diffuse parenchymal lung diseases (postgraduate course)

Approach To

Interstitial Lung Diseases

or

Diffuse Parenchymal Lung

Diseases

Gamal Rabie Agmy, MD, FCCP

Professor of Chest Diseases, Assiut university

The interstitium of the lung is not normally visible radiographic-

ally; it becomes visible only when disease (e.g., edema,

fibrosis, tumor) increases its volume and attenuation.

The interstitial space is defined as continuum of loose

connective tissue throughout the lung composed of three

subdivisions:

(i) the bronchovascular (axial), surrounding the bronchi,

arteries, and veins from the lung root to the level of the

respiratory bronchiole

(ii) the parenchymal (acinar), situated between the alveolar

and capillary basement membranes

(iii) the subpleural, situated beneath the pleura, as well as in

the interlobular septae.

The Lung Interstitium

Secondary pulmonary lobular

anatomy

The terminal bronchiole in the center

divides into respiratory bronchioles with

acini that contain alveoli.

Lymphatics and veins run within the

interlobular septa

Centrilobular area in blue (left)

and perilymphatic area in yellow

(right)

Ideal ILD doctor

Radiologist

Pathologist

Pulmonologist

DPLD of known

cause (e.g. drugs,

dust exposure,

collagen vascular

disease)

Idiopathic

interstitial

pneumonias

Granulomatous

DPLD (e.g.

sarcoidosis)

Other forms of DPLD

(e.g. LAM, HX,

eosin. pneum. etc.)

Diffuse Parenchymal Lung Disease

IIP other than

idiopathic

pulmonary fibrosis

Idiopathic

pulmonary

fibrosis (IPF)

Desquamative interstitial

pneumonia (DIP)

Acute interstitial

pneumonia (AIP)

Lymphocytic interstitial

pneumonia (LIP)

Nonspecific interstitial

pneumonia (NSIP)

Cryptogenic organising

pneumonia (COP)

Respiratory bronchiolitis/

Interst. lung dis. (RBILD)

Incident Cases of ILD

Sarcoidosis

8%

Occupation

11% DILD

5% DAH

4%

CTD

9%

Other

11%

Pulmonary Fibrosis

52%

Coultas AJRCCM 1994; 150:967

(Incidence of IPF=26-31 per 100,000)

Adapted from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101.

Adapted from ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.

1970 Liebow and Carington

2002 ATS/ERS

UIP

NSIP

DIP-RBILD

AIP

UIP/IPF

NSIP

DIP RB-

ILD

AIP

Cellular

Fibrotic

COP

LIP

Historical Classification of IIP

UIP

DIP

UIP-BO

LIP

Giant cell IP

1997 Katzenstein

Major idiopathic interstitial pneumonias

Idiopathic pulmonary fibrosis

Idiopathic nonspecific interstitial pneumonia

Respiratory bronchiolitis-interstitial lung disease

Desquamative interstitial pneumonia

Cryptogenic organising pneumonia

Acute interstitial pneumonia

Rare idiopathic interstitial pneumonias

Idiopathic lymphoid interstitial pneumonia

Idiopathic pleuroparenchymal fibroelastosis

Unclassifiable idiopathic interstitial pneumonias

Table 2.Update of the classification of idiopathic interstitial pneumonias

Update of the classification of idiopathic

interstitial pneumonias

Rare IIPs

• Idiopathic Lymphoid Interstitial Pneumonia

• Idiopathic Pleuroparenchymal Fibroelastosis

• Acute Fibrinous and Organizing Pneumonia

• Bronchiolocentric Patterns of Interstitial Pneumonia

Revision of the IIP classification

• The main entities are preserved .

• However, there are several important changes.

• First, cryptogenic fibrosing alveolitis is removed, leaving idiopathic pulmonary fibrosis (IPF) as the sole clinical term for this diagnosis.

• Second, idiopathic nonspecific interstitial pneumonia (NSIP) is now accepted as a distinct clinical entity with removal of the term “provisional”.


• Third, major IIPs are distinguished from rare IIPs and unclassifiable cases.

• Fourth, rare histologic patterns of acute fibrinous and organizing pneumonia (AFOP) and interstitial pneumonias with a bronchiolocentric distribution are recognized.


• Fifth, the major IIPs are grouped into chronic fibrosing (IPF and NSIP; ), smoking-related (RB-ILD and DIP), acute/subacute IIPs (COP) and acute interstitial pneumonia [AIP]

• Sixth, a clinical disease behavior classification is proposed.

• Last, molecular and genetic features are reviewed.

IDIOPATHIC INTERSTITIAL PNEUMONIAS: CLASSIFICATION ACCORDING TO DISEASE

BEHAVIOR

Clinical Behavior Treatment Goal Monitoring Strategy

Reversible and self-limited

(e.g., many cases of RB-ILD)

Remove possible cause Short-term (3- to 6-mo)

observation to confirm

disease regression

Reversible disease with risk

of progression (e.g., cellular

NSIP and some fibrotic NSIP,

DIP, COP)

Initially achieve response

and then rationalize longer

term therapy

Short-term observation to

confirm treatment response.

Long-term observation to

ensure that gains are

preserved

Stable with residual disease

(e.g., some fibrotic NSIP)

Maintain status Long-term observation to

assess disease course

Progressive, irreversible

disease with potential for

stabilization (e.g., some

fibrotic NSIP)

Stabilize Long-term observation to

assess disease course

Progressive, irreversible

disease despite therapy

(e.g., IPF, some fibrotic

NSIP)

Slow progression Long-term observation to

assess disease course and

need for transplant or

effective palliation

Correlation with HRCT patterns

7 clinical-radiological-pathological categories

ATS/ERS International Multidisciplinary Consensus Classification of the

Idiopathic Interstitial Pneumonias, AJRCCM Vol 165. pp 277-304, 2002

UIP

+ NSIP

+ OP

+ DAD

+

DIP

+ RB

+

LIP

+

=

IPF

=

NSIP =

COP

=

AIP =

DIP

=

RB-ILD =

LIP

Idiopathic Pleuroparenchymal Fibroelastosis

PPFE is a rare condition that consists of fibrosis involving the pleura

and subpleural lung parenchyma, predominantly in the upper lobes.

HRCT shows dense subpleural consolidation with traction

bronchiectasis, architectural distortion, and upper lobe volume loss

http://www.atsjournals.org/doi/full/10.1164/rccm.201308-1483ST

The principal HRCT findings are bilateral basal

opacities and areas of consolidation .The dominant

histologic pattern is intraalveolar fibrin deposition and

associated organizing pneumonia

Acute Fibrinous and Organizing Pneumonia

http://www.atsjournals.org/doi/full/10.1164/rccm.201308-1483ST

Clinical Assessment

• History

• Physical Exam

• Chest Radiograph

• Pulmonary Function Testing

– At Rest

– Exercise

• Serologic Studies

• Tissue examination

History

• Age

• Gender

• Smoking history

• Medications

• Duration of symptoms

• Environmental exposure

• Occupational exposure

• Family history

History: Age and Gender

– LAM

– Tuberous sclerosis

– Pneumoconiosis

Age Gender

History: Smoking

• All of the following

DPLD are associated

with smoking except:

a) IPF

b) RBILD

c) DIP

d) HP

e) Histiocytosis X

• In Goodpasture‟s

syndrome

– 100% of smokers vs. 20%

of nonsmokers

experience pulmonary

hemorrhage

• Individuals exposed to

asbestos who smoke are

more likely to develop

asbestosis

www.pneumotox.com

History: Medications

Schwartz, ILD text book, 4th edition

History: Occupational and

Environmental

INORGANIC

ORGANIC: Hypersensitivity Pneumonitis

Occupational ????

2. Subacute Diseases (weeks to months)

• HSP, Sarcoid, Cellular NSIP, Drug,

“Chronic” EP, Bronchiolitis/ SAD __________________________________________________________________________________________________________________

3. Chronic Diseases (months to years)

• UIP, Fibrotic NSIP, Pneumoconioses,

CVD-related, Chronic HSP

Smoking (RBILD and PLCH)

1. Acute Diseases (Days to weeks)

• DAD (AIP), EP, Vasculitis/DPH, Drug, CVD ________________________________________________________________________________________________________________

History: Duration of Illness

Physical Findings

• Resting Tachypnea

• Shallow breathing

• Dry crackles

• Digital clubbing

• Pulmonary HTN

• Non-pulmonary

findings

http://162.129.70.33/images/lupuspernio_4_010505.jpg

Laboratory

ILD: Evaluation

• Rdiographic – CXR

– HRCT

• Physiologic testing – PFT

– Exercise test

• Lung Sampling

– BAL

– Lung biopsy: (TBBx, Surgical)

CXR: LlMITATIONS

• CXR is normal:

– in 10 to 15 % of symptomatic patients with proven infiltrative lung disease

– 30% of those with bronchiectasis

– ~ 60 % of patients with emphysema

• CXR has a sensitivity of 80% and a specificity of 82% percent for detection of DPLD

• CXR can provide a confident diagnosis in ~ 23 % of cases

A normal CXR does not rule

out the presence of DPLD

Cystic Lung Lesions

By

Gamal Rabie Agmy , MD , FCCP Professor of Chest Diseases ,Assiut University

DECREASED LUNG

ATTENUATION

Lung Cysts

Pulmonary fibrosis (Honeycombing)

Lymphangiomyomatosis

Langerhanscell histiocytosis

Lymphocytic Interstitial Pneumonia (LIP)

Differential Diagnosis

Rough Reticular Fine Reticular

Traction

Bronchiectasis

and

Interface

sign

Honey

combing

UIP UIP or NSIP

Usual Interstitial Pneumonia UIP

HRCT Findings

Reticular opacities, thickened intra- and

interlobular septa

Irregular interfaces

Honey combing and parenchymal distorsion

Ground glass opacities (never prominent)

Basal and subpleural predominance

Basal and subpleural distribution

UIP

Lymphangioleiomyomatosis (LAM)

HRCT Morphology

Thin-walled cysts (2mm - 5cm)

Uniform in size / rarely confluent

Homogeneous distribution

Chylous pleural effusion

Lymphadenopathy

in young women

Lymphangioleiomyomatosis (LAM)

Tuberous Sclerosis (young man)

Langerhans Cell Histiocytosis


HRCT Findings

Small peribronchiolar nodules (1-5mm)

Thin-walled cysts (< 1cm),

Bizarre and confluent

Ground glass opacities

Late signs: irreversible / parenchymal fibrosis Honey comb lung, septal thickening,

bronchiectasis

1 year later

Peribronchiolar Nodules Cavitating nodules and cysts


Langerhans Cell Histiozytosis

Key Features

Upper lobe predominance

Combination of cysts and noduli

Characteristic stages

Increased Lung volume

Sparing of costophrenic angle

S

M

O

K

I

N

G


Differential Diagnosis

Only small nodules Sarkoidosis, Silikosis

Only cysts idiopathic Fibrosis

LAM

Destruktive emphysema

A professional diver.............

.......after cessation of smoking

Benign lymphoproliferative

disorder Diffuse interstitial infiltration of

mononuclear cells

Not limited to the air ways as

in follicular Bronchiolitis

LIP

= Lymphocytic Interstitial Pneumonia

Sjögren: LIP

LIP

= Lymphocytic Interstitial Pneumonia

Rarely idiopathic

In association with: Sjögren‟s syndrome

Immune deficiency syndromes, AIDS

Primary biliary cirrhosis

Multicentric Castlemean‟s disease

Sjoegren disease

Dry eye and dry mouth

Fibrosis, bronchitis and bronchiolitis

LIP

Overlap

Sarcoid, DM/PM, MXCT

SLE, RA (pleural effusion)

Up to 40 x increased risk for lymphoma (mediastinal

adenopathy) and

2 x times increased risk for neoplasma

Summary..................................Quiz

Young woman Dry mouth Smoker

LAM LIP Histiocytosis

Emphysema Fibrosis (UIP)

Wegener„s disease

Rheumatoid Arthritis

Emphysema

histopathological definition

…..permanent abnormal enlargement of

airspaces distal to the bronchioles terminales

and

…...destruction of the walls of the involved

airspaces

Centrilobular Emphysema

Panlobular Emphysema

CLE and PLE in one Patient

Fibrosis and Emphysema

What is Your Diagnosis ?

Cystic Changes and Decreased Density

Quiz

LAM Emphysema Fibrosis

LCH Emphysema

Fibrosis Emphysema

Emphysema

Emphysema typically presents as

areas of low attenuation without

visible walls as a result of

parenchymal destruction.

EMPHYSEMA

Permanent, abnormal enlargement of air

spaces distal to the terminal bronchiole

and accompanied by the destruction of

the walls of the involved air spaces.

78

Centrilobular emphysema

Most common type

Irreversible destruction of alveolar

walls in the centrilobular portion of the

lobule

Upper lobe predominance and

uneven distribution

Strongly associated with smoking.

Centrilobular (proximal or

centriacinar) emphysema

Found most commonly in the upper lobes

Manifests as multiple small areas of low attenuation without a

perceptible wall, producing a punched-out appearance.

Often the centrilobular artery is visible within the

centre of these lucencies.

80

Centrilobular emphysema due to smoking. The periphery of

the lung is spared (blue arrows). Centrilobular artery (yellow

arrows) is seen in the center of the hypodense area.

Panlobular emphysema

Affects the whole secondary lobule

Lower lobe predominance

In alpha-1-antitrypsin deficiency, but

also seen in smokers with advanced

emphysema

PANLOBULAR EMPHYSEMA

Affects the entire secondary pulmonary

lobule and is more pronounced in the lower

zones

Complete destruction of the entire pulmonary

lobule.

Results in an overall decrease in lung

attenuation and a reduction in size of

pulmonary vessels

83

PANLOBULAR EMPHYSEMA

84

Panlobular emphysema

Paraseptal (distal acinar)

emphysema

Affects the peripheral parts of

the secondary pulmonary lobule

Produces subpleural lucencies.

86

Paraseptal emphysema

Bronchiectasis

Bronchiectasis is defined as localized bronchial

dilatation. (signet-ring sign)

bronchial wall thickening

lack of normal tapering with visibility of airways

in the peripheral lung

mucus retention in the broncial lumen

associated atelectasis and sometimes air

trapping

ABPA: glove-finger shadow due to mucoid impaction in central

bronchiectasis in a patient with asthma.

Signet-Ring Sign

A signet-ring sign represents an axial cut of a dilated bronchus

(ring) with its accompanying small artery (signet).

Tram Tracks

Bronchial dilation with lack of tapering .

HONEYCOMBING

Defined as - small cystic spaces with

irregularly thickened walls composed of

fibrous tissue.

Predominate in the peripheral and subpleural

lung regions

Subpleural honeycomb cysts typically occur

in several contiguous layers. D/D- paraseptal

emphysema in which subpleural cysts usually

occur in a single layer.

Indicates the presence of “END stage”

disease regardless of the cause.

94

Honeycombing

Honeycombing is defined by the presence of small cystic

spaces with irregularly thickened walls composed of

fibrous tissue.

Causes

Lower lobe predominance :

1. UIP or interstitial fibrosis

2. Connective tissue disorders

3. Hypersensitivity pneumonitis

4. Asbestosis

5. NSIP (rare)

Upper lobe predominance :

1. End stage sarcodosis

2. Radiation

3. Hypersensitivity Pneumonitis

4. End stage ARDS

96

Honeycombing

HRCT showing

subpleural

broncheolectasis

Honeycombing and traction bronchiectasis in UIP.

Typical UIP with honeycombing and traction

bronchiectasis in a patient with idiopathic

pulmonary fibrosis (IPF)

Distribution within the lung

Nodular Patternitie

By


Nodular Pattern

Nodular pattern A nodular pattern consists of multiple round opacities,

generally ranging in diameter from 1 mm to 1 cm

Nodular opacities may be described as miliary (1 to 2 mm,

the size of millet seeds), small, medium, or large, as the

diameter of the opacities increases

A nodular pattern, especially with predominant distribution,

suggests a specific differential diagnosis

Perilymphatic distribution

Centrilobular distribution

Random distribution

ARE NODULES IN CONTACT WITH PLEURA

NO

CENTRILOBULAR

YES

PERILYMPHATIC RANDOM

TO SUM UP..

• Random

– touch pleura

– scattered in lung

• Centrilobular

–away from pleura

• Perilymphatic

– around vessels, bronchi

– touch pleura or fissure

Size, Distribution, Appearance

Nodules and Nodular Opacities

Size

Small Nodules: <10 mm Miliary - <3 mm

Large Nodules: >10 mm Masses - >3 cms

Appearance

Interstitial opacity:

Well-defined, homogenous,

Soft-tissue density

Obscures the edges of vessels or adjacent structure

Air space:

Ill-defined, inhomogeneous.

Less dense than adjacent vessel – GGO

small nodule is difficult to identify

Interstitial

nodules Air space opacity

Miliary tuberculosis

sarcoidosis

in a lung transplant patient

with bronchopneumonia

RANDOM: no consistent relationship to any structures

PERILYMPHATIC: corresponds to distribution of lymphatics

CENTRILOBULAR: related to centrilobular structures Distribution

113

Angiocentric

Bronchocentric, ill Defined

Bronchocentric, well Defined

Lymphocentric

Disseminated histoplasmosis and nodular ILD.

CT scan shows multiple bilateral round circumscribed

pulmonary nodules.

Notice the nodules along the fissures indicating a

perilymphatic distribution (red arrows).

The majority of nodules located along the bronchovascular

bundle (yellow arrow).

Sarcoidosis

The majority of nodules located

along the bronchovascular bundle

(yellow arrow).

PERILYMPHATIC NODULES

Perilymphatic and Random distribution of

nodules , seen in sarcoidosis.

Centrilobular distribution

Hypersensitivity pneumonitis

Respiratory bronchiolitis in

smokers

infectious airways diseases

(endobronchial spread of

tuberculosis or

nontuberculous

mycobacteria,

bronchopneumonia)

Uncommon in

bronchioloalveolar

carcinoma, pulmonary

edema, vasculitis

Random distribution

Small random nodules

are seen in:

Hematogenous

metastases

Miliary tuberculosis

Miliary fungal infections

Sarcoidosis may mimick

this pattern, when very

extensive

Langerhans cell

histiocytosis (early

nodular stage)

Langerhans cell histiocytosis: early nodular stage before the typical cysts appear.

Differential diagnosis of a nodular

pattern of interstitial lung disease

SHRIMP Sarcoidosis

Histiocytosis (Langerhan cell

histiocytosis)


Rheumatoid nodules

Infection (mycobacterial, fungal, viral)

Metastases, Miliary TB

Microlithiasis, alveolar

Pneumoconioses (silicosis, coal

worker's, berylliosis)

Reticulonodular pattern A reticulonodular pattern results from a

combination of reticular and nodular opacities.

This pattern is often difficult to distinguish from a purely reticular or nodular pattern, and in such a case a differential diagnosis should be developed based on the predominant pattern.

If there is no predominant pattern, causes of both nodular and reticular patterns should be considered.

Reticular Pattern

Gamal Rabie Agmy, MD, FCCP

Professor of chest Diseases,

Assiut university

Linear Pattern A linear pattern is seen when there is

thickening of the interlobular septa,

producing Kerley lines.

Kerley B lines

Kerley A lines

The interlobular septa contain

pulmonary veins and lymphatics.

The most common cause of interlobular

septal thickening, producing Kerley A

and B lines, is pulmonary edema, as a

result of pulmonary venous

hypertension and distension of the

lymphatics. Kerley B lines

Kerley A lines

DD of Kerly Lines:

Pulmonary edema is the most common cause

Mitral stenosis

Lymphangitic carcinomatosis

Malignant lymphoma

Congenital lymphangiectasia

Idiopathic pulmonary fibrosis

Pneumoconiosis

Sarcoidosis

Reticular Pattern A reticular pattern results from the summation

or superimposition of irregular linear opacities.

The term reticular is defined as meshed, or in

the form of a network. Reticular opacities can be

described as fine, medium, or coarse, as the

width of the opacities increases.

A classic reticular pattern is seen with

pulmonary fibrosis, in which multiple curvilinear

opacities form small cystic spaces along the

pleural margins and lung bases (honeycomb

lung)

HRCT of the lung

Reticular pattern – definition

Glossary of Terms for Thoracic Imaging – Radiology 2008; 246:697

HRCT of the lung

thickening of the interstitial fiber network by

Reticular pattern – significance

fluid fibrous tissue infiltration by cells or other material

pulm. edema lymphangitic carcin. veno-occlusive dis. alveolar proteinosis IPF collagen vascular dis. drug-related fibrosis amyloidosis

Predominant pattern Associated / occasional finding sarcoidosis pneumoconiosis pulm. hemorrhage asbestosis

HRCT of the lung

Reticular pattern – HRCT

numerous, clearly visible interlobular septa outlining lobules of characteristic size and shape

interlobular septal thickening

very fine network of lines within visible lobules

intralobular interstitial thickening

several layers of air-filled cysts, 3-10 mm in diameter, with thick walls (1-3 mm)

honeycombing

Reticular pattern

Interlobular septal thickening – dd

smooth thickening

pulm. edema pulm. hemorrhage lymphangitic carc. lymphoma

nodular thickening

lymphangitic carc. sarcoidosis amyloidosis

irregular thickening

fibrosis

Reticular pattern

Interlobular septal thickening – pulmonary edema

smooth septal thickening, isolated or in combination with ground-glass opacity

peribronchovascular and subpleural interstitial th.

perihilar and gravitational distribution, bilateral findings of CHF

Reticular pattern

Interlobular septal th. – lymphangitic carcinomatosis

tumor filling of pulmonary vessels and lymphatics direct tumor infiltration of the interstitium vascular and lymphatic distension distally to tumor

emboli or obstruction

breast ca. lung ca. stomach ca. pancreas ca.

Secondary to:

prostate ca. adenoca. of

unknown origin

Reticular pattern

Interlobular septal th. – lymphangitic carcinomatosis

smooth or nodular septal thickening smooth or nodular thickening of peribronchovascular

interstitium and fissures thickening of the intralobular axial interstitium

focal or asymmetric distribution

Reticular pattern

Interlobular septal thickening – sarcoidosis

reticulation is not a predominat finding distorsion of the lung architecture and secondary

lobule anatomy is common, especially when septal thickening is present

upper lobe predominance

Reticulation or not reticulation ……

“crazy paving”

Reticulation or not reticulation ……

alveolar proteinosis

Reticular pattern

Interlobular septal thickening – “crazy paving”

scattered or diffuse ground-glass attenuation with superimposed interlobular septal thickening and intralobular lines

described in a variety of infectious, neoplastic, idiopathic, inhalation, and sanguineous disorders of the lung

Rossi SE – Radiographics 2003; 23:1509

Reticular pattern

Honeycombing – significance

air-containing cystic spaces having thick, fibrous walls lined by bronchiolar epithelium

fibrosis is present

UIP is likely the histologic pattern

IPF is very likely, in the absence of a known disease

Reticular pattern

Honeycombing – differential diagnosis

basal distribution

middle/upper distribution

chronic HP sarcoidosis

IPF collagen vasc. dis. asbestosis drugs

honeycombing / intralobular reticulation

basal and peripheral distribution

typical HRCT findings

sens. 77% spec. 72% PPV 85% PPV 96%*

Swigris JJ – Chest 2005; 127:275

lung biopsy in patients who do not show typical features

Reticular pattern

Honeycombing – idiopathic pulmonary fibrosis

* confident diagnosis

Reticular pattern

Honeycombing – collagen vascular diseases

rheumatoid arthritis and scleroderma almost indistinguishable from UIP due to IPF associated findings, typical of the disease, may help in the

differential diagnosis

Reticular pattern

Honeycombing – drug reaction

findings of fibrosis, similar to those seen in IPF peripheral and subpleural predominance highest incidence with cytotoxic agents temporal relationship between drug administration and

development of pulmonary abnormalities

Honeycombing – chronic hypersensitivity pneum.

possible association with poorly defined nodules, mosaic attenuation or air-trapping

upper and middle zone predominance

Reticular pattern

Intralobular interstitial thickening – significance

thickening of the pulmonary interstitium at a sublobular level isolated (fibrosis) in association with septal thickening or the “crazy paving” pattern

very fine linear structures below the resolution of HRCT (gg appearance)

Reticular pattern

adapted from: Webb RW – HRCT of the lung, III ed; 2001

interlobular septal thickening

irregular, lung distorsion

nodular smooth

• fibrosis (sarcoidosis,

asbestosis)

• pulm. edema • linf. carc. • hemorrhage

• sarcoidosis • linf. carc.

Reticular pattern


honeycombing

• IPF (60%) • collagen vascular dis. • drug reaction • asbestosis (uncommon)

subpleural, posterior LL predominance

• sarcoidosis • chronic HP • radiation

other distribution (UL; parahilar)

Reticular pattern


intralobular interstitial thickening

& septal thickening & GGO

isolated

NSIP

findings of fibrosis

honeycombing differential dx

Inconsistent with UIP pattern (any one of seven features

Possible UIP pattern (all three features)

UIP pattern (all four features)

•Upper or mid lung

predominance subpleural basal

predominance

•subpleural basal

predominance

•peribronchovascular

predominance reticular abnormality •reticular abnormality

•extensive ground glass

abnormality (extent > reticular abnormality)

•honeycombing with or

without traction

bronchiectasis

•profuse micronodules

(bilateral, predominantly upper lobes

Absence of features

listed as inconsistent

with UIP pattern

Absence of features

listed as inconsistent

with UIP pattern

•discrete cysts (multiple

bilateral, away from areas of honeycombing)

•diffuse mosaic attenuation/air

trapping (bilateral in three or more lobes)

•consolidation in broncho-

pulmonary segment(s)/lobe(s)

Radiological features of idiopathic pulmonary fibrosis: 2011

Focal septal thickening in lymphangitic carcinomatosis

Tree-in-bud

Centrilobular nodules m/b further characterized by presence or

absence of „„tree-in-bud.‟‟

Tree-in-bud -- Impaction of centrilobular bronchus with mucous,

pus, or fluid, resulting in dilation of the bronchus, with associated peribronchiolar inflammation .

Dilated, impacted bronchi produce Y- or V-shaped structures

This finding is almost always seen with pulmonary infections.

153

Tree-in-bud

Tree-in-bud describes the appearance of an irregular and often nodular

branching structure, most easily identified in the lung periphery.

Typical Tree-in-bud appearance in a patient with active TB.

Attenuation pattern

High Attenuation pattern

GROUND GLASS

CONSOLIDATION

Low Attenuation pattern

Emphysema

Lung cysts (LAM, LIP, Langerhans cell histiocytosis)

Bronchiectasis

Honeycombing

Dark bronchus sign in ground glass opacity.

Complete obscuration of vessels in consolidation.

Ground-glass opacity

Broncho-alveolar cell carcinoma with ground-glass

opacity and consolidation

Consolidation

Two patients with chronic consolidations as a result of COP

(cryptogenic organizing pneumonia)

Head cheese sign

It refers to mixed

densities which includes

# consolidation

# ground glass

opacities

# normal lung

# Mosaic perfusion

• Signifies mixed

infiltrative and

obstructive disease

Head cheese sign

Common cause are :

1. Hypersensitive pneumonitis

2. Sarcoidosis

3. DIP

163

Headcheese sign

Headcheese sign in

hypersensitivity

pneumonitis.

HRCT scan shows lung with

a geographic appearance,

which represents a

combination of patchy or

lobular ground-glass opacity (small arrows) and mosaic

perfusion (large arrows).

Mosaic Patternitie

By


Mosiac pattern

Where is the pathology ???????

in the areas with increased density meaning there is ground glass

in the areas with decreased density meaning there is air trapping

Pathology in black areas

Airtrapping: Airway

Disease

Bronchiolitis obliterans (constrictive bronchiolitis) idiopathic, connective tissue diseases, drug reaction,

after transplantation, after infection

Hypersensitivity pneumonitis granulomatous inflammation of bronchiolar wall

Sarcoidosis granulomatous inflammation of bronchiolar wall

Asthma / Bronchiectasis / Airway diseases

Airway Disease

what you see……

In inspiration sharply demarcated areas of seemingly increased

density (normal) and decreased density

demarcation by interlobular septa

In expiration „black‟ areas remain in volume and density

„white‟ areas decrease in volume and increase in

density

INCREASE IN CONTRAST

DIFFERENCES

AIRTRAPPING

Bronchiolitis

obliterans

Early Sarcoidosis

Chronic EAA


Extr. Allerg. Alveolitis (EAA) HRCT

Morphology

chronic: fibrosis

Intra- / interlobular septal thickening

Irregular interfaces

Traction bronchiectasis

acute - subacute

acinar (centrilobular) unsharp densities

ground glass (patchy - diffuse)

Pathology in white Areas

Alveolitis / Pneumonitis

Ground glass desquamative intertitial pneumoinia (DIP)

nonspecific interstitial pneumonia (NSIP)

organizing pneumonia

In expiration both areas (white and black) decrease in

volume and increase in density

DECREASE IN CONTRAST

DIFFERENCES

Cellular

NSIP

Mosaic Perfusion

Chronic pulmonary embolism

LOOK FOR

Pulmonary hypertension

idiopathic, cardiac disease, pulmonary

disease

CTEPH =

Chronic thrombembolic

pulmonary hypertension

Smoking-related ILDs

By


Histopathological Patterns of IIPs

Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

Age Genetic factors

Environmental factors Nature of injury

– Etiologic agent

– Recurrent vs single

– Endothelial vs epithelial

Histopathologic Pattern

DIP RB-ILD LIP COP NSIP AIP UIP

Inflammation Fibrosis

LUNG INJURY

Table 1. Smoking-related ILDs

http://pubs.rsna.org/na101/home/literatum/publisher/rsna/journals/content/radiographics/2008/radiographics.2008.28.issue-5/rg.285075223/production/images/large/g08se25t01x.jpeg

RB-ILD

Click image to enlarge

Epidemiologic and Clinical Features

*RB-ILD usually affects current smokers 30–40 years of

age with a 30 pack-year or greater history of cigarette

smoking.

*There is a slight male predominance.

*Mild cough and dyspnea are the most common

presenting symptoms.

*Inspiratory crackles are present in one-half of patients,

and digital clubbing is rare .

*PFT results may be normal or show a mixed obstructive-

restrictive pattern with reduced diffusing capacity .

RB-ILD



RB-ILD


Treatment and Outcome

Patients with RB-ILD generally have a good prognosis.

The condition of most patients remains stable or

improves, and no deaths have been attributed to RB-ILD,

to our knowledge. Progressive fibrotic lung disease does

not occur. Smoking cessation is the most important

treatment of RB-ILD. Corticosteroids have little role in

most cases, although beneficial results have been

reported in anecdotal symptomatic cases

Desquamative Interstitial Pneumonitis

It is considered a misnomer, as the predominant

pathologic feature is the intraalveolar accumulation of

pigmented macrophages and not desquamation of

epithelial cells as previously thought. The condition

represents the end spectrum of RB-ILD with similar

pathologic findings and an almost invariable

association with smoking.



*DIP is an uncommon form of IIP that primarily affects cigarette smokers in

their 4th or 5th decades. Males are affected nearly twice as often as

females. Approximately 90% of patients with DIP are smokers.

*DIP can occasionally be seen in nonsmokers in association with systemic

disorders, infections, and exposure to occupational or environmental

agents or drugs .

*Dyspnea and dry cough are the most common presenting symptoms, and

the onset is usually insidious. Inspiratory crackles are heard in 60% of

patients, and digital clubbing occurs in nearly one-half of patients .

*The most common and striking PFT abnormality is marked reduction in

diffusing capacity, with reductions of 50% or more being common.

Restrictive defects are also common. Patients with advanced disease may

have hypoxemia at rest or with exertion.



Treatment and Outcome *Smoking cessation is the primary treatment for DIP and may lead to disease regression.

*Most patients with DIP receive oral corticosteroids. Although no randomized trials

have demonstrated the efficacy of this therapy, it is generally recommended for

patients with significant symptoms, PFT abnormalities, and progressive disease.

*A higher percentage of patients with DIP respond to corticosteroid therapy than

do patients with UIP; approximately two-thirds of DIP patients show stabilization

or improvement of symptoms, and complete recovery is possible. The response to

corticosteroids is not uniform, as approximately 25% of patients may continue to progress despite treatment .

*The role of cytotoxic and other immunosuppressive agents remains undefined.

The 5- and 10-year survival rates are 95.2% and 69.6%, respectively .Late

relapse and recurrence in a transplanted lung have been reported


Pulmonary Langerhans Cell Histiocytosis

The term Langerhans cell histiocytosis refers to a group of diseases of unknown

etiology often recognized in childhood, in which Langerhans cell accumulations

involve one or more body systems, including bone, lung, pituitary gland, mucous

membranes, skin, lymph nodes, and liver. This disease is also referred to as

histiocytosis X or eosinophilic granuloma. The term pulmonary Langerhans cell histiocytosis refers to disease in adults that affects the lung, usually in isolation

and less commonly in addition to other organ systems



Epidemiologic and Clinical Features *Ninety percent to 100% of adults with PLCH are current or former smokers .The

condition is uncommon, with a prevalence of 3.4% in a series of 502 patients

undergoing surgical lung biopsy for chronic diffuse infiltrative lung disease .

*The peak occurrence is at 20–40 years of age. Men and women are equally affected. PLCH is more common in white patients. Up to 25% of patients are asymptomatic,

with the disease discovered incidentally during radiologic studies.

*The most common presenting symptoms are nonproductive cough and dyspnea.

Constitutional symptoms, such as weight loss, fever, night sweats, and anorexia, occur in up to one-third of patients. In 10% of patients, PLCH manifests as

spontaneous pneumothorax.



Epidemiologic and Clinical Features *PLCH in adults is usually isolated to the lungs. Extrapulmonary manifestations may

occur in 5%–15% of patients and include bone lesions, diabetes insipidus, and skin

lesions .

*Crackles and wheezes may occasionally be heard, and in advanced cases breath sounds are decreased. Clubbing is rare. At the time of presentation, PFTs show

normal results or demonstrate mild obstructive, restrictive, or mixed abnormalities;

however, the most frequent PFT abnormality is a reduction in diffusion capacity in

60%–90% of patients .

*The prevalence and severity of pulmonary hypertension in advanced PLCH are

much greater than in other chronic lung diseases and appear to be at least in part

independent of chronic hypoxemia and abnormal pulmonary mechanics. Intrinsic

pulmonary vascular disease characterized by a severe diffuse pulmonary

vasculopathy involving the pulmonary muscular arteries and interlobar veins is likely to be responsible .



Treatment and Outcome *Smoking cessation is essential and leads to stabilization of symptoms in most

patients. In a substantial proportion, this may be the only intervention required .

*Corticosteroids are the mainstay of medical therapy for PLCH. Chemotherapeutic

agents such as vinblastine, methotrexate, cyclophosphamide, etoposide, and cladribine have been used in patients with progressive disease unresponsive to

corticosteroids or with multiorgan involvement .

*Lung transplantation is considered for patients with advanced PLCH associated with

severe respiratory impairment and limited life expectancy. The natural history is variable and unpredictable in an individual patient .

*Approximately 50% of patients experience a favorable outcome with partial or

complete clearing of radiologic abnormalities and symptom resolution. In 30%–40% of

patients, symptoms of variable severity persist; in 10%–20%, recurrent pneumothorax or progressive respiratory failure with cor pulmonale occurs. A few cases of

recurrence despite smoking cessation have been reported.

Idiopathic Pulmonary Fibrosis

Relationship of IPF to Smoking *A relationship between cigarette smoking and IPF has been recognized for many

years. Alveolar wall fibrosis in addition to coexistent emphysema was

demonstrated at histopathologic analysis in early autopsy studies of smokers

dying from emphysema .A high prevalence of current or former smokers is noted

in series of IPF patients, varying from 41%–83%

*There is an independent strong association between smoking and the

development of familial interstitial pneumonia of various subtypes including UIP .

*Recent work suggests that smoking may have a detrimental effect on IPF survival, with survival and severity-adjusted survival being higher in nonsmokers

than in former smokers or in a combined group of former and current smokers



IPF is the most common form of idiopathic ILD, manifesting in the 6th–7th

decades with a slight male predominance.

Clinical features include gradually progressing dyspnea, chronic cough,

and bibasilar inspiratory crackles .

Digital clubbing is seen in approximately two-thirds of patients.

PFTs usually demonstrate a restrictive defect with reduced lung volumes

and diffusing capacity.

Rough Reticular

Traction

Bronchiectasis

and

Interface

sign

Honey

combing

UIP


Treatment and Outcome

The clinical course is gradual deterioration with a median survival of 2.5–3.5 years.

Treatment remains largely supportive; the response to steroids is poor, and no drug

therapy has clearly demonstrated a survival benefit.

A number of novel investigational agents are being studied, and lung transplantation

is an option .


Combined Pulmonary Fibrosis and Emphysema

The combination of emphysema in the upper lobes and fibrosis in the

lower lobes (CPFE) is being increasingly recognized as a distinct entity in

smokers .

Patients are almost exclusively men in their 6th and 7th decades.

Lung volumes are relatively preserved despite markedly impaired diffusion

capacity and hypoxemia during exercise.

Honeycombing, reticular opacities, and traction bronchiectasis are the

most frequent findings at high-resolution CT in the lower lungs, while the

upper lungs exhibit paraseptal and centrilobular emphysema



In some cases of CPFE, emphysema and fibrosis may co-occur in the

same area of the lung . The resultant low-attenuation emphysematous

foci may have apparent walls due to thickening of the adjacent

interlobular septa. Such a high-resolution CT pattern may be confused

with other cystic lung disease such as lymphangioleiomyomatosis and PLCH. Clinical correlation and attention to other imaging features such

as nodules in PLCH and diffuse cystic change in

lymphangioleiomyomatosis may be helpful.

There is a high prevalence of pulmonary hypertension in CPFE, and

this is a critical determinant of prognosis. Median survival is reported to

be 6.1 years, better than in patients with IPF alone but worse than

expected for emphysema in the absence of fibrosis.


Overlap and Relationship between the Different SR-ILDs

The clinical, radiologic, and histologic features overlap among the different SR-

ILDs. The overlap is most significant between RB-ILD and DIP. They may be

different components of the same histopathologic disease spectrum, representing

diverse degrees of severity of the same process caused by chronic smoking.

Respiratory bronchiolitis or DIP changes at histologic analysis are very common in patients with PLCH, correlating with the cumulative exposure to cigarette

smoke, and are often accompanied by significant ground-glass attenuation at

high-resolution CT .

Smokers who develop IPF often have RB-ILD and DIP changes at high-resolution CT and histopathologic analysis , and patients with DIP may develop a high-

resolution CT pattern of fibrotic NSIP over time .

A combination of SR-ILD–related high-resolution CT findings, such as ground-

glass opacities, cysts, micronodules, septal thickening, and honeycombing, can be seen in the same patient, confounding radiologic classification into a discrete

smoking-related entity.


Overlap and Relationship between the Different SR-ILDs

Diagnostic Approach to Patients with SR-ILDs

An integrated clinical, radiologic, and pathologic approach to the

diagnosis of SR-ILD is recommended, as with other diffuse

parenchymal lung diseases . The diagnostic process begins with a

clinical evaluation that includes history, physical examination,

chest radiography, and pulmonary function tests. High-resolution

CT plays an integral role in evaluation. In the appropriate clinical

context, the presence of typical changes at high-resolution CT,

such as nodules and cysts in PLCH and honeycombing and

emphysema in smoking-related IPF, renders the diagnosis almost

certain and may obviate further testing. Surgical lung biopsy is

indicated when the findings at high-resolution CT are relatively

nonspecific, as in RB-ILD and DIP, or when a confident definitive

diagnosis is needed.

Diagnostic Approach to Patients with SR-ILDs

A final diagnosis of an SR-ILD and identification of the

specific entity can be made with certainty only after the

pulmonologist, radiologist, and pathologist have reviewed all

of the clinical, radiologic, and pathologic data. Distinction of

SR-ILD from other forms of diffuse parenchymal lung

disease and recognition of the specific pattern of SR-ILD, in

particular the separation of RB-ILD, DIP, and PLCH from IPF,

have important clinical implications. Smoking cessation is an

important component in the management of SR-ILD, though

the natural history of SR-ILD and the influence of smoking on

the clinical course of these patients have not been fully

delineated. Smoking cessation may lead to improvement in

many patients with RB-ILD and general stabilization or

improvement in DIP and PLCH. In general, the prognosis for

RB-ILD, DIP, and PLCH is significantly better than that for

IPF.

Acute exacerbations in patients with idiopathic pulmonary fibrosis

By


Histopathological Patterns of IIPs

Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

Age Genetic factors

Environmental factors Nature of injury

– Etiologic agent

– Recurrent vs single

– Endothelial vs epithelial

Histopathologic Pattern

DIP RB-ILD LIP COP NSIP AIP UIP

Inflammation Fibrosis

LUNG INJURY

50%

Years

Resp

irato

ry

Fu

ncti

on

/Sym

pto

ms

1 2 3 4

FV

C

Traditional View of UIP/IPF Progression

Progression of IPF: Acute Exacerbation vs

Slow Decline

FVC = forced vital capacity

50%

Years

Resp

irato

ry

Fu

ncti

on

/Sym

pto

ms

1 2 3

Acute exacerbation

Step Theory of UIP/IPF Progression

Progression of IPF: Acute Exacerbation vs

Slow Decline F

VC

0 4

Am J Respir Cell Mol Biol. 2003;29(3 suppl):S1-S105.

=hits

Multiple Hypotheses for the

Pathogenesis of IPF • Inflammation causes fibrosis

• Noninflammatory (multiple hit) hypothesis: fibrosis results from epithelial injury and abnormal wound healing in the absence of chronic inflammation

• Vascular remodeling: aberrant vascular remodeling supports fibrosis, and may contribute to increased shunt and hypoxemia

Noble PW, Homer RJ. Clin Chest Med. 2004;25:749-758, vii.

Raghu G, Chang J. Clin Chest Med. 2004;25: 621-636, v. Strieter R. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

• Inflammation causes fibrosis – Inflammatory concept was dominant in the 1970s and

1980s

• IPF resulted from unremitting inflammatory response

to injury culminating in progressive fibrosis

– Role of inflammation remains controversial

• Lack of efficacy of corticosteroids


Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.

Injury Inflammation Fibrosis

Inflammatory Hypothesis

Injury

Epithelial cells

Slide courtesy of Paul Noble, MD.

Progression of Lung Fibrosis

Capillary

Endothelial

cells

?

Epithelial cells

Collagen

Myofibroblast

Cell death

Growth factors and other

products of epithelial

cell Injury

Slide courtesy of Paul Noble, MD.

Tissue Model of Lung Fibrosis

Capillary

Endothelial

cells

• Fibrosis results from epithelial/endothelial injury and abnormal wound healing in the absence of chronic inflammation – Recurrent, unknown injury to distal pulmonary parenchyma

causes repeated epithelial cell injury and apoptosis

– Loss of alveolar epithelium exposes basement membrane to oxidative injury and degradation

– Failure of re-epithelialization/re-endothelialization provides stimulus for persistent profibrotic growth factor production, persistent fibroblast proliferation, excessive deposition of ECM, and progressive fibrosis


Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v. Selman M, et al. Drugs. 2004;64:405-430.

Noninflammatory (multiple hit)

Hypothesis

Noninflammatory (multiple hit) Hypothesis

Recurrent

pulmonary

injury

Epithelial/

endothelial

injury and

apoptosis

Loss of basement

membrane

Failure of

re-epithelialization/

re-endothelialization

ECM

deposition Fibroblast

proliferation

Release of

profibrotic

growth factors

(TGF-b, PDGF,

IGF-1)

Progressive fibrosis with loss of

lung architecture

TGF-b = transforming growth factor-beta

PDGF = platelet derived growth factor IGF-1 = insulin-like growth factor-1


Raghu G, Chang J. Clin Chest Med. 2004;25:621-636, v.

Selman M, et al. Drugs. 2004;64:405-430.

• Aberrant vascular remodeling supports fibrosis and may contribute to increased shunt and hypoxemia

Increased angiogenesis results from imbalance of pro-angiogenic

chemokines (IL-8, ENA-78) and anti-angiogenic, IFN-inducible

chemokines (IP-10)

Vascular remodeling leads to anastomoses between the

systemic/pulmonary microvasculature, increasing right-to-left shunt,

contributing to hypoxemia

Chemokine

imbalance Increased

angiogenesis

Fibrosis


Strieter RM, et al. Am J Respir Cell Mol Biol. 2003;29(3 suppl):S67-S69.

Vascular Remodeling Hypothesis

Aberrant

vascular

remodeling

Defects in Host Defense Mechanisms

May Contribute to Fibrosis

• Defects in endogenous host defense

mechanisms (eg, IFN-g, PGE2 production) that

limit fibrosis after acute lung injury may

contribute to progressive fibrosis


NHLBI in an attempt to standardize the diagnostic

criteria used across studies . This committee defined

AEx-IPF as an acute, clinically significant deterioration

of unidentifiable cause and proposed five diagnostic criteria.

Definition of AEx-IPF

1- Previous or concurrent diagnosis of IPF 2- Unexplained worsening or development of dyspnea within 30

days 3- HRCT with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or

honeycomb pattern consistent with UIP pattern 4- No evidence of pulmonary infection by endotracheal aspirate

or BAL 5- Exclusion of alternative causes, including: • Left heart failure

• Pulmonary embolism • Identifiable cause of acute lung injury.

Diagnostic criteria for AEx-IPF

Incidence of AEx-IPF

*American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory

Society (JRS) and Latin American Thoracic Association (ALAT) on the diagnosis and treatment of IPF state that AEx- IPF occurs in approximately 5–10% of

patients with diagnosed IPF annually

*A recent retrospective study of data collected from 461 patients with diagnosed IPF found 1-year and 3-year incidences of AEx-IPF of 14.2% and 20.7%,

respectively .

*However, the incidence rates of AEx-IPF reported in clinical trials have tended to be lower than this.

Pathophysiology of AEx-IPF A variety of patterns of acute lung injury have been observed in AEx-IPF . The most common histopathological finding is diffuse

alveolar damage superimposed on the underlying usual interstitial pneumonia (UIP) pattern , but organizing pneumonia and extensive fibroblastic foci have also been reported.

Several hypotheses for the etiology of AEx-IPF have been

proposed. AEx-IPF may represent a sudden acceleration of the underlying disease process due to unknown acute injury to the lung, or a biologically distinct pathological process due to a

clinically occult condition, such as infection or gastroesophageal reflux disease (GERD)

Pathophysiology of AEx-IPF As AEx-IPF have a clinical presentation that shares a number of

features with viral respiratory infections (e.g. fever, cough, myalgia), it

has been suggested that occult viral infection may contribute to the

pathophysiology of AEx-IPF.

Several hypotheses for the etiology of AEx-IPF have been proposed. AEx-IPF may represent a sudden acceleration of the underlying disease process due to unknown acute injury to the lung, or a biologically distinct pathological process due to a clinically occult condition, such as infection or gastroesophageal reflux disease (GERD). However, the evidence supporting the involvement of viral infections in AEx- IPF is mixed .The most recent and extensive study, which used genomic-based technologies to investigate the role of viruses in the etiology of AEx-IPF, suggested that viral infection is not a common cause ofAEx-IPF.

Pathophysiology of AEx-IPF Activation of the immune system, disordered coagulation/fibrinolysis, and oxidative stress may all contribute to the pathophysiology of AEx-IPF. Immune cells (e.g. neutrophils, macrophages) ,inflammatory mediators (e.g. interleukin 6, high mobility group protein B1) ,markers of coagulation/fibrinolysis (e.g. protein C, thrombomodulin, and plasma activator inhibitor-1) , and markers of oxidative stress (thioredoxin 1) are all elevated in patients with AEx-IPF. Epithelial cell damage in patients with IPF is demonstrated by over-expression of matrix metalloproteinase (MMP)-7, MMP-9 , and Krebs von den Lungen- 6 (KL-6) . Accelerated epithelial cell proliferation, with increases in the proliferation markers CCNA2 and Ki-67, in patients with AEx-IPF may be a compensatory response to injury, and is associated with epithelial cell death. Transforming growth factor (TGF)-beta, a fibrogenic cytokine, is upregulated in IPF and galectin-3, a mediator of fibrosis induced by TGF-beta, is elevated in the lungs and serum of patients with stable IPF and AEx-IPF . Circulating bone marrowderived fibrocytes may also provide a source of lung fibroblasts and myofibroblasts, as the number of circulating fibrocytes has been shown to be higher in patients with IPF and AEx-IPF, compared with healthy subjects

Risk factors and precipitating factors for AEx-IPF

*Lower total lung capacity, lower forced vital capacity (FVC) and/or lower diffusing capacity of the lung for carbon

monoxide (DLco). *A higher degree of dyspnea (score ≥2 on the modified

Medical Research Council dyspnea scale) or of fibrosis on HRCT has been shown to increase the risk of AEx-IPF, as has the

presence of concomitant conditions such as emphysema or pulmonary hypertension.

*Invasive examinations such as bronchoscopy , bronchoalveolar lavage (BAL), and pulmonary resection for

lung cancer can precipitate AEx-IPF.

Risk factors and precipitating factors for AEx-IPF

*surgical lung biopsy is a precipitating factor for AEx-IPF; however, the risk of AEx-IPF from video-assisted thoracoscopic

operation appears to be elevated only in patients with severe physiologic impairment or substantial comorbidity

*In some patients with AEx-IPF, pepsin levels were found to be

elevated in BAL fluid, suggesting a possible role for GERD in the pathogenesis of AEx-IPF .There is some evidence to suggest that the treatment of GERD in patients with IPF

reduces mortality rates .

Impact of AEx-IPF on patients

*AEx-IPF are certainly a leading cause of hospitalization and death among patients with IPF. Median survival after an AEx-

IPF has been reported to be between 22 days and 4.2 months.

*There is some evidence that patients with better lung function (FVC, PaO2, DLCO) prior to AEx-IPF are more likely to

survive an AEx-IPF , suggesting that preservation of lung function may be an important way of reducing the impact of AEx-IPF in patients with IPF.

Management of AEx-IPF

*The latest international treatment guidelines state that supportive care remains the mainstay of treatment for AEx-IPF,

but also give a weak recommendation for the treatment of the majority of patients with AEx-IPF with corticosteroids.

*In clinical practice, the treatment of AEx-IPF is variable.

Corticosteroids (e.g. prednisone, methylprednisolone) are used in the majority of patients who suffer an AEx-IPF, usually in pulse doses. Preliminary data suggest that response to high-

dose corticosteroid treatment may depend on the type of HRCT lesion, with better responses achieved in those with a

peripheral pattern

Management of AEx-IPF

*Broad-spectrum antibiotics and immunosuppressants (cyclosporin or cyclophosphamide) are sometimes used in

addition to corticosteroids .However, the efficacy of immunosuppressants in the treatment of AEx-IPF is based on a few small retrospective studies that do not provide conclusive

evidence for benefit.

*Mechanical ventilation is often used in patients with AEx-IPF, but the data on its effects on outcomes are mixed.

*Other treatments for AEx-IPF that havebeen investigated in small studies include polymyxin Bimmobilized fiber column

(PMX) hemoperfusion and tacrolimus, a cytokine transcription inhibitor ,usually administered in addition to corticosteroids.

Reducing the risk of exacerbations

*A trial of sildenafil, a phosphodiesterase-5 inhibitor, showed a numerical reduction in AEx-IPF in patients given sildenafil versus

placebo (3 [3.4%] vs. 7 [7.6%]), but the number of events was small and the difference was not statistically significant .

*Imatinib, a tyrosine kinase inhibitor , bosentan, an endothelin receptor antagonist, the anticoagulant warfarin , and inhaled

Nacetylcysteine , numerically higher rates of AEx-IPF were found in the active treatment arms compared with the placebo arms.

*triple therapy with prednisone, azathioprine,and N-acetylcysteine in patients with IPF, a significantly higher rate of

AEx-IPF was observed in patients receiving triple therapy versus placebo


*Pirfenidone, an anti-fibrotic molecule that has been licensed for the

treatment of IPF in Japan, India, China, Europe, and Canada, but was not approved in the United States, has shown inconsistent effects on AEx-IPF. *Nintedanib (formerly known as BIBF 1120) is a tyrosine kinase inhibitor in clinical development for the treatment of IPF. It reported a lower incidence of AEx-IPF was observed in patients treated with nintedanib 300 mg/day than placebo (2.4 vs. 15.7 AEx-IPF per 100 patient years) *It is interesting that nintedanib may have an effect on AEx-IPF whereas the tyrosine kinase inhibitor imatinib, which inhibits the platelet-derived growth factor receptor (PDGFR), did not . Nintedanib is an inhibitor of PDGFR, vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR) and this specificity of inhibition may be key to its effects on AEx-IPF


*Anti-acid treatment might decrease the frequency of AEx-IPF by reducing the acidity of the microaspirate .

How To Approach

a Practical

Diagnosis?

An acute appearance suggests:

pulmonary edema

Pneumonia

Miliary TB

DAD

Rule no. 1

Reticulonodular lower lung predominant

distribution with decreased lung volumes

suggests: (APC)

1. Asbestosis

2. Aspiration (chronic)

3. Pulmonary fibrosis (idiopathic)

4.Collagen vascular disease

Rule no. 2

Asbestos-related

pleural disease and

asbestosis

Pulmonary fibrosis and rheumatoid arthritis.

Systemic sclerosis. A: PA chest radiograph shows a bibasilar and subpleural distribution of fine

reticular ILD. The presence of a dilated esophagus (arrows) provides a clue

to the correct diagnosis.

B: CT scan shows peripheral ILD and a dilated esophagus (arrow).

A middle or upper lung predominant distribution

suggests: (Mycobacterium Settle Superiorly in

Lung)

1. Mycobacterial or fungal disease

2. Silicosis

3. Sarcoidosis

4. Langerhans Cell Histiocytosis

Rule no. 3

Complicated silicosis. PA chest radiograph shows multiple

nodules involving the upper and middle lungs, with coalescence

of nodules in the left upper lobe resulting in early progressive

massive fibrosis

Sarcoidosis. CT scan shows nodular thickening of the bronchovascular

bundles (solid arrow) and subpleural nodules (dashed arrow), illustrating the

typical perilymphatic distribution of sarcoidosis.

Langerhan cell histiocytosis.

This 50-year-old man had a

30 pack-year history of

cigarette smoking.

A: PA chest radiograph

shows hyperinflation of the

lungs and fine bilateral

reticular ILD.

B: CT scan shows multiple

cysts (solid arrow) and

nodules (dashed arrow).

Associated lymphadenopathy suggests :

1.Sarcoidosis

2.neoplasm (lymphangitic carcinomatosis,

lymphoma, metastases)

3. infection (viral, mycobacterial, or fungal)

4. Silicosis

5-LAM

6-progressive systemic sclerosis

7-TB or fungal diseases

Rule no. 4

Simple silicosis.

A: CT scan with lung windowing shows numerous

circumscribed pulmonary nodules, 2 to 3 mm in diameter

(arrows).

B: CT scan with mediastinal windowing shows densely

calcified hilar (solid arrows) and subcarinal (dashed arrow)

nodes.

Associated pleural thickening and/or

calcification suggest asbestosis.

Rule no. 5

Associated pleural effusion suggests :

1.pulmonary edema

2.lymphangitic carcinomatosis

3.lymphoma

4.collagen vascular disease

Rule no. 6

Cardiogenic pulmonary edema.

PA chest radiograph shows enlargement of the cardiac

silhouette, bilateral ILD, enlargement of the azygos vein

(solid arrow), and peribronchial cuffing (dashed arrow).

Lymphangitic carcinomatosis. This 53-year-old man

presented with chronic obstructive pulmonary disease and

large-cell bronchogenic carcinoma of the right lung.

CT scan shows unilateral nodular thickening (arrows) and a

malignant right pleural effusion.

Associated pneumothorax suggests

lymphangioleiomyomatosis or LCH.

Rule no. 7

Lymphangioleiomyomatosis

(LAM).

A: PA chest radiograph shows a

right basilar pneumothorax and

two right pleural drainage

catheters. The lung volumes are

increased, which is

characteristic of LAM, and there

is diffuse reticular ILD.

B: CT scan shows bilateral thin-

walled cysts and a loculated

right pneumothorax (P).

Tell me the rules

again?

1. Acute

•P.Edema

•Pneumonia

2. Pleural effusion

•1.pulmonary edema

•2.lymphangitic carcinomatosis

•3.lymphoma

•4.collagen vascular disease 3.Pneumothorax

•lymphangioleiomyomatosis

•LCH 4.Predominantly Below with

reduced volume

1.Asbestosis

2. Aspiration (chronic)

3. Pulmonary fibrosis (idiopathic)

4.Collagen vascular disease

5. A middle or upper lung predominant

1. Mycobacterial or fungal disease

2. Silicosis

3. Sarcoidosis

4. Langerhans Cell Histiocytosis

6. Associated lymphadenopathy

1.Sarcoidosis

2.neoplasm (lymphangitic

carcinomatosis, lymphoma,

metastases)

3. infection (viral, mycobacterial, or

fungal)

4. silicosis

7. Pleural Thickening

and or Calcification

•Asbestosis

Approach to the ILD Patient

Martinez F, Flaherty K. Available at: http://www.chestnet.org/education/online/pccu/vol18/lessons03_04/lesson03.php.

Patient with Suspected

ILD

Hx, PE, CXR, PFT, Labs

STOPHRCT

Hx and HRCT

consistent

with IPF

Hx and HRCT

Dx of other

ILD

Suspected

other ILD

Atypical

clinical or CT

features of IPF

STOP STOP

STOP

VATS

UIP Non IIPLIPOPDADDIPNSIP RBILD

Yes

No

Yes

No

Dx likely by

bronch?

Is bronch

diagnostic?

Dx likely by

bronch?

Is bronch

diagnostic?

Yes

Yes

No

diffuse parenchymal lung diseases (postgraduate course)

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