respiratory investigation 53 (2015) 51 –59
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Original article
A prospective survey of idiopathic interstitial pneumonias in a web registry in Japan$ Masashi Bandoa,n, Yukihiko Sugiyamaa, Arata Azumab, Masahito Ebinac, Hiroyuki Taniguchid, Yoshio Taguchie, Hiroki Takahashif, Sakae Hommag, Toshihiro Nukiwah, Shoji Kudohi a
Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan Division of Pulmonary Medicine, Infection and Oncology, Nippon Medical School, Tokyo, Japan c Department of Respiratory Medicine, Tohoku Pharmaceutical University Hospital, Sendai, Japan d Department of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan e Department of Respiratory Medicine, Tenri Hospital, Tenri, Japan f Third Department of Internal Medicine, Sapporo Medical University Hospital, Sapporo, Japan g Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan h South Miyagi Medical Center, Miyagi, Japan i Respiratory Disease Center, Double-Barred Cross Hospital, Tokyo, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: There have been no prospective large-scale multicenter epidemiological
Received 11 July 2014
studies on the clinical course and treatment from the time of diagnosis of idiopathic
Received in revised form
interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current
14 October 2014
clinical situation of IIP in Japan.
Accepted 6 November 2014
Methods: This study was supported by a grant from the Ministry of Health, Labour and
Available online 4 December 2014 Keywords: Idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis Prospective multicenter epidemiological study Web registration
Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed. Results: A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively. Conclusions: This study should provide valuable information for understanding the current state of IIP in Japan. & 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.resinv.2014.11.001 2212-5345/& 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
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1.
respiratory investigation 53 (2015) 51 –59
Introduction
Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown etiology with a poor prognosis that follows a chronic and progressive course resulting in severe fibrosis and formation of irreversible honeycomb lung [1,2]. The natural course and prognosis of IPF varies for each patient, and is difficult to predict. Determination of the need for intervention and the development of effective treatment strategies depend on a multifaceted evaluation of the clinical course and the risk factors for poor prognosis [2,3]. IPF is categorized as an idiopathic interstitial pneumonia (IIP). To date, there have not been a large-scale prospective epidemiological study of the clinical course and treatment of IIP from the time of diagnosis in patients in Japan. We analyzed data on diagnoses, clinical findings, treatments, and disease course from an integrated internet database of IIP patients that was created with the participation of medical institutions across Japan that specialize in IIPs. This study was aimed at describing the current state of IIP in Japan and examining diagnostic findings and standards of care. This prospective survey on diffuse lung diseases that was conducted within the framework of a research project supported by the Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research.
2.
Materials and methods
2.1.
Patients and data collection
A research project for overcoming intractable diseases, the Clinical Research Group on Groundbreaking Treatment for IIPs, supported by the Ministry of Health, Labour and Welfare, embarked on the registration system in the 2003 fiscal year (FY). In FY 2005, the system of web registration of clinical details of IIP patients of the Diffuse Lung Diseases Research Group, which existed at that time as the project leader, was completed. These details included: IIP type; patient characteristics at initial visit (gender, age, age of onset, family history, smoking history, complications); clinical findings (initial symptoms, form of onset, main symptoms, presence or absence of clubbed fingers); serological findings (including presence or absence of elevated Krebs von den Lungen-6 factor [KL-6] and surfactant protein [SP] A and D [SP-A and SP-D]); pulmonary function parameters (including % predicted vital capacity [%VC], % predicted diffusing capacity for carbon monoxide [%DLco], partial pressure of Abbreviations: ALAT, Disease; ERS,
Latin American Thoracic Association; ATS,
European Respiratory Society; FVC,
Pulmonary Fibrosis; JRS, SpO2,
2.2.
Time-to-event distribution for overall survival was estimated using the Kaplan–Meier method and survival rate between groups was compared by log-rank test.
3.
Results
3.1.
Web registry and patient follow-up
As shown in Table 1, 436 patients from 19 institutions were newly registered in the database during FY 2006–2010 (321 IPF, 82 non-specific interstitial pneumonia [NSIP], 15 other, and 18 not entered). Of the 436 patients, 261 remained in the registry at one year after the registration period, and the number of follow-up cases continued to decrease over time to 74 cases in the fifth year after the initial registration period.
3.2.
Characteristic of the registered patients
Table 2 shows patient characteristics by diagnosis at the initial visit (gender, age, age of onset, family history of interstitial pneumonia, smoking history, and complications). IPF was the most frequent diagnosis, and accounted for 321 cases (73.6%). Among the IPF patients, 78.8% were male, 80% were older than 60 years, and 6.2% were those whose age of onset was younger than 50 years. Surgical lung biopsy was performed in 131 (40.8%) IPF patients; 28 (8.7%) had a family history of interstitial pneumonia. Regarding complications among the IPF patients, diabetes was observed in 10%, COPD in 4.0%, and lung cancer in 3.1%. Disease severity American Thoracic Society; COPD,
Vital Capacity; %DLco,
Chronic Obstructive Pulmonary
Idiopathic Interstitial Pneumonias; IPF,
Krebs von den Lungen-6; NAC,
Partial Pressure of Arterial Oxygen; SP-A,
Oxygen Saturation by pulse oximetry; VC,
Statistical analysis
Forced Vital Capacity; IIPs,
Japanese Respiratory Society; KL-6,
Interstitial Pneumonia; PaO2,
arterial oxygen [PaO2] at rest, and lowest oxygen saturation by pulse oximetry [SpO2] during 6 min walking); diagnostic imaging results (shadow distribution, presence or absence of honeycomb lung and traction bronchiectasis, presence or absence of ground glass opacity and infiltration); disease severity; treatment (no treatment, pirfenidone, inhaled Nacetylcysteine [NAC], steroids, immunosuppressive drugs, and others); clinical course; and cause of death. The severity grade of IPF was determined according to the severity classification of the Japanese Respiratory Society criteria [1]. Acute exacerbations were also assessed according to established criteria in Japan [4]. This study was approved by the Institutional Review Board of the Tohoku University (Approval date: January 17, 2005; Approved #: 2004-331). Informed consent was obtained from patients.
N-acetylcysteine; NSIP,
Surfactant Protein-A; SP-D,
Idiopathic Non-specific
Surfactant Protein-D;
% predicted diffusing capacity for carbon monoxide;
%VC, % predicted vital capacity ☆ The Diffuse Lung Diseases Research Group by a Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research. n Corresponding author. Tel.: þ81 285 58 7350; fax: þ81 285 44 3586. E-mail addresses: [email protected] (M. Bando), [email protected] (Y. Sugiyama), [email protected] (A. Azuma), [email protected], [email protected] (M. Ebina), [email protected] (H. Taniguchi), [email protected] (Y. Taguchi), [email protected] (H. Takahashi), [email protected] (S. Homma), [email protected] (T. Nukiwa), [email protected] (S. Kudoh).
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respiratory investigation 53 (2015) 51 –59
Table 1 – Initial registration and follow-up. New registration
Number of cases
Follow-up
Number of cases
FY 2006 FY 2007 FY 2008 FY 2009 FY 2010 Total
131 162 57 80 6 436
At the time of registration First year after registration Second year after registration Third year after registration Fourth year after registration Fifth year after registration
436 261 191 148 109 74
analysis showed that grade I disease was the most frequent (40.2%), while grade IV disease found in 17.4% of patients. In terms of the relationship between IPF severity and respiratory function test results, 80 of 127 patients (63.0%) with severity grade I had %VC of Z80, while %VC of o50 was observed in only 4 (3.1%) cases. Among 52 patients with IPF severity grade IV, 7 (13.5%) exhibited %VC of Z80 and 17 (32.7%) exhibited %VC of o50. Data on %DLco were often missing, particularly in severity grade IV (18 of 56 cases, 32.1%). Among 82 cases of NSIP, women and non-smokers accounted for the majority of patients, and 39.0% were aged 60 years or younger. There were no complications in 79.3% of patients in this group. Three patients had concomitant lung cancer, but there were no registered NSIP patients who also had COPD. Severity grade I was most frequently observed (37.8%), similar to the IPF cases, while grade IV severity was found in 12.2% of the registered NSIP cases.
3.3. Clinical symptoms and physical and serological findings at the initial visit Table 3 shows symptoms and form of onset (chronic, subacute, acute, or not entered) at the initial visit. Dyspnea on exertion (DOE) was the most frequent (45.2%) symptom in the IPF patients at the initial visit, and 28.3% of the IPF patients sought medical consultation because of abnormal chest X-ray or CT findings without symptoms. DOE was also the most frequent symptom at the initial visit for the NSIP patients (57.3%), and chronic onset was seen in 74.4% of cases. Table 4 shows physical findings (presence or absence of fine crackles and clubbed fingers) and presence or absence of elevated serum markers of IIP at the time of initial registration. Fine crackles were found in 96.0% and 95.3% of IPF and NSIP patients, respectively. Clubbed fingers were found in 33.0% and 19.5% of IPF and NSIP patients, respectively. Elevated KL-6 (Z500 U/mL) was seen in 81.0% of IPF and 93.9% of NSIP patients and elevated SP-D (Z110 ng/mL) was seen in 66.4% of IPF and 69.5% of NSIP patients. In addition, rheumatoid factor was positive in 50 of 277 IPF patients (18.1%), excluding those for whom data were not input, antinuclear antibody Z320 was observed in 15 of 279 patients for whom these data were input (5.4%), and antinuclear antibody Z1280 observed in 5 cases (1.8%). Among the NSIP patients, rheumatoid factor was positive in 16 of 77 cases (20.8%), antinuclear antibody Z320 was observed in 11 of 79 cases (13.9%), and antinuclear antibody Z1280 was observed in 2 cases (2.5%).
3.4.
Evolution of treatment of IPF
Fig. 1 shows the treatments (no treatment, inhaled N-acetylcysteine [NAC], steroids, immunosuppressive agents,
pirfenidone, and others) that were given for IPF during FY 2006–2008 (before pirfenidone introduction) and FY 2009–2013 (after pirfenidone introduction). Before FY 2009, most patients (78.7%) received no treatment. This reduced to 44.6% during FY 2009–2013, when pirfenidone monotherapy was given in 17.4% of cases and combination therapy of pirfenidone with other agents was used in 15.5% of cases. Conversely, there were only negligible changes in the rate of steroid monotherapy, which increased from 6.2% to 7.5% after 2009, and in rates of combination therapy using steroids and immunosuppressive agents, which increased slightly, from 11.2% to 13.1%, in the same period. NAC inhalation therapy was only reported in 3.8% of cases at the end of FY 2013, even when combination therapy with pirfenidone was available. Fig. 2A and B shows the types of treatment with respect to severity of IPF. Most patients (59.5%) with IPF severity grades I and II received no treatment during FY 2009–2013, while for patients with IPF severity grades III and IV, no treatment and pirfenidone were administered to 24.3% and 42.0%, respectively. Steroid monotherapy and combination therapy with steroids and immunosuppressive agents were administered in 5.4% and 10.8% of cases, respectively, among patients with severity grades I and II, and in 11.2% and 17.8% of cases, respectively, with severity grades III and IV.
3.5.
Clinical course and prognosis of IPF
Fig. 3 shows survival curves from the onset of symptoms and from the initial visit. The median survival times were 105 months [95% CI: 96–117] and 69 months [95% CI: 63–93], respectively. Fig. 4 shows the survival curves of IPF patients with symptoms and those without symptoms at the initial visit. The median survival times were 63 months [95% CI: 46–69] in symptomatic IPF patients and 105 months [95% CI: 69–114] in asymptomatic IPF patients, respectively. The prognosis was significantly worse in the symptomatic group than in the asymptomatic group (p¼ 0.0013, log-rank test). Acute exacerbation was the most frequent cause of death, reported in 66 of 113 (58.4%) patients for whom the cause of death was available, and the time to death due to acute exacerbation was commonly between 5 and 10 years after onset. The second most common cause of death for IPF patients was respiratory failure due to disease progression other than acute exacerbation.
4.
Discussion
An analysis of results of a prospective survey on IIPs from a web registry in Japan that has been conducted since FY 2005
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respiratory investigation 53 (2015) 51 –59
Table 2 – Patient characteristics. Survey items
Diagnosis IPF 321 cases
NSIP 82 cases
Other 15 cases
Not Entered 18 cases
Total 436 cases
Cases
%
Cases
%
Cases
%
Cases
%
Cases
253 68
78.8 21.2
36 46
43.9 56.1
10 5
66.7 33.3
14 4
77.8 22.2
313 123
67 67 68 77 41 1
20.9 20.9 21.2 24.0 12.8 0.3
32 20 16 10 4 0
39.0 24.4 19.5 12.2 4.9 0.0
7 3 2 1 2 0
46.7 20.0 13.3 6.7 13.3 0.0
4 6 2 3 2 1
22.2 33.3 11.1 16.7 11.1 5.6
110 96 88 91 49 2
Age of onset 50 years or older Less than 50 years Not entered
296 20 5
92.2 6.2 1.6
66 14 2
80.5 17.1 2.4
13 2 0
86.7 13.3 0.0
17 1 0
94.4 5.6 0.0
392 37 7
Family history Yes None Unknown Not entered
28 265 25 3
8.7 82.6 7.8 0.9
3 78 1 0
3.7 95.1 1.2 0.0
2 13 0 0
13.3 86.7 0.0 0.0
3 11 2 2
16.7 61.1 11.1 11.1
36 367 28 5
Smoking history Current smoker Ex-smoker Non-smoker Not entered
55 178 80 8
17.1 55.5 24.9 2.5
7 30 45 0
8.5 36.6 54.9 0.0
1 8 6 0
6.7 53.3 40.0 0.0
4 4 3 7
22.2 22.2 16.7 38.9
67 220 134 15
Complications None Lung cancer COPD Diabetes Other
196 10 13 32 51
61.1 3.1 4.0 10.0 15.9
65 3 0 2 9
79.3 3.7 0.0 2.4 11.0
12 0 1 2 0
80.0 0.0 6.7 13.3 0.0
9 2 0 2 2
50.0 11.1 0.0 11.1 11.1
282 15 14 38 62
Gender Male Female
Age r 60 61–65 66–70 71–75 r 76 Not entered
Table 3 – Symptom profile. Diagnosis IPF 321 cases
NSIP 82 cases
Other 15 cases
Not Entered 18 cases
Total 436 cases
Survey items
Cases
%
Cases
%
Cases
%
Cases
%
Cases
Symptoms at initial visit Dyspnea on exertion (DOE) Coughing Abnormal shadow on chest X-ray Other Not entered
145 72 91 3 10
45.2 22.4 28.3 0.9 3.1
47 21 11 1 2
57.3 25.6 13.4 1.2 2.4
7 3 5 0 0
46.7 20.0 33.3 0.0 0.0
7 4 4 0 3
38.9 22.2 22.2 0.0 16.7
206 100 111 4 15
Type of onset Chronic onset (3 months or more) Subacute onset (1–3 months) Acute onset (within 1 month) Not entered
306 10 1 4
95.3 3.1 0.3 1.2
61 18 2 1
74.4 22.0 2.4 1.2
6 4 5 0
40.0 26.7 33.3 0.0
15 0 0 3
83.3 0.0 0.0 16.7
388 32 8 8
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respiratory investigation 53 (2015) 51 –59
Table 4 – Physical findings and serum interstitial pneumonia markers. Diagnosis IPF 21 cases
NSIP 82 cases
Other 15 cases
Not entered 18 cases
Total 436 cases
Cases
%
Cases
Survey items
Cases
%
Cases
%
Cases
%
Fine crackles Yes None Unknown Not entered
308 10 1 2
96.0 3.1 0.3 0.6
78 3 0 1
95.1 3.7 0.0 1.2
13 2 0 0
86.7 13.3 0.0 0.0
9 0 0 9
50.0 0.0 0.0 50.0
408 15 1 12
Clubbed fingers Yes None Unknown Not entered
106 189 21 5
33.0 58.9 6.5 1.6
16 64 1 1
19.5 78.0 1.2 1.2
3 12 0 0
20.0 80.0 0.0 0.0
1 6 0 11
5.6 33.3 0.0 61.1
126 271 22 17
Elevated KL-6a Yes None Unknown Not entered
260 44 3 14
81.0 13.7 0.9 4.4
77 2 1 2
93.9 2.4 1.2 2.4
11 3 0 1
73.3 20.0 0.0 6.7
6 1 0 11
33.3 5.6 0.0 61.1
354 50 4 28
Elevated SP-Db Yes None Unknown Not entered
213 52 48 8
66.4 16.2 15.0 2.5
57 5 19 1
69.5 6.1 23.2 1.2
9 2 4 0
60.0 13.3 26.7 0.0
3 2 2 11
16.7 11.1 11.1 61.1
282 61 73 20
a b
KL-6, Krebs von den Lungen-6. SP-D, surfactant protein-D.
Fig. 1 – Evolution of treatments for IPF. NAC: N-acetylcysteine.
is reported here. In Japan, IIPs with severity grade III or IV are included in the Specific Disease Treatment Research program, which subsidizes medical expenses for patients with intractable diseases (Nanbyo diseases). For patients to receive these public funds, individual medical records are to be submitted annually to the prefecture by an attending physician. After record submission, each prefecture registers patients in a specific disease research analysis system
(Information-exchange System for Health and Welfare Administration [WISH] network) to optimize certification of intractable disease and chart nationwide trends among patients with these diseases. While epidemiological studies on IIPs using these individual clinical records have been conducted [5,6], records have tended to emphasize administrative details for the application of public funds. Furthermore, the input rate is very low, and the contents of the
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respiratory investigation 53 (2015) 51 –59
Fig. 2 – (A) Evolution of treatment of IPF with respect to severity, severity grades I–II. In most cases (59.5%) of IPF with severity grades I and II that were newly registered during the 2009–2013 fiscal years, no treatment was given, while steroid monotherapy and combination therapy with steroids and immunosuppressive agents were used in 5.4% and 10.8%, respectively. (B) Evolution of treatment of IPF with respect to severity, severity grades III–IV. In IPF cases of severity grades III and IV that were newly registered between the 2009 and 2013 fiscal years, no treatment was given for 24.3% of patients, and pirfenidone therapy was used for 39.3% of patients. Steroid monotherapy and combination therapy with steroids and immunosuppressive agents were administered to 11.2% and 17.8%, respectively.
registry are sometimes inaccurate. Therefore, trends among patients with Nanbyo diseases may not be accurately followed [5]. Reforms toward improved accuracy and more effective use of the current registration system of individual clinical records and data collection were proposed during the Health Science Council for Control of Intractable Diseases in January 2013. Consideration has also been given to development of a new input system and introduction of an intractable disease specialist (tentative title) who performs the registration. Meanwhile, the web registration system that was used to collect the data presented in the current report was implemented as a component of a research project for overcoming intractable diseases under the Ministry of Health, Labour and
Welfare Grant-in-Aid for Scientific Research. The information was received from a limited number of medical institutions that belong to the intractable disease study group. Therefore, unlike the aforementioned system, the reliability of data from the IIP registry used in this study is expected to be greater than that of an epidemiological study based on individual clinical records. To date, there have been no large-scale prospective epidemiological studies in Japan on the clinical course and treatment of IIPs from the time of diagnosis. In this study, IPF accounted for 73.6% of IIP cases (321/436) entered in the web registry over a five-year period, and clinical characteristics and treatment strategies for these patients were
57
From the time of the onset of symptoms 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 250
300
Time (months)
From the time of initial visit 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150
Survival distribution function estimates
Survival distribution function estimates
respiratory investigation 53 (2015) 51 –59
200
250
300
350
Time (months)
Fig. 3 – Kaplan–Meier plot of survival probability from the time of the onset of symptoms and the time of initial visit. The median survival times were 105 months [95% CI: 96–117] and 69 months [95% CI: 63–93], respectively.
Fig. 4 – Kaplan–Meier plot of survival probability in IPF patients with and without symptoms at the initial visit. The median survival times were 63 months [95% CI: 46–69] in symptomatic IPF patients and 105 months [95% CI: 69–114] in asymptomatic IPF patients. The prognosis was significantly worse in the symptomatic group compared with the asymptomatic group (p ¼0.0013, log-rank test). examined. The most prominent physical findings among the newly registered IPF patients were fine crackles (96.0%), and clubbed fingers were observed in 33.0%. These findings are consistent with those reported in western countries, where fine crackles and clubbed fingers were found in 480% and 25– 50% of IPF cases, respectively [7], as well as with those reported in previous studies in Japan, where these signs have been observed in approximately 90% and 30–60% of patients, respectively [1,8]. Thus, it is again recognized that fine crackles and clubbing are important physical findings for the diagnosis of IPF. As for the presence or absence of elevated KL-6 and SP-D levels at the time of registration, elevated KL-6 levels ( Z500 U/mL) were reported 81.0% of IPF cases, and elevated SP-D levels ( Z110 ng/mL) were seen in 66.4%. In previous reports [1,9], abnormally elevated KL-6 and SP-D levels were found in 87–93% of IPF patients, and these were detected at a rate of 77–87% even in mild cases (severity grades I and II). However, the rate of abnormally elevated SPD levels in the present study was slightly lower than has been previously reported [10].
The most notable point of this study was the result concerning the evolution of the treatment strategy for IPF since the introduction of the anti-fibrotic drug pirfenidone, which first became available in Japan, in advance of other countries, in December 2008. Before pirfenidone, no treatment was given for IPF in more than 75% of cases. Since pirfenidone, the number of untreated patients was reduced to 45% by FY 2013, and pirfenidone has been used in approximately 1/3 of cases. On the other hand, steroid monotherapy and combination therapy with steroids and immunosuppressive drugs were still used in approximately 20% of cases. In Japan, the empirical selection of steroids and immunosuppressive drugs to treat IPF in clinical practice is common, although it is not recommended under the 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) evidence-based guidelines for diagnosis and management of IPF [2]. In Japan, the second edition of the revised Guidelines for Diagnosis and Treatment of Idiopathic Interstitial Pneumonias [1] state that a combination of steroids and immunosuppressive drugs (i.e., cyclosporine, cyclophosphamide, azathioprine) is indicated as a treatment option for IIP including IPF because there are currently no clinical studies that report negative findings, although neither are there any large-scale studies that have demonstrated their effectiveness. Moreover, a prospective multicenter clinical comparative study analyzing the effectiveness of combination of steroids and cyclophosphamide or cyclosporine [11] found that there was no significant difference in the primary endpoint between the two groups, while the annual decrease in vital capacity (VC) was as small as 80 mL. It is necessary to continue to reexamine and reanalyze guidelines for diagnosis and treatment of IIPs, for which future revisions are planned. With regard to the prognosis of IPF patients, an average survival period from the time of diagnosis of 28–52 months has been reported in western countries [12–16], and King Jr et al. [12] reported median survival times of 80.8 months from the onset of symptoms and 35.2 months from the initial visit. We found survival times of 105 months from the onset of
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symptoms and 69 months from the time of the initial visit, and the prognosis from the initial visit was significantly worse in symptomatic patients than in asymptomatic patients. The longer survival times reported in our study, as compared with those reported in western countries, may have been related to disease severity. In the present study, 51.1% of the registered IPF patients had relatively mild disease (severity grades I and II), and 28.3% presented with abnormal chest X-ray or CT findings in the absence of symptoms. In studies from the western countries [12,17], the patients with IPF often did not present for medical care until an average of 2 years after the onset of symptoms such as DOE or coughing. Delayed access to specialized medical care has also been suggested as a risk factor for poor prognosis [17]. In Japan, CT examinations are freely ordered by the family doctor or for screening even before symptoms are noted, thus IPF has been detected even in asymptomatic individuals in whom interstitial lung lesions are detected incidentally, and such patients have been referred for immediate evaluations at specialized medical institutions upon the appearance of symptoms. In the present study, acute exacerbation, usually between 5 and 10 years from the onset of disease, accounted for more than half of the deaths that were reported in IPF patients. In reports from the West [3,13,14], respiratory-related deaths in IPF patients are frequent, and rapid exacerbation within 4 months occurred in 30% of cases. Acute exacerbation also accounted for deaths of 35–41% of patients in previous reports in Japan [5,18], and the finding that the death rate due to acute exacerbation was even higher in the present study is possibly because the data for this study were collected only from the specialized facilities of the intractable disease group. In any case, while the importance of acute exacerbation of IPF has increasingly been recognized internationally during the last few years, and a variety of findings have been reported, it is still necessary to further elucidate the mechanism of onset and the risk factors, including genetic factors and ethnicity-dependent differences in rates of occurrence, as well as to develop new treatments. In order to make feasible the widespread practical use of integrated data from a web registry such as the one reported here, it is very important to provide full consideration for protecting each patient's personal information, not only for the intractable disease study group, but also for research institutions, medical institutions, and companies that are involved in intractable disease research. Further, it is imperative that the research content and achievements are reported to patients, medical providers, and the nation at large. Various problems arising in the process of web registration in this study, including validity of input items, quality control, and others, will provide valuable information for the reform proposals for measures against intractable diseases, such as construction of a new collection system for patient data that are currently being considered.
5.
Conclusions
We analyzed integrated data on diagnoses, clinical findings, course, and treatment of IIPs, particularly cases of IPF, which
were registered in an Internet database by participating medical institutions across Japan that specialize in IIP. There have been no previous prospective large-scale multicenter epidemiological studies of IIPs in Japan. Therefore, this study should provide valuable information for understanding the current clinical situation of patients with IPF.
Conflict of interest Masashi Bando received lecture fees from Nippon Boehringer Ingelheim Co. Yukihiko Sugiyama received lecture fees from SHIONOGI & CO., and Nippon Boehringer Ingelheim Co. Hiroyuki Taniguchi received lecture fees from Asahi Kasei Pharma Corp. Toshihiro Nukiwa received lecture fees from SHIONOGI & CO., and Nippon Boehringer Ingerlheim Co., and travel fees, gifts, and others from SEKISUI MEDICAL CO. The other authors report no conflicts of interest.
Authors' contributions to the study Dr. Masashi Bando had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Yukihiko Sugiyama contributed to the study design and review and approval of the manuscript. Dr. Arata Azuma contributed to the study design and data collection. Dr. Masahito Ebina contributed to the study design and data collection. Dr. Hiroyuki Taniguchi contributed to the study design and data collection. Dr. Yoshio Taguchi contributed to the study design and data collection. Dr. Hiroki Takahashi contributed to the study design and data collection Dr. Sakae Homma contributed to the study design and data collection. Dr. Toshihiro Nukiwa contributed to the study conception and design, and data analysis. Dr. Shoji Kudoh contributed to the study design and review and approval of the manuscript.
Acknowledgments This study was supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labour and Welfare, Japan. The members of the Diffuse Lung Diseases Research Group of the Ministry of Health, Labour and Welfare Grantin-Aid for Scientific Research are. K. Chida, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu. N. Keicho, Research Institute National Center for Global Health and Medicine Tokyo. Y. Nakanishi, Research Institute for Diseases of the Chest, Graduate School of Medicine Sciences, Kyushu University, Fukuoka.
respiratory investigation 53 (2015) 51 –59
N. Inase, Department of Integrated Pulmonology, Tokyo Medical and Dental University, Tokyo. M. Nishimura, First Department of Medicine, Hokkaido University Hospital, Sapporo. Y. Inoue, Kinki-Chuo Chest Medical Center, Osaka. H. Mukae, Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka. A. Yokoyama, Kochi Medical School Hospital, Kochi H. Takizawa, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo. M. Mishima, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto. Y. Nishioka, Department of Internal Medicine and Molecular Therapeutics, Tokushima University, Tokushima. Y. Ishii, Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi. M. Munakata, Department of Pulmonary Medicine, Fukushima Medical University, Fukushima. N. Kohno, Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences Hiroshima University, Hiroshima. K. Kishi, Toranomon Hospital, Tokyo. T. Ogura, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa. K. Watanabe, Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka.
[6]
[7]
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r e f e r e n c e s [13]
[1] Japanese Respiratory Society’s Committee Formulating Diagnosis and Treatment Guideline for Diffuse Lung Diseases. Revised 2nd edition guidelines for diagnosis and treatment of idiopathic interstitial pneumonias, Nankodo, Tokyo, 2011. [2] Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824. [3] Ley B, Collard HR, King Jr TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431–40. [4] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821–9. [5] Natsuizaka M, Chiba H, Kuronuma K, et al. Epidemiological survey of Japanese patients with idiopathic pulmonary
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fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014;190:773–9. Ohno S, Nakaya T, Bando M, et al. Idiopathic pulmonary fibrosis—results from a Japanese nationwide epidemiological survey using individual clinical records. Respirology 2008;13:926–8. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000;161:646–64. Taguchi Y, Inoue T. Main symptoms and physical findings in clinical diagnostic criteria. Health, labour and welfare grantin-aid for scientific research, diffuse lung diseases research FY 2000 research report. 2001. p. 96–99. Ishikawa N, Hattori N, Yokoyama A, et al. Utility of KL-6/ MUC1 in the clinical management of interstitial lung disease. Respir Invest 2012;50:3–13. Ohnishi H, Yokoyama A, Kondo K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Cirt Care Med 2002;165:378–81. Miyazaki A, Azuma N, Inase T, et al. A randomized, doubleblind, multi-centered controlled trial of cyclosporine a vs. cyclophosphamide with corticosteroid in patients with idiopathic pulmonary fibrosis in Japan. In: Proceedings of the 2011 American Thoracic Society international conference. Denver, CO, USA. Chapter, http://dx.doi.org/10.1164/ ajrccm-conference.2011.183.1_MeetingAbstracts.A381210. 1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A3812; publication date 2011. King Jr TE, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001;164:1171–81. Martinez JF, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005;142:963–7. Fernandez Perez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis. Chest 2010;137:129–37. Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest 2011;140:221–9. Mura M, Porretta MA, Bargagli E, et al. Predicting survival in newly diagnosed idiopathic pulmonary fibrosis: a 3-year prospective study. Eur Respir J 2012;40:1001–109. Lamas DJ, Kawut SM, Bagiella E, et al. Delayed access and survival in idiopathic pulmonary fibrosis. A cohort study. Am J Respir Crit Care Med 2011;184:842–7. Kondoh Y, Taniguchi H, Katsuta T, et al. Risk factors of acute exacerbation of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2010;27:103–10.
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
A prospective survey of idiopathic interstitial pneumonias in a web registry in Japan$ Masashi Bandoa,n, Yukihiko Sugiyamaa, Arata Azumab, Masahito Ebinac, Hiroyuki Taniguchid, Yoshio Taguchie, Hiroki Takahashif, Sakae Hommag, Toshihiro Nukiwah, Shoji Kudohi a
Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan Division of Pulmonary Medicine, Infection and Oncology, Nippon Medical School, Tokyo, Japan c Department of Respiratory Medicine, Tohoku Pharmaceutical University Hospital, Sendai, Japan d Department of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan e Department of Respiratory Medicine, Tenri Hospital, Tenri, Japan f Third Department of Internal Medicine, Sapporo Medical University Hospital, Sapporo, Japan g Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan h South Miyagi Medical Center, Miyagi, Japan i Respiratory Disease Center, Double-Barred Cross Hospital, Tokyo, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: There have been no prospective large-scale multicenter epidemiological
Received 11 July 2014
studies on the clinical course and treatment from the time of diagnosis of idiopathic
Received in revised form
interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current
14 October 2014
clinical situation of IIP in Japan.
Accepted 6 November 2014
Methods: This study was supported by a grant from the Ministry of Health, Labour and
Available online 4 December 2014 Keywords: Idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis Prospective multicenter epidemiological study Web registration
Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed. Results: A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively. Conclusions: This study should provide valuable information for understanding the current state of IIP in Japan. & 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.resinv.2014.11.001 2212-5345/& 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
52
1.
respiratory investigation 53 (2015) 51 –59
Introduction
Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown etiology with a poor prognosis that follows a chronic and progressive course resulting in severe fibrosis and formation of irreversible honeycomb lung [1,2]. The natural course and prognosis of IPF varies for each patient, and is difficult to predict. Determination of the need for intervention and the development of effective treatment strategies depend on a multifaceted evaluation of the clinical course and the risk factors for poor prognosis [2,3]. IPF is categorized as an idiopathic interstitial pneumonia (IIP). To date, there have not been a large-scale prospective epidemiological study of the clinical course and treatment of IIP from the time of diagnosis in patients in Japan. We analyzed data on diagnoses, clinical findings, treatments, and disease course from an integrated internet database of IIP patients that was created with the participation of medical institutions across Japan that specialize in IIPs. This study was aimed at describing the current state of IIP in Japan and examining diagnostic findings and standards of care. This prospective survey on diffuse lung diseases that was conducted within the framework of a research project supported by the Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research.
2.
Materials and methods
2.1.
Patients and data collection
A research project for overcoming intractable diseases, the Clinical Research Group on Groundbreaking Treatment for IIPs, supported by the Ministry of Health, Labour and Welfare, embarked on the registration system in the 2003 fiscal year (FY). In FY 2005, the system of web registration of clinical details of IIP patients of the Diffuse Lung Diseases Research Group, which existed at that time as the project leader, was completed. These details included: IIP type; patient characteristics at initial visit (gender, age, age of onset, family history, smoking history, complications); clinical findings (initial symptoms, form of onset, main symptoms, presence or absence of clubbed fingers); serological findings (including presence or absence of elevated Krebs von den Lungen-6 factor [KL-6] and surfactant protein [SP] A and D [SP-A and SP-D]); pulmonary function parameters (including % predicted vital capacity [%VC], % predicted diffusing capacity for carbon monoxide [%DLco], partial pressure of Abbreviations: ALAT, Disease; ERS,
Latin American Thoracic Association; ATS,
European Respiratory Society; FVC,
Pulmonary Fibrosis; JRS, SpO2,
2.2.
Time-to-event distribution for overall survival was estimated using the Kaplan–Meier method and survival rate between groups was compared by log-rank test.
3.
Results
3.1.
Web registry and patient follow-up
As shown in Table 1, 436 patients from 19 institutions were newly registered in the database during FY 2006–2010 (321 IPF, 82 non-specific interstitial pneumonia [NSIP], 15 other, and 18 not entered). Of the 436 patients, 261 remained in the registry at one year after the registration period, and the number of follow-up cases continued to decrease over time to 74 cases in the fifth year after the initial registration period.
3.2.
Characteristic of the registered patients
Table 2 shows patient characteristics by diagnosis at the initial visit (gender, age, age of onset, family history of interstitial pneumonia, smoking history, and complications). IPF was the most frequent diagnosis, and accounted for 321 cases (73.6%). Among the IPF patients, 78.8% were male, 80% were older than 60 years, and 6.2% were those whose age of onset was younger than 50 years. Surgical lung biopsy was performed in 131 (40.8%) IPF patients; 28 (8.7%) had a family history of interstitial pneumonia. Regarding complications among the IPF patients, diabetes was observed in 10%, COPD in 4.0%, and lung cancer in 3.1%. Disease severity American Thoracic Society; COPD,
Vital Capacity; %DLco,
Chronic Obstructive Pulmonary
Idiopathic Interstitial Pneumonias; IPF,
Krebs von den Lungen-6; NAC,
Partial Pressure of Arterial Oxygen; SP-A,
Oxygen Saturation by pulse oximetry; VC,
Statistical analysis
Forced Vital Capacity; IIPs,
Japanese Respiratory Society; KL-6,
Interstitial Pneumonia; PaO2,
arterial oxygen [PaO2] at rest, and lowest oxygen saturation by pulse oximetry [SpO2] during 6 min walking); diagnostic imaging results (shadow distribution, presence or absence of honeycomb lung and traction bronchiectasis, presence or absence of ground glass opacity and infiltration); disease severity; treatment (no treatment, pirfenidone, inhaled Nacetylcysteine [NAC], steroids, immunosuppressive drugs, and others); clinical course; and cause of death. The severity grade of IPF was determined according to the severity classification of the Japanese Respiratory Society criteria [1]. Acute exacerbations were also assessed according to established criteria in Japan [4]. This study was approved by the Institutional Review Board of the Tohoku University (Approval date: January 17, 2005; Approved #: 2004-331). Informed consent was obtained from patients.
N-acetylcysteine; NSIP,
Surfactant Protein-A; SP-D,
Idiopathic Non-specific
Surfactant Protein-D;
% predicted diffusing capacity for carbon monoxide;
%VC, % predicted vital capacity ☆ The Diffuse Lung Diseases Research Group by a Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research. n Corresponding author. Tel.: þ81 285 58 7350; fax: þ81 285 44 3586. E-mail addresses: [email protected] (M. Bando), [email protected] (Y. Sugiyama), [email protected] (A. Azuma), [email protected], [email protected] (M. Ebina), [email protected] (H. Taniguchi), [email protected] (Y. Taguchi), [email protected] (H. Takahashi), [email protected] (S. Homma), [email protected] (T. Nukiwa), [email protected] (S. Kudoh).
53
respiratory investigation 53 (2015) 51 –59
Table 1 – Initial registration and follow-up. New registration
Number of cases
Follow-up
Number of cases
FY 2006 FY 2007 FY 2008 FY 2009 FY 2010 Total
131 162 57 80 6 436
At the time of registration First year after registration Second year after registration Third year after registration Fourth year after registration Fifth year after registration
436 261 191 148 109 74
analysis showed that grade I disease was the most frequent (40.2%), while grade IV disease found in 17.4% of patients. In terms of the relationship between IPF severity and respiratory function test results, 80 of 127 patients (63.0%) with severity grade I had %VC of Z80, while %VC of o50 was observed in only 4 (3.1%) cases. Among 52 patients with IPF severity grade IV, 7 (13.5%) exhibited %VC of Z80 and 17 (32.7%) exhibited %VC of o50. Data on %DLco were often missing, particularly in severity grade IV (18 of 56 cases, 32.1%). Among 82 cases of NSIP, women and non-smokers accounted for the majority of patients, and 39.0% were aged 60 years or younger. There were no complications in 79.3% of patients in this group. Three patients had concomitant lung cancer, but there were no registered NSIP patients who also had COPD. Severity grade I was most frequently observed (37.8%), similar to the IPF cases, while grade IV severity was found in 12.2% of the registered NSIP cases.
3.3. Clinical symptoms and physical and serological findings at the initial visit Table 3 shows symptoms and form of onset (chronic, subacute, acute, or not entered) at the initial visit. Dyspnea on exertion (DOE) was the most frequent (45.2%) symptom in the IPF patients at the initial visit, and 28.3% of the IPF patients sought medical consultation because of abnormal chest X-ray or CT findings without symptoms. DOE was also the most frequent symptom at the initial visit for the NSIP patients (57.3%), and chronic onset was seen in 74.4% of cases. Table 4 shows physical findings (presence or absence of fine crackles and clubbed fingers) and presence or absence of elevated serum markers of IIP at the time of initial registration. Fine crackles were found in 96.0% and 95.3% of IPF and NSIP patients, respectively. Clubbed fingers were found in 33.0% and 19.5% of IPF and NSIP patients, respectively. Elevated KL-6 (Z500 U/mL) was seen in 81.0% of IPF and 93.9% of NSIP patients and elevated SP-D (Z110 ng/mL) was seen in 66.4% of IPF and 69.5% of NSIP patients. In addition, rheumatoid factor was positive in 50 of 277 IPF patients (18.1%), excluding those for whom data were not input, antinuclear antibody Z320 was observed in 15 of 279 patients for whom these data were input (5.4%), and antinuclear antibody Z1280 observed in 5 cases (1.8%). Among the NSIP patients, rheumatoid factor was positive in 16 of 77 cases (20.8%), antinuclear antibody Z320 was observed in 11 of 79 cases (13.9%), and antinuclear antibody Z1280 was observed in 2 cases (2.5%).
3.4.
Evolution of treatment of IPF
Fig. 1 shows the treatments (no treatment, inhaled N-acetylcysteine [NAC], steroids, immunosuppressive agents,
pirfenidone, and others) that were given for IPF during FY 2006–2008 (before pirfenidone introduction) and FY 2009–2013 (after pirfenidone introduction). Before FY 2009, most patients (78.7%) received no treatment. This reduced to 44.6% during FY 2009–2013, when pirfenidone monotherapy was given in 17.4% of cases and combination therapy of pirfenidone with other agents was used in 15.5% of cases. Conversely, there were only negligible changes in the rate of steroid monotherapy, which increased from 6.2% to 7.5% after 2009, and in rates of combination therapy using steroids and immunosuppressive agents, which increased slightly, from 11.2% to 13.1%, in the same period. NAC inhalation therapy was only reported in 3.8% of cases at the end of FY 2013, even when combination therapy with pirfenidone was available. Fig. 2A and B shows the types of treatment with respect to severity of IPF. Most patients (59.5%) with IPF severity grades I and II received no treatment during FY 2009–2013, while for patients with IPF severity grades III and IV, no treatment and pirfenidone were administered to 24.3% and 42.0%, respectively. Steroid monotherapy and combination therapy with steroids and immunosuppressive agents were administered in 5.4% and 10.8% of cases, respectively, among patients with severity grades I and II, and in 11.2% and 17.8% of cases, respectively, with severity grades III and IV.
3.5.
Clinical course and prognosis of IPF
Fig. 3 shows survival curves from the onset of symptoms and from the initial visit. The median survival times were 105 months [95% CI: 96–117] and 69 months [95% CI: 63–93], respectively. Fig. 4 shows the survival curves of IPF patients with symptoms and those without symptoms at the initial visit. The median survival times were 63 months [95% CI: 46–69] in symptomatic IPF patients and 105 months [95% CI: 69–114] in asymptomatic IPF patients, respectively. The prognosis was significantly worse in the symptomatic group than in the asymptomatic group (p¼ 0.0013, log-rank test). Acute exacerbation was the most frequent cause of death, reported in 66 of 113 (58.4%) patients for whom the cause of death was available, and the time to death due to acute exacerbation was commonly between 5 and 10 years after onset. The second most common cause of death for IPF patients was respiratory failure due to disease progression other than acute exacerbation.
4.
Discussion
An analysis of results of a prospective survey on IIPs from a web registry in Japan that has been conducted since FY 2005
54
respiratory investigation 53 (2015) 51 –59
Table 2 – Patient characteristics. Survey items
Diagnosis IPF 321 cases
NSIP 82 cases
Other 15 cases
Not Entered 18 cases
Total 436 cases
Cases
%
Cases
%
Cases
%
Cases
%
Cases
253 68
78.8 21.2
36 46
43.9 56.1
10 5
66.7 33.3
14 4
77.8 22.2
313 123
67 67 68 77 41 1
20.9 20.9 21.2 24.0 12.8 0.3
32 20 16 10 4 0
39.0 24.4 19.5 12.2 4.9 0.0
7 3 2 1 2 0
46.7 20.0 13.3 6.7 13.3 0.0
4 6 2 3 2 1
22.2 33.3 11.1 16.7 11.1 5.6
110 96 88 91 49 2
Age of onset 50 years or older Less than 50 years Not entered
296 20 5
92.2 6.2 1.6
66 14 2
80.5 17.1 2.4
13 2 0
86.7 13.3 0.0
17 1 0
94.4 5.6 0.0
392 37 7
Family history Yes None Unknown Not entered
28 265 25 3
8.7 82.6 7.8 0.9
3 78 1 0
3.7 95.1 1.2 0.0
2 13 0 0
13.3 86.7 0.0 0.0
3 11 2 2
16.7 61.1 11.1 11.1
36 367 28 5
Smoking history Current smoker Ex-smoker Non-smoker Not entered
55 178 80 8
17.1 55.5 24.9 2.5
7 30 45 0
8.5 36.6 54.9 0.0
1 8 6 0
6.7 53.3 40.0 0.0
4 4 3 7
22.2 22.2 16.7 38.9
67 220 134 15
Complications None Lung cancer COPD Diabetes Other
196 10 13 32 51
61.1 3.1 4.0 10.0 15.9
65 3 0 2 9
79.3 3.7 0.0 2.4 11.0
12 0 1 2 0
80.0 0.0 6.7 13.3 0.0
9 2 0 2 2
50.0 11.1 0.0 11.1 11.1
282 15 14 38 62
Gender Male Female
Age r 60 61–65 66–70 71–75 r 76 Not entered
Table 3 – Symptom profile. Diagnosis IPF 321 cases
NSIP 82 cases
Other 15 cases
Not Entered 18 cases
Total 436 cases
Survey items
Cases
%
Cases
%
Cases
%
Cases
%
Cases
Symptoms at initial visit Dyspnea on exertion (DOE) Coughing Abnormal shadow on chest X-ray Other Not entered
145 72 91 3 10
45.2 22.4 28.3 0.9 3.1
47 21 11 1 2
57.3 25.6 13.4 1.2 2.4
7 3 5 0 0
46.7 20.0 33.3 0.0 0.0
7 4 4 0 3
38.9 22.2 22.2 0.0 16.7
206 100 111 4 15
Type of onset Chronic onset (3 months or more) Subacute onset (1–3 months) Acute onset (within 1 month) Not entered
306 10 1 4
95.3 3.1 0.3 1.2
61 18 2 1
74.4 22.0 2.4 1.2
6 4 5 0
40.0 26.7 33.3 0.0
15 0 0 3
83.3 0.0 0.0 16.7
388 32 8 8
55
respiratory investigation 53 (2015) 51 –59
Table 4 – Physical findings and serum interstitial pneumonia markers. Diagnosis IPF 21 cases
NSIP 82 cases
Other 15 cases
Not entered 18 cases
Total 436 cases
Cases
%
Cases
Survey items
Cases
%
Cases
%
Cases
%
Fine crackles Yes None Unknown Not entered
308 10 1 2
96.0 3.1 0.3 0.6
78 3 0 1
95.1 3.7 0.0 1.2
13 2 0 0
86.7 13.3 0.0 0.0
9 0 0 9
50.0 0.0 0.0 50.0
408 15 1 12
Clubbed fingers Yes None Unknown Not entered
106 189 21 5
33.0 58.9 6.5 1.6
16 64 1 1
19.5 78.0 1.2 1.2
3 12 0 0
20.0 80.0 0.0 0.0
1 6 0 11
5.6 33.3 0.0 61.1
126 271 22 17
Elevated KL-6a Yes None Unknown Not entered
260 44 3 14
81.0 13.7 0.9 4.4
77 2 1 2
93.9 2.4 1.2 2.4
11 3 0 1
73.3 20.0 0.0 6.7
6 1 0 11
33.3 5.6 0.0 61.1
354 50 4 28
Elevated SP-Db Yes None Unknown Not entered
213 52 48 8
66.4 16.2 15.0 2.5
57 5 19 1
69.5 6.1 23.2 1.2
9 2 4 0
60.0 13.3 26.7 0.0
3 2 2 11
16.7 11.1 11.1 61.1
282 61 73 20
a b
KL-6, Krebs von den Lungen-6. SP-D, surfactant protein-D.
Fig. 1 – Evolution of treatments for IPF. NAC: N-acetylcysteine.
is reported here. In Japan, IIPs with severity grade III or IV are included in the Specific Disease Treatment Research program, which subsidizes medical expenses for patients with intractable diseases (Nanbyo diseases). For patients to receive these public funds, individual medical records are to be submitted annually to the prefecture by an attending physician. After record submission, each prefecture registers patients in a specific disease research analysis system
(Information-exchange System for Health and Welfare Administration [WISH] network) to optimize certification of intractable disease and chart nationwide trends among patients with these diseases. While epidemiological studies on IIPs using these individual clinical records have been conducted [5,6], records have tended to emphasize administrative details for the application of public funds. Furthermore, the input rate is very low, and the contents of the
56
respiratory investigation 53 (2015) 51 –59
Fig. 2 – (A) Evolution of treatment of IPF with respect to severity, severity grades I–II. In most cases (59.5%) of IPF with severity grades I and II that were newly registered during the 2009–2013 fiscal years, no treatment was given, while steroid monotherapy and combination therapy with steroids and immunosuppressive agents were used in 5.4% and 10.8%, respectively. (B) Evolution of treatment of IPF with respect to severity, severity grades III–IV. In IPF cases of severity grades III and IV that were newly registered between the 2009 and 2013 fiscal years, no treatment was given for 24.3% of patients, and pirfenidone therapy was used for 39.3% of patients. Steroid monotherapy and combination therapy with steroids and immunosuppressive agents were administered to 11.2% and 17.8%, respectively.
registry are sometimes inaccurate. Therefore, trends among patients with Nanbyo diseases may not be accurately followed [5]. Reforms toward improved accuracy and more effective use of the current registration system of individual clinical records and data collection were proposed during the Health Science Council for Control of Intractable Diseases in January 2013. Consideration has also been given to development of a new input system and introduction of an intractable disease specialist (tentative title) who performs the registration. Meanwhile, the web registration system that was used to collect the data presented in the current report was implemented as a component of a research project for overcoming intractable diseases under the Ministry of Health, Labour and
Welfare Grant-in-Aid for Scientific Research. The information was received from a limited number of medical institutions that belong to the intractable disease study group. Therefore, unlike the aforementioned system, the reliability of data from the IIP registry used in this study is expected to be greater than that of an epidemiological study based on individual clinical records. To date, there have been no large-scale prospective epidemiological studies in Japan on the clinical course and treatment of IIPs from the time of diagnosis. In this study, IPF accounted for 73.6% of IIP cases (321/436) entered in the web registry over a five-year period, and clinical characteristics and treatment strategies for these patients were
57
From the time of the onset of symptoms 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 250
300
Time (months)
From the time of initial visit 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150
Survival distribution function estimates
Survival distribution function estimates
respiratory investigation 53 (2015) 51 –59
200
250
300
350
Time (months)
Fig. 3 – Kaplan–Meier plot of survival probability from the time of the onset of symptoms and the time of initial visit. The median survival times were 105 months [95% CI: 96–117] and 69 months [95% CI: 63–93], respectively.
Fig. 4 – Kaplan–Meier plot of survival probability in IPF patients with and without symptoms at the initial visit. The median survival times were 63 months [95% CI: 46–69] in symptomatic IPF patients and 105 months [95% CI: 69–114] in asymptomatic IPF patients. The prognosis was significantly worse in the symptomatic group compared with the asymptomatic group (p ¼0.0013, log-rank test). examined. The most prominent physical findings among the newly registered IPF patients were fine crackles (96.0%), and clubbed fingers were observed in 33.0%. These findings are consistent with those reported in western countries, where fine crackles and clubbed fingers were found in 480% and 25– 50% of IPF cases, respectively [7], as well as with those reported in previous studies in Japan, where these signs have been observed in approximately 90% and 30–60% of patients, respectively [1,8]. Thus, it is again recognized that fine crackles and clubbing are important physical findings for the diagnosis of IPF. As for the presence or absence of elevated KL-6 and SP-D levels at the time of registration, elevated KL-6 levels ( Z500 U/mL) were reported 81.0% of IPF cases, and elevated SP-D levels ( Z110 ng/mL) were seen in 66.4%. In previous reports [1,9], abnormally elevated KL-6 and SP-D levels were found in 87–93% of IPF patients, and these were detected at a rate of 77–87% even in mild cases (severity grades I and II). However, the rate of abnormally elevated SPD levels in the present study was slightly lower than has been previously reported [10].
The most notable point of this study was the result concerning the evolution of the treatment strategy for IPF since the introduction of the anti-fibrotic drug pirfenidone, which first became available in Japan, in advance of other countries, in December 2008. Before pirfenidone, no treatment was given for IPF in more than 75% of cases. Since pirfenidone, the number of untreated patients was reduced to 45% by FY 2013, and pirfenidone has been used in approximately 1/3 of cases. On the other hand, steroid monotherapy and combination therapy with steroids and immunosuppressive drugs were still used in approximately 20% of cases. In Japan, the empirical selection of steroids and immunosuppressive drugs to treat IPF in clinical practice is common, although it is not recommended under the 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) evidence-based guidelines for diagnosis and management of IPF [2]. In Japan, the second edition of the revised Guidelines for Diagnosis and Treatment of Idiopathic Interstitial Pneumonias [1] state that a combination of steroids and immunosuppressive drugs (i.e., cyclosporine, cyclophosphamide, azathioprine) is indicated as a treatment option for IIP including IPF because there are currently no clinical studies that report negative findings, although neither are there any large-scale studies that have demonstrated their effectiveness. Moreover, a prospective multicenter clinical comparative study analyzing the effectiveness of combination of steroids and cyclophosphamide or cyclosporine [11] found that there was no significant difference in the primary endpoint between the two groups, while the annual decrease in vital capacity (VC) was as small as 80 mL. It is necessary to continue to reexamine and reanalyze guidelines for diagnosis and treatment of IIPs, for which future revisions are planned. With regard to the prognosis of IPF patients, an average survival period from the time of diagnosis of 28–52 months has been reported in western countries [12–16], and King Jr et al. [12] reported median survival times of 80.8 months from the onset of symptoms and 35.2 months from the initial visit. We found survival times of 105 months from the onset of
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symptoms and 69 months from the time of the initial visit, and the prognosis from the initial visit was significantly worse in symptomatic patients than in asymptomatic patients. The longer survival times reported in our study, as compared with those reported in western countries, may have been related to disease severity. In the present study, 51.1% of the registered IPF patients had relatively mild disease (severity grades I and II), and 28.3% presented with abnormal chest X-ray or CT findings in the absence of symptoms. In studies from the western countries [12,17], the patients with IPF often did not present for medical care until an average of 2 years after the onset of symptoms such as DOE or coughing. Delayed access to specialized medical care has also been suggested as a risk factor for poor prognosis [17]. In Japan, CT examinations are freely ordered by the family doctor or for screening even before symptoms are noted, thus IPF has been detected even in asymptomatic individuals in whom interstitial lung lesions are detected incidentally, and such patients have been referred for immediate evaluations at specialized medical institutions upon the appearance of symptoms. In the present study, acute exacerbation, usually between 5 and 10 years from the onset of disease, accounted for more than half of the deaths that were reported in IPF patients. In reports from the West [3,13,14], respiratory-related deaths in IPF patients are frequent, and rapid exacerbation within 4 months occurred in 30% of cases. Acute exacerbation also accounted for deaths of 35–41% of patients in previous reports in Japan [5,18], and the finding that the death rate due to acute exacerbation was even higher in the present study is possibly because the data for this study were collected only from the specialized facilities of the intractable disease group. In any case, while the importance of acute exacerbation of IPF has increasingly been recognized internationally during the last few years, and a variety of findings have been reported, it is still necessary to further elucidate the mechanism of onset and the risk factors, including genetic factors and ethnicity-dependent differences in rates of occurrence, as well as to develop new treatments. In order to make feasible the widespread practical use of integrated data from a web registry such as the one reported here, it is very important to provide full consideration for protecting each patient's personal information, not only for the intractable disease study group, but also for research institutions, medical institutions, and companies that are involved in intractable disease research. Further, it is imperative that the research content and achievements are reported to patients, medical providers, and the nation at large. Various problems arising in the process of web registration in this study, including validity of input items, quality control, and others, will provide valuable information for the reform proposals for measures against intractable diseases, such as construction of a new collection system for patient data that are currently being considered.
5.
Conclusions
We analyzed integrated data on diagnoses, clinical findings, course, and treatment of IIPs, particularly cases of IPF, which
were registered in an Internet database by participating medical institutions across Japan that specialize in IIP. There have been no previous prospective large-scale multicenter epidemiological studies of IIPs in Japan. Therefore, this study should provide valuable information for understanding the current clinical situation of patients with IPF.
Conflict of interest Masashi Bando received lecture fees from Nippon Boehringer Ingelheim Co. Yukihiko Sugiyama received lecture fees from SHIONOGI & CO., and Nippon Boehringer Ingelheim Co. Hiroyuki Taniguchi received lecture fees from Asahi Kasei Pharma Corp. Toshihiro Nukiwa received lecture fees from SHIONOGI & CO., and Nippon Boehringer Ingerlheim Co., and travel fees, gifts, and others from SEKISUI MEDICAL CO. The other authors report no conflicts of interest.
Authors' contributions to the study Dr. Masashi Bando had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Yukihiko Sugiyama contributed to the study design and review and approval of the manuscript. Dr. Arata Azuma contributed to the study design and data collection. Dr. Masahito Ebina contributed to the study design and data collection. Dr. Hiroyuki Taniguchi contributed to the study design and data collection. Dr. Yoshio Taguchi contributed to the study design and data collection. Dr. Hiroki Takahashi contributed to the study design and data collection Dr. Sakae Homma contributed to the study design and data collection. Dr. Toshihiro Nukiwa contributed to the study conception and design, and data analysis. Dr. Shoji Kudoh contributed to the study design and review and approval of the manuscript.
Acknowledgments This study was supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labour and Welfare, Japan. The members of the Diffuse Lung Diseases Research Group of the Ministry of Health, Labour and Welfare Grantin-Aid for Scientific Research are. K. Chida, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu. N. Keicho, Research Institute National Center for Global Health and Medicine Tokyo. Y. Nakanishi, Research Institute for Diseases of the Chest, Graduate School of Medicine Sciences, Kyushu University, Fukuoka.
respiratory investigation 53 (2015) 51 –59
N. Inase, Department of Integrated Pulmonology, Tokyo Medical and Dental University, Tokyo. M. Nishimura, First Department of Medicine, Hokkaido University Hospital, Sapporo. Y. Inoue, Kinki-Chuo Chest Medical Center, Osaka. H. Mukae, Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka. A. Yokoyama, Kochi Medical School Hospital, Kochi H. Takizawa, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo. M. Mishima, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto. Y. Nishioka, Department of Internal Medicine and Molecular Therapeutics, Tokushima University, Tokushima. Y. Ishii, Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi. M. Munakata, Department of Pulmonary Medicine, Fukushima Medical University, Fukushima. N. Kohno, Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences Hiroshima University, Hiroshima. K. Kishi, Toranomon Hospital, Tokyo. T. Ogura, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa. K. Watanabe, Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka.
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