Interstitial Lung Disease

1. Interstitial Lung Disease Julye N. Carew, M.D. January 12, 2007

2. Interstitial Lung Diseases • Definition • Clinical Presentation and evaluation • Radiographic Features • Classification • Treatment • Prognosis

3. Definition • “Interstitial lung disease”- a misnomer • Few cells in the interstitium of the normal lung • Injury to basement membrane shared by epithelium and endothelium • Increased alveolar permeability and spillage of serum contents into the alveolar space and recruitment of fibroblasts • Collagen deposition • Also injury to small airways=respiratory bronchioles, alveolar ducts and terminal bronchioles

4. Alveolar/Interstitial Space Matrix Connectivetissue Murray and Nadel, Text of Resp. Medicine

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. Pathogenesis • UNKNOWN!!! • Some understanding of the mechanism of injury • Initiating injuries are likely multiple= inhaled, sensitization to allergens, circulatory • With continued injury, “repair” process continues with additional fibroproliferation that is unchecked

7. ILD • 81 in 100,000 prevalence in men • 67 in 100,000 in women • 32.5 in 100,000 incidence in men • 26 in 100,000 in women • 200 in 100,000 incidence in age >75 • 30-40% of all ILD “IPF”

8. ILD • 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

9. Evaluation of ILD • EXTENSIVE HISTORY • AGE, GENDER, UNDERLYING COMORBIDITIES, DRUGS, SMOKING, OCCUPATIONAL HISTORY, HOBBIES, PETS, FAMHX • DURATION OF SYMPTOMS • PHYSICAL EXAM • LABORATORIES • IMAGING • SPIROMETRY, LUNG VOLUMES AND DLCO

10. Laboratories • LFTs, CBC • ANA, RF, hypersensitivity panels, ANCA, anti-GBM • ?CRP, ESR

11. Pulmonary function • Spirometry • Lung volumes • Diffusion capacity

12. Spirometry UpToDate, 2007

13. Lung Volumes UpToDate, 2007

14. Diffusion capacity UpToDate, 2007

15. Diffusion Matrix Connectivetissue Murray and Nadel, Text of Resp. Medicine

16. Imaging • PA/LAT CXR • HRCT

17. GROUND GLASS Schwarz, ILD, 2003, RB

18. NODULAR GROUND GLASS Schwarz, ILD, 2003, HP

19. INTRALOBULAR SEPTAL THICKENING Schwarz, ILD, 2003, LC

20. RETICULAR INFILTRATES Schwarz, ILD, 2003, HP

21. HONEYCOMB LUNG Schwarz, ILD, 2003

22. HONEYCOMBLUNG

23. Clinical Classification • Connective Tissue Diseases • Drug-induced • Primary Unclassified • Occupational • Idiopathic Disorders

24. Clinical Classification-- CTD • Scleroderma • Polymyositis-dermatomyositis • Systemic lupus erythematosus • Rheumatoid arthritis** • Mixed connective tissue disease • Ankylosing spondylitis • Behcet’s • Sjogren’s syndrome

25. RA

26. Rheumatoid Arthritis • Interstitial fibrosis • Male predominance 3:1 • High titers of RF and rheumatoid nodules • Occurs in 33% of all RA patients • Usually patients are dyspneic, but also limited by joint disease • Therapies may cause fibrosis (gold, methotrexate, penicillamine)

27. RA Schwarz and King, ILD 2003

28. Drugs Antibiotics--nitrofurantoin, sulfasalazine, ethambutol Antiarrhythmics--amiodarone, tocainide, propranolol Anti-inflammatories--gold, penicillamine Anticonvulsants--dilantin Chemotherapeutic agents--mitomycin C, bleomycin, busulfan, cyclophosphamide, chlorambucil, methotrexate, azathioprine, BCNU [carmustine], procarbazine Therapeutic radiation Oxygen toxicity Narcotics Cocaine Paraquat

29. Sarcoidosis Eosinophilic granuloma Amyloidosis Lipoid pneumonia Lymphangitic carcinomatosis Broncholaveolar carcinoma Pulmonary lymphoma Gaucher's disease Niemann-Pick disease Hermansky-Pudlak syndrome Neurofibromatosis LAM Tuberous sclerosis Acute respiratory distress syndrome AIDS Bone marrow transplantation Postinfectious Eosinophilic pneumonia Alveolar proteinosis Diffuse alveolar hemorrhage syndromes Alveolar microlithiasis Metastatic calcification Primary- Unclassified

30. Occupational • Silicosis- tile, glass  • Asbestosis   • Hard-metal pneumoconiosis   • Coal worker's pneumoconiosis   • Berylliosis-fluorescent bulbs, dental, electronics  • Aluminum oxide fibrosis-abrasives  • Talc pneumoconiosis   • Siderosis (arc welder)-iron foundry, welders • Stannosis (tin)

31. Idiopathic

32. Idiopathic ILD • Diagnosis is made based upon clinical history, radiographic findings and pathology • Some pathologic findings are pathognomonic for a particular disease, while others are suggestive in the correct clinical setting

33. IPF • Major Criteria • • Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases • • 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 ] • • Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans • • Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis • Minor Criteria • • Age > 50 yr • • Insidious onset of otherwise unexplained dyspnea on exertion • • Duration of illness 3 mo • • Bibasilar, inspiratory crackles (dry or “Velcro” type in quality) IPF consensus statement, 2000, AJRCCM

34. Idiopathic pulmonary fibrosis Pathology=UIP Schwarz, ILD, 2003

35. Treatment • Very limited literature, NO RANDOMIZED TRIALS • ATS recommendations: • Prednisone 60 mg daily tapering or 20 mg plus Cytoxan 100-120 mg/day • Retrospective case review (n=78 with OLB), UIP=38, NSIP=28, RB/DIP=13 • At 6 months, 11% UIP, 29% NSIP, 80% RB/DIP improved Nicholson, AJRCCM, 2000

36. Treatment of IPF • Azathioprine

37. Treatment of IPF • 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 • NAC

38. Treatment of IPF • Gamma interferon • Th-1 cytokine that induces CD4 cells to the Th1 phenotype, inhibits the proliferation of fibroblasts and downregulates TGF-β • Administered subcu three times weekly • Flu-like symptoms • Mixed results with this drug in trials, but may be due to the fact that it needs to be used earlier in disease

39. Treatment of IPF • Pirfenidone • Pyridone molecule that inhibits TGF-β-stimulated collagen production • Ameliorates bleomycin-induced fibrosis in hamsters • Undergoing stage III trials

40. IPF King, et al., AJRCCM, 2001

41. DIP • Clinical classification=pathology • DISEASE OF SMOKERS!! • 4th-5th decades • Subacute cough and dyspnea • CT shows diffuse GG infiltrates • Smoking cessation

42. DIP Schwarz, ILD, 2003

43. DIP Leslie, Clinics in Chest Med, 2006

44. RB-ILD • SMOKING DISEASE!! • Similar to DIP, but pathology slightly different, in peribronchiolar distribution • Smoking cessation +/- steroids

45. RB-ILD Schwarz, ILD, 2003

46. LIP • Characterized by monotonous sheets of polyclonal lymphocytes • Clinical=pathology • Uncommon • Associated with Sjogren’s and AIDS • May remit with steroids and other ISD, progress to fibrosis, lead to infectious complications, or develop lymphoma

47. LIP Leslie, Clinics in Chest Med, 2006

48. NSIP • Originally represented “difficult to characterize” • Clearly represents a separate disease from IPF • Primary and secondary forms (HP, drugs, CVD, AIDS and transplants) • Second most common diagnosis • Middle-aged, majority smoker’s • Surgical biopsy required to make diagnosis • HOMOGENEOUS • ?? Early UIP

49. NSIP Leslie, Chest, 128:5, 2005

50. Interstitial pneumonias American Thoracic Society/European Respiratory Society classification of the idiopathic interstitial pneumonias Histologic pattern Clinico-radiologic-pathologic • UIP IPF • NSIP NSIP • Organizing pneumonia COP • Diffuse alveolar damage (DAD) AIP • Respiratory bronchiolitis pattern RBILD • Desquamative pattern DIP • Lymphoid pattern LIP