1. Idiopathic Interstitial Pneumonia
Trying to make sense of the letters
Michelle Thompson, MS4
February 2006

2. Idiopathic Interstitial Pneumonias (IIP’s)
Group of uncommon parenchymal lung diseases
Similar pattern of lung injury to those seen in collagen vascular disease, drug reactions, asbestosis and chronic hypersensitivity pneumonitis
“Idiopathic” reserved for conditions in which the cause of lung injury pattern is unknown

3. Classification
“So diverse are the different forms and so varied the conditions under which this change occurs that a proper classification is extremely difficult”
Osler speaking of IIP (1892)

4. Classification
A number of classification schemes, names and definitions have been associated with the IIP’s over the years leading to a great deal of confusion (and article titles referring to “alphabet soup”)
American Thoracic Society and European Respiratory Society (ATS/ERS) met in 2002 to clarify nomenclature and describe the clinical, radiologic and histologic patterns of these conditions
Participants included thoracic radiologists, pulmonologists and pulmonary pathologists

5. Idiopathic Interstitial Pneumonias (clinical nomenclature as proposed by ATS/ERS)
Include (in order of frequency):
Usual Interstitial Pneumonia (UIP)
Non-specific Interstitial Pneumonia (NSIP)
Cryptogenic Organizing pneumonia (COP)
Acute Interstitial Pneumonia (AIP)
Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD)
Desquamative Interstital Pneumonia (DIP)
Lymphoid Interstitial Pneumonia (LIP)

6. Diagnosis of IIP
ATS/ERS guidelines emphasize the importance of combined clinical, radiologic and histologic diagnosis of IIP’s
The MOST IMPORTANT distinction is between UIP and the other IIP’s due to prognostic and therapeutic implications

7. Diagnosis of IIP HIGHLIGHTS:
If HRCT gives confident diagnosis of UIP, no lung biopsy needed and diagnostic process is done
If equivocal findings on HRCT, then surgical lung biopsy considered
Figure from UpToDate, adapted from ATS/ERS guidelines

8. Usual Interstitial Pneumonia (UIP) Also known as Idiopathic pulmonary fibrosis (IPF)
Most common IIP
Primarily a fibrotic condition

9. Clinical Findings in UIP
Age >50
Slight male predominance
Symptoms usually present 6 months prior to presentation
Progressive shortness of breath, non-productive cough
Physical exam: end-inspiratory crackles at lung bases “velcro” lung
Lung function tests: restrictive pattern
Decreased DLCO

10. Histologic Findings in UIP
Histology:
Fibroblastic foci at the edge of dense scars
Subpleural, paraseptal and/or peribronchovascular distribution
Dense fibrosis causes remodeling of lung architecture and frequent honeycomb fibrosis
Two distinguishing characteristics from other IIP’s
Temporal heterogeneity: fibrotic lesions of different stages within same biopsy specimen
Spatial heterogeneity: patchy lung involvement

11. Histology of UIP Left to right:
Patchy fibrosis, subpleural distribution. Some lymphoid aggregates (black arrow). Areas of normal lung also present.
Fibroblastic focus (white arrow) adjacent to dense collagenous scar.
Figures from Lynch et al. 2005

12. Radiographic features of UIP
Radiographs
Bilateral and basilar irregular linear opacities (close to 100% of cases)
Ground glass opacities
Honeycombing
Loss of lung volumes
Normal radiograph in 2-8% of cases

13. Early changes UIP: peripheral, irregular linear opacities and normal lung volumes
Late features UIP: same patient 2 years later. Peripheral, irregular linear opacities and progressive loss of lung volume
Images from McAdams et al., 1996

14. Late features UIP showing bilateral, coarse, reticular opacities with architectural distortion, volume loss and honeycombing
Images from McAdams et al., 1996

15. CT features of UIP Reticular opacities with traction bronchiectasis
Honeycombing (96% of cases)
Ground glass opacity (less extensive than reticular pattern)
Architectural distortion reflecting fibrosis
Distribution: basal/peripheral and patchy

16. CT features of UIP
Left: left lower lobe shows peripheral ground-glass opacity and reticular patterns with traction bronchiectasis (arrow)
Right: same patient two years later with progression of ground-glass to reticular pattern and honeycombing and progression of traction bronchiectasis
Images from Lynch et al., 2005

17. Clinical Course in UIP
Gradual deterioration, with possible periods of rapid decline
Mean survival is years from time of diagnosis
As UIP is predominantly a fibrotic condition, does not typically respond to steroid treatment

18. Non-specific Interstitial Pneumonia (NSIP)
Second most frequently diagnosed IIP
more favorable prognosis than IPF/UIP
ATS/ERS guidelines stress that a finding of an NSIP pattern on biopsy should “prompt the clinician to redouble efforts to find potential causes” (collagen vascular disease, exposures)

19. Clinical findings in NSIP
Mean age of onset is 40-50
No sexual predominance
No association with cigarette smoking
Gradual onset, some patients may have subacute course
The median duration of symptoms before diagnosis is 6-31 mo in different series
Symptoms: progressive SOB, cough, fatigue
Half present with history of weight loss
Physical Exam: crackles at lung bases
Lung function tests: restrictive pattern with decreased DLCO

20. Histology of NSIP
Because features are “non-specific”, histology is difficult to define
Spatially homogenous alveolar wall thickening
Temporal homogenous pattern
Two main types:
1. Fibrotic: dense or loose interstitial fibrosis lacking temporal heterogeneity or patchy features
2. Cellular:
Mild-moderate interstitial chronic inflammation
Type II pneumocyte hyperplasia in areas of inflammation

21. Fibrotic NSIP
NSIP with fibrosing pattern. Alveolar walls (arrows) show thickening caused by fibrosis. No fibroblastic foci are present.
Image from Lynch et al., 2005

22. Cellular NSIP
Photomicrograph showing NSIP with cellular pattern. Alveolar walls (arrows) are infiltrated by a chronic inflammatory infiltrate.
Image from Lynch et al., 2005

23. Fibrotic vs. Cellular NSIP
Main importance is prognostic. Patients with predominant fibrosis have a poorer prognosis than those with cellular NSIP
Figure below shows survival curves for patients with UIP, fibrotic NSIP (FNSIP) and Cellular NSIP (CNSIP). Those with CNSIP are shown to have the best survival.
Figure from Lynch et al., 2005

24. Radiographic Features of NSIP
Irregular linear opacities
Air space consolidation
Bilateral and basilar pattern
Radiograph normal in 14% of cases

25. Radiographic features of NSIP
Basilar opacities and normal lung volumes
Image from McAdams et al., 1996

26. CT features of NSIP Scattered ground glass opacities
Basal predominance
Consolidation uncommon and honeycombing rare
Irregular linear opacities
Fibrosis (lobar volume loss, reticular pattern, and/or traction bronchiectasis)

27. CT features of NSIP
Top: Fibrotic NSIP. Ground glass opacity with traction bronchiectasis (arrows) Arrowhead indicating posterior displacement of left major fissure denoting volume loss
Bottom: Cellular NSIP. Ground glass opacity with reticular pattern.
Images from Lynch et al., 2005

28. Clinical Course of NSIP
Significantly better prognosis than UIP
Evidence for corticosteroid efficacy is from retrospective reviews of observational studies. (25-30% of patients improved)*
Relapse may occur
*Collard et al., 2003

29. Cryptogenic Organizing Pneumonia (COP) (IIP formerly known as BOOP)
Third most common IIP
Although process is primarily intraalveolar, it is included with IIP’s because of its idiopathic nature and because its appearance may overlap with other IIP’s

30. Organizing Pneumonia: (COP or BOOP)
Histology:
Organizing pneumonia-intraluminal organization in distal air spaces
Patchy distribution
Preservation of lung architecture
Uniform temporal appearance
Mild chronic interstitial inflammation
Edematous granulation-type tissue within airspaces: bronchioles and alveolar ducts and alveoli

31. Clinical findings in COP
Cough and shortness of breath
Relatively short duration of symptoms (1-6 months)
Patients often diagnosed first with pneumonia but fail to respond to antibiotics as not infectious etiology
Physical exam:
PFT’s: restrictive pattern
equal sex distribution but nonsmokers outnumber
smokers by 2:1. Mean age of onset is 55 yr
Continuing weight loss, sweats, chills, intermittent
fever, and myalgia are common. Localized or more widespread
crackles are frequently present,

32. Histology of COP Patchy areas of consolidation
Polypoid plugs of loose organizing connective tissue
Architecture of lung is preserved
All the connective tissue is the same age
Mild to moderate inflammation

33. COP histology From left to right:
low-power photomicrograph shows scattered areas of organizing pneumonia. Fibroblast plugs are identified as pale, round structures (arrows)
High power photomicrograph shows fibroblast plug in small brochiole
High power photomicrograph shows fibroblast plugs streaming from one alveolus to another
gross specimen showing branching fibroblast plugs (arrowheads)
Images from McAdams et al., 1996

34. Radiographic features of COP
Bilateral or unilateral areas of consolidation
Patchy distribution, but in minority of cases may be confined to the subpleural region
Small nodular opacities are seen in 10–50% of cases.
Lung volumes are normal in up to 75% of cases

35. Radiographic Features in COP
Multifocal, bilateral, basilar consolidations
Bilateral multifocal consolidations
Images from McAdams et al, 1996

36. CT features of COP Consolidation present in 90% of patients
Lower lung zones frequently involved
Air bronchograms present with consolidation
Mild bronchial dilatation in areas of consolidation

37. CT features in COP
Bilateral pulmonary consolidation with subpleural and perbronchovascular predominance and right pleural effusion
Images from Lynch et al., 2005

38. Clinical Course (COP)
Majority of patients recover completely with oral corticosteroids
Relapse common with steroid taper and/or cessation

39. Acute Interstitial Pneumonia (AIP)
Rapidly evolving lesion (days-weeks)
Histological findings of diffuse alveolar damage. Therefore, diagnosis of AIP should only be considered after the other causes of DAD (sepsis, shock, etc.) are ruled out.

40. Clinical Findings in AIP
Patients often have prior illness suggestive of viral URI
Constitutional symptoms: myalgias, arthralgias, fever, chills, malaise
Severe dyspnea on exertion developing over days
Median time from first symptom to presentation is 3 weeks
Hypoxemia progressing rapidly to respiratory failure
Mean age of 50
No sex predominance
No association with smoking
Physical exam: diffuse crackles
Lung function tests: restrictive pattern
Mechanical ventilation is usually required
The majority of patients fulfill the diagnostic clinical criteria for ARDS

41. Histology of AIP Histology: Diffuse alveolar damage
Acute phase: Edema and hyaline membranes
Organizing phase: Organizing alveolar septal fibrosis and pneumocyte hyperplasia
Uniform temporal appearance

42. Histology of AIP Left to right
High power photomicrograph demonstrating interstitial widening by edema and inflammatory cells. Hyaline membrane formation also apparent.
High power photomicrograph shows organization of the intraalveolar exudate and immature collagen deposition
Images from Lynch et al., 2005

43. Radiographic features of AIP
Diffuse bilateral opacities
Left: Initial radiograph shows bilateral and basilar consolidation
Right: Two weeks later with progressive, diffuse consolidation.
Images from McAdams et al., 1996

44. CT features of AIP Early exudation phase: Organizing stage:
Ground glass opacity-bilateral and patchy
Consolidation also evident
Organizing stage:
Distortion of bronchovascular bundles
Traction bronchiectasis
Although CT findings in AIP and ARDS overlap, patients with AIP are more likely to have symmetric lower lobe distribution and a greater prevelance of honeycombing

45. CT features of AIP Diffuse consolidation and air bronchograms
Image from McAdams et al., 1996

46. Clinical Course AIP No proven treatment, corticosteroids often used
Mortality rates high (>50%)
Those patients who recover may experience recurrence and/or chronic, progressive lung disease

47. Respiratory Bronchiolitis Interstitial Disease (RB-ILD)
Lesion found in cigarette smokers
Characterized by pigmented macrophages in respiratory bronchioles
Rarely symptomatic, minor airway dysfunction
RB-ILD is defined as the combination of clinically significant pulmonary symptoms, abnormal pulmonary function and imaging abnormalities associated with the pathologic lesion of respiratory bronchiolitis

48. Clinical Findings in RB-ILD
Heavy smokers with average exposure of more than 30 pack-years
Gradual onset
40-50 years of age
Generally mild symptoms of sob and cough (new or changed)
Some patients may present with significant dyspnea and hypoxemia
Male to female ratio of 2:1

49. Histology: RB-ILD Histology:
Bronchiolocentric alveolar macrophage accumulation
Mild bronchiolar/peribronchiolar fibrosis and chronic inflammation
Macrophages with “dusty-brown” appearance
Figure below: faintly pigmented alveolar macrophages (arrows) fill the lumen of respiratory bronchiole. Mild thickening of respiratory bronchiole wall.
Image from Lynch et al., 1996

50. Radiographic Features of RB-ILD
Wall thickening of central or peripheral bronchi (75% of patients)
Ground glass opacity (60% of patients)
Normal radiograph (14%)
Centrilobular emphysema also commonly seen as patients are heavy smokers

51. Radiographic features of RB-ILD
Linear opacities in lung bases with atelectasis in right lower lung
Image from McAdams et al., 1996

52. CT features of RB-ILD Centrilobular nodules Patchy ground glass
Thickening of central and peripheral airways
Upper lobe centrilobular emphysema
Air trapping
**CT findings in RB-ILD are similar to those seen in other, asymptommatic smokers. However, findings in patients with RB-ILD are usually more extensive

53. CT features in RB-ILD
RB-ILD in 41 year old with 30 pack-year smoking history. Widespread gound-glass opacification, with some poorly defined centrilobular nodules (arrowheads)
Image from Lynch et al., 2005

54. Clinical Course RB-ILD
Many patients improve after cessation of smoking
No reports of progression to dense pulmonary fibrosis

55. Desquamative Interstitial Pneumonia (DIP)
Considered to be most likely part of a spectrum of RB-ILD as is associated with smoking and has similar pathology
Very rare
Named desquamative because the primary finding on histology was thought to be desquamation of epithelial cells.
Now recognized as intra-alveolar macrophages

56. Clinical findings in DIP
Uncommon
Male to female ratio of 2:1
Progressive dyspnea, dry cough
May progress to respiratory failure
Digital clubbing (40%)

57. Histology of DIP Histology: Uniform involvement of lung parenchyma
Accumulation of alveolar macrophages
Mild-moderate fibrotic thickening of alveolar septa
Mild interstitial chronic inflammation
Modest infiltrate including lymphocytes, plasma cells
Feature distinguishing DIP from RB is that DIP affects the lung in a uniform diffuse manner and lacks the bronchiolocentric distribution seen in RB.

58. Histology of DIP
Photomicrograph shows DIP pattern. Alveolar spaces show diffuse alveolar macrophage accumulation and mild interstitial thickening caused by fibrous connective tissue (arrows)
Image from Lynch et al., 2005

59. Radiographic features of DIP
Normal in 3-22% of biopsy-proven cases
Patchy ground glass opacification
Lower zone/peripheral predominance
Figure: bilateral, basilar consolidations with no honeycombing or volume loss
Image from McAdams et al., 1996

60. CT features of DIP Ground glass opacification
Lower zone distribution (73%), peripheral (59%)
Irregular linear opacities and reticular pattern are frequent (59%), usually seen at lung bases
Honeycombing (33%) is peripheral and limited

61. CT features of DIP
Basal ground glass opacification with multiple peribronchovascular cysts (arrows)
Image from Lynch et al., 2005

62. Clinical Course of DIP The prognosis of DIP is generally good.
Most patients improve with smoking cessation and corticosteroids
Overall survival is about 70% after 10 yr

63. Lymphoid Interstital Pneumonia (LIP)
Very rare condition
regarded as a histologic variant of diffuse pulmonary lymphoid hyperplasia
Because of its’ rarity, important to do thorough investigation for collagen vascular disease and immunodeficiency

64. Clinical features of LIP
Poorly defined clinical presentation
More common in women
Usually diagnosed in fifth decade
Gradual onset over 3 years
Symptoms include SOB, fever, weight loss
Physical exam: crackles
Monoclonal increase in IgG or IgM (75%)

65. Histology of LIP Histology Diffuse interstitial infiltration
Alveolar septal distribution
Infiltrates mostly t-cells, plasma cells and macrophages
Lymphoid hyperplasia frequent
Photomicrograph shows LIP. Alveolar walls (arrows) are markedly infiltrated by lymphocytes and plasma cells.
Image from Lynch et al., 2005

66. Radiographic features of LIP
Two radiographic patterns:
Basilar with alveolar component
Diffuse with honeycombing

67. CT features of LIP Dominant finding: ground glass opacity
Perivascular cysts or perivascular honeycombing
Reticular abnormality (50%)
lung nodules
Widespread consolidation may occur
Diffuse ground glass opacification and multiple lung cysts
Image from Lynch et al., 2005

68. Clinical Course of LIP
Corticosteroids used for treatment: 2/3 of patients respond to therapy either with improvement or no progression of disease
1/3 of patients progress to diffuse fibrosis

69. Summary of IIP
Most important distinction is between UIP and other IIP’s as prognosis is greatly different
Start with thorough history and physical exam looking for possible etiologies of parenchymal lung disease before labeling “idiopathic”
Surgical lung biopsy not necessary if confident diagnosis of UIP possible with HRCT
Corticosteroids not useful in UIP as it is a fibrotic condition

70. References
American Thoracic Society, European Respiratory society Consensus Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine 2002; 165:
Lynch, D., Travis, W., Muller, N., Galvin, J., Hansell, D., Grenier, P., King, T. Idiopathic Interstitial Pneumonias: CT features. Radiology 2005; 236:10-21
Collard, H., King, T. Demystifying idiopathic interstitial pneumonia. Archives of Internal Medicine 2003; 163:17-29
McAdams, H., Rosado-de-Christenson, M., Wehunt, W., Fishback, N. The alphabet soup revisited: the chronic interstitial pneumonias in the 1990’s. Radiographics 1996; 16:
MacDonald, S., Rubens, M., Hansell, D., Copley, S., Desai, S., M. du Bois, R., Nicholson, A., Colby, T., Wells, A. Non-specific interstitial pneumonia and usual interstitial pneumonia: comparative appearances and diagnostic accuracy of thin-section CT. Radiology 2001; 221:
Colby, T. Pathological approach to idiopathic interstitial pneumonias: useful points for clinicians. Breathe 2004; 1:43-49.
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