1. 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

2. 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

3. Background ILD vs. IIP vs. IPF
New Concepts in ILD Diagnosis and Management
July 17, 2008
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)
Gregory P. Cosgrove, M.D.

4. 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:
American Thoracic Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:

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

6. 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

7. 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
2.17 (1.28 – 3.68)
Wood Dust
1.94 (1.34 – 2.81)
Metal Dust
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;

8. 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

9. 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

10. Guidelines, 2011
Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:

11. What is the burden of IPF?

12. 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)
I just want to take a minute to define this epidemiologist term:
So the mortality rate is defined as the number of disease-associated deaths divided by the total live population – not divided by the number with disease over time which would be the case fatality rate
We use this metric so that we can adjust for changes in the demographics of a population as opposed to reporting the number of absolute deaths… this is especially important when a disease occurs more often in a certain age group and the demographics of that age group are changing …
Such is the case with IPF/PF where it is know to occur more often in the older ages and this group of our population in increasing.
I will give an example …

13. First Large Scale Epidemiologic Studies of Death Certificate Data, Mortality Rates:
Investigator
Year
Category
Men
Women
Johnston et al., 1990
Idiopathic Pulmonary Fibrosis
(ICD )
Mortality Rate:
14 per Million ↑
(50% increase)
8 per Million ↑
(60% increase)
Mannino et al., 1996
(NCHS/MCOD)
1979-
1991
Pulmonary Fibrosis
(ICD /515)
50.9 per Million ↑
(5% increase)
27.2 per Million ↑
(27% increase)
In 1990, Johnston et al. published the first large scale epidemiology study in England and Wales, MR in men doubled to 14/M, MR in women increased by 60% to 8/M. The ICD-9 code for IPF was introduced in 1979 to respond to the disease, whereas prior to that IPF was coded as “post-inflammatory pulmonary fibrosis”. They found that combining the terms had an accuracy of 83%, but like others, that CFA made it to the death certificate only 38% of the time. They felt that these numbers were an underestimate of the true disease. This data reflects decedents dying from pulmonary fibrosis.
In 1996, Mannino used multiple cause of death data to determine mortality rates from PF in the US. This type of death certificate data is important in chronic diseases – when deaths may not be directly due the chronic disease (call the underlying cause of death) – but the chronic disease contributed to the death. The mortality rates increased over the study time: 5% in men to 50.9/M in 1991 and 27% in women to 27.2/M in 1991.
At the same time, Coultas was collecting data in Bernalillo County, New Mexico. He and his colleagues used several different methods to collect all cases of idiopathic pulmonary fibrosis in the county from 1988 to Here the definition of pulmonary fibrosis was based on the clinician noting the diagnosis of IPF in the medical chart.
Johnston I, et al. Br Med J 1990;301:
Mannino DE, et al. Am J Respir Crit Care Med 1996;153:

14. 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:

15. Percent Changes in the Age-Adjusted Mortality Rates:*
Men 5%
28%
Women
27%
41%
Total
14%
34%
* Mannino et al. AJRCCM 1996;153:
Olson AL et al. Am J Respir Crit Care Med 2007;176:

16. Mortality Rates & Percent Increase with Pulmonary Fibrosis
Men
Women
Age Strata
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:

17. Mortality Rates & Percent Increase with Pulmonary Fibrosis
Men
Women
Age Strata
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: 17

18. Mortality Rates & Percent Increase with Pulmonary Fibrosis
Men
Women
Age Strata
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: 18

19. Poisson Regression: Mortality rates significantly …
increased over time (p < )
increased with increasing age (p < )
were higher among men than women (p < )
accelerated more steeply in women ( p < )
Olson AL et al. Am J Respir Crit Care Med 2007;176:

20. UK Mortality 51 / million 5% increase per year 9.2 / million
Navaratnam et al. Thorax 2011;66:462.

21. 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?

22. Recent Studies - Incidence:
Investigator
Year
Category
Men
Women
Coultas et al.
Idiopathic Pulmonary Fibrosis
Incidence:
107 per Million per Million
Rhagu et al.
Incidence (both men & women):
163 per Million
Gribbin et al.
27.3 per Million  67.8 per Million
Coultas DB, et al. Am J Respir Crit Care Med 1994;150:
Rhagu G, et al. Am J Respir Crit Care Med 2006;174:
Gribbin J, et al. Thorax 2006;61:

23. Why the increasing burden?
Better treatment for other conditions? Lack of treatment for fibrosis? Exposures?

24. Underlying Cause of Death
The proportion of decedents dying from rather than with PF has also increased over time. Panos and colleagues6 examined six case series (N = 326) of decedents with IPF published between 1964 and 1983 and reported that 38.7% of decedents with IPF died from respiratory failure. Mannino and colleagues5 found that, from 1979 to 1991, 50% of patients with PF died from their disease – in our study that number was 60%. This may result from advances in the treatment of other conditions that afflict patients with PF (e.g., cardiovascular disease, etc.), while effective treatment for PF remains elusive. Changes in the classification schema for idiopathic interstitial pneumonias may also explain these findings. In 1997, Katzenstein and Myers29 proposed a classification system whereby the term “idiopathic pulmonary fibrosis” was reserved for patients with a histopathologic diagnosis of usual interstitial pneumonia, therefore excluding other histopathologic lesions with a more favorable prognosis. As a result, those patients diagnosed with IPF by this classification system were likely a more homogenous group with a poorer prognosis. From this dataset, we are unable to determine if coding differences, more sensitive diagnostic testing, changes in classification schema, or a true change in the proportion of patients dying from PF account for these changes.

25. What about other forms of PF (RA) …
Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.]

26. Prevalence of RA-ILD to RA
Olson AL, et al. AJRCCM 2010 Sep 17. [Epub ahead of print.]13

27. Exposures – Regional Variation

28. Age-Adjusted Annual Mortality Rate with Pulmonary Fibrosis by State, 1979 through 1991
Mannino et al. AJRCCM 1996;153:

29. Age-Adjusted Annual Mortality Rate with Pulmonary Fibrosis by State, 1992 through 2003

30. 1992 through 2003
1979 through 1991

31. 1992 through 2003
1979 through 1991

32. 1992 through 2003
1979 through 1991
Like a number of other investigators,3-5,21 we found geographic variation across the U.S. in the distribution of deaths among people with PF. Although the overall mortality rate in patients with PF has increased, there remain a number of areas in the U.S. with below average age-adjusted mortality rates. Geographic variation may develop for any of three reasons: 1) There are true differences in rates, 2) the identification of disease is different among local clinicians (perhaps because the diagnostic criteria are not explicit or are interpreted differently), and 3) there are differences in the rate of diagnostic test use (such as high-resolution computed tomography or lung biopsy).28 Although we were unable to determine the underlying cause of the geographic variation by using this data set, these differences warrant further exploration. If this variation represents true differences in mortality rates, it would argue that environmental factors may play a key role in the pathogenesis of IPF.

33. Natural History of Disease
“The natural history has been described as a 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.
Lung Function
Time
Raghu G et al. ATS/ERS/JRS/ALAT Statement. Am J Respir Crit Care Med. 2011;183:
Tourin O et al. In: Idiopathic Pulmonary Fibrosis, Eds. Meyer KC, Nathan SD, 2014.

34. 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;

35. 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;

36. 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…

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

38. Seasonal Variation of Pneumonia
Olson AL, et al. Chest 2009;136:16-22.

39. Seasonal Variation of IPF
Olson AL, et al. Chest 2009;136:16-22.

40. Seasonal Variation of COPD & Lung Cancer
Olson AL, et al. Chest 2009;136:16-22.

41. 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 COPD-associated 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:

42. Natural History of Disease
* = Acute exacerbation … Infection? Reflux?
Ley B, et al. Am J Respir Crit Care Med 2011;183:

43. Conclusion IPF is The burden of disease is increasing
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

44. 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

45. Questions?

46. Onset of Acute Exacerbation
vs.
Deaths from IPF/PF
Simon-Blancal V, et al. Respiration 2012;83:28-35

47. Does identifying an infection change outcome ?10 9 8
Huie TJ, et al. Respirology 2010;15:

48. Geography Study Years Prevalence (per million) Incidence Data US – NM
132 – 202
74 – 107
Population based
US – 20 states
2000
140 – 427
Insurance database
US – MN
279 – 630
88 – 174
Czech Rep
65 – 121
7.4 – 12.8
Clinical registry
Norway
234 43
Hospital records
Finland
1997 – 1998
160 – 180 NR
Clinic/hospital review
Greece
2004 34 9
Clinic survey UK 74
PC database
Turkey 49
Taiwan
7 – 64
6 – 14
National database
Japan
2005 29
Medical benefits

49. Recent Studies:
Regardless, because the population is expected to age, the absolute number of new cases based on incidence rates are expected to increase.
Fernàndez-Pèrez ER, et al. Chest 2010;137:

50. Racial Differences? Geography Study Years Prevalence (per million)
Incidence
Data
US – NM
132 – 202
74 – 107
Population based
US – 20 states
2000
140 – 427
163
Insurance database UK NR 74
PC database
Taiwan
7 – 64
6 – 14
National database
Japan
2005 29
Medical benefits
Lai CC et al. Respir Med 2012;106:
Ohno S et al. Respirology 2008;13:

51. 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.
38.7%
(N = 326)
Mannino et al.
50.0%
(N = 107,292)
Mannino DE, et al. Am J Respir Crit Care Med 1996;153:
Panos RJ, et al. Am J Med 1990;88: