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 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.

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. 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;165:277-304.

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 2.17 (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;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) 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 …

First Large Scale Epidemiologic Studies of Death Certificate Data, Mortality Rates: Investigator Year Category Men Women Johnston et al., 1990 1979-1988 Idiopathic Pulmonary Fibrosis (ICD-9 516.3) Mortality Rate: 14 per Million ↑ (50% increase) 8 per Million ↑ (60% increase) Mannino et al., 1996 (NCHS/MCOD) 1979- 1991 Pulmonary Fibrosis (ICD-9 516.3/515) 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 1990. 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;301:1021-1023. 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: 1979-1991* 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) 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) 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. 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;176:277-284. 18

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. 1988-1990 Idiopathic Pulmonary Fibrosis Incidence: 107 per Million 74 per Million Rhagu et al. 1996-2000 Incidence (both men & women): 163 per Million Gribbin et al. 1991-2003 27.3 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? Better treatment for other conditions? Lack of treatment for fibrosis? Exposures?

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.

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

Prevalence of RA-ILD to RA 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 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.

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;183:788-824. 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 Olson AL, et al. Chest 2009;136:16-22.

Seasonal Variation of 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 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 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;183:1698-1702.

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 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

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 ? 10 9 8 Huie TJ, et al. Respirology 2010;15:909-917.

Geography Study Years Prevalence (per million) Incidence 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 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 74 PC database Turkey 2007-2009 49 Taiwan 1997-1007 7 – 64 6 – 14 National database Japan 2005 29 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 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 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. 1964-1983 38.7% (N = 326) Mannino et al. 1979-1991 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.