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Idiopathic Pulmonary Fibrosis Epidemiology
CHAPTER 2
Idiopathic Pulmonary Fibrosis Epidemiology AMY L. OLSON, MD, MSPH • DAVID SPRUNGER, MD
THE EPIDEMIOLOGY OF IDIOPATHIC PULMONARY FIBROSIS Background
present in the population at a specific time divided by the number of persons in the population at that time.2
Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias1 and was once considered a rare, orphan disease. Epidemiologic studies suggest that the disease burden attributable to IPF is growing, underlining the importance of ongoing research into this devastating disease. Historically, several factors have hampered investigators in their conduct of large-scale, epidemiologic studies in IPF as follows: (1) the condition was thought to be too rare to study easily; (2) diagnostic criteria and disease assessment modalities were evolving, making the case definition a bit of a moving target; and (3) there was no specific code in the International Classification of Diseases (ICD) for IPF. The identification or, in some cases, development of large, population-level databases have helped to overcome some of these factors. For example, health insurance care claims databases have been used to determine incidence and prevalence estimates, and investigators have used death certificate databases to determine mortality rates. In addition, the generation of ICD codes that allow researchers to specifically identify IPF or other fibrotic lung diseases have been instrumental in promoting epidemiologic research using large databases. However, there are limitations associated with the use of these large datasets, including the inability to assess the fidelity of diagnostic codes.
The United States
Trends in Idiopathic Pulmonary Fibrosis Incidence and Prevalence The incidence of disease is the number of new cases that occur during a specified period of time in a population at risk for developing the disease, whereas the prevalence of disease is a ratio of the number of affected cases
In the early 1990s, a summary of the National Heart, Lung, and Blood Institute workshop stated that few data were available on the occurrence of IPF in the general population.3 In the wake of this summary, in 1994, Coultas and colleagues published a regional epidemiologic investigation into the incidence and prevalence of interstitial lung diseases (ILDs), including IPF, occurring in persons over the age of 18 years in the United States.4 Using data from 1988 through 1993, the authors established a population-based registry in Bernalillo County, New Mexico. In it, they examined primary care and pulmonary physician records, pathology reports, hospital discharge diagnoses, death certificates, and autopsy reports. The authors reported the incidence of IPF as 10.7 per 100,000 person-years in men and 7.4 per 100,000 person-years in women. The prevalence of IPF was 20.2 cases per 100,000 persons in men and 13.2 cases per 100,000 persons overall. When stratified by age and gender, both the incidence and prevalence of IPF was higher in men than in women, and each increased with increasing age. Raghu and colleagues examined the incidence and prevalence of IPF using data from a healthcare claims processing center from 1996 through 2000.5 The center services a plan that covers nearly 3 million people across 20 statesdmostly in the South Atlantic, South Central, and North Central regions of the United States. The authors estimated IPF incidence and prevalence for the entire United States. Using broad case-finding criteria (age > 18, at least one medical encounter for IPF [ICD-9 code 516.3], and no encounters with diagnostic codes for any other ILD after an encounter coded as IPF), they estimated an incidence of 16.3 per 100,000
3
4
Idiopathic Pulmonary Fibrosis
persons/year and a prevalence of 42.7 per 100,000 persons, respectively. Employing narrow case-finding criteria (the broad criteria plus at least one claim with a procedure code for a surgical lung biopsy, transbronchial biopsy, or thoracic computed tomography [CT]), they estimated the incidence and prevalence at 6.8 per 100,000 persons/year and 14.0 per 100,000 persons, respectively. Like Coultas and his coinvestigators, Raghu and colleagues found that both the incidence and prevalence of IPF increased with age, and both were higher in men than in women. Based on these two landmark studies, the incidence and prevalence of IPF appeared to increase over time, but as with any study using claims data, questions remained: were cases with non-IPF ILDs counted as IPF, and were cases of IPF missed? Using data from patients evaluated at the Mayo Clinic in Rochester from 1997 to 2005, FernándezPérez and colleagues completed a population-based, historical cohort study in Olmsted County, Minnesota.6 These authors also used both narrow and broad casefinding criteria. The narrow criteria included a usual interstitial pneumonia (UIP) pattern on surgical lung biopsy or a definite UIP pattern on thoracic highresolution CT (HRCT), whereas broad criteria included the less-strict pattern on HRCT scan of possible UIP. Using the narrow definition, the age- and sex-adjusted incidence (for people over the age of 50) was 8.8 cases per 100,000 person-years (95% CI ¼ 5.3e12.4), and using the broad definition, it was 17.4 cases per 100,000 person-years (95% CI ¼ 12.4e22.4). The ageand sex-adjusted prevalence (for those over the age of 50) was 27.9 cases per 100,000 persons (95% CI ¼ 10.4e45.4) and 63 cases per 100,000 persons (95% CI ¼ 36.4e89.6). Over the last 3 years of the study, incidence was on the decline. Given the low number of incidence cases (47 according to broad case-finding criteria), confidence is low that these statistics accurately reflected national trends during the study period (1997e2005). In a random sample of 5% of Medicare beneficiaries (65 years of age or older), Raghu and colleagues performed another study to generate estimates for the annual incidence and cumulative prevalence of IPF.7 Using ICD-9 codes 516.3 (IPF) and 515 (postinflammatory pulmonary fibrosis [PIPF]), they determined that from 2001 to 2011 the incidence of IPF remained stable (overall 93.7 cases per 100,000 person-years [95% CI ¼ 91.9e95.4]). But, the annual cumulative prevalence rose from 202.2 cases per 100,000 persons in 2001 to 494.2 cases per 100,000 persons in 2011. The authors also found that cases diagnosed in 2007 had
longer survival times (4.0 years [95% CI ¼ 3.8e4.5]) than those diagnosed before 2007 (3.3 years [95% CI ¼ 3.0e3.8]) and suggested that longer survival after diagnosis might explain the discrepancy between incidence and prevalence. In another epidemiologic study of IPF, investigators used an administrative, patient claims, insurance dataset that included data from more than 45 managed healthcare plans covering more than 89 million people for the years 2005e10.8 Using a narrow case definition, they determined that the annual incidence of IPF among people 18e64 years old decreased from 2.9 to 2.4 new cases per 100,000 person-years, while the annual prevalence ranged from 4.6 to 6.7 per 100,000 person-years from 2005 to 2010. Using a broad case definition, they reported that the annual incidence decreased from 5.1 to 3.6 new cases per 100,000 person-years from 2005 to 2010, and the annual prevalence ranged from 8.4 to 11.3 per 100,000 person-years over that time. In contrast to the stable incidence and increasing prevalence noted in the older Medicare population, the incidence declined in this younger cohort over time, while the prevalence plateaued. The results appeared to be driven by changes in statistics for younger patients (18e44 years): the likelihood of them being diagnosed (inappropriately, as patients younger than 50 years old rarely develop the disease) with IPF declined over time. Presumably, they were being appropriately diagnosed with known cause of pulmonary fibrosis (PF) (e.g., connective tissue diseaseerelated)da condition far more likely than IPF to cause PF in patients younger than 50 years. In a large research database, a case definition of IPF (defined as a diagnosis by a physician and no alternative diagnosis within the 6 months before or after) had a positive predictive value (PPV) of only 44.4% (95% CI ¼ 29.6e60.0%).9 This suggests incidence and prevalence estimates determined by using healthcare claims databases are likely to be overestimated. Correcting for the PPV and standardizing the claims cohort to the US population, for 2006e12, the incidence of IPF was calculated to be 14.6 per 100,000 person-years, and the prevalence was estimated at 125.2 per 100,000 persons.
The United Kingdom Epidemiologic studies from investigators in the United Kingdom also suggest an increase in the incidence of IPF over time. Gribbin and colleagues used a general practice database and applied diagnostic codes for “cryptogenic fibrosing alveolitis” and “idiopathic pulmonary fibrosis”dterms used interchangeably until
CHAPTER 2 recentlydto find that the overall incidence of IPF had doubled from 1991 to 2003.10 They estimated an overall crude incidence of IPF at 4.6 cases per 100,000 person-years, which equaled a yearly increase in incidence of 11% (rate ratio 1.11; 95% CI ¼ 1.09e1.13). Navaratnam and colleagues used the same database and a similar approach (included cases coded as “cryptogenic fibrosing alveolitis” or “idiopathic pulmonary fibrosis,” but also included cases coded as “diffuse pulmonary fibrosis,” “idiopathic fibrosing alveolitis NOS,” or “Hamman-Rich syndrome”) to determine statistics for the entity they termed IPF-clinical syndrome (IPF-CS).11 Between 2000 and 2008, the overall crude incidence of IPF-CS was 7.44 per 100,000 personyearsdnearly double the incidence rate of the prior decade. They estimated that the incidence of IPF-CS increased by 5% annually over this time period (rate ratio 1.05; 95% CI ¼ 1.03e1.06), although at a somewhat slower rate than the prior decade. Experts have posited that reasons for the increased incidence could be an uptick in the use of CT of the chest and/or the conduct of multinational drug trials for IPF, which could serve to raise awareness of the disease.12
Canada Hopkins and colleagues used two national administrative databases from the Canadian Institute for Health Information to estimate the incidence and prevalence of IPF in Canada from 2007 through 2011.13 For their broad case definition, incidence and prevalence in men was 21.3 per 100,000 person-years and 45.3 per 100,000 persons, respectively. Their narrow case definition yielded incidence and prevalence estimates in men of 10.5 per 100,000 person-years and 22.3 per 100,000 persons, respectively. For women, the broad case definition yielded incidence and prevalence estimates of 16.2 per 100,000 persons-years and 38.2 per 100,000 persons, respectively, whereas the narrow case definition produced incidence and prevalence estimates of 7.4 per 100,000 person-years and 17.7 per 100,000 persons, respectively. These estimates are similar to those generated for the United States and the United Kingdom.
Other countries Hyldgaard and coauthors conducted a single-center, observational cohort study of 431 patients with various ILDs (121 with IPF) living in Denmark between 2001 and 2011.14 The authors estimated an overall crude incidence rate for IPF of 4.1 cases per 100,000 personyears. And they found the incidence rose from 3.8 to 6.8 per 100,000 persons over the study period. The
Idiopathic Pulmonary Fibrosis Epidemiology
5
authors attribute this increase to centralized, specialized referral centers within the Danish healthcare system and increased access to HRCT over the study period. Other data, including those from a systematic review on the global incidence of IPF, suggest the worldwide incidence of IPF is increasing, and rates across countries appear to be converging. As more countries begin to collect large-scale data on IPF, a better understanding of the global incidence and disease burden of IPF will be possible.
Mortality Rates and Trends Over Time Mortality rate is the total number of deaths from a particular cause in 1 year divided by the number of people alive within the population at midyear. In the era of ICD-10 coding, using death certificate coding from 1999 onward, Hutchinson and colleagues recently examined the death certificates from 124 decedents whose deaths the authors had confirmed as due to IPF. Of these, 82% had a diagnostic code somewhere on the death certificate for IPF (J84.1) or ILD unspecified (ILD-U) (J84.9). This suggests that death certificate data may underestimate mortality rates by w 20%.15 It is unclear if these findings apply to death certificate data outside of the United Kingdom, and more research on the validity of death certificate data is needed.
The United States Mannino and colleagues used US death certificate data from 1979 to 1991 to calculate age-adjusted mortality from PF (ICD-9 codes 516.3 [IPF] and 515 [PIPF]).16 They determined that mortality from PF had increased from 48.6 deaths per million to 50.9 deaths per million from the late 1970s to the early 1990s. They found a 4.7% increase in mortality among men and a 27.1% increase among women. This study was the first in which PF mortality was reported to vary between regions of the United States: mortality rates were highest in the West and Southeast and lowest in the Midwest and Northeast. Using the same database, our group examined US death certificate data from 1992 to 2003. We observed an increase from 49.7 deaths per million to 64.3 deaths per million (for a relative 29.4% increase) among men, and from 42.3 deaths per million to 58.4 deaths per million (for a relative 38.1% increase) among women. We also found that mortality rates increased with increasing age and were higher in men than in women but were increasing more steeply in women than in men.17 Hutchinson and coinvestigators examined the same dataset for the years 2000e10.18 Including only
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Idiopathic Pulmonary Fibrosis
decedents in whom J84 (includes IPF and ILD-U) was coded as the “underlying cause of death” (UCD), they observed that mortality rates had increased by 1% per year (annual increase 1.01; 95% CI ¼ 1.011e1.014). The age-adjusted mortality rate in 2010 for decedents whose UCD was coded as J84 was 7.8 per 100,000 persons (which equates to 78 deaths per million). Like other UCD analyses, these estimates are subject to potential extreme underreporting bias.
Other countries In a study of death certificates from England and Wales, Australia, Canada, Japan, Northern Ireland, New Zealand, Scotland, Spain, and Sweden collected between 2000 and 2010, deaths in which J84 was the UCD increased between 1% and 4% per year in all countries except Northern Ireland where data were limited (only available from 2009 to 2011) and the increases were much larger (25%).18 In a metaanalysis of data from the United States and these eight countries, there was a 2% annual increase in mortality over time (rate ratio, 1.02; 95% CI ¼ 1.01e1.03). Agestandardized mortality rates varied by country: those with the lowest mortality rates included Sweden (4.68 per 100,000) and New Zealand (5.55 per 100,000); those with mortality rates similar to the United States included Australia (6.49 per 100,000) and Canada (7.52 per 100,000); and those with the highest mortality rates included England and Wales (9.84 per 100,000) and Japan (10.26 per 100,000). The reasons for this apparent global heterogeneity remain unclear, but if real, are presumably due at least in part to genetic variation.
Risk Factors Like many other epidemiologic studies, those conducted to examine risk factors for IPF have been subject to a number of limitations, including recall and misclassification biases.
Cigarette smoking Cigarette smoking is a risk factor for IPF and familial pulmonary fibrosis (FPF). In a study of 248 cases of IPF identified between 1989 and 1993 and 491 controls matched for age, sex, and geography, ever-smoking was associated with a 60% increased odds of IPF (OR ¼ 1.6; 95% CI ¼ 1.1e2.2).19 Among former smokers, those who had recently quit (within 2.5 years) had the highest risk for the development of IPF (OR ¼ 3.5%; 95% CI ¼ 1.1e11.9), whereas those who quit more remotely (at least 25 years prior) had the lowest risk (OR ¼ 1.3; 95% CI ¼ 0.7e2.3).
In a Japanese cohort, smokers with a 20.0e39.9 pack-year history had an increased risk for IPF (OR ¼ 2.26; 95% CI ¼ 1.3e3.8). Those with a less than 20.0 pack-year history or a 40.0 pack-year history or greater were not at increased risk.20 Authors of a metaanalysis that included US and Japanese studies and another three studies from the United Kingdom or Japan found ever-smoking conferred a 58% increase in the odds of IPF (summary OR ¼ 1.58; 95% CI ¼ 1.27e1.97).21 They estimated that 49% of cases of IPF could be prevented by eliminating cigarette smoking. Data are similar for FPF. In a study of 309 cases of FPF and 360 unaffected family members, ever-smoking was associated with a greater than threefold odds of developing FPF (OR ¼ 3.6; 95% CI ¼ 1.3e9.8) while adjusting for age and gender.22
Occupational and environmental exposures Results from several studies suggest an association between dust and/or dusty environments and IPF. In a metaanalysis of five case-controlled studies published between 1990 and 2005, results suggested a significant association between metal dust exposure and the development of IPF (summary OR ¼ 2.44, 95% CI ¼ 1.74e3.40).21,23 In one study, the association held only for those with 5 years of exposure, suggesting a dose-response relationship.24 In an analysis of the pension fund archives from a metal engineering company, investigators found no relationship between metal dust exposure and IPF, except in people exposed for greater than 10 years (OR ¼ 1.71; 95% CI ¼ 1.09e2.68).25 In two other studies, there was no relationship between exposure to metal dusts and IPF, but the investigators did not consider the extent or duration of exposure.26,27 According to a metaanalysis of five case-control studies, there is an association between exposure to wood dusts and IPF (summary OR ¼ 1.94; 95% CI ¼ 1.34e2.81).23 However, in two of the five individual studies, no association was identified, suggesting the risk may be relevant for only certain woods. In support of this, in another study, there was an association between birch or hardwood dust and IPF; there was no association between fir dust exposure and IPF.26 Exposure to livestock has been found to be associated with IPF (summary OR ¼ 2.17; 95% CI ¼ 1.20e2.26).23 Results from one study suggest a dose-response relationship: for the subgroup of subjects with <5 years of exposure, there was no association; however, for the subgroup with more than 5 years of exposure, there was a strong association with the
CHAPTER 2 development of IPF (OR ¼ 3.3; 95% CI ¼ 1.3e8.3).24 Other studies of farming (or residing in a region in which farming is common) corroborate these findings.23,24,28 In one study, there was an association between exposure to agricultural chemicals specifically and IPF (OR ¼ 3.32; 95% CI ¼ 1.22e9.05).28 Exposure to sand, stone, or silica dusts have been found to be associated with the development of IPF (summary OR ¼ 1.97; 95% CI ¼ 1.09e3.55).23,29 Other exposures with associations with IPF include hair dressing, raising birds, or residing in an urban/ polluted area.23,29 In sum, inhalational exposures of various kinds are associated with IPF; however, whether these exposures have roles in the pathogenesis of IPF is uncertain and warrants additional evaluation.
SUMMARY Although IPF was once considered an orphan disease, studies suggest that mortality rates are similar to certain common malignancies. Epidemiologic research has helped elevate knowledge of IPF at the population level, but many questions remain to be explored. Doing so will likely lead to an even greater understanding of accurate epidemiologic trends and by extension, risk factors will increase understanding of IPF pathobiology.
REFERENCES
1. Raghu G. Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011. Eur Respir J. 2011;37(4):743e746. 2. Gordis L. Measuring the occurrence of disease. In: Leon G, ed. Epidemiology. Philadelphia, PA: Elsevier Saunders; 2004: 32e47. 3. Cherniack RM, Crystal RG, Kalica AR. NHLBI workshop summary. Current concepts in idiopathic pulmonary fibrosis: a road map for the future. Am Rev Respir Dis. 1991;143(3):680e683. 4. Coultas D, et al. The epidemiology of interstitial lung disease. Am J Respir Crit Care Med. 1994;150:967e972. 5. Raghu G, et al. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006; 174(7):810e816. 6. Fernandez Perez ER, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a populationbased study. Chest. 2010;137(1):129e137. 7. Raghu G, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014; 2(7):566e572.
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8. Raghu G, et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48(1):179e186. 9. Esposito DB, et al. Idiopathic pulmonary fibrosis in United States automated claims. Incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med. 2015; 192(10):1200e1207. 10. Gribbin J, et al. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006;61(11):980e985. 11. Navaratnam V, et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011;66(6):462e467. 12. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000; 161(2 Pt 1):646e664. 13. Hopkins RB, et al. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur Respir J. 2016;48(1):187e195. 14. Hyldgaard C. A cohort study of Danish patients with interstitial lung diseases: burden, severity, treatment and survival. Dan Med J. 2015;62(4):B5069. 15. Hutchinson J, et al. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795e806. 16. Mannino DM, Etzel RA, Parrish RG. Pulmonary fibrosis deaths in the United States, 1979-1991. An analysis of multiple-cause mortality data. Am J Respir Crit Care Med. 1996;153(5):1548e1552. 17. Olson AL, et al. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007;176(3):277e284. 18. Hutchinson JP, et al. Increasing global mortality from idiopathic pulmonary fibrosis in the twenty-first century. Ann Am Thorac Soc. 2014;11(8):1176e1185. 19. Baumgartner K, et al. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155:242e248. 20. Miyake Y, et al. Occupational and environmental factors and idiopathic pulmonary fibrosis in Japan. Ann Occup Hyg. 2005;49(3):259e265. 21. Taskar V, Coultas D. Exposures and idiopathic lung disease. Semin Respir Crit Care Med. 2008;29(6):670e679. 22. Steele MP, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med. 2005; 172(9):1146e1152. 23. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3(4): 293e298. 24. Baumgartner KB, et al. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers. Am J Epidemiol. 2000;152(4):307e315. 25. Hubbard R, et al. Risk of cryptogenic fibrosing alveolitis in metal workers. Lancet. 2000;355(9202):466e467.
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26. Gustafson T, et al. Occupational exposure and severe pulmonary fibrosis. Respir Med. 2007;101(10):2207e2212. 27. Harris JM, Cullinan P, McDonald JC. Occupational distribution and geographic clustering of deaths certified to be cryptogenic fibrosing alveolitis in england and wales. Chest. 2001;119(2):428e433.
28. Iwai K, et al. Idiopathic pulmonary fibrosis: epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med. 1994;150:670e675. 29. Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing alveolitis? A case control study of environmental exposure to dust. BMJ. 1990;301:1015e1017.
Idiopathic Pulmonary Fibrosis Epidemiology AMY L. OLSON, MD, MSPH • DAVID SPRUNGER, MD
THE EPIDEMIOLOGY OF IDIOPATHIC PULMONARY FIBROSIS Background
present in the population at a specific time divided by the number of persons in the population at that time.2
Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias1 and was once considered a rare, orphan disease. Epidemiologic studies suggest that the disease burden attributable to IPF is growing, underlining the importance of ongoing research into this devastating disease. Historically, several factors have hampered investigators in their conduct of large-scale, epidemiologic studies in IPF as follows: (1) the condition was thought to be too rare to study easily; (2) diagnostic criteria and disease assessment modalities were evolving, making the case definition a bit of a moving target; and (3) there was no specific code in the International Classification of Diseases (ICD) for IPF. The identification or, in some cases, development of large, population-level databases have helped to overcome some of these factors. For example, health insurance care claims databases have been used to determine incidence and prevalence estimates, and investigators have used death certificate databases to determine mortality rates. In addition, the generation of ICD codes that allow researchers to specifically identify IPF or other fibrotic lung diseases have been instrumental in promoting epidemiologic research using large databases. However, there are limitations associated with the use of these large datasets, including the inability to assess the fidelity of diagnostic codes.
The United States
Trends in Idiopathic Pulmonary Fibrosis Incidence and Prevalence The incidence of disease is the number of new cases that occur during a specified period of time in a population at risk for developing the disease, whereas the prevalence of disease is a ratio of the number of affected cases
In the early 1990s, a summary of the National Heart, Lung, and Blood Institute workshop stated that few data were available on the occurrence of IPF in the general population.3 In the wake of this summary, in 1994, Coultas and colleagues published a regional epidemiologic investigation into the incidence and prevalence of interstitial lung diseases (ILDs), including IPF, occurring in persons over the age of 18 years in the United States.4 Using data from 1988 through 1993, the authors established a population-based registry in Bernalillo County, New Mexico. In it, they examined primary care and pulmonary physician records, pathology reports, hospital discharge diagnoses, death certificates, and autopsy reports. The authors reported the incidence of IPF as 10.7 per 100,000 person-years in men and 7.4 per 100,000 person-years in women. The prevalence of IPF was 20.2 cases per 100,000 persons in men and 13.2 cases per 100,000 persons overall. When stratified by age and gender, both the incidence and prevalence of IPF was higher in men than in women, and each increased with increasing age. Raghu and colleagues examined the incidence and prevalence of IPF using data from a healthcare claims processing center from 1996 through 2000.5 The center services a plan that covers nearly 3 million people across 20 statesdmostly in the South Atlantic, South Central, and North Central regions of the United States. The authors estimated IPF incidence and prevalence for the entire United States. Using broad case-finding criteria (age > 18, at least one medical encounter for IPF [ICD-9 code 516.3], and no encounters with diagnostic codes for any other ILD after an encounter coded as IPF), they estimated an incidence of 16.3 per 100,000
3
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Idiopathic Pulmonary Fibrosis
persons/year and a prevalence of 42.7 per 100,000 persons, respectively. Employing narrow case-finding criteria (the broad criteria plus at least one claim with a procedure code for a surgical lung biopsy, transbronchial biopsy, or thoracic computed tomography [CT]), they estimated the incidence and prevalence at 6.8 per 100,000 persons/year and 14.0 per 100,000 persons, respectively. Like Coultas and his coinvestigators, Raghu and colleagues found that both the incidence and prevalence of IPF increased with age, and both were higher in men than in women. Based on these two landmark studies, the incidence and prevalence of IPF appeared to increase over time, but as with any study using claims data, questions remained: were cases with non-IPF ILDs counted as IPF, and were cases of IPF missed? Using data from patients evaluated at the Mayo Clinic in Rochester from 1997 to 2005, FernándezPérez and colleagues completed a population-based, historical cohort study in Olmsted County, Minnesota.6 These authors also used both narrow and broad casefinding criteria. The narrow criteria included a usual interstitial pneumonia (UIP) pattern on surgical lung biopsy or a definite UIP pattern on thoracic highresolution CT (HRCT), whereas broad criteria included the less-strict pattern on HRCT scan of possible UIP. Using the narrow definition, the age- and sex-adjusted incidence (for people over the age of 50) was 8.8 cases per 100,000 person-years (95% CI ¼ 5.3e12.4), and using the broad definition, it was 17.4 cases per 100,000 person-years (95% CI ¼ 12.4e22.4). The ageand sex-adjusted prevalence (for those over the age of 50) was 27.9 cases per 100,000 persons (95% CI ¼ 10.4e45.4) and 63 cases per 100,000 persons (95% CI ¼ 36.4e89.6). Over the last 3 years of the study, incidence was on the decline. Given the low number of incidence cases (47 according to broad case-finding criteria), confidence is low that these statistics accurately reflected national trends during the study period (1997e2005). In a random sample of 5% of Medicare beneficiaries (65 years of age or older), Raghu and colleagues performed another study to generate estimates for the annual incidence and cumulative prevalence of IPF.7 Using ICD-9 codes 516.3 (IPF) and 515 (postinflammatory pulmonary fibrosis [PIPF]), they determined that from 2001 to 2011 the incidence of IPF remained stable (overall 93.7 cases per 100,000 person-years [95% CI ¼ 91.9e95.4]). But, the annual cumulative prevalence rose from 202.2 cases per 100,000 persons in 2001 to 494.2 cases per 100,000 persons in 2011. The authors also found that cases diagnosed in 2007 had
longer survival times (4.0 years [95% CI ¼ 3.8e4.5]) than those diagnosed before 2007 (3.3 years [95% CI ¼ 3.0e3.8]) and suggested that longer survival after diagnosis might explain the discrepancy between incidence and prevalence. In another epidemiologic study of IPF, investigators used an administrative, patient claims, insurance dataset that included data from more than 45 managed healthcare plans covering more than 89 million people for the years 2005e10.8 Using a narrow case definition, they determined that the annual incidence of IPF among people 18e64 years old decreased from 2.9 to 2.4 new cases per 100,000 person-years, while the annual prevalence ranged from 4.6 to 6.7 per 100,000 person-years from 2005 to 2010. Using a broad case definition, they reported that the annual incidence decreased from 5.1 to 3.6 new cases per 100,000 person-years from 2005 to 2010, and the annual prevalence ranged from 8.4 to 11.3 per 100,000 person-years over that time. In contrast to the stable incidence and increasing prevalence noted in the older Medicare population, the incidence declined in this younger cohort over time, while the prevalence plateaued. The results appeared to be driven by changes in statistics for younger patients (18e44 years): the likelihood of them being diagnosed (inappropriately, as patients younger than 50 years old rarely develop the disease) with IPF declined over time. Presumably, they were being appropriately diagnosed with known cause of pulmonary fibrosis (PF) (e.g., connective tissue diseaseerelated)da condition far more likely than IPF to cause PF in patients younger than 50 years. In a large research database, a case definition of IPF (defined as a diagnosis by a physician and no alternative diagnosis within the 6 months before or after) had a positive predictive value (PPV) of only 44.4% (95% CI ¼ 29.6e60.0%).9 This suggests incidence and prevalence estimates determined by using healthcare claims databases are likely to be overestimated. Correcting for the PPV and standardizing the claims cohort to the US population, for 2006e12, the incidence of IPF was calculated to be 14.6 per 100,000 person-years, and the prevalence was estimated at 125.2 per 100,000 persons.
The United Kingdom Epidemiologic studies from investigators in the United Kingdom also suggest an increase in the incidence of IPF over time. Gribbin and colleagues used a general practice database and applied diagnostic codes for “cryptogenic fibrosing alveolitis” and “idiopathic pulmonary fibrosis”dterms used interchangeably until
CHAPTER 2 recentlydto find that the overall incidence of IPF had doubled from 1991 to 2003.10 They estimated an overall crude incidence of IPF at 4.6 cases per 100,000 person-years, which equaled a yearly increase in incidence of 11% (rate ratio 1.11; 95% CI ¼ 1.09e1.13). Navaratnam and colleagues used the same database and a similar approach (included cases coded as “cryptogenic fibrosing alveolitis” or “idiopathic pulmonary fibrosis,” but also included cases coded as “diffuse pulmonary fibrosis,” “idiopathic fibrosing alveolitis NOS,” or “Hamman-Rich syndrome”) to determine statistics for the entity they termed IPF-clinical syndrome (IPF-CS).11 Between 2000 and 2008, the overall crude incidence of IPF-CS was 7.44 per 100,000 personyearsdnearly double the incidence rate of the prior decade. They estimated that the incidence of IPF-CS increased by 5% annually over this time period (rate ratio 1.05; 95% CI ¼ 1.03e1.06), although at a somewhat slower rate than the prior decade. Experts have posited that reasons for the increased incidence could be an uptick in the use of CT of the chest and/or the conduct of multinational drug trials for IPF, which could serve to raise awareness of the disease.12
Canada Hopkins and colleagues used two national administrative databases from the Canadian Institute for Health Information to estimate the incidence and prevalence of IPF in Canada from 2007 through 2011.13 For their broad case definition, incidence and prevalence in men was 21.3 per 100,000 person-years and 45.3 per 100,000 persons, respectively. Their narrow case definition yielded incidence and prevalence estimates in men of 10.5 per 100,000 person-years and 22.3 per 100,000 persons, respectively. For women, the broad case definition yielded incidence and prevalence estimates of 16.2 per 100,000 persons-years and 38.2 per 100,000 persons, respectively, whereas the narrow case definition produced incidence and prevalence estimates of 7.4 per 100,000 person-years and 17.7 per 100,000 persons, respectively. These estimates are similar to those generated for the United States and the United Kingdom.
Other countries Hyldgaard and coauthors conducted a single-center, observational cohort study of 431 patients with various ILDs (121 with IPF) living in Denmark between 2001 and 2011.14 The authors estimated an overall crude incidence rate for IPF of 4.1 cases per 100,000 personyears. And they found the incidence rose from 3.8 to 6.8 per 100,000 persons over the study period. The
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authors attribute this increase to centralized, specialized referral centers within the Danish healthcare system and increased access to HRCT over the study period. Other data, including those from a systematic review on the global incidence of IPF, suggest the worldwide incidence of IPF is increasing, and rates across countries appear to be converging. As more countries begin to collect large-scale data on IPF, a better understanding of the global incidence and disease burden of IPF will be possible.
Mortality Rates and Trends Over Time Mortality rate is the total number of deaths from a particular cause in 1 year divided by the number of people alive within the population at midyear. In the era of ICD-10 coding, using death certificate coding from 1999 onward, Hutchinson and colleagues recently examined the death certificates from 124 decedents whose deaths the authors had confirmed as due to IPF. Of these, 82% had a diagnostic code somewhere on the death certificate for IPF (J84.1) or ILD unspecified (ILD-U) (J84.9). This suggests that death certificate data may underestimate mortality rates by w 20%.15 It is unclear if these findings apply to death certificate data outside of the United Kingdom, and more research on the validity of death certificate data is needed.
The United States Mannino and colleagues used US death certificate data from 1979 to 1991 to calculate age-adjusted mortality from PF (ICD-9 codes 516.3 [IPF] and 515 [PIPF]).16 They determined that mortality from PF had increased from 48.6 deaths per million to 50.9 deaths per million from the late 1970s to the early 1990s. They found a 4.7% increase in mortality among men and a 27.1% increase among women. This study was the first in which PF mortality was reported to vary between regions of the United States: mortality rates were highest in the West and Southeast and lowest in the Midwest and Northeast. Using the same database, our group examined US death certificate data from 1992 to 2003. We observed an increase from 49.7 deaths per million to 64.3 deaths per million (for a relative 29.4% increase) among men, and from 42.3 deaths per million to 58.4 deaths per million (for a relative 38.1% increase) among women. We also found that mortality rates increased with increasing age and were higher in men than in women but were increasing more steeply in women than in men.17 Hutchinson and coinvestigators examined the same dataset for the years 2000e10.18 Including only
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decedents in whom J84 (includes IPF and ILD-U) was coded as the “underlying cause of death” (UCD), they observed that mortality rates had increased by 1% per year (annual increase 1.01; 95% CI ¼ 1.011e1.014). The age-adjusted mortality rate in 2010 for decedents whose UCD was coded as J84 was 7.8 per 100,000 persons (which equates to 78 deaths per million). Like other UCD analyses, these estimates are subject to potential extreme underreporting bias.
Other countries In a study of death certificates from England and Wales, Australia, Canada, Japan, Northern Ireland, New Zealand, Scotland, Spain, and Sweden collected between 2000 and 2010, deaths in which J84 was the UCD increased between 1% and 4% per year in all countries except Northern Ireland where data were limited (only available from 2009 to 2011) and the increases were much larger (25%).18 In a metaanalysis of data from the United States and these eight countries, there was a 2% annual increase in mortality over time (rate ratio, 1.02; 95% CI ¼ 1.01e1.03). Agestandardized mortality rates varied by country: those with the lowest mortality rates included Sweden (4.68 per 100,000) and New Zealand (5.55 per 100,000); those with mortality rates similar to the United States included Australia (6.49 per 100,000) and Canada (7.52 per 100,000); and those with the highest mortality rates included England and Wales (9.84 per 100,000) and Japan (10.26 per 100,000). The reasons for this apparent global heterogeneity remain unclear, but if real, are presumably due at least in part to genetic variation.
Risk Factors Like many other epidemiologic studies, those conducted to examine risk factors for IPF have been subject to a number of limitations, including recall and misclassification biases.
Cigarette smoking Cigarette smoking is a risk factor for IPF and familial pulmonary fibrosis (FPF). In a study of 248 cases of IPF identified between 1989 and 1993 and 491 controls matched for age, sex, and geography, ever-smoking was associated with a 60% increased odds of IPF (OR ¼ 1.6; 95% CI ¼ 1.1e2.2).19 Among former smokers, those who had recently quit (within 2.5 years) had the highest risk for the development of IPF (OR ¼ 3.5%; 95% CI ¼ 1.1e11.9), whereas those who quit more remotely (at least 25 years prior) had the lowest risk (OR ¼ 1.3; 95% CI ¼ 0.7e2.3).
In a Japanese cohort, smokers with a 20.0e39.9 pack-year history had an increased risk for IPF (OR ¼ 2.26; 95% CI ¼ 1.3e3.8). Those with a less than 20.0 pack-year history or a 40.0 pack-year history or greater were not at increased risk.20 Authors of a metaanalysis that included US and Japanese studies and another three studies from the United Kingdom or Japan found ever-smoking conferred a 58% increase in the odds of IPF (summary OR ¼ 1.58; 95% CI ¼ 1.27e1.97).21 They estimated that 49% of cases of IPF could be prevented by eliminating cigarette smoking. Data are similar for FPF. In a study of 309 cases of FPF and 360 unaffected family members, ever-smoking was associated with a greater than threefold odds of developing FPF (OR ¼ 3.6; 95% CI ¼ 1.3e9.8) while adjusting for age and gender.22
Occupational and environmental exposures Results from several studies suggest an association between dust and/or dusty environments and IPF. In a metaanalysis of five case-controlled studies published between 1990 and 2005, results suggested a significant association between metal dust exposure and the development of IPF (summary OR ¼ 2.44, 95% CI ¼ 1.74e3.40).21,23 In one study, the association held only for those with 5 years of exposure, suggesting a dose-response relationship.24 In an analysis of the pension fund archives from a metal engineering company, investigators found no relationship between metal dust exposure and IPF, except in people exposed for greater than 10 years (OR ¼ 1.71; 95% CI ¼ 1.09e2.68).25 In two other studies, there was no relationship between exposure to metal dusts and IPF, but the investigators did not consider the extent or duration of exposure.26,27 According to a metaanalysis of five case-control studies, there is an association between exposure to wood dusts and IPF (summary OR ¼ 1.94; 95% CI ¼ 1.34e2.81).23 However, in two of the five individual studies, no association was identified, suggesting the risk may be relevant for only certain woods. In support of this, in another study, there was an association between birch or hardwood dust and IPF; there was no association between fir dust exposure and IPF.26 Exposure to livestock has been found to be associated with IPF (summary OR ¼ 2.17; 95% CI ¼ 1.20e2.26).23 Results from one study suggest a dose-response relationship: for the subgroup of subjects with <5 years of exposure, there was no association; however, for the subgroup with more than 5 years of exposure, there was a strong association with the
CHAPTER 2 development of IPF (OR ¼ 3.3; 95% CI ¼ 1.3e8.3).24 Other studies of farming (or residing in a region in which farming is common) corroborate these findings.23,24,28 In one study, there was an association between exposure to agricultural chemicals specifically and IPF (OR ¼ 3.32; 95% CI ¼ 1.22e9.05).28 Exposure to sand, stone, or silica dusts have been found to be associated with the development of IPF (summary OR ¼ 1.97; 95% CI ¼ 1.09e3.55).23,29 Other exposures with associations with IPF include hair dressing, raising birds, or residing in an urban/ polluted area.23,29 In sum, inhalational exposures of various kinds are associated with IPF; however, whether these exposures have roles in the pathogenesis of IPF is uncertain and warrants additional evaluation.
SUMMARY Although IPF was once considered an orphan disease, studies suggest that mortality rates are similar to certain common malignancies. Epidemiologic research has helped elevate knowledge of IPF at the population level, but many questions remain to be explored. Doing so will likely lead to an even greater understanding of accurate epidemiologic trends and by extension, risk factors will increase understanding of IPF pathobiology.
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