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  1. 1. Interstitial Lung Disease Julye N. Carew, M.D. January 12, 2007
  2. 2. Interstitial Lung Diseases <ul><li>Definition </li></ul><ul><li>Clinical Presentation and evaluation </li></ul><ul><li>Radiographic Features </li></ul><ul><li>Classification </li></ul><ul><li>Treatment </li></ul><ul><li>Prognosis </li></ul>
  3. 3. Definition <ul><li>“ Interstitial lung disease”- a misnomer </li></ul><ul><li>Few cells in the interstitium of the normal lung </li></ul><ul><li>Injury to basement membrane shared by epithelium and endothelium </li></ul><ul><li>Increased alveolar permeability and spillage of serum contents into the alveolar space and recruitment of fibroblasts </li></ul><ul><li>Collagen deposition </li></ul><ul><li>Also injury to small airways=respiratory bronchioles, alveolar ducts and terminal bronchioles </li></ul>
  4. 4. Alveolar/Interstitial Space Murray and Nadel, Text of Resp. Medicine Connective tissue Matrix
  5. 5. Pathogenesis Epithelial cell apoptosis with loss of basement membrane integrity: production of growth factors in response to alveolar epithelial injury with hyperplastic type II cells and myofibroblast recruitment Noble, et al. Clinics in Chest Med, Dec 2004
  6. 6. Pathogenesis <ul><li>UNKNOWN!!! </li></ul><ul><li>Some understanding of the mechanism of injury </li></ul><ul><li>Initiating injuries are likely multiple= inhaled, sensitization to allergens, circulatory </li></ul><ul><li>With continued injury, “repair” process continues with additional fibroproliferation that is unchecked </li></ul>
  7. 7. ILD <ul><li>81 in 100,000 prevalence in men </li></ul><ul><li>67 in 100,000 in women </li></ul><ul><li>32.5 in 100,000 incidence in men </li></ul><ul><li>26 in 100,000 in women </li></ul><ul><li>200 in 100,000 incidence in age >75 </li></ul><ul><li>30-40% of all ILD “IPF” </li></ul>
  8. 8. ILD <ul><li>Due to increasing numbers of cytotoxic drugs, increased detection of occupational lung disease and increasing life expectancy, as well as better imaging and diagnostic testing the incidence of these diseases is expected to rise </li></ul>
  9. 9. Evaluation of ILD <ul><li>EXTENSIVE HISTORY </li></ul><ul><li>AGE, GENDER, UNDERLYING COMORBIDITIES, DRUGS, SMOKING, OCCUPATIONAL HISTORY, HOBBIES, PETS, FAMHX </li></ul><ul><li>DURATION OF SYMPTOMS </li></ul><ul><li>PHYSICAL EXAM </li></ul><ul><li>LABORATORIES </li></ul><ul><li>IMAGING </li></ul><ul><li>SPIROMETRY, LUNG VOLUMES AND DLCO </li></ul>
  10. 10. Laboratories <ul><li>LFTs, CBC </li></ul><ul><li>ANA, RF, hypersensitivity panels, ANCA, anti-GBM </li></ul><ul><li>?CRP, ESR </li></ul>
  11. 11. Pulmonary function <ul><li>Spirometry </li></ul><ul><li>Lung volumes </li></ul><ul><li>Diffusion capacity </li></ul>
  12. 12. Spirometry UpToDate, 2007
  13. 13. Lung Volumes UpToDate, 2007
  14. 14. Diffusion capacity UpToDate, 2007
  15. 15. Diffusion Murray and Nadel, Text of Resp. Medicine Connective tissue Matrix
  16. 16. Imaging <ul><li>PA/LAT CXR </li></ul><ul><li>HRCT </li></ul>
  17. 17. Schwarz, ILD, 2003, RB GROUND GLASS
  18. 18. Schwarz, ILD, 2003, HP NODULAR GROUND GLASS
  19. 19. Schwarz, ILD, 2003, LC INTRALOBULAR SEPTAL THICKENING
  20. 20. Schwarz, ILD, 2003, HP RETICULAR INFILTRATES
  21. 21. Schwarz, ILD, 2003 HONEYCOMB LUNG
  22. 22. HONEYCOMB LUNG
  23. 23. Clinical Classification <ul><li>Connective Tissue Diseases </li></ul><ul><li>Drug-induced </li></ul><ul><li>Primary Unclassified </li></ul><ul><li>Occupational </li></ul><ul><li>Idiopathic Disorders </li></ul>
  24. 24. Clinical Classification-- CTD <ul><li>Scleroderma </li></ul><ul><li>Polymyositis-dermatomyositis </li></ul><ul><li>Systemic lupus erythematosus </li></ul><ul><li>Rheumatoid arthritis** </li></ul><ul><li>Mixed connective tissue disease </li></ul><ul><li>Ankylosing spondylitis </li></ul><ul><li>Behcet’s </li></ul><ul><li>Sjogren’s syndrome </li></ul>
  25. 25. RA
  26. 26. Rheumatoid Arthritis <ul><li>Interstitial fibrosis </li></ul><ul><li>Male predominance 3:1 </li></ul><ul><li>High titers of RF and rheumatoid nodules </li></ul><ul><li>Occurs in 33% of all RA patients </li></ul><ul><li>Usually patients are dyspneic, but also limited by joint disease </li></ul><ul><li>Therapies may cause fibrosis (gold, methotrexate, penicillamine) </li></ul>
  27. 27. RA Schwarz and King, ILD 2003
  28. 28. Drugs <ul><li>Antibiotics-- nitrofurantoin, sulfasalazine, ethambutol </li></ul><ul><li>Antiarrhythmics-- amiodarone, tocainide, propranolol </li></ul><ul><li>Anti-inflammatories-- gold, penicillamine </li></ul><ul><li>Anticonvulsants-- dilantin </li></ul><ul><li>Chemotherapeutic agents-- mitomycin C, bleomycin, busulfan, cyclophosphamide, chlorambucil, methotrexate, azathioprine, BCNU [carmustine], procarbazine </li></ul><ul><li>Therapeutic radiation </li></ul><ul><li>Oxygen toxicity </li></ul><ul><li>Narcotics </li></ul><ul><li>Cocaine Paraquat </li></ul>
  29. 29. Primary- Unclassified <ul><li>Sarcoidosis </li></ul><ul><li>Eosinophilic granuloma </li></ul><ul><li>Amyloidosis </li></ul><ul><li>Lipoid pneumonia </li></ul><ul><li>Lymphangitic carcinomatosis </li></ul><ul><li>Broncholaveolar carcinoma </li></ul><ul><li>Pulmonary lymphoma </li></ul><ul><li>Gaucher's disease </li></ul><ul><li>Niemann-Pick disease </li></ul><ul><li>Hermansky-Pudlak syndrome </li></ul><ul><li>Neurofibromatosis </li></ul><ul><li>LAM </li></ul><ul><li>Tuberous sclerosis </li></ul><ul><li>Acute respiratory distress syndrome </li></ul><ul><li>AIDS </li></ul><ul><li>Bone marrow transplantation </li></ul><ul><li>Postinfectious </li></ul><ul><li>Eosinophilic pneumonia </li></ul><ul><li>Alveolar proteinosis </li></ul><ul><li>Diffuse alveolar hemorrhage syndromes </li></ul><ul><li>Alveolar microlithiasis </li></ul><ul><li>Metastatic calcification </li></ul>
  30. 30. Occupational <ul><li>Silicosis- tile, glass  </li></ul><ul><li>Asbestosis   </li></ul><ul><li>Hard-metal pneumoconiosis   </li></ul><ul><li>Coal worker's pneumoconiosis   </li></ul><ul><li>Berylliosis-fluorescent bulbs, dental, electronics  </li></ul><ul><li>Aluminum oxide fibrosis-abrasives  </li></ul><ul><li>Talc pneumoconiosis   </li></ul><ul><li>Siderosis (arc welder)-iron foundry, welders </li></ul><ul><li>Stannosis (tin) </li></ul>
  31. 31. Idiopathic Autoimmune pulmonary fibrosis (inflammatory bowel disease, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia) Lymphocytic interstitial pneumonia (Sjögren's syndrome, connective tissue disease, AIDS, Hashimoto's thyroiditis) Nonspecific interstitial pneumonitis Cryptogenic organizing pneumonia Respiratory bronchiolitis Desquamative interstitial pneumonitis Familial idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis “IPF” Acute interstitial pneumonitis (Hamman-Rich syndrome)
  32. 32. Idiopathic ILD <ul><li>Diagnosis is made based upon clinical history, radiographic findings and pathology </li></ul><ul><li>Some pathologic findings are pathognomonic for a particular disease, while others are suggestive in the correct clinical setting </li></ul>
  33. 33. IPF <ul><li>Major Criteria </li></ul><ul><ul><li>• Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases </li></ul></ul><ul><ul><li>• Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1 /FVC ratio) and impaired gas exchange [increased AaPo2 with rest or exercise or decreased DLCO ] </li></ul></ul><ul><ul><li>• Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans </li></ul></ul><ul><ul><li>• Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis </li></ul></ul><ul><li>Minor Criteria </li></ul><ul><ul><li>• Age > 50 yr </li></ul></ul><ul><ul><li>• Insidious onset of otherwise unexplained dyspnea on exertion </li></ul></ul><ul><ul><li>• Duration of illness 3 mo </li></ul></ul><ul><ul><li>• Bibasilar, inspiratory crackles (dry or “Velcro” type in quality) </li></ul></ul>IPF consensus statement, 2000, AJRCCM
  34. 34. Idiopathic pulmonary fibrosis <ul><li>Pathology=UIP </li></ul>Schwarz, ILD, 2003
  35. 35. Treatment <ul><li>Very limited literature, NO RANDOMIZED TRIALS </li></ul><ul><li>ATS recommendations: </li></ul><ul><li>Prednisone 60 mg daily tapering or 20 mg plus Cytoxan 100-120 mg/day </li></ul><ul><li>Retrospective case review (n=78 with OLB), UIP=38, NSIP=28, RB/DIP=13 </li></ul><ul><li>At 6 months, 11% UIP, 29% NSIP, 80% RB/DIP improved </li></ul>Nicholson, AJRCCM, 2000
  36. 36. Treatment of IPF <ul><li>Azathioprine </li></ul>
  37. 37. Treatment of IPF <ul><li>Colchicine 1998 and 2000 studies (Douglas et al., AJRCCM) compared colchicine to prednisone and other combinations and showed no difference in survival in any of the groups but with fewer side effects with Colchicine </li></ul><ul><li>NAC </li></ul>
  38. 38. Treatment of IPF <ul><li>Gamma interferon </li></ul><ul><li>Th-1 cytokine that induces CD4 cells to the Th1 phenotype, inhibits the proliferation of fibroblasts and downregulates TGF- β </li></ul><ul><li>Administered subcu three times weekly </li></ul><ul><li>Flu-like symptoms </li></ul><ul><li>Mixed results with this drug in trials, but may be due to the fact that it needs to be used earlier in disease </li></ul>
  39. 39. Treatment of IPF <ul><li>Pirfenidone </li></ul><ul><li>Pyridone molecule that inhibits TGF- β -stimulated collagen production </li></ul><ul><li>Ameliorates bleomycin-induced fibrosis in hamsters </li></ul><ul><li>Undergoing stage III trials </li></ul>
  40. 40. IPF King, et al., AJRCCM, 2001
  41. 41. DIP <ul><li>Clinical classification=pathology </li></ul><ul><li>DISEASE OF SMOKERS!! </li></ul><ul><li>4 th -5 th decades </li></ul><ul><li>Subacute cough and dyspnea </li></ul><ul><li>CT shows diffuse GG infiltrates </li></ul><ul><li>Smoking cessation </li></ul>
  42. 42. DIP Schwarz, ILD, 2003
  43. 43. DIP Leslie, Clinics in Chest Med, 2006
  44. 44. RB-ILD <ul><li>SMOKING DISEASE!! </li></ul><ul><li>Similar to DIP, but pathology slightly different, in peribronchiolar distribution </li></ul><ul><li>Smoking cessation +/- steroids </li></ul>
  45. 45. RB-ILD Schwarz, ILD, 2003
  46. 46. LIP <ul><li>Characterized by monotonous sheets of polyclonal lymphocytes </li></ul><ul><li>Clinical=pathology </li></ul><ul><li>Uncommon </li></ul><ul><li>Associated with Sjogren’s and AIDS </li></ul><ul><li>May remit with steroids and other ISD, progress to fibrosis, lead to infectious complications, or develop lymphoma </li></ul>
  47. 47. LIP Leslie, Clinics in Chest Med, 2006
  48. 48. NSIP <ul><li>Originally represented “difficult to characterize” </li></ul><ul><li>Clearly represents a separate disease from IPF </li></ul><ul><li>Primary and secondary forms (HP, drugs, CVD, AIDS and transplants) </li></ul><ul><li>Second most common diagnosis </li></ul><ul><li>Middle-aged, majority smoker’s </li></ul><ul><li>Surgical biopsy required to make diagnosis </li></ul><ul><li>HOMOGENEOUS </li></ul><ul><li>?? Early UIP </li></ul>
  49. 49. NSIP Leslie, Chest, 128:5, 2005
  50. 50. Interstitial pneumonias <ul><li>American Thoracic Society/European Respiratory Society classification of the idiopathic interstitial pneumonias </li></ul><ul><li>Histologic pattern Clinico-radiologic-pathologic </li></ul><ul><li>UIP IPF </li></ul><ul><li>NSIP NSIP </li></ul><ul><li>Organizing pneumonia COP </li></ul><ul><li>Diffuse alveolar damage (DAD) AIP </li></ul><ul><li>Respiratory bronchiolitis pattern RBILD </li></ul><ul><li>Desquamative pattern DIP </li></ul><ul><li>Lymphoid pattern LIP </li></ul>

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