- ANCA associated pathogenesis - activation of circulating neutrophils and Mo; </li></ul><ul><li>in situ - formation of immune complexes; adhesion of activated neutrophils; oxidative burst, degranulation - endothelial cell injury / increased vascular permeability - development of capillaritis </li></ul>34
    36. 36. Diffuse Alveolar Hemorrhage <ul><li>association WG - 43% capillaritis, 7% DAH </li></ul><ul><li>Microscopic polyarteritis -30% SLE - 7% </li></ul><ul><li>Goodpasture - 75% </li></ul><ul><li> Beh ç et, H-S Purpura - 6.5% </li></ul><ul><li>IgA nephropathy – 1%-3% </li></ul><ul><li>APS - 1% - 3% </li></ul>35
    37. 37. Flowcytometric BALF analysis DAH erythrocytes are lysed elevated activated neutrophils Additional findings: hemoptysis, mucosal/skin hemorrhagic ulcerations and arthritis MPO -ANCA + serum chest-CT- diffuse pulmonary infiltrates Diclofenac - induced small vessel vasculitis rather than an idiopathic 36
    38. 38. Autoimmune - Mediated Lung Disease in conclusion <ul><li>serology - autoantibodies </li></ul><ul><li>immunologic diagnosis - BALF - hemorrhagic alveolitis - over 80% of the cells are activated, peripheral blood neutrophils </li></ul><ul><li>immunofluorescence - linear or granular deposition of immune complexes along glomerular / alveolar basement membrane, pulmonary arteries, veins </li></ul><ul><li>treatment - immune suppression (corticosteroid, cyclophosphamide), plasmapheresis </li></ul><ul><li>Add IVIG - 250 - 400mg/kg/d - no relapse ! </li></ul>37
    39. 39. Interstitial Lung Disease with BALF Neutrophilia <ul><li>Idiopathic pulmonary fibrosis (15-40 %) </li></ul><ul><li>Cryptogenic organizing pneumonia (40-70 %) </li></ul><ul><li>Inorganic dust diseases Asbestosis Silicosis </li></ul><ul><li>Cigarette smoking (<10%) </li></ul><ul><li>Pulmonary Langerhans cell histiocytosis (Histiocytosis X) </li></ul><ul><li>Hypersensitivity pneumonitis (acute) </li></ul><ul><li>Sarcoidosis (advanced) </li></ul><ul><li>DAH </li></ul>38
    40. 40. Idiopathic Pulmonary Fibrosis Consensus 2000 <ul><li>definition - a specific form of fibrosing interstitial pneumonia of unknown origin; manifests over several years; histopathologic pattern of usual interstitial pneumonitis upon analysis of a surgical lung biopsy </li></ul><ul><li>epidemiology – 20.2 men and 13.2 women per 100 000; mean age 66 </li></ul><ul><li>familial IPF 0.5%-2% of all IPF cases </li></ul><ul><li>etiology - unknown, the need of genetic markers is open </li></ul><ul><li>- samples of DNA are collected for future investigation of genetic markers - Human Genome Project </li></ul><ul><li>- the pathologic process is a consequence of the interaction between inflammatory cells, pulmonary epithel. cells and endothelial cells with a stimulation of fibrogenesis </li></ul>definition, etiology, epidemiology 39
    41. 41. <ul><li>major immunologic features </li></ul><ul><li>- immune complexes are present in serum and in the lungs in the early, active phase </li></ul><ul><li>- immune complexes activate the lung macrophages, which release a neutrophil’s chemokines; neutrophils became activated and generate reactive, oxygen radicals & growth signals for mesenchymal cells </li></ul><ul><li>- the cell-cell interactions, inflammatory mediators and growth factors stimulate the fibrogenesis - fibroproliferative plaque </li></ul><ul><li>immunologic pathogenesis - the antigenic stimuli remain unknown; the immune complexes don’t trigger the C, but are priming the lung Ma, Eos, Lympho, Neu and the parenchymal epithelial and endothelial cells </li></ul>immunologic features and pathogenesis Idiopathic Pulmonary Fibrosis 40
    42. 42. Idiopathic Pulmonary Fibrosis Immune Pathogenesis 41
    43. 43. Idiopathic Pulmonary Fibrosis <ul><li>clinical picture - insidious onset, dyspnea, nonproductive cough, dry bibasilar crackles, trommestikkfinger </li></ul><ul><li>immunologic diagnosis </li></ul><ul><li>blood- ANA, RF, increased Ig </li></ul><ul><li>BALF - cellular alveolitis consisting of Ma, Neu, Ly, Eos </li></ul><ul><li>BALF analysis estimates the course of the disease </li></ul><ul><li>acute stage </li></ul><ul><li>cellular alveolitis (Ma & Neu, Eos, rare Lympho ) </li></ul><ul><li>subacute stage </li></ul><ul><li>cellular depletion - parenchymal destruction with fibrosis </li></ul><ul><li>Differential Diagnosis- clinical; X-ray/HRCT; pathological pattern </li></ul>clinical features, course, immunoligic diagnosis, DD 42
    44. 44. <ul><li>Chronic aspiration </li></ul><ul><li>Rheumatic diseases, collagen vascular disease </li></ul><ul><li>APS - fibrosing alveolitis </li></ul><ul><li>Eosinophilic lung infiltrates </li></ul><ul><li>Hypersensitivity pneumonitis </li></ul><ul><li>Infections - mycobacteria, viral, fungial </li></ul><ul><li>Pneumoconiosis </li></ul><ul><li>Irradiation </li></ul><ul><li>Sarcoidosis </li></ul>Differential Diagnosis If you could exclude the known causes for pulmonary fibrosis You can make the diagnosis IPF ! Idiopathic Pulmonary Fibrosis 43
    45. 45. Idiopathic Pulmonary Fibrosis General BALF Results <ul><li>lymphocytosis - god GK response </li></ul><ul><li>low Neu, high CD4/CD8, low CD8+/S6F1 </li></ul><ul><li>increased Neu - early mortality, non GK response </li></ul><ul><li>increased Neu + Eo - god cylophosphamide response </li></ul><ul><li>nonresponders – sustained elevation of Neu and Eos </li></ul>44
    46. 46. Flowcytometric BALF analysis Pulmonary fibrosis elevated neutrophils - 61% phenotypicaly activated patterns CD62L- / CD11b++/ CD16+ positiv ACA serum 45
    47. 47. Pulmonary Eosinophilic Syndromes Classification <ul><li>Idiopathic Acute Eosinophilic Pneumonia </li></ul><ul><li>Idiopathic Chronic Eosinophilic Pneumonia </li></ul><ul><li>Churg-Strauss Syndrome </li></ul><ul><li>Idiopathic Hypereosinophilic Syndrome </li></ul><ul><li>Helminthic Infection-related eosinophilic lung diseases </li></ul><ul><li>Fungal Infection-related eosinophilic lung diseases </li></ul><ul><li>Drug- and Toxin-induced eosinophilic lung diseases </li></ul><ul><li>Neoplasms - Peripheral and/or localized pulmonary eosinophilic infiltration </li></ul>46
    48. 48. Pulmonary Eosinophilic Syndromes Main Diagnostic Criteria <ul><li>Peripheral blood eosinophilia ( >500 Eos/mm 3 ) </li></ul><ul><li>BAL should be performed </li></ul><ul><li>Increased eosinophils in BALF: </li></ul><ul><li>a cut-off of ≥25% for the diagnosis of AEP </li></ul><ul><li>a cut-off of ≥40 percent for the diagnosis of CEP </li></ul><ul><li>Radiographically or tomographically identified pulmonary abnormalities - need to be combined with other diagnostic methods </li></ul><ul><li>Lung tissue eosinophilia demonstrated in transbronchial or open lung biopsies </li></ul><ul><li>Serology - CRP, IgE levels, ELISA for coccidioidomycosis, ABPA, helminthes infections – can help to support diagnoses </li></ul>47
    49. 49. Interstitial lung disease associated with BALF Eosinophilia <ul><li>High count (>30%) </li></ul><ul><li>Tropical pulmonary eosinophilia (40%-70%) </li></ul><ul><li>Eosinophilic pneumonia (>40%) </li></ul><ul><li>Mild to moderate counts (<30%) </li></ul><ul><li>Idiopathic pulmonary fibrosis (<10%) </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>Pulmonary Langerhans cell histiocytosis (Histiocytosis X) </li></ul><ul><li>Drug-induced pneumonitis </li></ul><ul><li>Connective tissue disease </li></ul>48
    50. 50. Flowcytometric analysis Peripheral Eosinophilia Discrimination of ACTIVATED Eos High sideward scatter High degree of autofluorescence CD16-/ CD49d+ CD69+/ HLA -DR+ 49
    51. 51. References <ul><li>Demedts M et al. Eur Respir J Suppl.2001, 32, 2-16. </li></ul><ul><li>Crapo JD et al. Am J Respir Crit Care Med, 2000, 162 (5), 1983-6. </li></ul><ul><li>Statement on Sarcoidosis. Am J Respir Crit Care Med, 1999, 160, 2, 736-755. Statement on Sarcoidosis. Am Fam Physician, 2001, 15, 6, 553-556. </li></ul><ul><li>Andreeva H. et al. Allergy & Asthma, 6, 2001, 25-30. </li></ul><ul><li>Israel-Assayag E et al. Am J Respir Crit Care Med, 1999, 159,1830- 34. </li></ul><ul><li>Mittoo S et al. Respir Med, 2009, 103 (8): 1152-8. </li></ul><ul><li>Meltzer EB&Noble PW. Orph J Rare Dis, 2008, 26, 3-8. </li></ul><ul><li>Marchand E&Cordier J-F. Orph J Rare Dis, 2006, 1, 1-11. </li></ul><ul><li>BAL Cooperative Group. Am Rev Respir Dis, 1990, 141:169. </li></ul>50
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