the clinical presentation & epidemiology of ipf the clinical presentation & epidemiology of...

The Clinical Presentation & The Clinical Presentation & Epidemiology of IPFEpidemiology of IPF

Amy L. Olson, MD, MSPHAmy L. Olson, MD, MSPH

Assistant ProfessorAssistant Professor

National Jewish Health National Jewish Health

Interstitial Lung Disease Program & Autoimmune Lung CenterInterstitial Lung Disease Program & Autoimmune Lung Center

April 2014April 2014

ObjectivesObjectives

Overview of ILD/IPFOverview of ILD/IPF Clinical Presentation of IPFClinical Presentation of IPF

Epidemiologic Risk FactorsEpidemiologic Risk Factors

The Rising Burden of DiseaseThe Rising Burden of Disease Mortality & Incidence RatesMortality & Incidence Rates

Natural History of DiseaseNatural History of Disease Acute exacerbations of IPFAcute exacerbations of IPF

BackgroundBackgroundILD vs. IIP vs. IPFILD vs. IIP vs. IPF

ILD = Describes over 150 ILD = Describes over 150 entities that affect the lung entities that affect the lung parenchyma, resulting in parenchyma, resulting in inflammation and/or fibrosis inflammation and/or fibrosis Systemic DiseasesSystemic Diseases Exposures Exposures GeneticGenetic

IIP = Idiopathic ILDsIIP = Idiopathic ILDs

IPF = IPF = Most common (~55%)Most common (~55%) Most fibrotic Most fibrotic Worst survival (~2-3 years)Worst survival (~2-3 years)

Current Definition of IPFCurrent Definition of IPF

Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:788-824.

Specific form of chronic, Specific form of chronic, progressive fibrosing progressive fibrosing interstitial pneumonia of interstitial pneumonia of unknown causeunknown cause occurring primarily in older occurring primarily in older

adultsadults limited to the lungslimited to the lungs has typical pathologic and/or has typical pathologic and/or

imaging pattern imaging pattern Usual Usual Interstitial Pneumonia (UIP).Interstitial Pneumonia (UIP).

Exclusion of known Exclusion of known causes of ILD … causes of ILD …

Prognosis Prognosis

Strand MJ. Chest 2014 April 3. [Epub ahead of print]

Clinical PresentationClinical Presentation

History of Present Illness:Age > 50Men > 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 symptomsNOT associated with obvious antigen (MOLD, BIRD) exposures

Clinical PresentationClinical Presentation Social, Occupational, Environmental HistorySocial, 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 PresentationClinical Presentation

Family HistoryFamily History ~ 5% of patient with IPF have 1~ 5% of patient with IPF have 1stst degree degree

relatives with lung fibrosisrelatives with lung fibrosis Telomerase Mutations ~ 15%Telomerase Mutations ~ 15% Family members may develop disease at an Family members may develop disease at an

earlier ageearlier age

Clinical PresentationClinical Presentation Physical ExaminationPhysical Examination

VS: Hypoxemia (may only be evident with ambulation)VS: Hypoxemia (may only be evident with ambulation) PULMONARY: Late bibasilar inspiratory crackles PULMONARY: Late bibasilar inspiratory crackles

(Velco® crackles)(Velco® crackles) CARDIAC: Pronounced P2 (pulmonary hypertension)CARDIAC: Pronounced P2 (pulmonary hypertension) EXT: Clubbing EXT: Clubbing

Guidelines, 2011Guidelines, 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?What is the burden of IPF?

Mortality, Incidence, & Mortality, Incidence, & PrevalencePrevalence

Mortality Rate Mortality Rate = Number of Disease-Associated Deaths= Number of Disease-Associated Deaths

Total Live PopulationTotal Live Population

Mortality Rate Mortality Rate ≈≈ Incidence Incidence (when disease duration is relatively short and lethal)(when disease duration is relatively short and lethal)

Incidence Incidence = Number of New Cases of Disease= Number of New Cases of Disease

Population at RiskPopulation at Risk

First Large Scale Epidemiologic First Large Scale Epidemiologic Studies of Death Certificate Data, Studies of Death Certificate Data,

Mortality Rates:Mortality Rates:

InvestigatorInvestigator YearYear CategoryCategory MenMen WomenWomen

Johnston et Johnston et al., 1990 al., 1990

1979-1979-19881988

Idiopathic Idiopathic Pulmonary Pulmonary FibrosisFibrosis

(ICD-9 516.3) (ICD-9 516.3)

Mortality Rate:Mortality Rate:

14 per Million 14 per Million ↑↑(50% increase)(50% increase)


8 per Million 8 per Million ↑↑ (60% increase)(60% increase)

Mannino et Mannino et al., 1996 al., 1996 (NCHS/MCOD)(NCHS/MCOD)

1979-1979-

19911991

Pulmonary Pulmonary FibrosisFibrosis

(ICD-9 (ICD-9 516.3/515)516.3/515)


50.9 per Million 50.9 per Million ↑↑(5% increase)(5% increase)


27.2 per Million 27.2 per Million ↑↑(27% 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:Death Certificate Data: 1992 through 2003 1992 through 2003 (~22 million records)(~22 million records)

Removed codes with Removed codes with CTDz, HP, asbestosis, CTDz, HP, asbestosis, and radiation fibrosis. and radiation fibrosis.

In In menmen, the rate , the rate increased by increased by 28%28% from 48 to 62 per from 48 to 62 per 1,000,000.1,000,000.

In In womenwomen, the rate , the rate increased by increased by 41%41% from 40 to 56 per from 40 to 56 per 1,000,000.1,000,000.

Olson AL et al. Am J Respir Crit Care Med 2007;176:277-284.

Percent Changes in the Percent Changes in the Age-Adjusted Mortality Rates:Age-Adjusted Mortality Rates:

* Mannino et al. AJRCCM 1996;153:1548-1552.

% Change, % Change,

1979-1991*1979-1991*

% Change, % Change,

1992-20031992-2003

MenMen 5%5% 28%28%

WomenWomen 27%27% 41%41%

TotalTotal 14%14% 34%34%


Mortality Rates & Percent Increase Mortality Rates & Percent Increase with Pulmonary Fibrosiswith Pulmonary Fibrosis

Men Women

Age Strata Mortality Rateper 1,000,000

(2003)

Percent Increase

(from 1992)

Mortality Rateper 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%


Poisson Regression:Poisson Regression:

Mortality rates significantly …Mortality rates significantly … increased over time (p < 0.0001)increased over time (p < 0.0001) increased with increasing age (p < 0.0001)increased with increasing age (p < 0.0001) were higher among men than women (p < 0.0001)were higher among men than women (p < 0.0001) accelerated more steeply in women ( p < 0.0001) accelerated more steeply in women ( p < 0.0001)


UK Mortality

Navaratnam et al. Thorax 2011;66:462.

51 / million

9.2 / million

5% increase per year

Limitations:Limitations: Why are the mortality rates increasing?Why are the mortality rates increasing?

Changes in death certificate coding?Changes in death certificate coding? Changes in clinical diagnostic accuracy?Changes in clinical diagnostic accuracy?

High Resolution CT scansHigh Resolution CT scans AwarenessAwareness

Consensus statement for the diagnosis/treatment ofConsensus statement for the diagnosis/treatment of IPF IPF Randomized Controlled Trials IPFRandomized Controlled Trials IPF

Changes in the incidence driving mortality Changes in the incidence driving mortality rate?rate?

Recent Studies - Incidence:Recent Studies - Incidence:

InvestigatorInvestigator YearYear CategoryCategory MenMen WomenWomen

Coultas et Coultas et al. al.

1988-1988-19901990


Incidence:Incidence:

107 per Million 74 per Million107 per Million 74 per Million

Rhagu et al.Rhagu et al. 1996-1996-20002000


Incidence (both men & women):Incidence (both men & women):

163 per Million163 per Million

Gribbin et Gribbin et al.al.

1991-1991-20032003


Incidence (both men & women):Incidence (both men & women):27.3 per Million 27.3 per Million 67.8 per Million 67.8 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?Why the increasing burden?

Better treatment for other conditions?Better treatment for other conditions?

Lack of treatment for fibrosis?Lack of treatment for fibrosis?

Exposures?Exposures?

Underlying Cause of Death with Pulmonary Fibrosis,Panos et al. (1964-1983) vs. MCOD (1992-2003)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Panos et al. MCOD

Underlying Cause of Death

Pro

po

rtio

n o

f D

ea

ths

Pulmonary Fibrosis

Ischemic Heart Disease

Congestive Heart Failure

Lung Cancer

Pulmonary Embolism

Pneumonia

Cerebrovascular Disease

Other

Underlying Cause of DeathUnderlying Cause of Death

What about other forms of PF What about other forms of PF (RA) …(RA) …

Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.]

Prevalence of RA-ILD to RAPrevalence of RA-ILD to RA

Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.]13

0

2

4

6

8

10

12

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Year

Pre

va

len

ce

of

RA

-IL

D

in R

A D

ec

ed

en

ts (

%)

Women

Men

Exposures –Exposures –Regional Variation Regional Variation

Age-Adjusted Annual Mortality Rate with Age-Adjusted Annual Mortality Rate with Pulmonary Fibrosis by State, Pulmonary Fibrosis by State,

1979 through 19911979 through 1991

Mannino et al. AJRCCM 1996;153:1548-1552.

Age-Adjusted Annual Mortality Rate with Age-Adjusted Annual Mortality Rate with Pulmonary Fibrosis by State, Pulmonary Fibrosis by State,

1992 through 20031992 through 2003

1992 through 2003

1979 through 1991

Natural History of DiseaseNatural History of Disease

““The natural history has been described as a The natural history has been described as a progressive decline progressive decline in subjective and objective in subjective and objective pulmonary function until eventual death from pulmonary function until eventual death from respiratory failure or complicating comorbidity.” respiratory failure or complicating comorbidity.”

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.

Time

Lung

Fun

ctio

n Placebo arms of 8 RCTs report adecline in FVC of 0.15 to 0.22 L/year.


The placebo arm of the The placebo arm of the γγ-interferon trial for IPF -interferon trial for IPF found that found that 89% of deaths were considered to be due to IPF 89% of deaths were considered to be due to IPF

progressionprogression of these, 47% had an apparent ‘acute clinical decline.’ of these, 47% had an apparent ‘acute clinical decline.’

At the same time, there was an increasing At the same time, there was an increasing recognition of recognition of acute exacerbations acute exacerbations of IPF.of IPF.

Martinez FJ, et al. Ann Intern Med 2005;963-967.


Acute Exacerbations of Acute Exacerbations of DiseaseDisease Worsening of dyspnea, < 30 Worsening of dyspnea, < 30

daysdays Decrease in PaO2Decrease in PaO2 New radiographic opacitiesNew radiographic opacities No apparent cause (infection, No apparent cause (infection,

CHF, PE).CHF, PE).

Different pathologic pattern Different pathologic pattern (DAD, OP)(DAD, OP)

Poor outcomePoor outcome ETIOLOGY?ETIOLOGY?

Infection, Reflux, Thoracic Infection, Reflux, Thoracic ProceduresProcedures

Martinez FJ, et al. Ann Intern Med 2005;963-967.

Infection?Infection?

Our hypothesis – that death and these acute Our hypothesis – that death and these acute exacerbations are the result of infectionsexacerbations are the result of infections

Previous data had found rates of particular Previous data had found rates of particular respiratory infections are higher in the respiratory infections are higher in the winter winter

If infection was driving death/acute If infection was driving death/acute exacerbations, mortality rates from PF exacerbations, mortality rates from PF would display seasonal variation too…would display seasonal variation too…

Seasonal VariationSeasonal VariationNumbers of Deaths from Pulmonary Fibrosis by Month (and Season), 1992-2003

800

1000

1200

1400

1600

1800

Dec* Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov

Month of Death (Season Grouping)

Nu

mb

ers

of

De

ath

s

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003(Winter) (Fall)(Summer)(Spring)

Olson AL, et al. Chest 2009;136:16-22.

Seasonal Variation of PneumoniaSeasonal Variation of Pneumonia

Percent Increase in Monthly Mortality Rate from Pneumonia by Season

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

All records with pneumonia

Pe

rce

nt

Incr

ea

se (

with

su

mm

er

as

the

re

fere

nce

)

fall

winter

spring

*

*

†

†


Seasonal Variation of IPFSeasonal Variation of IPF


Seasonal Variation of COPD & Lung CancerSeasonal Variation of COPD & Lung Cancer

Percent Increase in Monthly Mortality Rate from COPD and Lung Cancer by Season

0.0%

4.0%

8.0%

12.0%

16.0%

20.0%

24.0%

28.0%

32.0%

All records withCOPD

All records withCOPD excluding

those withpneumonia

All records with LungCancer

All records with LungCancer excluding

those withpneumonia

Pe

rce

nt

Inc

rea

se

(w

he

n c

om

pa

red

to

su

mm

er)

fall

winter

spring

*

*

*

†*

*

‡*


Seasonal VariationSeasonal Variation

Seasonal variation in PF-associated mortality exists Seasonal variation in PF-associated mortality exists Mortality rates are higher in the winter followed by Mortality rates are higher in the winter followed by

the springthe spring This mirrors the seasonal variation in COPD-This mirrors the seasonal variation in COPD-

associated mortality – known to be higher in the associated mortality – known to be higher in the winter months and result from viral and bacterial winter months and result from viral and bacterial exacerbations of diseaseexacerbations of disease

Infectious triggers? Infectious triggers? No viral etiology has been identified to dateNo viral etiology has been identified to date

Whootton SC, et al. Am J Respir Crit Care 2011;183:1698-1702.


Ley B, et al. Am J Respir Crit Care Med 2011;183:431-440.

* = Acute exacerbation … Infection? Reflux?

ConclusionConclusion

IPF is IPF is the most common of the IIPsthe most common of the IIPs the most fibroticthe most fibrotic holds the worst prognosisholds the worst prognosis a diagnosis of exclusiona diagnosis of exclusion

The burden of disease is increasingThe burden of disease is increasing Why?Why?

The natural history is variableThe natural history is variable Acute ExacerbationsAcute Exacerbations May yield additional insight into the etiology of disease May yield additional insight into the etiology of disease

Acknowledgements:Acknowledgements:

Kevin K. BrownKevin K. Brown Jeffrey J. SwigrisJeffrey J. Swigris Josh SolomonJosh Solomon Evans R. Fernandez- PerezEvans R. Fernandez- Perez Aryeh FischerAryeh Fischer Tristan HuieTristan Huie Stephen K. FrankelStephen K. Frankel Gregory CosgroveGregory Cosgrove David SprungerDavid Sprunger Carla WilsonCarla Wilson Peter HensonPeter Henson Ganesh RaghuGanesh Raghu

Questions?Questions?

Onset of Acute Exacerbation

vs.

Deaths from IPF/PF

Simon-Blancal V, et al. Respiration 2012;83:28-35

Does identifying an infection Does identifying an infection change outcome ?change outcome ?

Huie TJ, et al. Respirology 2010;15:909-917.

N

10

9

8

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:Recent Studies: Regardless, because the population is expected to age, Regardless, because the population is expected to age,

the absolute number of new cases based on 2003-2005 the absolute number of new cases based on 2003-2005 incidence rates are expected to increase.incidence rates are expected to increase.

Fernàndez-Pèrez ER, et al. Chest 2010;137:129-137.

Racial Differences?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:Previous Studies:

At the same time, an increasing proportion At the same time, an increasing proportion of patients with IPF were dying from it and of patients with IPF were dying from it and not from comorbid conditions. not from comorbid conditions.

InvestigatorInvestigator YearYear Percentage of Patients Dying Percentage of Patients Dying

From Pulmonary FibrosisFrom Pulmonary Fibrosis

Panos et al.Panos et al. 1964-1964-19831983

38.7%38.7%

(N = 326)(N = 326)

Mannino et al.Mannino et al. 1979-1979-19911991

50.0%50.0%

(N = 107,292)(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.

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