American Journal of Respiratory and Critical Care Medicine

Rationale: Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations.

Objectives: To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences.

Methods: We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis.

Measurements and Main Results: The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity.

Conclusions: The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.

Scientific Knowledge on the Subject

Several large-scale epidemiologic studies of idiopathic pulmonary fibrosis (IPF) have been conducted predominantly in Western countries, whereas little is known about epidemiologic status of IPF in Asian countries. It remains unclear whether ethnic differences exist between Asian and Western populations.

What This Study Adds to the Field

The current status of IPF in Japan was characterized for the first time through our study. As a result of comparison with other countries, we found differences in the sex ratio as well as the rate of death caused by acute exacerbation and cardiovascular disease compared with Western countries. This difference may suggest that the status of IPF is affected by ethnic factors.

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, life-threatening disease of unknown cause. IPF occurs primarily in older adults, is limited to the lungs, and is associated with the histopathologic and/or radiologic patterns of usual interstitial pneumonia (13). Many patients with IPF have a relatively slow clinical course; however, some patients experience acute respiratory deterioration. When a cause for acute decline cannot be identified, the term acute exacerbation (AE) of IPF has been used (4).

Little is known about the epidemiology of IPF. In older studies, epidemiologic status was not determined on the basis of a uniform definition of IPF. The prevalence varied depending on the diagnostic criteria used (5). In 2000, the American Thoracic Society (ATS) collaborated with the European Respiratory Society (ERS) and developed a consensus statement for the diagnosis and treatment of IPF (2), which was further revised in 2011 (1). These statements offer an opportunity for more precise epidemiologic studies.

Most epidemiologic studies of IPF have been reported in Western communities. There are few studies reported from Asian communities. Jeon and coworkers (6) reported regarding prognostic factors and causes of death in Korean patients with IPF. They pointed out the difference in the cause of death between Korea and Western countries. Ohno and coworkers (7) presorted the results of epidemiologic survey of Japanese IPF. However, their survey was unable to determine the exact epidemiologic status because of exclusion of cases of milder diseases. To understand the status of total IPF among Japanese, a large-scale study including the cases of milder diseases is required.

It is currently unclear if ethnic difference exists in IPF. It is necessary to compare epidemiologic studies internationally, in particular between Asian and Western populations. It is meaningful to provide precise epidemiologic status of Asian populations using diagnostic criteria based on international consensus. The Japanese Ministry of Health, Labor and Welfare conducted a cohort study on Hokkaido prefecture (population, 5.6 million). The purpose of this study is to provide the epidemiologic status of IPF in Japan and to investigate ethnic differences between Japanese and Western populations.

Study Design

This is a retrospective cohort study based on clinical records of patients with IPF who were given the Certificate of Medical Benefit (CMB) in Hokkaido prefecture (Figure 1) from January 1, 2003 to December 31, 2007. The Japanese Ministry of Health, Labor and Welfare issues a CMB to patients who qualify for its medical expense assistance program for diseases of unknown cause and diseases for which there is no established treatment. Physicians who have made a diagnosis of IPF submit the clinical records, high-resolution computed tomography findings, and the result of pathologic diagnosis (when a surgical biopsy has been performed) to the local municipality. A committee comprising three pulmonologists who specialize in interstitial lung disease examines each case and grants CMBs to those patients with IPF who satisfy the diagnostic criteria for IPF (2). The data used in the present study were provided to the researchers by Hokkaido prefecture after being organized into databases and converted to electronic files. All patients were rendered anonymous in these files.

Survival was assessed through September 30, 2011. Hokkaido prefecture interviewed patients’ doctors to identify deaths and causes of death. Doctors who certified that the patients were dead were questioned directly regarding the cause of death, including AE. A total of 96.5% of these doctors participated in the interviews, and according to replies received from those physicians, the vital status of 521 (94.2%) patients was confirmed.

This study was approved by the institutional review board of the Sapporo Medical University School of Medicine.

Study Subjects and Case Definition

The study subjects included 553 patients with IPF; 62 were confirmed by surgical lung biopsy. Patients with IPF were identified based on chest high-resolution computed tomography findings, pathology, and medical records according to the ATS/ERS consensus classification (2). AE was defined using the Japanese criteria (8). These criteria are basically consistent with the criteria proposed by Collard and coworkers in 2007 (4).

Incidence and Prevalence

Cumulative incidence was calculated for the same year (2008) as used for prevalence calculations and using patients other than those used as subjects in the present study (2003–2007). It was calculated using the number of new patients for 1 year and mid-year population statistics for 2008 in Hokkaido. Prevalence was calculated using the total number of patients with IPF who were issued CMBs in Hokkaido as of July 1, 2008.

Statistical Analyses

Results are given as means ± SDs for continuous variables and percentages for categorical and ordinal variables. Statistical comparisons were made by chi-square and Fisher exact tests for categorical variables, one-way analysis of variance for continuous variables, and Kruskal-Wallis tests for ordinal variables. The survival analysis was completed according to the methods of Kaplan-Meier. Univariate Cox regression analysis was used to determine the ability of each variable to predict mortality. Additionally, the multivariate Cox regression analysis was used to identify significant variables after controlling simultaneously for potential confounders. All variables with a P value of less than 0.25 in the univariate analyses and clinically significant variables were entered into the multivariate Cox regression analysis. Statistical analysis was conducted using SPSS software (SPSS statistics version 19.0; IBM, Chicago, IL).

Baseline Characteristics

The clinical characteristics and laboratory test results of patients with IPF are shown in Table 1. Their mean age was 70.0 ± 9.0 years, 72.7% were men, 67.6% were smokers, and 4.8% were familial form of interstitial pneumonia. For pulmonary function test results, 40% of subjects had VC values less than 60% of predicted. In % diffusing capacity of carbon monoxide (DlCO), 57% of subjects had DlCO value less than 60% of predicted. The laboratory test results showed trends for increased Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein (SP)-A, pulmonary surfactant SP-D, and lactate dehydrogenase (LDH) (9, 10). Neutrophils in bronchoalveolar lavage (BAL) fluid were also elevated (9.8 ± 14.5%). The percentage that was positive for antinuclear antigen was 23.6% and that for rheumatoid factor was 17.6%.

Table 1. Baseline Characteristics of Patients with IPF

 N (%)Mean ± SD
Patients553 
Age, yr52870.0 ± 9.0
Male/female402 (72.7)/151 (27.3) 
Smoking  
 Never/current or former169 (32.4)/352 (67.6) 
FIP  
 Yes/no20 (4.8)/420 (95.2) 
PaO2  
 ≥80165 (33.7) 
 70–80*140 (28.6) 
 60–70*108 (22.2) 
 <6077 (15.7) 
PFT %pred  
 %VC  
  ≥80175 (38.9) 
  60–80*96 (21.2) 
  40–60*72 (16.0) 
  <40108 (23.9) 
 %DlCO  
  ≥8051 (15.7) 
  60–80*88 (27.1) 
  40–60*98 (30.2) 
  <4087 (27.0) 
KL-6, U/ml4151569.2 ± 1,204.8
SP-D, ng/ml386314.9 ± 221.4
SP-A, ng/ml195122.3 ± 85.7
LDH, IU/L268351.1 ± 197.9
BAL  
 Lymphocytes, %8416.5 ± 18.4
 Neutrophils, %849.8 ± 14.5
ANA, positive/negative98 (23.6)/317 (76.4) 
RF, positive/negative75 (17.6)/350 (82.4) 
Clubbed fingers, yes/no235 (45.9)/277 (54.1) 

Definition of abbreviations: ANA = antinuclear antigen; BAL = bronchoalveolar lavage; %DlCO = % predicted carbon monoxide diffusing capacity; FIP = familial form of interstitial pneumonia; IPF = idiopathic pulmonary fibrosis; KL-6 = Krebs von den Lungen-6; LDH = lactate dehydrogenase; PFT = pulmonary function tests; RF = rheumatoid factor; SP-A = surfactant protein-A; SP-D = surfactant protein-D; %VC = % predicted vital capacity.

Values are given as mean ± SD or n (%). The total does not equal 553 because there were missing values in the data file.

*Ranges include lower endpoints and do not include upper endpoints.

Incidence and Prevalence

The cumulative incidence and prevalence were 2.23 and 10.0 per 100,000 population, respectively. Figure 2 shows the age- and sex-specific cumulative incidence and prevalence. The age-specific cumulative incidence of IPF for males was higher than that for females in the groups of 50 years old or more. The highest cumulative incidence for males and females was in the 70–79 age group (14.05 per 100,000 population) and the 60–69 age group (3.41 per 100,000 population), respectively. The age-specific prevalence was also higher in males than in females in all age groups. The age group with the highest prevalence was the same (the 60–69 age group) for males (44.44 per 100,000 population) and females (13.65 per 100,000 population). The total population of Hokkaido according to July 2008 statistics was 5,572,770. Of these, 2,909,000 (52.2%) were women, 4,471,950 (80.7%) were urban dwellers, and 1,099,820 (19.7%) were rural dwellers.

Survival Time and Predictors

Figure 3 shows the survival curve for all patients with IPF; the median survival time for all patients was 35.0 months. The predictors of IPF mortality by univariate analysis using Cox proportional hazards regression models are shown in Table 2. Age, PaO2 at rest, %VC, %DlCO, neutrophils in BAL fluid, and having clubbed fingers were significant predictors of IPF mortality. From multivariate analysis, age, %VC, and %DlCO were a significant predictor of IPF mortality (Table 3). The result of neutrophil counts in BAL in univariate analysis was significant but was excluded from multivariate analysis because of the quantity of missing data.

Table 2. Predictors of Mortality in Patients with IPF by Univariate Analysis

ParametersNHazard Ratio95% CIP Value
Age, yr4921.0231.010–1.0360.001
Sex    
 Male3681.000  
 Female1390.9450.736–1.2120.654
Smoking    
 Never1561.000  
 Current/former smoker3280.9500.743–1.2140.680
FIP    
 No3651.000  
 Yes201.2520.729–2.1500.415
PaO24530.9840.977–0.992<0.001
%VC4200.9630.945–0.972<0.001
%DlCO3030.9770.969–0.985<0.001
KL-6, U/ml3851.0001.000–1.0000.307
SP-D, ng/ml3611.0001.000–1.0010.623
SP-A, ng/ml1860.9990.997–1.0010.398
LDH, IU/L2461.0001.000–1.0010.603
BAL%    
 Lymphocytes, %811.0010.986–1.0160.886
 Neutrophils, %811.0201.003–1.0380.019
ANA    
 Negative2991.000  
 Positive941.1400.857–1.5220.391
RF    
 Negative3241.000  
 Positive710.9310.678–1.2900.671
Clubbed fingers    
 Negative2591.000  
 Positive2181.3991.112–1.7600.004

Definition of abbreviations: ANA = antinuclear antigen; BAL = bronchoalveolar lavage; CI = confidence interval; %DlCO = % predicted carbon monoxide diffusing capacity; FIP = familial form of interstitial pneumonia; IPF = idiopathic pulmonary fibrosis; KL-6 = Krebs von den Lungen-6; LDH = lactate dehydrogenase; RF = rheumatoid factor; SP-A = surfactant protein-A; SP-D = surfactant protein-D; %VC = % predicted vital capacity.

Table 3. Predictors of Mortality in Patients with IPF by Multivariate Analysis

ParametersHazard Ratio95% CIP Value
Age, yr1.0251.005–1.0450.012
Sex   
 Male1.000  
 Female0.8100.521–1.2590.350
Smoking   
 Never1.000  
 Current/former smoker1.0260.656–1.6040.910
PaO20.9950.979–1.0100.500
%VC0.9640.948–0.980<0.001
%DlCO0.9830.974–0.993<0.001
Clubbed fingers   
 Negative1.000  
 Positive1.2170.862–1.7160.264

Definition of abbreviations: CI = confidence interval; %DlCO = % predicted carbon monoxide diffusing capacity; IPF = idiopathic pulmonary fibrosis; %VC = % predicted vital capacity.

Causes of Death

Figure 4 shows the proportions for the causes of IPF deaths. A total of 328 patients (59.3% of patients with IPF) died from various causes. The total number of patients who died because of AE and chronic respiratory failure accounted for 64% of all deaths. In fact, the percentage of AE deaths was as high as 40%. Our comparison of male and female patients who died of AE showed that 73% were males, which is nearly an exact match to the sex ratio (72% males) of the total patients with IPF. Eleven percent died of lung cancer, 7% died of pneumonia, and 3% died of cardiovascular disease.

We present results from an epidemiologic study to determine the current status of Japanese patients with IPF. A number of epidemiology studies have been conducted on patients with IPF in Japan to date. Nagai and coworkers (11) reported the results of a hospital-based historical cohort study of Japanese patients with IPF before the ATS/ERS statement in 2000. Ohno and coworkers (7) conducted a nationwide epidemiologic survey of patients with idiopathic interstitial pneumonias; however, this survey was unable to determine the precise status due to the exclusion of milder disease cases because of the limitations of the system.

In the same East Asia area, Jeon and coworkers (6) hypothesized that there may be prognostic factors and causes of death in patients with IPF in Asia that are different from those that have been reported in Western countries. They pointed out an interesting result of an epidemiologic study that showed that respiratory failure and pulmonary infection were more common causes of death in patients with IPF in Korea. The study by Jeon and coworkers (6) was based on clinical records of 88 patients with IPF who were referred to one facility. Our study was a large-scale investigation of 553 patients with IPF regardless of severity where patient diagnoses were based on international consensus. This study revealed the precise status of Japanese patients with IPF for the first time and allowed for the investigation of differences from patients with IPF in other regions.

According to reports from the United States after the ATS/ERS statement in 2000, Fernandez-Perez and coworkers (12) reported annual incidence and prevalence rates of 8.8 and 27.9 per 100,000, respectively, whereas in 2006, Gribbin and coworkers (13) reported an annual incidence of 4.6 per 100,000 in the United Kingdom. The cumulative incidence and prevalence rates in the present study (2.23 and 10.0 per 100,000, respectively) were lower than those results. However, more recent reports from Europe indicate that the 2013 prevalence in France was 4.1 per 100,000 (14) and incidence in Denmark was 1.3 per 100,000 person-years (15), which are lower than the results of our study. Thus, as can be seen, reports from different countries show differing data. One cause of this disparity may be differences in the methods used to extract the subjects and the case definitions used.

In our study, incidence in males was 2.7-fold higher than that in females, and this rate was higher than those reported by Fernandez-Perez and coworkers in the United States and Gribbin and coworkers in the United Kingdom. Both of them reported that the incidences in males are 1.5-fold higher than that in females (12, 13). The average age of onset according to our study was 70.0 ± 9.0 years, which was similar to the average age (70 yr) reported in Western studies (12, 13). Fernandez-Perez and coworkers (12) reported that the proportion of smokers among patients with IPF, including both ex-smokers and current smokers, in the United States was 59.6%. However, the proportion of smokers in the general American population from 2007 to 2010 was reported to be 46% (16). In our study, the smoking rate of patients with IPF was 67.6%. This was a higher proportion than the smoking rate of 57.1% per total population in Hokkaido revealed by an investigation in 2007. Similarly, in Japan and the United States, there is a tendency for the smoking rate among patients with IPF to be higher in comparison with the general population. The result that the onset of IPF is associated with smoking was considered.

In international comparison about sex ratio of smoking rates based on the statistics reported in 2002 by the World Health Organization, a large difference in the sex ratio was observed with approximately four times as many men as women who were smokers in Japan. By contrast, this large difference in sex ratio was not observed in other countries, with men approximately 1.2 times more likely to smoke than women in the United States and 1.1 times more likely in the United Kingdom. This difference in the smoking rate may be associated with the fact that the proportion of male patients with IPF is also higher in Japan than in western countries. The median survival time following a definitive diagnosis in Western studies was reportedly 33–51 months (12, 1719), which was in accordance with our result (35 mo).

According to reports from the United States and Europe, 16–27% of deaths in patients with IPF were due to cardiovascular disease, suggesting that this is an important cause of death in IPF (12, 20). However, cardiovascular disease accounted for 3% of deaths in the present study, and in an Asian study conducted by Jeon and coworkers it accounted for 2% of deaths. The results in Asian populations are clearly lower than Western populations. The most common cause of death in Japanese patients with IPF was AE with a frequency of 40%, which was similar with that of 46% in a previous report by Jeon and coworkers in Korea (6), whereas Fernandez-Perez and coworkers (12) in the United States reported 18%. Kondoh and coworkers (21) reported the first case of AE of IPF in the world from Japan in 1993. Japanese patients with IPF with AE presented with diffuse alveolar damage (DAD) on histopathologic examination, and such cases resulted in a high mortality rate. However, AE of IPF has not been well recognized in Western countries, showing a different clinical picture from Japan. This discrepancy in AE may indicate an ethnic difference, particularly between the East Asian and Western populations.

A similar example of the difference in clinical pictures between Japanese and Western people is provided by drug-induced lung disease. The incidence of gefitinib-induced lung injury is 3.98% in Japan, which is approximately 13-fold higher than the corresponding rate in the United States. The incidence of leflunomide-induced lung injury in Japan was 1.81%, approximately 100-fold higher than western countries. The mortality rate from these drug-induced lung diseases was as high as 40%, with all deaths related to the DAD pattern (22). It is noteworthy that among the cases of dermatomyositis/polymyositis, fatal cases with less conspicuous myositis negative for Jo-1 (amyopathic dermatomyositis) leading to DAD may be more frequent in East Asia (23). These ethnic differences in the incidence of lung diseases including IPF-AE suggest the existence of specific genes associated with lung vulnerability in Japanese or East Asian populations. The identification of any specific genes associated with lung vulnerability will be an important clue in future elucidation of IPF or IPF-AE.

There have been some studies regarding IPF prognosis that revealed decreased forced VC as the most important common prognostic factor (2427), whereas other factors included decreased DlCO (26, 27), hypoxemia on exertion (28, 29), and high levels of mucin-like glycoprotein KL-6 (9), pulmonary SP-A (10, 30, 31) and SP-D (10, 31), and neutrophil counts in BAL (32). In the present study, multivariate analysis revealed a significant difference between age, %VC, and %DlCO. The fact that baseline %VC and baseline %DlCO were independent prognostic factors indicates that pulmonary function is an important prognostic factor, as reported in previous studies (2427). Conversely, KL-6, SP-A, and SP-D were not important prognostic factors for mortality, unlike previous reports in some articles. The reasons for this discrepancy are unclear. One potential explanation for the different findings is difference of statistical analysis. In previous studies, statistical analysis was performed using separating biomarkers as arbitrary values and by investigating differences in prognosis between the high-value group and the low-value group. However, in this study, analyses were performed by treating all values as continuous variables.

This study has some limitations. First, this was a retrospective study based on clinical records, and there were some items with missing values included in the statistical analysis. Neutrophil counts in BAL have been reported to be associated with prognosis in the past (32). The result of neutrophil counts in BAL in our univariate analysis was significant but was excluded from multivariate analysis because of the quantity of missing data. Second, AE was the most common cause of death in our study and this pathobiologic process was extremely important in IPF prognosis. However, we did not have information on AE onsets, so we could not directly analyze the incidence and predictors of AE. Hence, it is critical to conduct a future study for analyzing these factors and comparing the results internationally. Third, case extraction relies on the treating physician to refer a patient to the CMB. The number of latent patients with IPF who were not referred to the CMB is unknown.

The current status of IPF in Japan was clarified for the first time through our study. As a result of comparison with other countries, we found differences in the sex ratio as well as the rate of death caused by AE and cardiovascular disease compared with Western countries. This difference may suggest that the status of IPF is affected by ethnic factors.

The authors thank Dr. Sumiyo Asakura for data retrieval.

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Correspondence and requests for reprints should be addressed to Hirofumi Chiba, M.D., Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, South-1 West-16 Chuo-ku, Sapporo 060-8556, Japan. E-mail:

Supported by a grant-in-aid for and by members of interstitial lung diseases from the Japanese Ministry of Health, Labor and Welfare.

Author Contributions: M.N., H.C., K. Kuronuma, M.O., K. Kudo, and H.T. contributed to the conception, design, conduct, analysis, and reporting the study. M.M. contributed to the analysis. M.B. and Y.S. contributed to the conception and design. All authors participated in preparation, review, and critical revision of the report, which has been approved by each author.

Originally Published in Press as DOI: 10.1164/rccm.201403-0566OC on August 27, 2014

Author disclosures are available with the text of this article at www.atsjournals.org.

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190
7

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