1
Joseph P. Lynch, III, MD, FCCP, FERS
Holt and Jo Hickman Endowed Chair ofAdvanced Lung Diseases and Lung Transplantation
Professor of Clinical Medicine, Step IX
Division of Pulmonary & Critical Care Medicine, Clinical Immunology and Allergy
The David Geffen School of Medicine at UCLA
Idiopathic Pulmonary Fibrosis (IPF)
Disclosures (2018): speaker fees (Genentec)
Interstitial Lung Disease
Clinical features:
Cough
Dyspnea
Restrictive PFTs (low VC, TLC)
2
Idiopathic pulmonary fibrosis (IPF)
Most common interstitial lung disease
Usual interstitial pneumonia (UIP)
pattern on surgical lung biopsy
Nonspecific Interstitial Pneumonia
• Clinical features overlap with IPF
• Much better response to therapy
• Need surgical lung Bx to diagnose
• Distinguishing IPF from
NSIP and other ILDs
important since prognosis
and treatment differ
3
Idiopathic Pulmonary Fibrosis (IPF)
• Affects older adults (> 55 y)
Progression inevitable
• Mortality > 70% at 5 years
Years
Survival: UIP, NSIP, other ILDs
0 2 4 6 8 10 12 14 16 18
0
20
40
60
80
100
UIP
NSIP
Other ILD
Survival %
Mayo Clinic
Bjoraker, AJRCCM, 1998:157;199
4
Survival in UIP, NSIP and RBILD
RBILD
NSIP
UIP
Flaherty, Eur Respir J 2002;19;275
Survival in UIP and NSIP
Nicholson, AJRCCM 2000; 162: 2213
Brompton, UK
5
Interstitial Lung Diseases
> 150 causes
Infectious (TB, fungi, PCP)
Environmental (HP, metals; drugs)
Connective Tissue Disease (CTD)
Idiopathic (IPF, LIP, OP, sarcoidosis)
Interstitial Lung Disease
Laboratory evaluation
Serologies for CTD
Hypersensitivity pneumonia
Infection (PPD, histo, cocci IgG, IgM)
6
Environmental History
• Exposures (work, home, hobbies)
• Toxins, irritants (drugs, chemicals)
• Cigarette smoking (LCH; DIP, RB)
Drugs may cause pulmonary toxicity
Amiodarone
Methotrexate
Nitrofurantoin
Sulfasalazine
Chemotherapy
(Bleomycin; busulfan)
Pneumoconioses
Beryllium
Silica
Hard metals (cobalt, tungsten carbide)
Asbestos
7
IPF: Differential Diagnosis
Connective Tissue Disease
Pneumoconiosis
Chronic Hypersensitivity Pneumonia
Pulmonary Complications of CTD
• Interstitial Lung Disease may affect all CTDs
• Histological patterns same as idiopathic IPs
• Multiple patterns may be observed
8
Distinguishing IPF from other ILDs
Thin section HRCT scans
Surgical (VATS) Lung Biopsy
Interstitial Lung Disease (ILD)
Surgical lung biopsy essential to diagnose some ILDs (e.g., NSIP, HP)
Thin-section HRCT (1-2 mm) can diagnose some, but not all, cases IPF
Interstitial Lung Disease (ILD)
Thin-section (1-2 mm) HRCT in some cases may be pathognomonic
(e.g., IPF with honeycombing)
9
Honeycomb cysts (UIP)
Epidemiology of Idiopathic
Pulmonary Fibrosis (IPF)
Idiopathic Pulmonary Fibrosis
Primarily affects elderly
Not seen in children
10
Prevalence IPF according to age
3
177
0
20
40
60
80
100
120
140
160
180
200
35-44 75+
pre
vale
nce
pe
r 100
,000
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+
pre
vale
nce
pe
r 100
,000
Raghu, AJRCCM 2006:174;810
USA (1996-2000)
Age (years)
Prevalence IPF according to age
1.12.6
6.4
19.3
0
5
10
15
20
25
18-34 35-44 45-54 55-64
pre
va
len
ce p
er
10
0,0
00
Raghu, Eur Respir J 2016:48;179
USA (2004-2010) age 18-64 (> 40 million adults
Age (years)
11
Deaths due to IPF according to age
1.8 7.1
30.6
82.7
138
0
20
40
60
80
100
120
140
160
45-54 55-64 65-74 75-84 85+
de
ath
s/1
00,0
00
Olson, AJRCCM 2007:176;277
USA (1992-2003)
Age (years)
IPF: incidence and Prevalence > 65 years
93.7 93.7
202
495
0
100
200
300
400
500
2001 2011
incidence
prevalenceper
100,000
Raghu, Lancet Respir Med 2014:2;566
Medicare (5%), USA (2001-2011)
Median age newly diagnosed IPF was 79.4 years
Risk Factors for IPF
Age (predominantly elderly)
More common in males
Genetic (familial)
Chu, Semin Respir Crit Care Med 2016:37;321
12
Idiopathic Pulmonary Fibrosis
Familial IPF
0.5 to 10% of cases of IPF
No clear genetic mutation
Isolated mutations in kindreds
Familial IPF: Mutations
Surfactant protein C and A
Mucin genes (MUC5B)
Telomerase (hTERT and hTR)
Chu, Semin Respir Crit Care Med 2016:37;321
Risk Factors for IPF
Smoking
Occupational (dusts, metals, sand)
Gastroesophageal reflux (?)
Chu, Semin Respir Crit Care Med 2016:37;321
13
IPF: Histology
• Usual Interstitial Pneumonia
(UIP pattern)
Usual Interstitial Pneumonia (UIP)
• Heterogeneity
• Fibroblastic foci
• Honeycombing
14
Transition to uninvolved lung present in the biopsy
Pathology of UIP/IPF
Fibroblastic focus-high power
15
• Distinguishing IPF from
NSIP and other ILDs
important since prognosis
and treatment differ
Chronic Interstitial Lung Disease
5
106
28
5
22
-10
10
30
50
70
90
110
IPF fibrotic NSIP cellular NSIP RBILD/DIP HP
Flaherty, Eur Respir J 2002:19;276
(U of Michigan) Surgical Lung Bx (n=169) 1989-2000
#
Prognosis of IPF/UIP and Other ILDs
Surgical biopsies n=169 (U Mich, 1989-2000)
Histological UIP most important feature determining mortality
UIP/IPF RR mortality 28.5 compared to other ILDs (p < 0.001)
Flaherty, Eur Respir J 2012:19;276
16
• Surgical (VATS) lung biopsy
is required to diagnose NSIP
Nonspecific interstitial pneumonia
Histological criteria for NSIP:
Temporal homogeneity
(lesions of same age)
Lacks features of other IIPs
(UIP, AIP, DIP/RBILD)
Nonspecific interstitial pneumonia
Cellular and fibrotic types
Fibrotic worse prognosis
17
Honeycombing
18
Can CT distinguish
IPF from NSIP?
UIP/IPF: HRCT Features
Patchy, heterogeneous
Lower lobes, subpleural
Reticular (linear) lines
Honeycomb cysts
Ground glass minimal or absent
19
Honeycomb cysts (UIP)
CT criteria (IPF vs NSIP)
Key discriminatory elements:
Honeycombing
Ground glass opacities
“Typical” CT (i.e., with
honeycombing) is specific
for UIP/IPF and eliminates
need for surgical lung biopsy
20
HRCT appearance vs survival
Su
rviv
al
(%)
Time from presentation (years)
Daniil, AJRCCM 1999;160:899
CT “atypical” of IPF
CT “typical” of IPF
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7
Honeycombing reflects:
more advanced disease
worse prognosis
Honeycomb change in any
lobe (CT-fib > 2) associated
with higher mortality
168 cases IIP (U Mich)
Flaherty, Eur Resp J 2002:19;276
21
CT fib > 2 worse survival
All lobes < 2
At least one lobe > 2
Flaherty Eur Respir J 2002:19;275
168 cases IIP (U Mich)
Honeycombing
No honeycombing
NSIP and IPF Overlapping Features
Distinguishing fibrotic NSIP
from IPF is difficult
Treatment differs (NSIP vs IPF)
Nonspecific Interstitial Pneumonia (NSIP)
• Immunosuppressive therapy and/or prednisone may be effective, particularly in cellular variants of NSIP
22
Idiopathic Pulmonary Fibrosis (IPF)
• Immunosuppressive therapy or prednisone not effective for IPF and may be harmful
Idiopathic Pulmonary Fibrosis (IPF)
• Median survival ~ 4 yrs
• Medical therapy (anti-fibrotic agents) marginally effective
• ? survival advantage
23
CT criteria (IPF vs NSIP)
Ground glass opacities
strongly favor NSIP
Nonspecific interstitial pneumonia
24
HRCT scan: NSIP vs IPF
IPF NSIP
Honeycombing +++ +/-
Ground glass +/- +++
IPF and NSIP
Discriminatory features
• Age
HRCT (GGO vs HC)
25
IPF and NSIP
Discriminatory features
• Older age favors IPF
Honeycombing (IPF)
Discriminating IPF from other ILDs
UIP (n=97); other ILD (n=38) (1995-2006)
No honeycombing on HRCT
No connective tissue disease
All had surgical lung biopsy
Fell, AJRCCM 2010:181;832
Discriminating IPF from other ILDs
Age and extent CT interstitial
score most predictive of IPF
Gender, desaturation, distance
walked on 6MWT, PFTs did not
discriminate IPF from other ILD
Fell, AJRCCM 2010:181;832
26
Age Powerful Predictor of IPF
Age > 70 yrs, > 95% had IPF
Age > 75 yrs, 100% had IPF
Fell, AJRCCM 2010:181;832
“Atypical” CT patterns are
non-specific; could represent
IPF or NSIP or other ILDs
• Need surgical lung biopsy
Surgical Lung Biopsy
22,000 SLB in USA for ILD (2000-2011)
Mortality (in-hospital):
1.7% (elective)
16.0% (non-elective)
Hutchinson, AJRCCM 2016 (May 15);1161
27
Surgical (VATS) Lung Biopsy
Risk excessive if advanced
age or unstable or high 02
requirements
Idiopathic Pulmonary Fibrosis
•Clinical course
•Prognostic factors
•Best parameters to follow
Idiopathic Pulmonary Fibrosis (IPF)
• Median survival ~ 4 yrs
• Medical therapy (anti-fibrotic agents) marginally effective
• ? survival advantage
28
Idiopathic Pulmonary Fibrosis (IPF)
• immunosuppressive agents
or steroids are not beneficial
• Lung Transplant Best Option
Therapy for IPF
Early referral for lung transplant
May lose “window for transplant”
29
•IPF: course highly variable
and unpredictable
IPF: Pulmonary Function Tests
Serial PFTs 3-4 months
Spirometry, DLCO
6-minute walk tests
Course may be fulminant even
after initial indolent progression
PFTs may be stable for prolonged
periods
Acute exacerbations may be fatal
30
Increased Mortality if:
• Older age
Severe impairment PFTs
Hypoxemia
Honeycombing on CT
Pulmonary hypertension
PFTs in IPF: Prognostic Significance
• Not surprisingly, severe
impairment or decline in FVC,
DLCO, oxygenation, or 6MWD
predicts worse mortality
Changes in FVC at 6 months
IPF (n=80); NSIP (n=29) (U Mich)
> 10% decline FVC at 6 months
independent predictor mortality
(HR 2.47)
Flaherty, AJRCCM 2003:168;543
31
Serial PFTs Predict Prognosis
IPF (n=81) (Denver)
> 10% decline FVC at 6 or 12 mo
assoc with higher mortality
Collard, AJRCCM 2003:168;538
Serial PFTs Predict Prognosis
IPF (n=131); NSIP (n=48) (Korea)
> 10% decline FVC at 6 mo
best predictor of mortality
Jegal, AJRCCM 2005:171;169
• Declining FVC warrants
consideration for lung transplant
• However, fatalities can occur
even with prolonged stability
32
0
10
20
30
40
50
60
70
80
90
100
Jan-
06
May
-06
Sep-0
6
Jan-
07
May
-07
Sep-0
7
Jan-
08
May
-08
Sep-0
8
Jan-
09
May
-09
Sep-0
9
Jan-1
0
May
-10
FVC % pred
FEV1 % pred
DLCO % pred
SLT
68 m MK
Complications of IPF
•Acute exacerbations of IPF
•Pulmonary Hypertension
•Lung cancer (5-15%)
Acute Exacerbations of IPF
Incidence 19-35% < 2 years
Resembles ARDS
Diffuse lung damage (DAD)
Ground glass opacities (CT)
33
Risk Factors for AE-IPF
More severe disease
Prednisone or IS therapy
Winter months
Pulmonary hypertension
Thoracic surgery (VATS)
34
? Cause for AE-IPF
? Infection (viral)
AE- IPF: Treatment
Optimal treatment not clear
Randomized trials lacking
? value of steroid therapy
Song, Eur Respir J 2011:39;357
Prognosis of AE-IPF
56.2
18.510
0
10
20
30
40
50
60
70
80
90
100
1-year 5-year
surv
iva
l (%
)
all
requiring MV
AE-IPF, Korea (n=163)
Song, ERJ 2011:39;357
35
Severe AE-IPF
Prognosis if require MV
poor (> 90% mortality)
Unless on lung transplant
list, consider DNI/DNR
IPF-associated PAH
Pulmonary Hypertension
• PAH in 28-84% of patients with advanced IPF
• PAH markedly worsens survival
36
Pulmonary hypertension in IPF
• 2-D echo to assess sPAP
• ? If treatment of PAH affects
outcome
• Anecdotal responses to PAH-
specific agents but RCT lacking
PAH due to lung disease
• PAH-specific therapy may
have role in patients with
severe PAH as a bridge to
lung transplantation
Shino, Semin Respir Crit Care Med (Oct 2013)
Idiopathic Pulmonary Fibrosis
•Medical Treatment
•Lung Transplant
37
Idiopathic Pulmonary Fibrosis
• Course and “pace” of disease
highly variable
• Lung transplant 1st line but only
for selected patients
• Who should receive novel agents?
Treatment of IPF
• High dose prednisone was
standard of care for > 40 years
despite no evidence for benefit
Idiopathic Pulmonary Fibrosis
• Despite lack of randomized,
placebo-controlled trials,
prednisone + azathioprine used
for more than 3 decades
38
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
00
5
10
15
20
25
Mortality Hospitalizations AE
#
AZ + pred + NAC (n=77)
placebo (n=78)
N Engl J Med 2012:366:1968
39
Therapy of IPF
Other immunosuppressive agents unlikely to be efficacious
e.g., mycophenolate mofetil
IPF: which target?
• Multiple “targets” (cells,
cytokines, inflammation, fibrosis)
• Mechanisms of injury and fibrosis
overlap and redundant
• Pirfenidone (Esbriet)
• Nintedanib (Ofev)
FDA Approved Oct 15, 2014
40
Treatment of IPF
• In clinical trials, pirfenidone
and nintedanib slow rate of
decline but differences small
(DFVC 2-4%) at 1 yr
Pirfenidone for IPF
CAPACITY I (006) (n=344)
• pirfenidone (oral) vs placebo
CAPACITY II (004) (n=435)
Noble, Lancet 2011:377:1760
Pirfenidone for IPF
• No difference survival, DLCO,
6MWT, D02 sat
• Less decline FVC at 72 weeks
[Capacity II (004); not Capacity I (006)]
41
CAPACITY (004 + 006): DFVC 72 wks
-9-8
-8.5-9.6
-12.4
-11
-14
-12
-10
-8
-6
-4
-2
0
DF
VC
(%
) at
72
wee
ks
pirfenidone
placebo
Noble, Lancet 2011:377;1760
006 (n=344) 004 (n= 435) Pooled pirfen 2403
Pirfenidone for IPF
ASCEND Trial (52 wks):
Primary end-point:
disease progression
(D FVC > 10% or death)
King, N Engl J Med May 29, 2014
Pirfenidone for IPF
Pirfenidone 2403 mg/day (n=278)
Placebo (n=277)
King, N Engl J Med 2014:370;2083
42
Pirfenidone (ASCEND) Study
16.5
4
31.8
7.2
0
5
10
15
20
25
30
35
Decline FVC > 10% Death
%
pirfenidone(n=278)
placebo(n=277)
King, N Engl J Med 2014:370;2083
p = 0.1
p < 0.001
52 weeks
Pirfenidone Trials (IPF)
2023
16.5
35
27
31.8
0
5
10
15
20
25
30
35
40
pirfen 004 (72 wk) pirfen 006 (72 wk) NEJM 2014 (1 yr)
DF
VC
(%
) pirfenidone
placebo
> 10% decline FVC
Pirfenidone for IPF
• Slows rate of progression
• Impact on mortality uncertain
43
• Nintedanib (Ofev)
• Tyrosine kinase inhibitor
Nintedanib for IPF
Nintedanib 150 mg bid or placebo
52 weeks; change FVC
IMPULSIS-1 (n=511)
IMPULSIS-2 (n=544)
Richeldi, N Engl J Med 2014:370:2072
44
Nintedanib for IPF
Primary endpoint:
• D FVC at 52 weeks
Richeldi, N Engl J Med, May 29, 2014
Nintedanib: DFVC 52 wks
-2.8-3.1
-6 -6.2-7
-6
-5
-4
-3
-2
-1
0
DF
VC
(%
) at
52
wee
ks
nintedanib
placebo
Richeldi, N Engl J Med 2014:370;2072
Impulsis-1 Impulsis-2
Nintedanib: DFVC 52 wks
29.4 30.4
43.1
36.1
0
5
10
15
20
25
30
35
40
45
50
DF
VC
(>
10%
dec
lin
e)
nintedanib
placebo
Richeldi, N Engl J Med 2014:370;2072
Impulsis-1Impulsis-2
45
Nintedanib: Mortality 52 wks
5.5
7.8
0
1
2
3
4
5
6
7
8
9
mor
tali
ty %
nintedanib
placebo
Richeldi, N Engl J Med 2014:370;2072
p=0.14
Impulsis-1 + 2
RJ
46
Lung transplant for IPF
• Survival post-LT worse
in IPF compared to
other diagnoses
(may reflect age, comorbidities)
Yusen, J Heart Lung Transplant Oct 2013 :32(10)
Survival by Diagnosis (Jan 1990-June 2011)
47
Single or Bilateral Transplant?
• Bilateral lung transplant for IPF,
but not COPD, confers modest
improvement in survival
Single or Bilateral Transplant?
USA, LT (adults) May 2005-Dec 31, 2012:
• IPF (n=4,134) (SLT in 49%)
• COPD (n=3,174) (SLT in 41%)
Schaffer, JAMA 2015:313;936
Single or Bilateral Transplant?
After controlling for confounders,
BLT better survival than SLT in IPF
but not in COPD
Schaffer, JAMA 2015:313;936
48
Single or Bilateral LT?
50.4
6465.2 67.7
0
10
20
30
40
50
60
70
IPF COPD
surv
ival (
month
s)
SLT BLT
Schaffer, JAMA 2015;313;936
USA, 5/05 -12/31/12p=0.23p < 0.001
Lung Transplant for Elderly
ISHLT Guidelines (2006)
• Age > 65 “relative
contraindication” to LT
Orens, JHLT 2006:25;745
Survival by LT Recipient Age (Adults)
J Heart Lung Transplant Oct 2013
Jan 1990-June 2011
49
Lung Transplant for Elderly
UNOS, 1999-2006
8,363 adult LT recipients
Mortality (30 d, 90 d, 1-yr)
Weiss J Am Coll Surg 2009:208;400
Lung Transplantation
9.5 9.5 8.9 9.3
27
17.2 17.2 18.721.4
42
0
5
10
15
20
25
30
35
40
45
18-45y 46-55 y 56-60 y 61-69 y 70+
% m
ort
alit
y
90-day
1-year
Weiss, J Am Coll Surg 2009;208;400
Age as predictor of mortality