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Original Research Diffuse Lung Disease

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Association Between Occupational Dust Exposure and Prognosis of Idiopathic Pulmonary Fibrosis A Korean National Survey Sang Hoon Lee, MD; Dong Soon Kim, MD, PhD; Young Whan Kim, MD, PhD; Man Pyo Chung, MD, PhD; Soo Taek Uh, MD, PhD; Choon Sik Park, MD, PhD; Sung Hwan Jeong, MD, PhD; Yong Bum Park, MD; Hong Lyeol Lee, MD, PhD; Jeong Sup Song, MD, PhD; Jong Wook Shin, MD, PhD; Nam Soo Yoo, MD, PhD; Eun Joo Lee, MD, PhD; Jin Hwa Lee, MD, PhD; Yangin Jegal, MD; Hyun Kyung Lee, MD; and Moo Suk Park, MD, PhD

Previous studies have investigated the relationship between occupational and environmental agents and idiopathic pulmonary fibrosis (IPF). However, there have been few studies regarding the prognosis of patients with IPF according to patient occupation. BACKGROUND:

METHODS: We investigated whether occupational dust exposure was associated with clinically decreased lung function and poor prognosis. The Korean Interstitial Lung Disease Research Group conducted a national survey to evaluate the clinical, physiologic, radiologic, and survival characteristics of patients with IPF. A total of 1,311 patients with IPF were stratified into five groups according to their occupation: (1) unemployed or homemakers (n 5 628); (2) farmers, fishers, or ranchers (n 5 230); (3) sales or service personnel (n 5 131); (4) clerical or professional personnel (n 5 151); and (5) specific dust-exposed workers (n 5 171).

The mean age of subjects at diagnosis, was 67.5 ⫾ 9.7 years. Current smokers were 336 patients, 435 were exsmokers, and 456 were never smokers. Dust-exposed workers showed early onset of IPF (61.3 ⫾ 8.6 years; P , .001) and a longer duration of symptoms at diagnosis (17.0 ⫾ 28.2 months; P 5 .004). Aging (P 5 .001; hazard ratio [HR], 1.034; 95% CI, 1.014-1.054), FVC % predicted at diagnosis (P 5 .004; HR, 0.984; 95% CI, 0.974-0.995), and dust-exposure occupation (P 5 .033; HR, 1.813; 95% CI, 1.049-3.133) were associated with mortality.

RESULTS:

These findings indicate that occupational dust may be an aggravating factor associated with a poor prognosis in IPF. CHEST 2015; 147(2):465-474

CONCLUSIONS:

Manuscript received April 23, 2014; revision accepted September 3, 2014; originally published Online First October 2, 2014. ABBREVIATIONS: Dlco 5 diffusing capacity of the lung for carbon monoxide; HR 5 hazard ratio; HRCT 5 high-resolution CT; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fibrosis; PFT 5 pulmonary function test; RR 5 relative risk; TLC 5 total lung capacity AFFILIATIONS: From the Division of Pulmonary Medicine, Department of Internal Medicine (Dr S. H. Lee), Yonsei University, College of Medicine, Yonsei University Health Service, Seoul; Division of Pulmonary and Critical Care Medicine (Dr D. S. Kim), University of Ulsan College of Medicine, Asan Medical Center, Seoul; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute (Dr Y. W. Kim), Seoul National University College of Medicine, Seoul; Division of Pulmonary and Critical Care Medicine (Dr Chung), Samsung Medical Center, Sungkyunkwan University School of Medicine,

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Seoul; Division of Allergy and Respiratory Medicine, Department of Internal Medicine (Dr Uh), Soonchunhyang University Seoul Hospital, Seoul; Division of Allergy and Respiratory Medicine, Department of Internal Medicine (Dr C. S. Park), Soonchunhyang University Bucheon Hospital, Bucheon; Division of Pulmonology, Department of Internal Medicine (Dr Jeong), Gachon University Gil Medical Center, Incheon; Division of Pulmonary, Allergy & Critical Care Medicine, Department of Internal Medicine (Dr Y. B. Park), Hallym University Kangdong Sacred Heart Hospital, Seoul; Pulmonary Division, Department of Internal Medicine (Dr H. L. Lee), Inha University Hospital, Incheon; Pulmonary Division, Department of Internal Medicine (Dr Song), St. Mary’s Hospital, Catholic University College of Medicine, Seoul; Division of Pulmonary Medicine, Department of Internal Medicine (Dr Shin), Chung Ang University College of Medicine, Seoul; Division of Pulmonary Medicine (Dr Yoo), National Medical Center, Seoul; Division of Respiratory and

465

Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse progressive lung disease that usually results in a fatal outcome. The disease manifests histologically as usual interstitial pneumonia of unknown etiology. Further, it is associated with irreversible, worsening pulmonary function tests (PFTs), increasing respiratory symptoms, and eventually, considerable morbidity and mortality.1 Although the clinical course is unpredictable and highly variable, the prognosis is very poor, with respiratory failure being the primary cause of death.2 Previous studies have suggested that occupational and environmental agents may contribute to the etiology of the disease or play a role in the its manifestations. These agents include cigarette smoke3; agriculture/farming4; stone, sand, or metal dust5; diesel exhaust particles6; chemical

Materials and Methods Study Subjects The Korean ILD Research Group, comprising 54 universities and teaching hospitals with pulmonary specialists (n 5 82), enrolled patients newly diagnosed with IPF from January 1, 2003, to December 31, 2007. The diagnosis of IPF was established based on pulmonologic, radiologic, and pathologic evaluations, according to the 2002 criteria of the American Thoracic Society/European Respiratory Society.14 Additionally, the Scientific Committee of the Korean Academy of Tuberculosis and Respiratory Diseases reviewed all enrolled patients. Patients with collagen-vascular disease or a history of ingesting drugs or agents known to cause pulmonary fibrosis were excluded from the study. Silicosis and coal-worker pneumoconiosis were excluded for individuals who had a history of exposure to either silica or coal dust, with a finding of nodular or reticulonodular opacities without evidence of pulmonary fibrosis on high-resolution CT (HRCT) scan. The patients’ medical records were entered into the Korean ILD web-based registry (www.ild.or.kr). In total, 2,186 patients were registered, but some patients were excluded if they had other idiopathic interstitial pneumo-

Critical Care Medicine, Department of Internal Medicine (Dr E. J. Lee), Korea University Anam Hospital, Korea University College of Medicine, Seoul; Department of Internal Medicine (Dr J. H. Lee), Ewha Womans University School of Medicine, Ewha Medical Research Institute, Seoul; Division of Pulmonary Medicine, Department of Internal Medicine (Dr Jegal), Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan; Division of Critical Care and Pulmonary Medicine, Department of Internal Medicine (Dr H. K. Lee), Inje University Busan Paik Hospital, Busan; and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (Dr M. S. Park), Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Moo Suk Park, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, 250 Seongsan-ro, Seodaemun-gu, Seoul 120-752, South Korea; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0994

466 Original Research

fumes7; and wood dust.8 In addition, microbial agents,9 gastroesophageal reflux,10 and genetic factors11,12 have been suggested to be involved in IPF. This information may also be helpful for planning individualized therapeutic strategies and predicting individual prognoses. Some casecontrol studies4,6,8,13 have examined the occupational and environmental risk factors associated with IPF; however, the clinical features and prognostic factors related to the patients’ occupations have not been well studied to date. The Korean Interstitial Lung Disease (ILD) Research Group carried out a national, multicenter survey to evaluate the clinical, physiologic, and radiologic aspects. In this study, we evaluated the clinical features and prognostic factors of 1,311 Korean patients with IPF, according to their occupation.

nias according to the American Thoracic Society/European Respiratory Society guidelines.14 Additionally, 374 patents with incomplete data related to their occupational history were excluded. Consequently, 1,311 medical records of patients with IPF were included in this study (Fig 1). Occupational history was investigated by patients’ self-report. A total of 145 job activities were investigated. The mean number of years worked was 23.9 ⫾ 11.4. These collected occupational data were coded using the International Standard Classification of Occupation and the Korean Standard Classification of Occupation.15,16 We initially stratified the coded data into 10 major groups (managers; professionals; technicians and associate professionals; clerical support workers; services and sales workers; skilled agriculture, forestry and fishery workers; craft and related trades workers; plant and machine operators and assemblers; elementary occupations; armed forces occupations). To further simplify these classifications, we subcategorized the groups into the following five groups, considering occupation previously proven to be related to IPF: (1) unemployed or homemakers; (2) farmers, fishers, or ranchers; (3) sales or service personnel; (4) clerical or professional personnel; and (5) workers exposed to specific types of dust (wood, metal, sand, stone, diesel, or chemical). For each patient, age, sex, smoking status and amount smoked, symptom duration, diagnostic method, initial PFT results, arterial blood gas analysis, comorbidities, HRCT scan findings, survival, and occupation were examined. The average follow-up duration was 17.7 ⫾ 15.8 months. Statistical Analysis Continuous variables were analyzed using analysis of variance, and categorical variables were analyzed using the Pearson x2 test. Data are shown as mean ⫾ SD for continuous variables and number for categorical variables. The effects of clinical, physiologic, radiologic, and occupational features on survival were assessed using the Cox proportional hazard models. The duration of survival after diagnosis was used for survival analysis. The results were expressed as the relative hazard ratio (HR) for death; the estimated survival curves were stratified by occupational group. An adjusted P value , .05 was considered statistically significant. All statistical analyses were carried out using SPSS, version 18 (IBM Corp). Ethics Statement This study protocol was reviewed and approved by the Institutional Review Board of Yonsei University Health Service, Severance Hospital (IRB approval number: 4-2009-0372), which deemed that informed consent was unnecessary.

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Figure 1 – Flowchart of patient selection. Patients (n 5 2,186) were enrolled at 54 centers in Korea and 1,311 patients were divided to one of the five groups. *Dust-exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation. AIP 5 acute interstitial pneumonia; BOOP 5 bronchiolitis obliterans organizing pneumonia; DIP 5 desquamative interstitial pneumonia; ILD 5 interstitial lung disease; LIP 5 lymphocytic interstitial pneumonia; NSIP 5 nonspecific interstitial pneumonia; RB-ILD 5 respiratory bronchiolitis-associated interstitial lung disease.

Results Table 1 demonstrates the baseline clinical characteristics of the 1,311 patients with IPF according to their occupational group. The mean age of the patients at the time of diagnosis was 67.5 ⫾ 9.7 years. However, the mean age for the dust-exposure group was 61.3 ⫾ 8.6 years, the youngest among the occupational groups. There was also a statistically significant difference in the number of men compared with women, within each group. There was no significant difference among the five groups regarding amount of smoking (P 5 .112). The duration of symptoms was significantly different among the groups (P 5 .004). In the dustexposure group, the duration of symptoms was 17.0 ⫾ 28.2 months, the longest of any of the occupational groups. Fifty-eight percent of patients in the sales or service personnel group and 57.3% of the patients in the dust-exposure group were diagnosed by examination of surgical lung biopsy specimens. These proportions were higher than those of the other

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groups. We calculated the GAP index using gender (G), age (A), two lung physiology variables (P) (FVC and diffusing capacity of the lung for carbon monoxide [Dlco]), as Ley et al17 suggested. The sales and service group and dust-exposure group had relatively low GAP scores than other groups (P , .001). Occupational classifications are shown in Figure 2, revealing a significant difference according to sex (P , .001). Women were less likely than men to be employed (in this study only 23.8% of women were employed). The results of the baseline PFT, arterial blood gas analysis, and HRCT scan findings are summarized in Table 2. In the PFT, the percentage of predicted total lung capacity (TLC % predicted) and Dlco % predicted were significantly different among the groups (both P 5 .001). However, there were no significant differences in the FVC % predicted and FEV1 % predicted. Measurements of Pao2 differed significantly among the 467

TABLE 1

] Clinical Characteristics of Patients With Idiopathic Pulmonary Fibrosis According to Occupation

Variables

Unemployed or Homemakers Group (n 5 628)

Age, y

70.5 ⫾ 9.1

Farming, Fishing, or Ranching Group (n 5 230) 68.6 ⫾ 9.0

Sales or Service Group (n 5 131) 63.3 ⫾ 8.7

Clerical or Professional Group (n 5 151) 64.2 ⫾ 9.8

Dust-Exposure Groupa (n 5 171) 61.3 ⫾ 8.6

P Value ,.001b

350 (55.7)

193 (83.9)

108 (82.4)

135 (89.4)

160 (93.6)

,.001

36.9 ⫾ 22.0

37.8 ⫾ 20.0

38.2 ⫾ 23.7

31.7 ⫾ 19.9

34.7 ⫾ 18.4

.112

Nonsmoker

314 (50.0)

47 (20.4)

34 (26.0)

31 (20.5)

30 (17.5)

,.001

Current smoker

124 (19.7)

71 (30.9)

40 (30.5)

36 (23.8)

65 (38.0)

Exsmoker

153 (24.4)

84 (36.5)

48 (36.6)

79 (52.3)

71 (41.5)

Unknown

37 (5.9)

28 (12.2)

9 (6.9)

5 (3.3)

5 (2.9)

Sex, male, No. (%) Smoking, pack-y Smoking status, No. (%)

Duration of symptoms at diagnosis, mo

8.4 ⫾ 17.7

9.2 ⫾ 14.1

13.5 ⫾ 22.3

14.1 ⫾ 24.6

17.0 ⫾ 28.2

202 (32.2)

86 (37.4)

76 (58.0)

81 (53.6)

98 (57.3)

.004b

Diagnostic method, No. (%) Surgical Clinical

426 (67.8)

144 (62.6)

55 (42.0)

70 (46.4)

73 (42.7)

3.27 ⫾ 1.34

3.33 ⫾ 1.33

2.69 ⫾ 1.53

2.80 ⫾ 1.42

2.71 ⫾ 1.28

Alive

242 (38.5)

76 (33.0)

65 (49.6)

82 (54.3)

72 (42.1)

Dead

159 (25.3)

53 (23.0)

38 (29.0)

23 (15.2)

42 (24.6)

Lost to follow-up

227 (36.1)

101 (43.9)

28 (21.4)

46 (30.5)

57 (33.3)

GAP indexc

,.001 ,.001b ,.001

Outcome, No. (%)

Data are given as mean ⫾ SD unless otherwise indicated. GAP 5 gender, age, and physiology Dust-exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation. bThe following post hoc comparisons were significant at the P 5 .05 level (all other comparisons were nonsignificant): unemployed or homemakers group vs sales or service group, clerical or professional group, and dust exposure group; farming, fishing, or ranching group vs sales or service group, clerical or professional group, and dust-exposure group (age); unemployed or homemakers group vs dust-exposure group (duration of symptoms at diagnosis). Unemployed or homemakers group vs sales or service group, clerical or professional group, and dust-exposure group; and farming, fishing or ranching group vs sales or service group, clerical or professional group, and dust-exposure group (GAP index). cThe physiology component of GAP includes two lung physiology variables: FVC and diffusing capacity of the lung for carbon monoxide. a

five groups (P 5 .001). The honeycomb appearance on HRCT scan for the 1,311 patients with IPF was investigated by radiologists in this study. Honeycombing was observed in 63.1% of the clerical or professional group patients, the lowest percentage among the five groups (P 5 .005). We examined the various comorbidities associated with patients with IPF, including pulmonary TB, diabetes mellitus, hypertension, cardiovascular disease, liver disease, and lung cancer (Table 3). There were no significant differences among the groups with regard to these comorbidities. Age, sex, pulmonary function (GAP predictors), Pao2, honeycombing on the HRCT scan, and occupation were analyzed using the multivariate Cox proportional hazard regression models (Table 4). The relative risk (RR) increased significantly with patient age (P 5 .001; HR, 1.034; 95% CI, 1.014-1.054). A significantly lower RR was associated with the FVC % predicted (P 5 .004; HR, 468 Original Research

0.984; 95% CI, 0.974-0.995). However, sex, Dlco, Pao2, and CT scan findings did not influence the RR for mortality. There was a significant association observed between survival and occupation (P 5 .013). The dustexposure group showed the highest RR for mortality among the groups. The Cox proportional hazard model plots, differentiated by occupational groups, are shown in Figure 3 (P , .001). Additionally, survival plots of dust-exposure subgroups are shown in Figure 4. The Wood or chemical dust-exposure group showed the worst prognosis. This subgroup displayed approximately 11.0% decline of FVC % predicted for 1 year. We also conducted a survival analysis adjusting GAP stage and occupation (Table 5). An advanced GAP stage was associated with a poor prognosis (P , .001); dustexposure occupation did trend toward poor prognosis (P 5 .066). The causes of death in 231 of 315 deceased patients were investigated in our study. These were acute respiratory failure (n 5 104; 45.0%), pneumothorax (n 5 2; 0.9%),

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its associated mortality. In fact, a study conducted at a major engineering company demonstrated a dose-effect relationship between metal-dust exposure and IPF mortality.21 Additionally, steel, brass, and lead are known to be associated with IPF.8 Taskar and Coultas22 conducted a meta-analysis and demonstrated a significant association between the increased risk for IPF and sand/stone/silica exposure (OR, 1.97; 95% CI, 1.09-3.55). Underground miners exposed to dust and diesel exhaust show persistently increased numbers of inflammatory cells, such as macrophages and neutrophils, in their sputa.23 Inhalation of diesel exhaust also induces lung fibrosis.24 Increased transforming growth factor b expression in primary fibroblasts and an increased risk for IPF has also been demonstrated among patients who have been subjected to chemical inhalation.7,25 In our study, the patients in the dust-exposure group, mostly individuals who were occupationally exposed to these types of particulates, demonstrated an even worse prognosis than other patients.

Figure 2 – Occupational classification by sex. A, Occupations classification of female patients (n 5 365). B, Occupation classifications of male patients (n 5 946). There is a significant occupational difference by sex (x2 test P , .001). *Dust exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation.

massive hemoptysis (n 5 1; 0.4%), pneumonia (n 5 74; 32.0%), other infection (n 5 6; 2.6%), pulmonary TB (n 5 1; 0.4%), heart failure or cardiovascular disease (n 5 7; 3.0%), lung cancer (n 5 20; 8.7%), and others (n 5 16; 6.9%).

Discussion Occupational dust exposure has been identified as a risk factor for IPF in many previous studies. This study shows continuous occupational dust exposure could lead to compromised lung function and poor prognosis. Environmental and occupational exposure contributes to the pathogenesis of IPF in genetically susceptible patients. Cumulative wood-dust exposure accelerates lung function decline, as represented by the annual decrease in FEV1 and the cumulative incidence proportion of FEV1/FVC , 70% among female woodworkers.18 Wood dust is also associated with other respiratory disorders, such as asthma, chronic bronchitis, nasopharyngeal cancer, and lung cancer.8,19,20 Occupational exposure to metal dust tends to increase the incidence of IPF and

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Age plays an important role in IPF. Aging is accompanied by increasing cellular dysfunction, stem cell senescence, and the accumulation of cell damage.26 As a result, the incidence of IPF increases with age, and older patients have been shown to have a worse prognosis than younger patients.27,28 Similar to previous studies, the present study demonstrated that aging increases the RR for mortality. The dust exposure group, however, was the youngest among the occupational groups in the current study. Exposure to wood, metal, sand, stone, diesel particulates, or chemical agents is thought to induce chronic pulmonary inflammation and lead to IPF at a relatively young age. Therefore, in the dust-exposure group, these particulates may act like accelerants. In our study, there was a distinct sex difference among the groups. In the dust-exposure group, male patients predominated compared with the other groups. Johnston et al29 reported that IPF mortality was higher in traditionally industrialized areas and that deaths due to IPF were more common among men. They suggested that environmental or occupational exposure may be an important risk factor.29 Similarly, occupational differences by sex may be a reason for the higher incidence of IPF among men than women in our study. We expected the dust-exposure group to have an associated decline in lung function. Although the TLC % predicted was lowest in the dust-exposure group, the other

469

TABLE 2

] Lung Function at Diagnosis, Blood Gas Analysis, and High-Resolution CT Scan Finding According to Occupation

Unemployed or Homemakers Group (n 5 628)

Farming, Fishing, or Ranching Group (n 5 230)

Sales or Service Group (n 5 131)

Clerical or Professional Group (n 5 151)

Dust-Exposure Groupa (n 5 171)

P Value

FVC % predicted

74.8 ⫾ 19.3

76.7 ⫾ 17.6

76.4 ⫾ 17.5

77.0 ⫾ 17.8

75.0 ⫾ 18.2

.542

Variables

FEV1 % predicted

86.5 ⫾ 21.0

86.1 ⫾ 19.2

87.8 ⫾ 19.3

86.3 ⫾ 18.1

83.5 ⫾ 19.9

.429

TLC % predicted

84.0 ⫾ 18.7

88.7 ⫾ 20.8

86.1 ⫾ 19.2

80.2 ⫾ 19.1

79.4 ⫾ 18.3

.001b

DLCO % predicted

58.8 ⫾ 20.8

62.9 ⫾ 21.2

67.2 ⫾ 22.6

68.5 ⫾ 23.8

65.7 ⫾ 21.1

,.001b

PaO2, mm Hg

77.0 ⫾ 21.1

77.4 ⫾ 23.1

84.1 ⫾ 24.3

84.2 ⫾ 18.8

83.5 ⫾ 20.5

.001b

PaCO2, mm Hg

37.3 ⫾ 8.3

37.3 ⫾ 7.2

37.4 ⫾ 7.8

38.2 ⫾ 6.7

37.5 ⫾ 5.6

Honeycombing

454 (73.5)

180 (79.6)

100 (78.1)

94 (63.1)

120 (70.2)

.881 .005

Data are presented as mean ⫾ SD unless otherwise indicated. TLC 5 total lung capacity; DLCO 5 diffusing capacity of the lung for carbon monoxide. Dust-exposure group includes wood, metal, sand, stone, diesel or chemical exposure-related occupation. bThe following post hoc comparisons were significant at the P 5 .05 level; all other comparisons were nonsignificant: farming, fishing, or ranching group vs clerical or professional group and dust-exposure group (TLC % predicted); unemployed or homemakers group vs sales or service group, clerical or professional group and dust-exposure group (DLCO % predicted); unemployed or homemakers group vs sales or service group and clerical or professional group (PaO2, mm Hg). a

estimated lung function values (Table 2) showed mixed results. This may be because the current study groups were not age- or sex-matched. The mean age of the patients in the dust-exposure group was lower than those of the other groups and the proportion of men was higher in this group than in the others, possibly skewing the results. FVC is thought to be a strong predictor of mortality among patients with IPF27,30; in our study, the FVC % predicted at the time of diagnosis appears to be associated with the risk for mortality, as in previous studies. Visual HRCT scan scoring of the extent of disease appears to be a predictor of mortality in patients with IPF. Although honeycombing was associated with an increased RR, it was not significantly associated with survival in our study. The previous study31 used the HRCT scan scoring system for predicting survival; how-

TABLE 3

ever, our study involved a multicenter and retrospective design, meaning that IPF severity was not scored by HRCT scan. Miyake et al32 reported that clerical and related work showed a significantly decreased risk for IPF-related mortality.32 Similar to their study, clerical and professional personnel had a better prognosis than any of the other groups. This group also showed overall favorable results, especially with respect to FVC % predicted, Dlco % predicted, Pao2, and honeycombing. The suggested reason is that, generally, this type of work does not fall under the “dust effect.” Additionally, professionals tend to have a higher socioeconomic status with easier access to health services. Regular health examinations are probably helpful for detecting IPF and for decreasing the extent of IPF aggravation.

] Comorbidities of Idiopathic Pulmonary Fibrosis Patients According to Occupation

Variables TB

Unemployed or Homemakers Group (n 5 628)

Farming, Fishing, or Ranching Group (n 5 230)

Sales or Service Group (n 5 131)

88 (14.0)

20 (8.7)

15 (11.5)

13 (8.6)

24 (14.0)

.242

46 (20.0)

26 (19.8)

23 (15.2)

33 (19.3)

.757

34 (22.5)

43 (25.1)

.496

8 (5.3)

9 (5.3)

.503

Diabetes mellitus

111 (17.7)

Hypertension

136 (21.7)

Clerical or Professional Group (n 5 151)

Dust-Exposure Groupa (n 5 171)

P Value

42 (18.3)

32 (24.4)

12 (5.2)

11 (8.4)

13 (2.1)

4 (1.7)

5 (3.8)

4 (2.6)

4 (2.3)

.754

43 (6.8)

17 (7.4)

9 (6.9)

10 (6.6)

13 (7.6)

.995

Other CVD

48 (7.6)

Liver disease Lung cancer

Data given as No. (%) unless otherwise indicated. CVD 5 cardiovascular disease. Dust exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation.

a

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TABLE 4

] Analysis of Survival in Idiopathic Pulmonary Fibrosis Patients by Multiple Cox Proportional Hazard Models

Patients, No. (N 5 1,311)

Variables Age

…

Sex, M/F (%)

Mean ⫾ SD 67.5 ⫾ 9.7

946:365 (72.2)

Relative Hazard Ratio

95% CI

P Value

1.034

1.014-1.054

.001

…

1.493

0.955-2.335

.079

1,201

75.6 ⫾ 18.5

0.984

0.974-0.995

.004

DLCO % predicted at diagnosis

966

62.6 ⫾ 21.7

0.997

0.989-1.005

.495

PaO2 at diagnosis

877

79.3 ⫾ 21.7

0.995

0.985-1.004

.287

Honeycombing

948

…

1.153

0.750-1.774

.517

Occupation

…

…

…

…

.013

Unemployed or homemakers group

628

…

…

…

…

Farming, fishing, or ranching group

230

…

0.924

0.552-1.548

.765

Sales or service group

131

…

1.656

1.974-2.814

.063

Clerical or professional group

151

…

0.545

0.254-1.166

.118

Dust-exposure group

171

…

1.813

1.049-3.133

.033

FVC % predicted at diagnosis

a

F 5 female; M 5 male. See Table 2 legend for expansion of other abbreviations. Dust-exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation.

a

Our study showed relative higher acute respiratory failure (n 5 104; 45.0%) and lower cardiovascular disease (n 5 7; 3.0%) than other studies as the immediate cause of death. We investigated the various comorbidities in patients with IPF. Table 3 showed relatively low frequency of cardiovascular disease than other studies.33 We think that racial or ethnic differences could affect the results.

Figure 3 – Survival analysis for patients with idiopathic pulmonary fibrosis in Korea according to occupation: A plot of survival probability based on the Cox proportional hazard model adjusting for age, sex, pulmonary function, Pao2, and honeycombing seen on high-resolution CT scan. *Dust exposure group includes wood, metal, sand, stone, diesel or chemical exposure-related occupation.

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Ley et al17 suggested the GAP model to predict mortality in patients with IPF. The GAP index and staging system provides clinicians a simple clinical prediction of IPF using sex, age, and PFT results. In addition to GAP stage, several other prognostic predictors can be helpful to clinicians for more precise estimation of prognosis: a lower 6-min walk test distance, hypoxemia at rest, comorbidity, and quantitative HRCT scan analysis.33-36 In this study, initial Pao2, honeycombing, and occupation were available for more accurate survival analysis (Table 4). In this analysis, the dustexposure group was associated with poor prognosis. However, Table 5 shows a trend toward results on occupation contrary to the GAP index. This may be due to error in recording the “cannot perform” category of Dlco. This constraint probably provoked the non-significant result on occupation in this retrospective study. Recently, genetic findings in IPF have advanced IPF diagnosis.37 The mucin 5b gene (MUC5B), surfactant protein C (SFTPC), surfactant protein A2 (SFTPA2), telomerase reverse transcriptase (TERT), and telomerase RNA component (TERC) are significantly associated with IPF.38,39 Genetic studies like these conducted in the occupational dust-exposure group could be helpful for preventing IPF and for decreasing the extent of IPF aggravation. Furthermore, we think epidemiologic studies on pulmonary fibrosis (including IPF) related to occupational dust exposure are needed for more accurate

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Figure 4 – Survival analysis for dustexposure subgroups: A plot of survival probability based on Cox proportional hazard model. Variables included in model are age, pulmonary function, Pao2, combined honeycombing seen on high-resolution CT scan, and dust. Sex was excluded in this subgroup analysis because of the small number of women (n 5 11).

understanding about the role of occupational dust, as some studies showed.40,41 This study has some limitations. First, 374 cases with missing occupational information were excluded in this study. This sizable number of patients may act as a potential factor for selection bias. Second, in some cases, it was difficult to distinguish between IPF and occupational ILD or chronic hypersensitivity pneumonitis. However, we distinguished the chronic hypersensitivity pneumonitis by history, clinical presentation, and laboratory results. As a result, we think the proportions had a minimal effect on this study. Third, this

TABLE 5

study involved a retrospective design, involving a recall bias. Some patients classified in the unemployed or homemakers group might have previously had a job that led to exposure misclassification, but this was not captured in the survey. And the subjects’ weekly working hours and level of dust inhalation were not considered in this study, which could provide additional important information on dust exposure. Further large, prospective studies with a well-organized registry will be needed. In conclusion, patients in the dust-exposure group showed earlier onset of IPF, relatively longer symptom

] Analysis of Survival in Idiopathic Pulmonary Fibrosis Patients According to the GAP Index and Occupation by Cox Proportional Hazard Modelsa

Variables GAP stage

Patients, No.

Relative Hazard Ratio

95% CI

P Value

964

…

…

,.001

Stage I

596

…

…

Stage II

334

1.821

1.359-2.441

,.001

34

2.435

1.360-4.360

.003

Stage III Occupation

…

.066

Unemployed or homemakers group

628

…

…

Farming, fishing, or ranching group

230

1.105

0.750-1.627

… .614

Sales or service group

131

1.389

0.904-2.135

.133

Clerical or professional group

151

0.678

0.398-1.156

.153

Dust-exposure groupb

171

1.466

0.985-2.180

.059

See Table 1 legend for expansion of abbreviation. Multivariate analysis adjusted GAP stage and occupation. bDust-exposure group includes wood, metal, sand, stone, diesel, or chemical exposure-related occupation. a

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durations, and worse prognoses than those in the other groups. Age, FVC, and employment in a dust-exposure occupation were found to be significantly associated with mortality in patients with IPF. These findings sug-

Acknowledgments Author contributions: M. S. P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. S. H. L. served as principal author. S. H. L., D. S. K., Y. W. K., M. P. C., S. T. U., C. S. P., S. H. J., Y. B. P., H. L. L., J. S. S., J. W. S., N. S. Y., E. J. L., J. H. L., Y. J., H. K. L., and M. S. P. contributed to the study concept and design, and acquisition, analysis, and interpretation of the data; S. H. L. and M. S. P. contributed to drafting or revising the manuscript; and S. H. L., D. S. K., Y. W. K., M. P. C., S. T. U., C. S. P., S. H. J., Y. B. P., H. L. L., J. S. S., J. W. S., N. S. Y., E. J. L., J. H. L., Y. J., H. K. L., and M. S. P. approved the final version of the manuscript.

8.

9.

10.

11.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

12.

Other contributions: We are grateful to all members of The Korean ILD Research Group who helped gather the data for analysis.

13.

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