Potential Risk Factors for IPF

Although the etiology of idiopathic pulmonary fibrosis (IPF) is unknown, several potential risk factors have been described.

Age

A diagnosis of IPF is rare before age 50129 and most patients with IPF present in the 6th-7th decades of life.1

Cigarette Smoking

There is a strong link between smoking and IPF, especially for those with a greater than 20 pack-years history.30 Tobacco smoke exposure is a risk factor for both sporadic32 and familial IPF,31 and tobacco history may be associated with more rapid disease progression.22

Environmental and Occupational Exposures

A number of environmental and occupational exposures have been associated with increased risk for IPF.1 Although caution should be taken in interpreting the results of several studies that predate the consensus criteria for the diagnosis of IPF, multiple studies have reported significant risk associated with a variety of dusts and particulates.3233

Metal Dust

Early investigations into the role of metal dust in IPF included several case-control studies and a meta-analysis. An association between metal dust exposure and IPF was found in each of these initial studies32 and the meta-analysis found metal dust exposure to be significantly associated with IPF (OR = 2.44, 95% CI = 1.74-3.4).32 Of note, a dose-response relationship between metal dust exposure and IPF was found in 2 of the studies.3334

More recent studies have had mixed results in regard to the association between metal dust exposure and IPF. A case-controlled study conducted in Sweden of 140 patients with IPF and 757 matched controls did not find an association between metal dust exposure and IPF (OR = 0.9; 95% CI = 0.51-1.59).35

Another study utilized data from US death certificates from 1999 to 2003 and industry/occupation codes to determine industry risks for IPF.36 Each IPF case was matched to 4 controls based on sex, age, race, and state of residence.36 From 1999-2003, there were 84,010 deaths resulting from IPF. There was an increase in the proportionate mortality (PM) for IPF cases whose industry was recorded as “metal mining” (PM = 2.4; 95% CI = 1.3-4.0) or “fabricated structural metal products” (PM = 1.9; 95% CI = 1.1-3.1).36

Wood Dust

Several studies have evaluated the risk of wood dust exposure with IPF, with mixed results. Only one of the 5 case-control studies reported a significant association of wood dust exposure with IPF.3738 However, when the 5 case-controlled studies were combined in a meta-analysis, a statistically significant increased risk for IPF was associated with exposure to wood dusts.32

Sand, Stone, and Silica

An increased risk of IPF in patients exposed to sand, stone, or silica was found in 3 of 4 case-controlled studies.38 In a meta-analysis that included all 4 studies, exposure to sand, stone, and silica was significantly associated with IPF (summary OR = 1.97; 95% CI = 1.09-3.55).32

Livestock and Farming

Several case-controlled studies have found an increased risk of IPF in patients with livestock-related exposures and agriculture/farming-related exposures.32 Two case-controlled studies, one conducted in the US33 and one conducted in the UK,39 found an increased risk of IPF among those who had worked with livestock (meta-analysis OR = 2.17; 95% CI = 1.28-3.68).32 In the US study a dose-response relationship between livestock exposure and IPF was found with a significantly increased risk of IPF among those with 5 or more years of exposure (OR = 3.3; 95% CI = 1.3-8.3) but no increased risk of IPF among those with less than 5 years of exposure (OR = 2.1; 95% CI = 0.7-6.1).33

Microbial Agents

The role of chronic exposure to various viruses including Epstein-Barr virus,40 hepatitis C virus,41 human herpes viruses (HHV)-740 and HHV-8,40 and cytomegalovirus40 in the etiology of IPF has been examined in several studies. Confounding factors including immunosuppressive therapy have limited these studies.1 In spite of extensive study, at present, the role of infection in IPF remains uncertain.1

Gastroesophageal Reflux Disease (GERD)

A number of studies have shown a strong association between GERD, through its presumed association with microaspiration, and IPF.424344 One large study, a Veterans Administration case-controlled study (N=101,366 patient cases), found a significant link between GERD-associated erosive esophagitis or esophageal strictures and pulmonary fibrosis (OR, 1.36; 95% CI, 1.25 to 1.48; P-value=.0001).43 Additionally, studies utilizing esophageal 24-hour pH monitoring indicate that GERD is very common among patients with IPF, with a prevalence of 67% to 88% for distal esophageal reflux and 30% to 71% for proximal esophageal reflux,4445 even in the absence of classical reflux symptoms.4245

A pathogenic mechanism by which chronic microaspiration could lead to IPF has been suggested.45 A weakened lower esophageal sphincter may allow gastric fluid to travel in a retrograde manner up into the esophagus and enter the airway. Although most gastric refluxates are likely cleared by normal host defenses without clinical sequelae, in some cases the lung epithelium may be directly injured by gastric acid, bile, or particulates. Chronic microaspiration of gastric refluxate may cause repeated injury to the epithelium over time in genetically predisposed individuals. This may lead to granulomatous pneumonitis, dysregulated wound healing, and eventually lung fibrosis.45

In spite of the strong association between GERD and IPF, a causal relationship is not clear. Further study will be necessary to clarify the role of GERD in IPF pathogenesis.1

Genetic Factors

Family history is a strong risk factor for IPF; in one recent study, a family history of IPF increased odds for development of disease 6-fold.46 Genetic factors linked to IPF have been investigated in both familial forms of IPF (ie, cases in which 2 or more members of the same biological family are affected) and in sporadic cases of IPF.1 The criteria used to diagnose IPF in familial and sporadic cases are identical – they are clinically and histologically indistinguishable.1

Traditionally, it was believed that genetic transmission (familial forms of IPF) accounted for less than 5% of cases of IPF4748; however, several more recent studies suggest this may be an underestimation.464950 In familial cases of pulmonary fibrosis, the most likely mode of genetic transmission is autosomal dominant with variable penetrance.31 Candidate gene studies have identified mutations in two surfactant proteins515253 as well as multiple components of the telomerase complex.545556 These studies have provided insights into the pathogenesis of lung fibrosis; however it appears these mutations do not commonly occur in sporadic IPF cases.

In sporadic IPF, there has been significant progress in identifying single nucleotide polymorphisms associated with the disease. In 2011, a common polymorphism in the promoter of a mucin gene (MUC5B) was found to be strongly associated with an increased risk of familial interstitial pneumonia and sporadic IPF in an allele dose-dependent manner.5758 More recent studies confirmed this finding and determined that more than 10 additional loci have been associated with IPF and cumulatively may be responsible for as much as 33% of the genetic risk for IPF.59 Of significant interest is the fact that some gene polymorphisms (TOLLIP,60 MUC5B,61 TLR362) have been associated with specific outcomes in patients with IPF. This suggests that the outcome of patients with IPF is determined at least in part by genetic factors. It is not yet clear if these gene variants associated with outcome in IPF can be incorporated into prognostic models to affect the clinical care of patients.60

Given the state of understanding at this time, current guidelines do not recommend routine genetic testing as part of the clinical evaluation of patients with either familial or sporadic IPF, though genetic counseling may be considered in some cases.1

Content contributed by:
Jonathan A. Kropski, MD
Vanderbilt University