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
Connective tissue
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 Connective tissue
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. HONEYCOMB LUNG

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. Primary- Unclassified
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

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 Acute interstitial pneumonitis (Hamman-Rich syndrome)
Idiopathic pulmonary fibrosis “IPF”
Familial idiopathic pulmonary fibrosis
Desquamative interstitial pneumonitis
Respiratory bronchiolitis
Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonitis
Lymphocytic interstitial pneumonia (Sjögren's syndrome, connective tissue disease, AIDS, Hashimoto's thyroiditis)
Autoimmune pulmonary fibrosis (inflammatory bowel disease, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia)

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 Minor 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 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 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