Joseph P.

Lynch, III, MD
Professor of Clinical Medicine, Step VIII
Division of Pulmonary & Critical Care Medicine
The David Geffen School of Medicine at UCLA
Idiopathic Pulmonary Fibrosis (ACCP-1)
Idiopathic Pulmonary Fibrosis (IPF)
Most common of idiopathic interstitial
pneumonias
Associated with usual interstitial
pneumonia (UIP) pattern
Idiopathic Interstitial Pneumonias
ATS/ERS Classification
7 histological patterns
Clinical-radiographic-pathology
Am J Respir Crit Care Med 2002:165;277
Idiopathic Interstitial Pneumonias:
ATS/ERS Classification 2002
Histology CRP Dx
(1) Usual (UIP) IPF
(2) Desquamative DIP
(3) Respiratory bronchiolitis RB-ILD
(4) Diffuse alveolar damage AIP
(5) Nonspecifc NSIP
IIPs: ATS/ERS Classification 2002
Histology CRP Dx
(6) Lymphoid LIP
(7) Cryptogenic organizing pneumonia (COP)

Idiopathic Pulmonary Fibrosis (IPF)
Mortality > 50% at 3-5 years
No effective medical therapy
Histological pattern: UIP
Idiopathic Pulmonary Fibrosis (IPF)
Limited to the lung
Extrapulmonary features suggest
another disease (e.g., CTD)
Nonspecific Interstitial Pneumonia
Features overlap with UIP
Prognosis of NSIP better than UIP
(5-y survival 82%)
Travis, AJRCCM 2008:177;1338
Idiopathic Pulmonary Fibrosis (IPF)
Breathlessness (> 90%)
Nonproductive cough (> 70%)
Bibasilar crackles (> 85%)
Clubbing (> 25%)
Idiopathic Pulmonary Fibrosis
Pulmonary Function Tests:
Decreased lung volumes (VC, TLC)
Normal expiratory flow rates (FEV
1
)
Reduced DL
CO

Widened A-a 0
2
gradient
Idiopathic Pulmonary Fibrosis
Clinical features:
Chronic, progressive fibrosis
Older adults (typically > age 55)
Mortality high (30-70% at 5 y)
Prevalence of IPF
14 to 42.7 cases (per 100,000)
More common in males
More common in smokers (current
or former)
IPF: Prevalence and Incidence
42.7
16.3
14
6.8
0
5
10
15
20
25
30
35
40
45
prevalence incidence
p
r
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v
a
l
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n
c
e

p
e
r

1
0
0
,
0
0
0
liberal
conservative
Raghu, AJRCCM 2006:174;810
USA (1996-2000)
Idiopathic Pulmonary Fibrosis
Primarily a disease of the elderly
Prevalence IPF according to age
3
177
0
20
40
60
80
100
120
140
160
180
200
35-44 75+
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n
c
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p
e
r

1
0
0
,
0
0
0
Coultas, AJRCCM 1994:150;967
New Mexico
Age (years)
Prevalence IPF according to age
4
227
0
50
100
150
200
250
18-34 75+
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p
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1
0
0
,
0
0
0
Raghu, AJRCCM 2006:174;810
USA (1996-2000)
Age (years)
Deaths due to IPF according to age
18
71
306
827
1380
0
200
400
600
800
1000
1200
1400
1600
45-54 55-64 65-74 75-84 85+
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Olson, AJRCCM 2006:176;277
USA (2008)
Age (years)
Epidemiology of IPF
Cause unknown:
Aging
? Environmental causes
(dust, metals, irritants, etc)
Genetic factors
Risk Factors for IPF
Smoking
Agricultural farming; livestock
Wood dust; metal dust
Stone/sand
Taskar, Proc Am Thor Soc 2006:3;293
Risk Factors for IPF
Gastroesophageal reflux
>60% IPF patients awaiting lung
transplant have GERD
Familial IPF
0.5-3.7% cases IPF are Familial:
Probable multiple mutations
(surfactant protein C, telomerase)
Polymorphisms
(TNF-a, IL-2 receptor antagonist)
Familial IPF: Risk Factors
111 families; 309/669 (45%)
affected
Ever smoking (67.3%) p < 0.001
Male gender (55.7%) p < 0.001
Steele, AJRCCM 2005:172;1146
Pathogenesis of IPF
More than one factor (genes;
environmental) likely involved in IPF
(initiation and evolution)
Idiopathic Pulmonary Fibrosis
Q1. Which HRCT feature is most
characteristic of IPF?
a) Ground glass opacities
b) Homogeneous involvement
c) Predilection for subpleural regions
d) Hilar or mediastinal lymphadenopathy
Interstitial Lung Diseases
High resolution CT scan:
1-2 mm thin sections
Pattern may be pathognomonic
IPF/UIP: HRCT features
Patchy, heterogeneous
Lower lobes, subpleural
Reticular opacities
Honeycomb cysts
Ground glass not prominent
Honeycomb cysts (UIP)
UIP: subpleural, patchy
Coarse GGO: UIP
Usual Interstitial Pneumonia (UIP)
Geographic heterogeneity
Subpleural
Basilar

Usual interstitial pneumonia (UIP)
Histological criteria for UIP:
Heterogeneity (geographic, temporal)
(fibrosis; inflammation; cysts; normal lung)
Honeycomb change
Fibroblastic foci
(in inflamed, fibrotic, and honeycomb areas)

Transition to uninvolved lung present in the biopsy
Pathology of UIP/IPF
Fibroblastic focus-high power
Therapy for IPF
Few placebo-controlled trials
No proven survival benefit
? Impact of therapy
Idiopathic Interstitial Pneumonias
IPF/UIP must be distinguished from
other IIPs
(prognosis much different)
Bjoraker, AJRCCM. 1998;157:199 Years
Survival: UIP, other ILDs
0 2 4 6 8 10 12 14 16 18
0
20
40
60
80
100
UIP
NSIP
Others
Mayo Clinic
% survival
Survival in UIP, NSIP and RBILD
RBILD
NSIP
UIP
Flaherty, Eur Respir J 2002:19;275
U Michigan
Idiopathic Pulmonary Fibrosis
Literature misleading:
Surgical lung biopsies in a minority of
patients with IPF
Prognosis differs between various
idiopathic interstitial pneumonias
Prognosis of IPF/UIP
Steroid-responsive IPF may
represent disorders other than UIP
(e.g., NSIP, DIP, RBILD, etc.)
Idiopathic Interstitial Pneumonias
IIPs due to cigarette smoking:
Desquamative Interstitial Pneumonia
(DIP)
Respiratory Bronchiolitis ILD (RBILD)
Desquamative interstitial pneumonia
Clinical features of DIP:
> 90% in cigarette smokers
Ground glass opacities on HRCT
Excellent prognosis
Desquamative interstitial pneumonia
Histological features:
Intra-alveolar macrophages
Temporally homogeneous
Preserved lung architecture
No honeycomb change
Respiratory bronchiolitis ILD (RBILD)
> 90% in smokers
? Variant of DIP
Severe fibrosis rare
Excellent prognosis
Respiratory Bronchiolitis
Pigmented macrophages within
respiratory bronchioles
Bronchiolocentric
Marker of cigarette smoking
Acute interstitial pneumonia (A.I.P.)
Distinct forms
Idiopathic
Acute exacerbation of IPF
Acute interstitial pneumonia (A.I.P.)
Histology
Diffuse lung damage (DAD)
Hyaline membranes
Diffuse, homogeneous, fibrosis
Lymphocytic Interstitial Pneumonia
Etiology not known
Often associated with HIV or
autoimmune disorder
Nonspecific Interstitial Pneumonia
Q2. Which feature is not characteristic ?
a) Ground glass opacities on HRCT
b) Histology is temporally uniform
c) Honeycombing not dominant feature
d) Fibroblastic foci universally found
Nonspecific interstitial pneumonia
Described in 1994
Natural history not defined
Prognosis better than UIP/IPF
Ground glass opacities on HRCT
HRCT scan: NSIP vs UIP
UIP NSIP
Honeycombing +++ +/-
Ground glass +/- +++
Nonspecific interstitial pneumonia
Nonspecific interstitial pneumonia
Histological criteria for NSIP:
Temporal homogeneity
(lesions of same age)
Lacks features of other CILDs
(UIP, AIP, DIP/RBILD, LIP)
Nonspecific interstitial pneumonia
Cellular NSIP
Fibrotic NSIP

NSIP fibrosis
Nonspecific interstitial pneumonia
Comprises 13-48% of idiopathic
interstitial pneumonias from
retrospective studies (1998-2006)
No prospective studies published
Nonspecific interstitial pneumonia
Course may be subacute (weeks)
Prognosis more favorable than UIP
May respond to steroid Rx
Role of Surgical Lung Biopsy
Exclude alternative etiologies
(e.g., PAP; HP; LCH; sarcoidosis)
Identify pattern of idiopathic I.P.
Idiopathic interstitial pneumonias
Compared to UIP, other idiopathic
interstitial pneumonias show:
Better presence to steroids
Improved survival
Bjoraker, AJRCCM. 1998;157:199 Years

Survival for UIP vs NSIP
0 2 4 6 8 10 12 14 16 18
0
20
40
60
80
100
UIP
NSIP
Others
Mayo Clinic
Intralobar and inter-observer variability
Significant histologic variability:
Between lobes, individual patients
In 26% patients, both NSIP and UIP
Consensus not uniform
Flaherty, AJRCCM, 2001:164;1722
U Michigan
Prognostic Importance of SLBx
Presence of UIP in any lobe is strong
predictor of mortality

UIP (Concordant or Discordant) on
biopsy confers a poor prognosis
Flaherty, AJRCCM 2001:164;1722
U Michigan
IPF: Role of HRCT
HRCT Scans:
Confirm or exclude diagnosis
Assess pattern and extent
Assess prognosis
Can HRCT diagnose UIP?
Can CT obviate VATS lung Bx?
Diagnosis of UIP by HRCT specific
(> 90%) if all CT features present
CT less sensitive than VATS lung Bx
Interstitial Lung Disease
VATS biopsy not necessary if:
Clinical course, HRCT classical
Elderly or debilitated patient
Surgical Lung Biopsies for ILD
VATS biopsy preferred when:
Clinical or HRCT not classical
No contradictions to VATS
Idiopathic Pulmonary Fibrosis (IPF)
Q3. Which feature is not associated with a
worse prognosis in IPF ?
a) Severe impairment in vital capacity or DL
CO

b) Ground glass opacities on HRCT
c) Usual interstitial pneumonia on lung biopsy
d) Honeycomb pattern on HRCT
HRCT Pattern
Ground glass v honeycomb change
Narrow differential diagnosis
Prognostic significance
Significance of CT pattern
Extensive ground glass opacities
suggests diagnosis other than UIP
Diagnosis of UIP can be assumed if
classical CT features are present
IPF: HRCT Features
Patchy, heterogeneous
Lower lobes, subpleural
Reticular (linear) lines
Honeycomb cysts
Ground glass minimal or absent
UIP: subpleural, patchy
Patchy, heterogeneous
IPF: HRCT Features
Patchy, heterogeneous
Lower lobes, subpleural
Reticular (linear) lines
Honeycomb cysts
Ground glass minimal or absent
Honeycomb cysts (UIP)
Honeycombing on HRCT
IPF and Emphysema
Lung cancer complicating IPF
UIP: HRCT Features
Proclivity for basilar regions:
Worsens as descend from upper
to lower lobes
IPF: HRCT Features
Patchy, heterogeneous
Lower lobes, subpleural
Reticular (linear) lines
Honeycomb cysts
Ground glass minimal or absent
Coarse GGO: UIP
IPF: HRCT features
Honeycombing:
Irreversible
Unresponsive to therapy
If prominent, prognosis poor
Idiopathic pulmonary fibrosis
Classical CT scan for IPF
correlates with diagnosis of UIP
and high mortality
Idiopathic pulmonary fibrosis
Survival worse if:
HRCT typical of IPF
UIP on surgical lung biopsy
Daniil, AJRCCM 1999:160;899
HRCT appearance vs survival
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(
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Time from presentation (years)
Daniil, AJRCCM 1999;160:899
CT atypical of CFA
CT typical of CFA
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7
HRCT-fib > 2 predicted worse survival
All lobes < 2
At least one
lobe > 2
Flaherty Eur Respir J 2002:19;275
I.I.P.s
Prognostic value of HRCT
Typical CT findings of IPF
(honeycombing, reticulation)
predict poor prognosis
Prognostic value of HRCT
Ground glass opacities on CT may
be reversible (inflammatory
component)
HRCT features
Ground Glass Opacities
If prominent feature, not UIP
Ground Glass Patterns (HRCT)
Idiopathic interstitial pneumonias other
than UIP (e.g., NSIP, DIP, AIP)
Hypersensitivity pneumonia
Cryptogenic organizing pneumonia
Pulmonary Alveolar Proteinosis
Desquamative Interstitial
Pneumonia
Hypersensitivity pneumonia (HP)
Discriminating IPF from Other ILDs
Surgical Bx:
IPF (n=98); other ILD (n=38)
No honeycombing on HRCT
Clinical parameters (6-MWT; PFTs)
Fell, AJRCCM 2010:3181:832
Discriminating IPF from ILD
PFTs, 6MWT distance, 02 sat,
gender not discriminatory
Age and interstitial score on HRCT
scan discriminated
Fell, AJRCCM 2010:3181:832
Discriminating IPF from ILD
Parameter Odds ratio
Age 1.09/year
HRCT int score 10.44/unit
Fell, AJRCCM 2010:3181:832
Fells, AJRCCM 2010:181;832
Solid black = IPF
Grey shaded = non-IPF
Discriminating IPF from other ILDs
Medical therapy has not
been shown to improve
survival in IPF
Idiopathic Pulmonary Fibrosis
Mortality high (30-50% at 3 y)
Rate of progression variable
Subset stabilize (+/- Rx)
Therapy for IPF
Placebo-controlled trials have not
shown benefit in any parameter
Idiopathic Pulmonary Fibrosis
Given poor prognosis, patients
desire therapy and physicians
often offer treatment
Idiopathic Pulmonary Fibrosis
Old concept of pathogenesis:
? Begins as alveolitis
Ongoing alveolitis leads to fibrosis
Alveolitis may be reversible
Treatment of IPF
High dose prednisone was
standard of care for > 40 years
despite no firm evidence for
benefit
Treatment of IPF
Immunosuppressive (IS) agents
added as therapy in late 1970s
Azathioprine (Imuran
R
)
Cyclophosphamide (Cytoxan
R
)
Idiopathic Pulmonary Fibrosis
Interpreting efficacy of treatment
difficult since course variable
Stabilization common and
cannot be assumed to reflect
response to therapy
Azathioprine for IPF
PANTHER Study (IPFnet)
terminated early (Oct 2011) due to
higher mortality and morbidity in
AZA + prednisone + NAC arm
N Engl J Med May 24, 2012:366:1968
PANTHER STUDY: IPF
8
23
5
1
7
0
0
5
10
15
20
25
Mortality Hospitalizations AE
#
AZ + pred + NAC (n=77)
placebo (n=78)
N Engl J Med 2012:366:1968
Does IPF Respond to Therapy?
Older literature of IPF
misleading
Steroid-responsive IPF likely
represented entities distinct from
UIP (e.g. NSIP, DIP, RBILD, HP)
NSIP and UIP
? Evolution from NSIP to UIP
? If treating inflammatory
component of NSIP may alter
course
NSIP vs UIP
Prognosis:
Cellular NSIP Excellent
Fibrotic NSIP Intermediate
UIP Poor
Acute Exacerbations of IPF
Incidence 8-23%
Resembles ARDS
Diffuse lung damage (DAD)
Ground glass opacities (CT)
Acute Exacerbations of IPF
Mortality high (> 50% in hospital)
Anecdotal responses to pulse
methylprednisolone
Randomized trials lacking
Swigris, Semin Respir Crit Care Med 2006:27;659
Acute Exacerbations of IPF
14.2
20.8
0
5
10
15
20
25
1-year 2-year
%

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Song, Eur Respir J 2011:37:356
461 pts IPF (Korea)
Acute Exacerbations (AE) of IPF
Retrospective (IPF pts; n=461)
Hospitalized for AE (n=96; 20.8%)
Risk factors for AE:
older age, low FVC, low DLCO,
immunosuppressive Rx
Song, Eur Respir J 2011:37;356
Acute Exacerbations (AE) of IPF
Median survival 2.2 months
5-year survival 18.4%
Therapy no definite effect
Song, Eur Respir J 2011:37;356
IPF-associated PAH

Pulmonary Hypertension and IPF
PAH is independent risk factor for
mortality in IPF
PAH and IPF: survival
4.8
4.1
0.7
0
1
2
3
4
5
6
SPAP < 35 SPAP 36-50 SPAP > 50
survival
(years)
Median survival
Nadrous, Chest, 2005:128;2393
Pulmonary Hypertension and IPF
PAH increases mortality
2-D echo to assess sPAP
? If treating PAH affects outcome
Lung Transplantation for IPF
Failure of medical therapy
Limited life expectancy (2-4 y)
Post-Tx, 2-3 y survival 60-80%
Late mortality, chronic rejection
When should lung
transplant be considered?
Window of opportunity
for lung transplant
Lung Transplant for IPF
ATS/ERS Consensus Statement IPF:
List when:
Severe functional impairment
Oxygen dependency
Deteriorating course
ADULT LUNG TRANSPLANTATION
Kaplan-Meier Survival by Procedure Type
(Transplants: January 1990 June 2006)
Diagnosis: Idiopathic Pulmonary Fibrosis
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10
Years
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IPF/Single lung (N=2,641)
IPF/Double lung (N=1,290)
N=87
N=27
P = 0.0133
ISHLT
2008

N at risk at 5 years = 196
N at risk at 5 years = 566
J Heart Lung Transplant 2008;27: 937-983
Idiopathic Pulmonary Fibrosis
New concept of pathogenesis:
Epithelial injury
Abnormal fibroblast phenotype
Inflammation minor role
Pathogenesis of IPF
Cytokines, chemokines
(profibrotic)
Altered fibroblast phenotype
Excessive collagen synthesis
N-acetyl cysteine (NAC) in IPF
RPCT (Europe) (n=182)
Slight slowing rate of decline in
FVC and DL
CO
at 1 y (NAC)
Changes small; doubtful clinical
significance
Demedts N Engl J Med 2005:353;2229
Randomized trials for IPF (in progress)
Pirfenidone
N-acetyl cysteine (NAC)
BIBF 1120 (TKI)
Trimethoprim/sulfa in IPF
RPCT (UK, Wales) (n=181)
IPF or fibrotic NSIP
Placebo or T/S 960 b.i.d x 12 mo
No effect FVC, DL
CO
, 6MWT at 1 y
Lower all-cause mortality T/S cohort
Shulgina, Thorax 2013:68;155
Trimethoprim/sulfa in IPF
In T/S cohort (per protocol):
Lower all-cause mortality
Less respiratory infections
Less increasing 02 requirements
No difference intention-to-treat
between groups
Shulgina, Thorax 2013:68;155
T/S for IPF
19
5.7
22
23
0
5
10
15
20
25
Mortality 12 mo (ITT) Mortality 12 mo (per protocol)
%

d
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h
s
T/S (n=95)
placebo
(n=86)
Shulgina, Thorax 2013:366:1968
Joseph P. Lynch, III, MD
Professor of Clinical Medicine, Step VIII
Division of Pulmonary & Critical Care Medicine
The David Geffen School of Medicine at UCLA
Cryptogenic Organizing Pneumonia
Cryptogenic Organizing Pneumonia
COP synonymous with:
Bronchiolitis obliterans
organizing pneumonia (BOOP)
Usually responds to steroids
Cryptogenic Organizing Pneumonia
Idiopathic
Toxic fumes
Radiation therapy
Chemotherapy
Drugs, exogenous agents
Cryptogenic Organizing Pneumonia
Collagen vascular disease
Inflammatory bowel disease
Bone marrow, lung transplant
Lower respiratory tract infection
(Legionellae, viruses, Mycoplasma)
COP (BOOP)
Subacute onset (2-12 weeks)
Cough, dyspnea, fever
Antecedent RTI (> 30%)
Mimics pneumonia (CAP)
COP (BOOP): incidence
Prevalence 1.1 per 10,000 admissions

67 cases, 2,500 open lung Bx (1950-80)
29 cases, 200 hospitals Japan, 1986-88


Medicine, 1995:74:201
N Engl J Med 1985:312;152
Chest 1992:102:21S
BOOP
PhysicaI ndings (n=50)
Rales 68%
Wheezing 4%
Clubbing 0%
Epler, N Engl J Med 1985:312;152
BOOP
Pulmonary function tests (n=50)
Restrictive defect 72%
Reduced DL
CO
86%
Obstructive (smokers) 20%



Epler, N Engl J Med 1985:312;152
COP: Radiographic Findings
Focal alveolar opacities (60-80%)
Air-bronchograms
Segmental or lobar; wax and
wane
Reticulonodular infiltrates (10-30%)
Normal or hyperinflation (4-10%)
COP: HRCT Features
Focal alveolar infiltrates (> 80%)
Peribronchiolar nodules
Reticulonodular infiltrates (25%)
Honeycombing not seen
Cryptogenic Organizing Pneumonia
HRCT features of COP (43 pts)
Consolidation 34 (79%)
Ground glass 26 (60%)
Nodules 13 (30%)
Lee, AJR 1994:162;543
Cryptogenic Organizing Pneumonia
Q4. Which is not a feature of COP?
a) Inflammatory cells in alveolar septae
b) Foamy macrophages
c) Honeycombing and severe fibrosis
d) Granulation tissue within bronchioles
COP: Histopathology
Organizing granulation tissue
Intraluminal; obliterates bronchioles
Extends to alveolar ducts and spaces
(organizing pneumonia)
Honeycombing absent
Cryptogenic Organizing Pneumonia
Brompton Hospital, 1982-90 (n=11)
Salient features (TBBs + in 7 of 11):
Polyps of granulation tissue
Preserved alveolar architecture
Interstitial infiltrates (acute,
chronic)
Dina, Histopathology 1993:23;541
Cryptogenic Organizing Pneumonia
Pathogenesis speculative
Inhaled antigens causes
bronchiolar injury
Elicit local immune response
Inflammatory and reparative R
Treatment of COP
Corticosteroids Rx of choice
Complete recovery in 65%
Responses often dramatic
May relapse after cessation
Corticosteroids for COP
Literature review, 252 pts
Complete recovery 65%
Partial response 27%
Died 8%
Alasaly, Medicine 1995:74;201
Corticosteroids for COP
Retrospective, 48 pts
Relapses in 58%
9 pts (18%) > 3 relapses
Long term outlook good (even if
relapse)
No death attributable to COP
Lazor, AJRCCM 2000;162;571
Corticosteroids for COP
Most relapses < 6 months
Responded to re-treatment
Moderate dose steroid effective (0.75
mg/kg x 4 wks, 10 mg by 3 mo)
6 months Rx adequate in many
Lazor, AJRCCM 2000;162;571
Corticosteroids for COP
U Navarra (Spain), 1995-2010 (n=91)
77 treated steroids; 80.5% responded
6 died respiratory failure
Predictors of good prognosis:
Age < 38 y; non-smoker
Pardo, Hum Pathol 2013;44;718
COP: Survival
97
86
73
0
10
20
30
40
50
60
70
80
90
100
2-yr 5-yr 10-y
%

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Pardo, Hum Pathol 2013:44:718
Spain, 1995-2010, n=91