The Clinical Presentation &
Epidemiology of IPF
Amy L. Olson, MD, MSPH
Assistant Professor
National Jewish Health
Interstitial Lung Disease Program & Autoimmune Lung Center
April 2014
Objectives
 Overview of ILD/IPF
 Clinical Presentation of IPF
 Epidemiologic Risk Factors
 The Rising Burden of Disease
 Mortality & Incidence Rates
 Natural History of Disease
 Acute exacerbations of IPF
Background
ILD vs. IIP vs. IPF
 ILD = Describes over 150
entities that affect the lung
parenchyma, resulting in
inflammation and/or fibrosis
 Systemic Diseases
 Exposures
 Genetic
 IIP = Idiopathic ILDs
 IPF =
 Most common (~55%)
 Most fibrotic
 Worst survival (~2-3 years)
Current Definition of IPF
 Specific form of chronic,
progressive fibrosing
interstitial pneumonia of
 unknown cause
 occurring primarily in older
adults
 limited to the lungs
 has typical pathologic
and/or imaging pattern
Usual Interstitial
Pneumonia (UIP).
 Exclusion of known
causes of ILD …
Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med.
2011;183:788-824.
Prognosis
Strand MJ. Chest 2014 April 3. [Epub ahead of print]
Clinical Presentation
History of Present Illness:
Age > 50
Men > Women
Dyspnea: typically subacute, insidious onset
“I first noticed I was breathless playing with my
grandchildren 2 years ago, but I thought I was just
out of shape.”
+/- Dry cough
+/- Fatigue/Low stamina
NOT associated with pain, weakness, swollen joints,
rash, or other systemic symptoms
NOT associated with obvious antigen (MOLD, BIRD)
exposures
Clinical Presentation
 Social, Occupational, Environmental History
Exposure
No.
Studies
OR (95% CI)
Smoking
5
1.58 (1.27 – 1.97)
Agriculture/Farming
2
1.65 (1.20 – 2.26)
Livestock
2
2.17 (1.28 – 3.68)
Wood Dust
5
1.94 (1.34 – 2.81)
Metal Dust
5
2.44 (1.74 – 3.40)
Stone/Sand/Silica
4
1.97 (1.09 – 3.55)
Taskar V, Coultas DB. Proc Am Thorac Soc 2006;293-298.
Clinical Presentation
 Family History
 ~ 5% of patient with IPF have 1st degree
relatives with lung fibrosis
 Telomerase Mutations ~ 15%
 Family members may develop disease at an
earlier age
Clinical Presentation
 Physical Examination
 VS: Hypoxemia (may only be evident with
ambulation)
 PULMONARY: Late bibasilar inspiratory crackles
(Velco® crackles)
 CARDIAC: Pronounced P2 (pulmonary hypertension)
 EXT: Clubbing
Guidelines, 2011
Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med.
2011;183:788-824.
What is the burden of IPF?
Mortality, Incidence, &
Prevalence
Mortality Rate = Number of Disease-Associated Deaths
Total Live Population
Incidence =
Number of New Cases of Disease
Population at Risk
Mortality Rate ≈ Incidence
(when disease duration is relatively short and lethal)
First Large Scale Epidemiologic
Studies of Death Certificate Data,
Mortality Rates:
Investigator
Johnston et
al., 1990
Mannino et
al., 1996
(NCHS/MCOD)
Year
19791988
19791991
Category
Men
Women
Idiopathic
Pulmonary
Fibrosis
(ICD-9 516.3)
Mortality Rate:
Mortality Rate:
14 per Million ↑
8 per Million ↑
(50% increase)
(60% increase)
Pulmonary
Fibrosis
(ICD-9
516.3/515)
Mortality Rate:
Mortality Rate:
50.9 per Million ↑ 27.2 per Million ↑
(5% increase)
(27% increase)
Johnston I, et al. Br Med J 1990;301:1021-1023.
Mannino DE, et al. Am J Respir Crit Care Med 1996;153:1548-1152.
Death Certificate Data:
1992 through 2003
(~22 million records)
Removed codes with
CTDz, HP, asbestosis,
and radiation fibrosis.
In men, the rate
increased by 28%
from 48 to 62 per
1,000,000.
In women, the rate
increased by 41%
from 40 to 56 per
1,000,000.
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
Percent Changes in the
Age-Adjusted Mortality Rates:
% Change,
1979-1991*
% Change,
1992-2003
Men
5%
28%
Women
27%
41%
Total
14%
34%
* Mannino et al. AJRCCM 1996;153:1548-1552.
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
Mortality Rates & Percent Increase
with Pulmonary Fibrosis
Men
Women
Age Strata
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
45 to 54 years
17.2
13.9%
13.4
28.8%
55 to 64 years
66.7
10.8%
45.6
28.4%
65 to 74 years
268.5
24.7%
152.6
38.5%
75 to 84 years
721.6
42.4%
397.6
47.6%
> 85 years
1256.7
28.6%
793.1
45.8%
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
Mortality Rates & Percent Increase
with Pulmonary Fibrosis
Men
Women
Age Strata
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
45 to 54 years
17.2
13.9%
13.4
28.8%
55 to 64 years
66.7
10.8%
45.6
28.4%
65 to 74 years
268.5
24.7%
152.6
38.5%
75 to 84 years
721.6
42.4%
397.6
47.6%
> 85 years
1256.7
28.6%
793.1
45.8%
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
Mortality Rates & Percent Increase
with Pulmonary Fibrosis
Men
Women
Age Strata
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
Mortality Rate
per 1,000,000
(2003)
Percent
Increase
(from 1992)
45 to 54 years
17.2
13.9%
13.4
28.8%
55 to 64 years
66.7
10.8%
45.6
28.4%
65 to 74 years
268.5
24.7%
152.6
38.5%
75 to 84 years
721.6
42.4%
397.6
47.6%
> 85 years
1256.7
28.6%
793.1
45.8%
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
Poisson Regression:
 Mortality rates significantly …




increased over time (p < 0.0001)
increased with increasing age (p < 0.0001)
were higher among men than women (p < 0.0001)
accelerated more steeply in women ( p < 0.0001)
Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.
UK Mortality
51 / million
5% increase per year
9.2 / million
Navaratnam et al. Thorax 2011;66:462.
Limitations:
 Why are the mortality rates increasing?
 Changes in death certificate coding?
 Changes in clinical diagnostic accuracy?
 High Resolution CT scans
 Awareness
 Consensus statement for the diagnosis/treatment of IPF
 Randomized Controlled Trials IPF
 Changes in the incidence driving mortality
rate?
Recent Studies - Incidence:
Investigator
Year
Category
Men
Women
Coultas et
al.
19881990
Idiopathic
Pulmonary
Fibrosis
Incidence:
107 per Million
Rhagu et al.
19962000
Idiopathic
Pulmonary
Fibrosis
Incidence (both men & women):
163 per Million
Gribbin et
al.
19912003
Idiopathic
Pulmonary
Fibrosis
Incidence (both men & women):
27.3 per Million  67.8 per Million
74 per Million
Coultas DB, et al. Am J Respir Crit Care Med 1994;150:967-972.
Rhagu G, et al. Am J Respir Crit Care Med 2006;174:810-816.
Gribbin J, et al. Thorax 2006;61:980-985.
Why the increasing burden?
Better treatment for other conditions?
Lack of treatment for fibrosis?
Exposures?
Underlying Cause of Death
Underlying Cause of Death with Pulmonary Fibrosis,
Panos et al. (1964-1983) vs. MCOD (1992-2003)
0.7
Pulmonary Fibrosis
0.6
Ischemic Heart Disease
Congestive Heart Failure
Proportion of Deaths
0.5
Lung Cancer
Pulmonary Embolism
Pneumonia
0.4
Cerebrovascular Disease
Other
0.3
0.2
0.1
0
Panos et al.
MCOD
Underlying Cause of Death
What about other forms of PF
(RA) …
60
10000
9000
50
8000
7000
6000
Women, Age-adjusted Mortality Rate
Men, Age-adjusted Mortality Rate
30
5000
Women, Actual Number of Deaths
Men, Actual Number of Deaths
Number of Deaths
Mortality Rate
(per 1,000,000 Population)
40
4000
20
3000
2000
10
1000
0
0
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
Year
Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.]
Prevalence of RA-ILD to RA
12
10
Prevalence of RA-ILD
in RA Decedents (%)
8
6
4
Women
2
Men
0
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
Year
Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.] 13
Exposures –
Regional Variation
Age-Adjusted Annual Mortality Rate with
Pulmonary Fibrosis by State,
1979 through 1991
Mannino et al. AJRCCM 1996;153:1548-1552.
Age-Adjusted Annual Mortality Rate with
Pulmonary Fibrosis by State,
1992 through 2003
1992 through 2003
1979 through 1991
1992 through 2003
1979 through 1991
1992 through 2003
1979 through 1991
Natural History of Disease
 “The natural history has been described as a
Lung Function
progressive decline in subjective and objective
pulmonary function until eventual death from
respiratory failure or complicating comorbidity.”
Placebo arms of 8 RCTs report a
decline in FVC of 0.15 to 0.22 L/year.
Time
Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.
Tourin O et al. In: Idiopathic Pulmonary Fibrosis, Eds. Meyer KC, Nathan SD, 2014.
Natural History of Disease
 The placebo arm of the γ-interferon trial for IPF
found that
 89% of deaths were considered to be due to IPF
progression
 of these, 47% had an apparent ‘acute clinical decline.’
 At the same time, there was an increasing
recognition of acute exacerbations of IPF.
Martinez FJ, et al. Ann Intern Med 2005;963-967.
Natural History of Disease
 Acute Exacerbations of
Disease
 Worsening of dyspnea, <
30 days
 Decrease in PaO2
 New radiographic opacities
 No apparent cause
(infection, CHF, PE).
 Different pathologic
pattern (DAD, OP)
 Poor outcome
 ETIOLOGY?
 Infection, Reflux, Thoracic
Procedures
Martinez FJ, et al. Ann Intern Med 2005;963-967.
Infection?
Our hypothesis – that death and these acute
exacerbations are the result of infections
Previous data had found rates of particular
respiratory infections are higher in the
winter
If infection was driving death/acute
exacerbations, mortality rates from PF
would display seasonal variation too…
Seasonal Variation
Numbers of Deaths from Pulmonary Fibrosis by Month (and Season), 1992-2003
1800
1992
1993
1600
Numbers of Deaths
1994
1995
1400
1996
1997
1200
1998
1999
1000
2000
2001
800
2002
Dec*
Jan
(Winter)
Feb
Mar
Apr
(Spring)
May
Jun
Jul
(Summer)
Aug
Sep
Oct
(Fall)
Nov
2003
Month of Death (Season Grouping)
Olson AL, et al. Chest 2009;136:16-22.
Seasonal Variation of Pneumonia
Percent Increase in Monthly Mortality Rate
from Pneumonia by Season
70.0%
Percent Increase
(with summer as the reference)
*
60.0%
50.0%
40.0%
*
30.0%
20.0%
fall
winter
†
10.0%
†
spring
0.0%
All records with pneumonia
Olson AL, et al. Chest 2009;136:16-22.
Seasonal Variation of IPF
Olson AL, et al. Chest 2009;136:16-22.
Seasonal Variation of COPD & Lung Cancer
Percent Increase in Monthly Mortality Rate
from COPD and Lung Cancer by Season
32.0%
*
Percent Increase
(when compared to summer)
28.0%
*
24.0%
20.0%
*
*
16.0%
fall
12.0%
winter
8.0%
4.0%
†
‡
*
*
spring
0.0%
All records with
COPD
All records with
COPD excluding
those with
pneumonia
All records with Lung All records with Lung
Cancer
Cancer excluding
those with
pneumonia
Olson AL, et al. Chest 2009;136:16-22.
Seasonal Variation
 Seasonal variation in PF-associated mortality
exists
 Mortality rates are higher in the winter followed
by the spring
 This mirrors the seasonal variation in COPDassociated mortality – known to be higher in
the winter months and result from viral and
bacterial exacerbations of disease
 Infectious triggers?
 No viral etiology has been identified to date
Whootton SC, et al. Am J Respir Crit Care 2011;183:1698-1702.
Natural History of Disease
* = Acute exacerbation … Infection? Reflux?
Ley B, et al. Am J Respir Crit Care Med 2011;183:431-440.
Conclusion
 IPF is




the most common of the IIPs
the most fibrotic
holds the worst prognosis
a diagnosis of exclusion
 The burden of disease is increasing
 Why?
 The natural history is variable
 Acute Exacerbations
 May yield additional insight into the etiology of
disease
Acknowledgements:












Kevin K. Brown
Jeffrey J. Swigris
Josh Solomon
Evans R. Fernandez- Perez
Aryeh Fischer
Tristan Huie
Stephen K. Frankel
Gregory Cosgrove
David Sprunger
Carla Wilson
Peter Henson
Ganesh Raghu
Questions?
Onset of
Acute
Exacerbation
vs.
Deaths from
IPF/PF
Simon-Blancal V, et al. Respiration 2012;83:28-35
Does identifying an infection
change outcome ?
N
10
9
8
Huie TJ, et al. Respirology 2010;15:909-917.
Geography
Study Years
Prevalence
(per million)
Incidence
(per million)
Data
US – NM
1988-1990
132 – 202
74 – 107
Population
based
US – 20 states
2000
140 – 427
68 - 163
Insurance
database
US – MN
1997-2005
279 – 630
88 – 174
Population
based
Czech Rep
1981-1990
65 – 121
7.4 – 12.8
Clinical registry
Norway
1984-1998
234
43
Hospital
records
Finland
1997 – 1998
160 – 180
NR
Clinic/hospital
review
Greece
2004
34
9
Clinic survey
UK
2000-2009
NR
74
PC database
Turkey
2007-2009
NR
49
Clinic survey
Taiwan
1997-1007
7 – 64
6 – 14
National
database
Japan
2005
29
NR
Medical
benefits
Recent Studies:
 Regardless, because the population is expected to age,
the absolute number of new cases based on 2003-2005
incidence rates are expected to increase.
Fernàndez-Pèrez ER, et al. Chest 2010;137:129-137.
Racial Differences?
Geography
Study Years
Prevalence
(per million)
Incidence
(per million)
Data
US – NM
1988-1990
132 – 202
74 – 107
Population
based
US – 20 states
2000
140 – 427
163
Insurance
database
UK
2000-2009
NR
74
PC database
Taiwan
1997-2007
7 – 64
6 – 14
National
database
Japan
2005
29
NR
Medical
benefits
Lai CC et al. Respir Med 2012;106:1566-1574.
Ohno S et al. Respirology 2008;13:926-926.
Previous Studies:
 At the same time, an increasing proportion
of patients with IPF were dying from it and
not from comorbid conditions.
Investigator
Year
Percentage of Patients Dying
From Pulmonary Fibrosis
Panos et al.
19641983
38.7%
(N = 326)
Mannino et al.
19791991
50.0%
(N = 107,292)
Mannino DE, et al. Am J Respir Crit Care Med 1996;153:1548-1152.
Panos RJ, et al. Am J Med 1990;88:396-404.