1. No category

NEW APPROACHES TO
MANAGING
IDIOPATHIC
PULMONARY FIBROSIS
Presented By:
Magd Mohamed Galal
Professor Of Chest Diseases
Al Azhar University
Faculty Of Medicine For Girls
Interstitial Lung Disease
(ILD)
Diffuse parenchymal lung
diseases (DPLDs).
 Definition:
A group of disorders that involve
the distal lung parenchyma,or
space between the epithelial and
endothelial basement membranes.
Diffuse Parenchymal Lung Disease
DPLD of known
cause eg drugs
Or association eg
Collagen vascular
disease
Idiopathic
Interstitial
Pneumonia (IIP)
Granulomatous
DPLDs eg
sarcoidosis
Idiopathic pulmonary
Fibrosis (IPF)
Other forms of
DPLD
Eg LAM ,HX ect.
IIP other than IPF
Desquamative interstitial
pnumonia
Respiratory bronchiolitis
Interstitial lung disease
Acute interstitial
pneumonia
Cryptogenic organizing
pneumonia
Non specific interstitial
Pneumonia (provisional)
Lymphocytic interstitial
pneumonia
General Diagnostic
Approach
Of DPLDs
IDIOPATHIC
PULMONARY
FIBROSIS
(Cryptogenic Pulmonary
Fibrosis)
OVERVIEW
 Prevalence: 13–20/100,000 in US
(approximately 35,000-55,000 cases)
 Onset: Usually between 50 and 70 yr
 Clinical presentation





Progressive dyspnea on exertion
Paroxysmal cough, usually nonproductive
Abnormal breath sounds on chest auscultation
Abnormal chest x-ray or HRCT
Restrictive pulmonary physiology with reduced
lung volumes and DLCO and widened A-aPO2
Coultas DB et al. Am J Respir Crit Care Med. 1994;150:967.
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
CLASSIFICATION OF IIP
(IMMUNOCOMPETENT HOST)
Idiopathic
interstitial
pneumonia
(IIP)
Idiopathic
Respiratory
Desquamative bronchiolitispulmonary
interstitial
fibrosis/Usual
associated
pneumonia interstitial lung
interstitial
(DIP)
pneumonia
disease
(UIP)
(RBILD)
Acute
interstitial
pneumonia
(AIP)
Nonspecific
interstitial
pneumonia
(NSIP)
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
INTERNATIONAL
CONSENSUS STATEMENT ON
IPF: HISTOLOGY
 UIP is essential to diagnosis of IPF


Idiopathic, progressive, diffuse fibrosing
inflammatory process
Involves lung parenchyma
 Surgical lung biopsy recommended in
patients with suspected IPF, especially those
with atypical clinical or radiographic features
 Major purpose of histologic examination is to
distinguish UIP from other histologic subsets
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
of IIP
DIAGNOSIS OF IPF
 Major criteria




Exclusion of other known causes of ILD
Abnormal pulmonary function studies
Bibasilar reticular abnormalities on HRCT scan
No histologic or cytologic features on
transbronchial lung biopsy or BAL analysis
supporting another diagnosis
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646.
DIAGNOSIS OF IPF
Minor criteria
 Age
>50 yr
 Insidious onset of otherwise
unexplained exertional dyspnea
 Duration of illness 3 mo
 Bibasilar, dry (“Velcro”) inspiratory
crackles
Pulmonary Function






Reduction in all lung volume
Increased static elastic recoil
Rapid shallow rapid breathing
Impaired single –breath diffusing capacity (DLco)
Impaired oxygenation at rest and exercise
Exercise induced alveolar –arterial O2 gradient correlates
better with histologic abnormalities than do lung volumes
or DLco.
 Exercise testing with arterial cannulations:
 Widening A-aPo2
 Respiratory alkalosis
 Decreased O2 consumption
 Increased dead space (VD/VT)
 Increased MV for level of O2consumption
 Low O2 pulse
 6 walk test + oximetry easier ,better for disease
progression and regression.
HRCT in IPF
 Bibasilar interstitial and intra lobular
reticular opacities.
 Interlobular septal thickening
 Sub pleural honeycomb changes ,
 Traction bronchiectasis in lower
lobes,
 Without pleural abnormalities.
HRCT FINDINGS IN IPF
Slide courtesy of G Raghu, MD.
BAL
 Normally contains 95-98% macrophages and very few





neutrophils, lymphocytes, or eosinophils.
The predominance of certain subgroups of cells in patients
with DPLD might be helpful in the differential diagnosis.
Neutrophils are often predominant in smokers and in
patients with IPF, Hypersensitivity pneumonitis, or Collagen
vascular diseases
Lymphocytic predominance is seen mainly in patients with
sarcoidosis or Hypersensitivity pneumonitis.
Eosinophils predominate in patients with chronic
eosinophilic pneumonia, Loeffler syndrome, or ChurgStrauss angiitis
.On the other hand, BAL may yield a specific diagnosis in
DPLD, patients with certain findings such as: Asbestos bodies (which indicate asbestosis).
 Silica-filled macrophages (silicosis).
 Periodic acid-Schiff (PAS)-stained
lipoproteinaceous material (pulmonary alveolar
proteinosis).
 X bodies (eosinophilic granuloma).
HISTOPATHOLOGIC
ELEMENTS OF UIP
 Heteroganous areas of end stage fibrosis
and honeycombing, with areas of active
proliferation of fibroblast (suggesting
diffuse ongoing microscopic alveolar
epithelial injury.
 Fibroblastic foci
 Minimal interstitial inflammation (primary
proliferative process)
 Honey combing (common) cystic space is
lined by bronchial epithelium.
UIP interstitial inflammation mild &patchy. The
fibro tic zones are composed mainly of dense
collagen, & oldest disease is seen peripherally in
lung lobule or acinus.
Slide courtesy of KO Leslie, MD.
TEMPORAL
HETEROGENEITY OF UIP
Slide courtesy of KO Leslie, MD.
Interstitial inflammation and fibrosis
with alveolar wall thickening
INFLAMMATION AND
FIBROSIS IN UIP
Temporal
heterogeneity
Slide courtesy of KO Leslie, MD.
Peripheral accentuation of fibrosis
Alveolar septal infiltrate of lymphocytes
& plasma cells
CHRONIC INTERSTITIAL
INFLAMMATION IN UIP
Hyperplasia of type 2 pneumocytes.
Slide courtesy of KO Leslie, MD.
FIBROBLASTIC FOCI IN UIP
Slide courtesy of KO Leslie, MD.
Evidence Of Pulmonary
Hypertension
CONTRASTING
PATHOLOGIC
FEATURES OF IIP
.
Feature
UIP
DIP/RBILD
AIP
NSIP
Temporal appearance
Variegated
Uniform
Uniform
Uniform
Interstitial inflammation Scant
Scant
Scant Usuallyprominent
Collagen fibrosis
Variable, diffuse No Variable, diffuse
in DIP; focal, mild
in RBILD
Patchy
Fibroblast proliferation Fibroblastic foci No
r
Diffuse Occasional, diffuse,
rare fibroblastic foci
Organizing pneumonia No
No
No Occasional, focal
Honeycomb changes
Yes
No
No
Intraalveolar macrophage
Occasional, focal
Diffuse in DIP;
No Occasional, patchy
accumulation
Hyaline membranes
Rare
peribronchiolar in
RBILD
No
No
Occasional,
focal
No
Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
NSIP
 Either pure inflammatory or dense
fibrosis (predominance of cellular
pattern or fibro tic pattern).
 Must exclude (HSP, drug, and collagen
vascular disease).
 Pathology, uniform of same age (as a
result of single insult).
 Fibroblastic foci & Honey combing are
rare
PATHOGENESIS OF
PULMONARY
FIBROSIS
PATHOGENESIS AND
COURSE OF UIP
UIP
Multiple microscopic foci of injury occurring over many years
Focal fibroblast proliferation (fibroblastic foci)
Collagen deposition
Recurrent microscopic injury
Progressive clinical course
Death
Katzenstein ALA et al. Am J Respir Crit Care Med. 1998;157:1301.
MOLECULAR BIOLOGY OF
PULMONARY REPAIR
Cellular phase
Triggering
event
Fibrotic phase
Endothelial cell
Angiostasis
Monocyte
+
ELR- CXC
TNF-a
IL-1
MØ
IL-1
TNF-a
+
ELR+ CXC
fibroblast
IL-12
IL-18
ELR- CXC
Normal alveoli
ELR+ CXC
Cellular phase
ELR+ CXC
–
IFN-g
Lymphocyte
Extracellular
matrix
ELR- CXC
Angiogenesis
Endothelial cell
ELR+ CXC
ELR- CXC
ELR- CXC
Slide courtesy of RM Strieter, MD.
Homeostasis
ELR+ CXC
Fibro tic phase
INFLAMMATORY RESPONSE OF
THE LUNG
Circulating
leukocyte
Recognition
Fixed
macrophage
Capillary Antigen
endothelial
cell
Capillary
Monocyte
Recruitment
Removal
Phagocytic Fibrous matrix
Infiltrating
leukocyte (scar issue)
leukocyte
(macrophage)
Activated
Resolution
leukocyte
Chemotactic
Fibroblast
cytokine wave
Slide courtesy of RM Strieter, MD.
Th1 AND Th2 RESPONSES
Th1
Increased
IFN-gIFN-g
Increased
Increased
IncreasedIL-2
IL-2
Increased
IncreasedIL-12
IL-12
Increased
IncreasedIL-18
IL-18IFN-g
Cell-Mediated
Immunity
TISSUE
RESTORATION
Increased IL-2
Increased IL-12
Increased IL-18
Th2
Increased IL-4
Increased IL-5
Increased IL-10
Increased IL-13
Antibody-Mediated
Immunity
Fibroblast Activation
and
Matrix Deposition
FIBROSIS
Slide courtesy of RM Strieter, MD.
ROLE OF Th1 AND Th2
RESPONSES IN REPAIR
PROCESS
Cytokine Activation
Phase
Fibrotic Phase
Th2 Type
IL-4/IL-13
(+)
ExtracellularMatrix
(Fibrosis)
Chemokines
IL10
(-)
Th1 Type
Fibroblast
IFN-g
IL-12
IL-18
(-)
Resolution
Slide courtesy of RM Strieter, MD.
ROLE OF TGF-b AND IFN-g IN
REPAIR PROCESS
TGF-b receptor
IFN-g receptor
Activation of Jak/STAT1
Smad3-4
Smad7
IFN-g inhibits
activation of
Smad3-Smad4 and
induces Smad7
Increase of TGF-b–dependent
gene transcription
Inhibition of TGF-b–dependent
gene transcription
Ulloa L et al. Nature. 1999;397:710.
MOLECULAR BIOLOGY OF
IPF: SUMMARY
 Shift to increased production of Th2
cytokines and decreased production of Th1
cytokines resulting from unknown lung injury
 Over expression of Th2 cytokine TGF-b
stimulates angiogenesis, fibroblast activation,
deposition of ECM, and fibro genesis
 Th1 cytokine IFN-g counters effects of TGF-b,
but IFN-g production decreased in IPF
  IFN-g may have therapeutic role in
management of IPF
PROGNOSTIC
FACTORS IN IPF
 Figure 4. Kaplan-Meier survival curves for patients grouped by combining
HRCT and histopathologic features as follows: histopathologic pattern
showing NSIP and HRCT interpreted as indeterminate or NSIP (n=23, dotted
line); histopathologic pattern showing UIP and HRCT interpreted as
indeterminate or NSIP (n=46, dashed line); and histopathologic pattern
showing UIP and HRCT interpreted as UIP (n=27, solid line), p=0.001. + =
last follow-up visit; circle = death.
CAUSE OF DEATH
IPF
[N=543]
1-7 year FU
60% Died
[N=326]
Respiratory Lung Pulmonary Pulmonary Cardiovascular Other
failure
18%
cancer embolism infection
disease
3%
10%
39%
3%
27%
Panos RJ et al. Am J Med. 1990;88:396.
RISK FACTORS FOR
PROGRESSIVE DISEASE
 Age: >50 yr
 Gender: male
 Dyspnea: moderate to severe with exertion
 History of cigarette smoking
 Lung function: moderate to severe loss




(especially gas exchange with exercise)
BAL fluid: neutrophilia or eosinophilia at
presentation
HRCT scan: reticular opacities or honeycomb
changes
Response to corticosteroids: poor
Pathology: more fibrosis, fibroblastic foci
HRCT ABNORMALITIES AND
CHANGES IN LUNG FUNCTION
Frequency of Improvement in
Lung Function (%)
100
75
50
25
0
N=4
N=12
Ground Glass
Mixed
N=11
Reticular
HRCT Appearance
Wells AU et al. Am Rev Respir Dis. 1993;148:1076.
HRCT APPEARANCE VS
SURVIVAL IN IPF
100
Survival (%)
90
CT appearance atypical of CFA
70
60
50
40
30
20
10
CT appearance typical of CFA
0
0
1
2
3
4
5
6
7
Time from Presentation (yr)
Daniil ZD et al. Am J Respir Crit Care Med.
1999;160:899.
BAL CELLULARITY AND
STEROID RESPONSIVENESS
Responders (N=8)
100
*
Prevalence (%)
Non responders (N=19)
75
*
* p<0.05
*
50
25
0
Lymphocytes Neutrophils
>11%
>4%
Eosinophils
>3%
Rudd RM et al. Am Rev Respir Dis. 1981;124:1.
APPROACHES TO
THERAPY
The hope of achieving stability as
scarred lung cannot regenerate.
Start treatment in patient who are
symptomatic :
 In those with a 30-40% reduction in
lung function indices.
 With evidence of disease progression
on serial lung function testing.
THERAPEUTIC
APPROACHES TO IPF
 Corticosteroids
 Other
immunosuppressives


Azathioprine
Cyclophosphamide
 Antifibrotic agents
 Colchicine
 D-Penicillamine
 IFN-g
 IFN-b
 Pirfenidone
 Antioxidant agents
 Glutathione
 N-acetylcysteine
 Others
 Agents that block
neutrophil adhesion
molecules
 Inhibitors of specific
fibrogenic cytokines
and growth factors
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646
CLINICAL RESPONSE TO THERAPY
IN IPF
Stable or Improved (%)
100
Prednisolone +
Cyclophosphamide
Prednisolone
50
0
1
3
12
24
36
Months
Johnson MA et al. Thorax. 1989;44:280.
EFFECT OF THERAPY ON
SURVIVAL IN IPF
100
Prednisone
Prednisone + Colchicine
Prednisone + D-Penicillamine
Prednisone + Colchicine
+ D-Penicillamine
Survival (%)
80
60
40
20
0
0
10
20
30
40
Months
50
60
70
Selman M et al. Chest. 1998;114:507.
NEW TARGETS FOR
THERAPEUTIC
INTERVENTION
 Greater insight into pathogenesis of IPF using
molecular biological approaches
 Wide range of potential mediators identified
 Targets might include



Initial injurious agent
Earliest pathogen tic event
Final common pathway leading to fibrosis
Lung Transplantation
 Indication:
 Severe ,end stage lung disease.
 Medical therapy ineffective.
 Substantial limitation in activities of daily life.
 Limited life expectancy(<18 months)
 End stage lung disease:
 Severe dyspnoea
 Honeycombing or pulmonary hypertension.
 Severe physiologic derangement
 TLC<60% (A-a)Po2 at rest >30
 Severe exercise desaturation or (A-a)Po2 widening.
 Clinical /radiological/physiologic score >70.
Treatment Of Complications
 Supportive therapy to minimize morbidity.
 O2 therapy


Oxygen concentrators
Portable liquid oxygen
 Diuretic therapy
 Opiate.
 Treatment of PE ,infection.