Risk Factors for IPF

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Risk Factors for IPF

Potential risk factors for IPF

IPF is a chronic fibrosing lung disease of unknown cause(s)1

However, many factors have been associated with increased risk of developing IPF1

IPF, idiopathic pulmonary fibrosis.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Increased age is one of the most common risk factors for IPF

The patient's age at presentation is an important consideration1,2
 
IPF typically occurs in individuals between 50 and 70 years of age1,3 

IPF is only rarely found in patients younger than 404

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Fell et al. Am J Respir Crit Care Med. 2010;181:832-837.
3. Castriotta RJ et al. Chest. 2010;138(3):693-703.
4. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:8.

Age is one of the most common risk factors for IPF (cont.)

In older people, the most common type of ILD is IPF2
 
Older age is highly associated with risk of IPF2

Age ≥70    95% PPV for IPF
Age ≥75   ~100% PPV for IPF

ILD, interstitial lung disease; PPV, positive predictive value.

2. Fell CD et al. Am J Respir Crit Care Med. 2010;181(8):832-837.

Male gender is a common risk factor for IPF

The prevalence of interstitial lung disease is 20% higher in men than in women5

In a study of 920 patients with IPF, 62% were men6


5. Coultas DB et al. Am J Respir Crit Care Med. 1994;150(4):967-72.  
6. Gribbin J et al. J Thorax. 2006;61:980-985.
7. Douglass WW et al. Am J Respir Crit Care Med. 2000; 161:1172-1178. 
8. King TE et al. Am J Respir Crit Care Med. 2001;164:1171-1181.

A history of smoking is a common risk factor for IPF

There is a strong association between smoking and IPF, especially for those with a greater than 20 pack-years history9
 
9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.

A history of smoking is a common risk factor for IPF (cont.)

Exposure to tobacco smoke is a risk factor for both sporadic and familial IPF10,11
 
9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.
10. Steele MP et al. Am J Respir Crit Care Med. 2005;172(9):1146-1152.
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.

A history of smoking is a common risk indicator for IPF (cont.)

Additionally, tobacco history may be associated with more rapid disease progression12
 
9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.
12. Selman M et al. PLoS One. 2007;2(5):e482.

A number of environmental and occupational exposures have been indicated in IPF risk

A number of environmental and occupational exposures have been associated with increased risk for IPF13
 
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.

Metal dust has been associated with risk of developing IPF

Some early case-controlled studies, as well as a meta-analysis, showed an association between metal dust exposure and risk of developing IPF11,13,14
 
However, more recent studies have produced mixed results11,15
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
15. Gustafson T et al. Respir Med. 2007;101:2207–2212.

Metal dust has been associated with risk of developing IPF (cont.)

A case-controlled study conducted in Sweden of 140 patients with IPF and 757 matched controls found no association between metal dust exposure and IPF15
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
15. Gustafson T et al. Respir Med. 2007;101(10):2207-2212.

Metal dust has been associated with risk of developing IPF (cont.)

Another study used data from US death certificates from 1999 to 2003 and industry/occupation codes to determine industry risks for IPF16
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
16. Pinheiro GA et al. Int J Occup Environ Health. 2008;14(2):117-123.

Metal dust has been associated with risk of developing IPF (cont.)

Each of the 84,010 deaths attributed to IPF was matched to 4 controls based on sex, age, race, and state of residence16
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
16. Pinheiro GA et al. Int J Occup Environ Health. 2008;14(2):117-123.

Metal dust has been associated with risk of developing IPF (cont.)

The proportionate mortality rate increased for records that listed occupation as “metal mining” or “fabricated structural metal products”16

11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
16. Pinheiro GA et al. Int J Occup Environ Health. 2008;14(2):117-123.

The link between wood dust and risk of IPF is less well established than metal dust

Studies that have evaluated the risk of wood dust exposure with IPF have produced mixed results11,14,17

11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-8.
14. Hubbard R et al. Lancet. 2000;355:466–467.
17. Scott J et al. BMJ. 1990;301(6759):1015-7.

The link between wood dust and risk of IPF is less well established (cont.)

Only 1 of the 5 case-controlled studies reported a significant association of wood dust exposure with IPF14,18
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-8.
14. Hubbard R et al. Lancet. 2000;355:466–467.
17. Scott J et al. BMJ. 1990;301(6759):1015-7.
18. Olson AL et al. Clin Chest Med. 2012;33(1):41-50.

The link between wood dust and risk of IPF is less well established (cont.)

However, a meta-analysis of the 5 case-controlled studies showed a statistically significant association between exposure to wood dust and increased risk for developing IPF11
 
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-8.
14. Hubbard R et al. Lancet. 2000;355:466–467.
17. Scott J et al. BMJ. 1990;301(6759):1015-7.

Exposure to sand, stone, or silica dust has been linked to increased risk of developing IPF

Out of 4 case-controlled studies that evaluated the risk of IPF in patients exposed to sand, stone, or silica, 3 showed an increased risk with exposure to these factors17,19-21

13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.
19. Hubbard R et al. Lancet. 1996;347(8997):284-289.
20. Mullen J et al. J Occup Environ Med. 1998; 40:363-367.
21. Miyake Y et al. Ann Occup Hyg. 2005; 49:259-265.

Exposure to sand, stone, or silica dust has been linked to increased risk of developing IPF (cont.)

In a meta-analysis of all 4 studies, exposure to sand, stone, or silica was significantly associated with IPF11

11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
19. Hubbard R et al. Lancet. 1996;347(8997):284-289.
20. Mullen J et al. J Occup Environ Med. 1998; 40:363-367.

Livestock and farming exposures are linked to the risk of developing IPF

Several case-controlled studies have found an increased risk of IPF in patients with livestock-related exposures and agriculture/farming-related exposures11

11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.

Livestock and farming exposures are linked to the risk of developing IPF (cont.)

Two case-controlled studies, one conducted in the US and one conducted in the UK, found an increased risk of IPF among those who had worked with livestock11,13,17

11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.

Livestock and farming exposures are linked to the risk of developing IPF (cont.)

In the US study, a dose-response relationship was found between livestock exposure and IPF, with a significantly increased risk of IPF among those with 5 or more years of exposure13

13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.

Livestock and farming exposures are linked to the risk of developing IPF (cont.)

There was no increased risk of IPF among those with less than 5 years of exposure13

13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.

Specific viral exposures are linked to increased risk of IPF

Several studies have examined the role of chronic viral infection in IPF22,23
   Epstein-Barr virus
   Hepatitis C virus 
   HHV-7, HHV-8
   Cytomegalovirus

HHV, human herpes virus.

22. Tang YW et al. J Clin Microbiol. 2003;41(6):2633-2640.
23. Arase Y et al. World J Gastroenterol. 2008;14(38):5880-5886.

Specific viral exposures are linked to increased risk of IPF (cont.)

Confounding factors such as immunosuppressive therapy in the patient study population have limited these studies1
 
Despite extensive study, at present, the role of infection in IPF remains uncertain1
 
1. Raghu G. Am J Respir Crit Care Med. 2011;183(6):788-824.
22. Tang YW et al. J Clin Microbiol. 2003;41(6):2633-2640.
23. Arase Y et al. World J Gastroenterol. 2008;14(38):5880-5886

GERD stands out in its association with IPF

A number of studies have shown a strong association between IPF and GERD, through its presumed association with microaspiration24-26

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.

GERD stands out in its association with IPF (cont.)

It is hypothesized that chronic microaspiration may contribute to IPF through a weakened lower esophageal sphincter that may allow gastric fluid to travel up into the esophagus and enter the airway27

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.

GERD stands out in its association with IPF (cont.)

Most gastric refluxates are likely cleared by normal host defenses without clinical sequelae27

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.

GERD stands out in its association with IPF (cont.)

However, in genetically predisposed individuals, chronic microaspiration of gastric refluxate may cause repeated injury to the epithelium over time27

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.

GERD stands out in its association with IPF (cont.)

Repeated injury may lead to granulomatous pneumonitis, dysregulated wound healing, and eventually lung fibrosis27

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.

GERD stands out in its association with IPF (cont.)

One large case-controlled study analyzed cases of pulmonary fibrosis from the Veterans Administration database (N=101,366 patient cases)25

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.

GERD stands out in its association with IPF (cont.)

GERD-associated erosive esophagitis or esophageal strictures showed a significant association with pulmonary fibrosis25

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.

GERD stands out in its association with IPF (cont.)

Studies that have employed 24-hour esophageal pH monitoring indicate that GERD is very common among patients with IPF even in the absence of classic reflux symptoms24,26-27
   Distal esophageal reflux was present in 67%-88% of cases
   Proximal esophageal reflux was found in 30%-71% of cases

24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.

GERD stands out in its association with IPF (cont.)

Despite the strong association between GERD and IPF, it is not clear that GERD actually causes IPF1
 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
24. Raghu G et al. Eur Respir J. 2006;27(1):136-142..
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.
26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
 
 

Certain genetic mutations are associated with increased risk of developing IPF

Genetic factors have been identified in both sporadic and familial forms of IPF (ie, cases in which 2 or more members of the same biological family are affected)28
 
28. Fernandez BA et al. Respir Res. 2012;13:64.

Certain genetic mutations are associated with increased risk of developing IPF (cont.)

At least 2% of IPF cases are likely due to familial (genetic) transmission28-32
 
28. Fernandez BA et al. Respir Res. 2012;13:64.
29. Garcia-Sancho C et al. Respir Med. 2011;105(12):1902-1907.
30. Hodgson U et al. Thorax. 2002;57(4):338-342.
31. Marshall RP et al. Thorax. 2000;55(2):143-146.
32. Loyd JE. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S47-S50.

Certain genetic mutations are associated with increased risk of developing IPF (cont.)

One study found that a family history of IPF was significantly associated with an increased chance for developing IPF29

28. Fernandez BA et al. Respir Res. 2012;13:64.
29. Garcia-Sancho C et al. Respir Med. 2011;105(12):1902-1907.

Certain genetic mutations are associated with increased risk of developing IPF (cont.)

Up to 31% of cases of sporadic IPF are also linked to specific genetic mutations33
 
For more information about genetic mutations associated with IPF, please go to About IPF: Molecular Understanding

28. Fernandez BA et al. Respir Res. 2012;13:64
33. Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.

Summary

  • Many of the risks for IPF are modifiable, although some of the most common are not34
  • The most strongly associated risk factors with IPF are age and smoking history1-2,9-11 A number of environmental exposures are also indicated in increased risk of developing IPF1,11,14
    • Exposure to livestock and agriculture
    • Jobs and/or hobbies that produce dust or particulate matter

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Fell et al. Am J Respir Crit Care Med. 2010;181:832-837.
9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.
10. Steele MP et al. Am J Respir Crit Care Med. 2005;172(9):1146-1152.
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
34. Johannson KA et al. Chest. 2015; 147(4): 1161–1167.
 

References

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Fell CD et al. Am J Respir Crit Care Med. 2010;181(8):832-837.
3. Castriotta RJ et al. Chest. 2010;138(3):693-703.
4. Meltzer EB et al. Orphanet J Rare Dis. 2008;3:8.
5. Coultas DB et al. Am J Respir Crit Care Med. 1994;150(4):967-72.  
6. Gribbin J et al. J Thorax. 2006;61:980-985. 
7. Douglass WW et al. Am J Respir Crit Care Med. 2000; 161:1172-1178. 
8. King TE et al. Am J Respir Crit Care Med. 2001;164:1171-1181. 

9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.
10. Steele MP et al. Am J Respir Crit Care Med. 2005;172(9):1146-1152.;
11. Taskar VS et al. Proc Am Thorac Soc. 2006;3(4):293-298.
12. Selman M et al. PLoS One. 2007;2(5):e482.
13. Baumgartner KB et al. Am J Epidemiol. 2000;152(4):307-315.
14. Hubbard R et al. Lancet. 2000;355(9202):466-467.
15. Gustafson T et al. Respir Med. 2007;101(10):2207-2212.
16. Pinheiro GA et al. Int J Occup Environ Health. 2008;14(2):117-123.
17. Scott J et al. BMJ. 1990;301(6759):1015-1017.
18. Olson AL et al. Clin Chest Med. 2012;33(1):41-50.
19. Hubbard R et al. Lancet. 1996;347(8997):284-289.
20. Mullen J et al. J Occup Environ Med. 1998; 40:363-367.
21. Miyake Y et al. Ann Occup Hyg. 2005; 49:259-265.
22. Tang YW et al. J Clin Microbiol. 2003;41(6):2633-2640.
23. Arase Y et al. World J Gastroenterol. 2008;14(38):5880-5886.
24. Raghu G et al. Eur Respir J. 2006;27(1):136-142.
25. El-Serag HB et al. Gastroenterology. 1997;113(3):755-760.

References

26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808.
27. Lee JS et al. Am J Med. 2010;123(4):304-311.
28. Fernandez BA et al. Respir Res. 2012;13:64.
29. Garcia-Sancho C et al. Respir Med. 2011;105(12):1902-1907.
30. Hodgson U et al. Thorax. 2002;57(4):338-342.
31. Marshall RP et al. Thorax. 2000;55(2):143-146.
32. Loyd JE. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S47-S50.
33. Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.
34. Johannson KA et al. Chest. 2015; 147(4): 1161–1167.