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)
Desquamativeinterstitial
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%
CoultasAJRCCM 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 pneumoniasUpdate 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

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

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

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

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

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

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
histopathological definition
…..permanent abnormal enlargement of
airspaces distal to the bronchioles terminales
and
…...destruction of the walls of the involved
airspaces

What is Your Diagnosis ?
Cystic Changes and Decreased Density
Quiz

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

Paraseptal (distal acinar)
emphysema
Affects the peripheral parts of
the secondary pulmonary lobule
Produces subpleural lucencies.
86

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-fingershadow dueto mucoid impaction in central
bronchiectasisin a patientwith asthma.

Signet-Ring Sign
A signet-ring sign represents an axial cut of a dilated bronchus
(ring) with its accompanying small artery (signet).

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
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)

Nodular Patternitie
By

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 lymphatic
CENTRILOBULAR: related to centrilobular structuresDistribution
113

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
KerleyA 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
nodularsmooth
•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

Inconsistentwith UIP
pattern (any one of
seven features
PossibleUIP pattern (all
three features)
UIP pattern (all four
features)
•Upperor mid lung
predominance
subpleural basal
predominance
•subpleural basal
predominance
•peribronchovascular
predominance
reticular abnormality•reticular abnormality
•extensive groundglass
abnormality(extent> reticular
abnormality)
•honeycombing with or
without traction
bronchiectasis
•profuse micronodules
(bilateral, predominantlyupper
lobes
Absence of features
listed as inconsistent
with UIP pattern
Absence of features
listed as inconsistent
with UIP pattern
•discrete cysts (multiple
bilateral, awayfrom areas of
honeycombing)
•diffuse mosaic attenuation/air
trapping (bilateralin three or
more lobes)
•consolidationin broncho-
pulmonarysegment(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-buddescribesthe appearance of an irregularand often nodular
branchingstructure, most easily identifiedin 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.

Broncho-alveolar cell carcinoma with ground-glass
opacity and 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

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
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

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

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
ThannickalVJ,et al. Annu Rev Med.2004;55:395-417.
Age
Genetic factors
Environmental factors
Nature of injury
– Etiologic agent
– Recurrentvs single
– Endothelialvs epithelial
Histopathologic Pattern
DIP RB-ILD LIP COP NSIP AIP UIP
Inflammation
Fibrosis
LUNG INJURY

RB-ILD
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
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 associationwith 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.
Restrictivedefects are also common. Patients with advanced disease may
have hypoxemia at rest or with exertion.

*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

*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.

*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 .

*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

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

50%
Years
Respiratory
Function/Symptoms
1 2 3 4
FVC
Traditional View of UIP/IPF Progression
Progression of IPF: Acute Exacerbation vs
Slow Decline
FVC = forced vital capacity

50%
Years
Respiratory
Function/Symptoms
1 2 3
Acute exacerbation
Step Theory of UIP/IPF Progression
Progression of IPF: Acute Exacerbation vs
Slow Decline
FVC
0 4
Am J RespirCell Mol Biol. 2003;29(3suppl):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, HomerRJ. Clin ChestMed.2004;25:749-758,vii.
Raghu G, Chang J. Clin ChestMed.2004;25:621-636,v.
Strieter R. Am J RespirCell Mol Biol. 2003;29(3suppl):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
Injury Inflammation Fibrosis
Inflammatory Hypothesis

Injury
Epithelial cells
Slide courtesyof PaulNoble,MD.
Progression of Lung Fibrosis
Capillary
Endothelial
cells
?

Epithelial cells
Collagen
Myofibroblast
Cell death
Growth factors and other
products of epithelial
cell Injury
Slide courtesyof PaulNoble,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
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= transforminggrowth factor-beta
PDGF = plateletderived growth factor
IGF-1 = insulin-like growth factor-1
Raghu G, Chang J.Clin ChestMed.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 RespirCell Mol Biol. 2003;29(3suppl):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)

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.

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).

1. Acute
•P.Edema
•Pneumonia
2. Pleural effusion
•1.pulmonary edema
•2.lymphangitic carcinomatosis
•3.lymphoma
•4.collagen vascular disease
3.Pneumothorax
•lymphangioleiomyom
atosis
•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
STOP
HRCT
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)

Diffuse parenchymal lung diseases (Postgraduate course)

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Diffuse parenchymal lung diseases (Postgraduate course)