idiopathic interstitial pneumonia

Idiopathic Interstitial Pneumonia

Trying to make sense of the letters

Michelle Thompson, MS4February 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): 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

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: 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’s1. 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 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

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

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

Irregular linear opacities Air space consolidation Bilateral and basilar pattern Radiograph normal in 14% of cases

Radiographic features of NSIP

Basilar opacities and normal lung volumes

Image from McAdams et al., 1996

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)

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. (25-30% 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)

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

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,

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

COP histology

From left to right: 1. low-power photomicrograph shows scattered areas of organizing pneumonia. Fibroblast plugs are identified as

pale, round structures (arrows)2. High power photomicrograph shows fibroblast plug in small brochiole3. High power photomicrograph shows fibroblast plugs streaming from one alveolus to another 4. gross specimen showing branching fibroblast plugs (arrowheads)

Images from McAdams et al., 1996

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

Radiographic Features in COP

Multifocal, bilateral, basilar consolidations

Bilateral multifocal consolidations

Images from McAdams et al, 1996

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

CT features in COP

Bilateral pulmonary consolidation with subpleural and perbronchovascular predominance and right pleural effusion

Images from Lynch et al., 2005

Clinical Course (COP)

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

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

Histology: 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 right1. 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

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

CT features of AIP

Early exudation phase: 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

CT features of AIP

Diffuse consolidation and air bronchograms

Image from McAdams et al., 1996

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

Respiratory Bronchiolitis Interstitial Disease (RB-ILD)

Respiratory Bronchiolitis: 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

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 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

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

Radiographic features of RB-ILD

Linear opacities in lung bases with atelectasis in right lower lung

Image from McAdams et al., 1996

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

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

Clinical Course RB-ILD

Many patients improve after cessation of smoking

No reports of progression to dense pulmonary fibrosis

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

Clinical findings in DIP

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

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.

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

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

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

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

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

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. Basilar with alveolar component2. Diffuse with honeycombing

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

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. Non-specific 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. UpToDate