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Risk Factors for IPF

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Most Common Risk Factors for IPF

Potential risk factors for IPF

IPF is a chronic fibrosing lung disease of unknown cause(s)1,2

 

However, many factors have been associated with increased risk of developing IPF1,2

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

1. Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 2. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

2

IPF, idiopathic pulmonary fibrosis.

Gender

Increased age is one of the most common risk factors for IPF2

The patient's age at presentation is an important consideration2,3

 

IPF typically occurs in individuals between 60 and 70 years of age1,4 

1. Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 2. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824. 3. Fell et al. Am J Respir Crit Care Med. 2010;181:832-837. 4. Castriotta RJ et al. Chest. 2010;138(3):693-703.

IPF is only rarely found in patients younger than 501

3

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Age is one of the most common risk factors for IPF2(cont.)

In older people, the most common type of ILD is IPF3

 

Older age is highly associated with risk of IPF3

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

Age ≥70    95% PPV for IPF

Age ≥75   ~100% PPV for IPF

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

4

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Male gender is a common risk factor for IPF5-8

5

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

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 IPF1,9

There is a strong association between smoking and IPF, especially for those with a greater than 20 pack-years history9

 

1. Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 9. Baumgartner KB et al. Am J Respir Crit Care Med. 1997;155(1):242-248.

6

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

A history of smoking is a common risk factor for IPF1,9(cont.)

Exposure to tobacco smoke is a risk factor for both sporadic and familial IPF10,11

 

1. Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 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.

7

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

A history of smoking is a common risk indicator for IPF1,9 (cont.)

Additionally, tobacco history may be associated with more rapid disease progression12

 

1. Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 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.

8

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

A number of environmental and occupational exposures have been indicated in IPF risk13

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.

9

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Metal dust has been associated with risk of developing IPF11,13,14

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.

10

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Metal dust has been associated with risk of developing IPF11,13,14(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.

 

 

0.9

Odds ratio

0.51

1.59

95% CI

 

11

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Metal dust has been associated with risk of developing IPF11,13,14(cont.)

Another study used data from US death certificates from 1999 to 2003 and industry/occupation codes to determine industry risks for IPF16

 

12

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Metal dust has been associated with risk of developing IPF11,13,14(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.

13

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Fabricated structural metal products

Metal dust has been associated with risk of developing IPF11,13,14(cont.)

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

 

 

2.4

Proportionate mortality rate

1.3

4.0

95% CI

 

 

 

1.9

1.1

3.1

95% CI

 

Metal mining

14

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

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 dust11,14,17

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

15

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

The link between wood dust and risk of IPF is less well established11,14,17 (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.

16

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

The link between wood dust and risk of IPF is less well established11,14,17(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.

17

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Exposure to sand, stone, or silica dust has been linked to increased risk of developing IPF13,19,20

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.

 

18

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Exposure to sand, stone, or silica dust has been linked to increased risk of developing IPF 13,19,20(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.

 

 

2.0

Odds ratio

1.1

3.6

95% CI

 

19

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Livestock and farming exposures are linked to the risk of developing IPF13,17

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.

20

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Livestock and farming exposures are linked to the risk of developing IPF13,17(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.

 

 

2.2

Odds ratio

1.3

3.7

95% CI

 

21

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Livestock and farming exposures are linked to the risk of developing IPF13,17(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

 

 

 

3.3

Odds ratio

1.3

8.3

95% CI

 

22

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

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Livestock and farming exposures are linked to the risk of developing IPF13,17(cont.)

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

 

 

 

2.1

Odds ratio

0.7

6.1

95% CI

 

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

23

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Specific viral exposures are linked to increased risk of IPF22,23

Several studies have examined the role of chronic viral infection in IPF22,23

Epstein-Barr virus

Hepatitis C virus 

HHV-7, HHV-8 Cytomegalovirus

 

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

HHV, human herpes virus.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Specific viral exposures are linked to increased risk of IPF22,23(cont.)

Confounding factors such as the use of immunosuppressive therapy in the patient study population have limited these studies2

 

Despite extensive study, at present, the role of infection in IPF remains uncertain2

 

2. 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

25

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26

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.

26

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(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.

27

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(cont.)

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

28

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(cont.)

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

 

29

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26 (cont.)

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

 

30

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(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.

31

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(cont.)

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

 

 

1.4

Odds ratio

1.3

1.5

95% CI

(P=0.0001)

 

32

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.

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(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.

33

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

GERD stands out in its association with IPF24-26(cont.)

Despite the strong association between GERD and IPF, it is not clear that GERD actually causes IPF2

 

34

2. 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.

 

 

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Certain genetic mutations are associated with increased risk of developing IPF28

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.

35

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Certain genetic mutations are associated with increased risk of developing IPF28(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.

36

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Certain genetic mutations are associated with increased risk of developing IPF28(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.

37

 

 

6.1

Odds ratio

2.3

15.9

95% CI

(P <0.0001)

 

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Certain genetic mutations are associated with increased risk of developing IPF28(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.

38

Age

Smoking

Metal dust

Wood dust

Silica, sand, stone

Livestock/farming

Viral exposure

GERD

Genetics

Gender

Summary

39

2. Raghu G et al. Am J RespirCrit Care Med. 2011;183(6):788-824. 3. Fell et al. Am J RespirCrit Care Med. 2010;181:832-837. 9. Baumgartner KB et al. Am J RespirCrit Care Med. 1997;155(1):242-248. 10. Steele MP et al. Am J RespirCrit 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. 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. 26. Tobin RW et al. Am J Respir Crit Care Med. 1998;158(6):1804-1808. 28. Fernandez BA et al. Respir Res. 2012;13:64. 34. Johannson KA et al. Chest. 2015; 147(4): 1161–1167.

  • Many of the risks for IPF are modifiable, although some of the most common are not34
    • –Modifiable risk factors include smoking and environmental exposures
    –Non-modifiable risk factors include age, viral exposures, GERD, and genetic mutations
  • The most strongly associated risk factors with IPF are age and smoking history2-3,9-11
  • Non-modifiable risk factors such as viral exposures, GERD, and genetic mutations are also associated with an increased risk of developing IPF22-26, 28
  • A number of environmental exposures are associated with developing IPF2,11,14
    • –Exposure to livestock and agriculture
    –Jobs and/or hobbies that produce dust or particulate matter

     

    References

    1.Raghu G et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68.
    2.Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
    3.Fell et al. Am J Respir Crit Care Med. 2010;181:832-837.
    4.Castriotta RJ et al. Chest. 2010;138(3):693-703.
    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;101:2207–2212.
    16.Pinheiro GA et al. Int J Occup Environ Health. 2008;14(2):117-123.
    17.Scott J et al. BMJ. 1990;301(6759):1015-7.
    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.

     

    40

    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.

     

    41