Idiopathic Interstitial Pneumonia

Trying to make sense of the letters

Michelle Thompson, MS4
February 2006

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
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)
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
Idiopathic Interstitial Pneumonias
(clinical nomenclature as proposed by ATS/ERS)

Include (in order of frequency):
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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)
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
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
Usual Interstitial Pneumonia
(UIP)
Also known as Idiopathic pulmonary fibrosis (IPF)


Most common IIP
Primarily a fibrotic condition
Clinical Findings in UIP
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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
Histologic Findings in UIP
Histology:


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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
1.
Temporal heterogeneity: fibrotic lesions of different stages
within same biopsy specimen
2.
Spatial heterogeneity: patchy lung involvement
Histology of UIP

Left to right:
1.
Patchy fibrosis, subpleural distribution. Some lymphoid aggregates (black arrow). Areas of normal
lung also present.
2.
Fibroblastic focus (white arrow) adjacent to dense collagenous scar.
Figures from Lynch et al. 2005
Radiographic features of UIP

Radiographs
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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

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

Late features UIP showing
bilateral, coarse, reticular
opacities with architectural
distortion, volume loss and
honeycombing
Images from McAdams et al., 1996
CT features of UIP
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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
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
Clinical Course in UIP

Gradual deterioration, with possible periods of rapid
decline

Mean survival is 2.5-3.5 years from time of diagnosis

As UIP is predominantly a fibrotic condition, does not
typically respond to steroid treatment
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)
Clinical findings in NSIP
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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
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
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
Cellular NSIP

Photomicrograph showing NSIP with
cellular pattern. Alveolar walls (arrows)
are infiltrated by a chronic inflammatory
infiltrate.
Image from Lynch et al., 2005
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
Radiographic Features of NSIP
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Irregular linear opacities
Air space consolidation
Bilateral and basilar pattern
Radiograph normal in 14% of cases
Radiographic features of NSIP
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Basilar opacities and
normal lung volumes
Image from McAdams et al., 1996
CT features of NSIP
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Scattered ground glass opacities
Basal predominance
Consolidation uncommon and honeycombing
rare
Irregular linear opacities
Fibrosis (lobar volume loss, reticular pattern,
and/or traction bronchiectasis)
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
Clinical Course of NSIP

Significantly better prognosis than UIP

Evidence for corticosteroid efficacy is from
retrospective reviews of observational studies. (2530% of patients improved)*

Relapse may occur
*Collard et al., 2003
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
Organizing Pneumonia: (COP or BOOP)
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Histology:
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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
Clinical findings in COP
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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,
Histology of COP
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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
COP histology
From left to right:

1.
2.
3.
4.
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
Radiographic features of COP
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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
Radiographic Features
in COP
 Multifocal, bilateral,
basilar consolidations

Bilateral multifocal
consolidations
Images from McAdams et al, 1996
CT features of COP
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Consolidation present in 90% of patients
Lower lung zones frequently involved
Air bronchograms present with consolidation
Mild bronchial dilatation in areas of
consolidation
CT features in COP
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Bilateral pulmonary consolidation with subpleural
and perbronchovascular predominance and right
pleural effusion
Images from Lynch et al., 2005
Clinical Course (COP)
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Majority of patients recover completely with
oral corticosteroids

Relapse common with steroid taper and/or
cessation
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.
Clinical Findings in AIP
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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
Histology of AIP
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Histology:
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Diffuse alveolar damage
Acute phase: Edema and hyaline membranes
Organizing phase: Organizing alveolar septal
fibrosis and pneumocyte hyperplasia
Uniform temporal appearance
Histology of AIP

Left to right
1.
High power photomicrograph demonstrating interstitial widening by edema and inflammatory
cells. Hyaline membrane formation also apparent.
2.
High power photomicrograph shows organization of the intraalveolar exudate and immature
collagen deposition
Images from Lynch et al., 2005
Radiographic features of AIP
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Diffuse bilateral opacities
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Left: Initial radiograph shows bilateral and basilar consolidation
Right: Two weeks later with progressive, diffuse consolidation.
Images from McAdams et al., 1996
CT features of AIP
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Early exudation phase:
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Organizing stage:
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Ground glass opacity-bilateral and patchy
Consolidation also evident
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
CT features of AIP
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Diffuse consolidation
and air bronchograms
Image from McAdams et al., 1996
Clinical Course AIP

No proven treatment, corticosteroids often
used
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Mortality rates high (>50%)
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Those patients who recover may experience
recurrence and/or chronic, progressive lung
disease
Respiratory Bronchiolitis Interstitial
Disease (RB-ILD)
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Respiratory Bronchiolitis:
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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
Clinical Findings in RB-ILD
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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
Histology: RB-ILD
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Histology:
 Bronchiolocentric alveolar macrophage accumulation
 Mild bronchiolar/peribronchiolar fibrosis and chronic inflammation
 Macrophages with “dusty-brown” appearance
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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
Radiographic Features of RB-ILD
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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
Radiographic features of RB-ILD
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Linear opacities in lung
bases with atelectasis in
right lower lung
Image from McAdams et al., 1996
CT features of RB-ILD
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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
CT features in RB-ILD
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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
Clinical Course RB-ILD
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Many patients improve after cessation of
smoking
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No reports of progression to dense pulmonary
fibrosis
Desquamative Interstitial Pneumonia
(DIP)
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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
Clinical findings in DIP
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Uncommon
Male to female ratio of 2:1
Progressive dyspnea, dry cough
May progress to respiratory failure
Digital clubbing (40%)
Histology of DIP
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Histology:
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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.
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
Radiographic features of DIP
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Normal in 3-22% of biopsyproven 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
CT features of DIP
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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
CT features of DIP

Basal ground glass
opacification with
multiple
peribronchovascular
cysts (arrows)
Image from Lynch et al., 2005
Clinical Course of DIP

The prognosis of DIP is generally good.

Most patients improve with smoking
cessation and corticosteroids
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Overall survival is about 70% after 10 yr
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
Clinical features of LIP
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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%)
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
Radiographic features of LIP

Two radiographic patterns:
1.
2.
Basilar with alveolar component
Diffuse with honeycombing
CT features of LIP
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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
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
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
References
1.
American Thoracic Society, European Respiratory society Consensus Classification of the Idiopathic Interstitial
Pneumonias. American Journal of Respiratory and Critical Care Medicine 2002; 165:277-304
2.
Lynch, D., Travis, W., Muller, N., Galvin, J., Hansell, D., Grenier, P., King, T. Idiopathic Interstitial Pneumonias: CT
features. Radiology 2005; 236:10-21
3.
Collard, H., King, T. Demystifying idiopathic interstitial pneumonia. Archives of Internal Medicine 2003; 163:17-29
4.
McAdams, H., Rosado-de-Christenson, M., Wehunt, W., Fishback, N. The alphabet soup revisited: the chronic interstitial
pneumonias in the 1990’s. Radiographics 1996; 16:1009-1033
5.
MacDonald, S., Rubens, M., Hansell, D., Copley, S., Desai, S., M. du Bois, R., Nicholson, A., Colby, T., Wells, A. Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances and diagnostic accuracy of
thin-section CT. Radiology 2001; 221:600-605
6.
Colby, T. Pathological approach to idiopathic interstitial pneumonias: useful points for clinicians. Breathe 2004; 1:43-49.
7.
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