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Clarithromycin has limited effects in non-elderly, non-severe patients with seasonal influenza virus A infection
Journal of Infection (2012) 64, 343e345
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Clarithromycin has limited effects in non-elderly, non-severe patients with seasonal influenza virus A infection
Dear Editor, We read with interest the paper by Viasus and colleagues concerning the role of immunomodulatory therapies (corticosteroids, macrolides and statins) in severe cases with pandemic influenza A (H1N1) 2009.1 They concluded that these therapies used upon hospital admission did not prevent the development of severe disease in adults complicated by pneumonia.1 However, no study has determined the clinical role of immunomodulatory medicine in mild cases of influenza, including during pandemic influenza A 2009 virus infection. In Japan, since April 1st 2011, the pandemic influenza A (H1N1) 2009 has been simply called influenza 2009, and that in the 2010/2011 season has been regarded as the usual seasonal influenza. We examined the effect of concurrent therapy using the 14-member macrolide clarithromycin (CAM) and neuraminidase inhibitors in non-severe patients infected influenza A virus on an outpatient clinic basis. Open-label prospective cohort study was carried out at thirteen hospitals. The study was approved by the institutional Ethics Committee, Oita University Hospital. Written informed consent was obtained from all patients before enrollment. All non-immunosuppressed adults, who visited hospital with influenza A virus infection from December 2010 to March 2011, were included (Table 1). All patients in this study had an influenza-like illness with laboratory-confirmed influenza A virus infection. In addition to patients who showed signs of pneumonia at the time of their visit, patients with comorbid chronic diseases such as diabetes mellitus, COPD, and diseases that required treatment with an oral corticosteroid or immunosuppressant were excluded from this study. Patients diagnosed with influenza A infection were divided in a random manner by attending physicians into two groups: patients who were treated with an oral neuraminidase inhibitor at the regular dose for an adult for 5 days and those who were treated with a combination of the inhibitor and CAM at 400 mg/day for 5 days. Although the physicians had sole discretion regarding the selection of
the treatment regimen, this study was not able to be randomized because such a randomized-controlled trial at this time was deemed to be ethically unacceptable. Antipyretics were used on an as-needed basis. All patients were followed for 5e7 days, and their compliance with treatment was verified. The clinical manifestations of influenza, including body temperature, cough, sputum, sore throat, nasal secretions, and general malaise (Tables 1 and 2), were recorded. The clinical episodes of a total of 141 outpatients with influenza A, including 67 patients treated with a neuraminidase inhibitor alone and 74 treated with combination therapy, were analyzed. The prevalence of disease signs/ symptoms on the hospital visit, and concomitant drug use were similar between the two groups, except for the history of vaccination for the flu within a year (Table 1). At the time of the hospital visit, a cough was present in 96% and 95% of patients in each group. However, 13 patients in each group did not have cough at the time of onset of pyrexia, as shown in Table 2. Table 2 compares the duration of disease manifestations within the period of one week. There was no significant increase in the efficacy of treatment on the duration of disease signs/symptoms when CAM was added, as indicated by the analysis of the whole patient population. However, as shown in the lower half of Table 2, a subdivision analysis according to symptoms at the time of onset of pyrexia revealed that the duration of cough in patients without cough at the onset of pyrexia was significantly shortened by the combined treatment. There were two patients, one each in each group, who developed pneumonia, but no other cases of severe disease related to influenza were seen in the entire subject population. Although the study by Viasus et al.1 showed that the use of immunomodulatory therapies did not prevent the development of severe disease in adult patients with pandemic influenza A 2009 complicated by pneumonia, there is a possibility that their study subjects could have included patients who did not receive prompt treatment because all of the subjects already showed pneumonia on admission. Nevertheless, according to their report, patients who received macrolides developed severe disease less often, although it was not statistically significant in a multivariate analysis.1 According to a retrospective study2 of children with influenza in 2005e2007, a significant decrease in the prevalence of cough was recorded in the group treated
0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.12.002
344 Table 1
Letter to the Editor Baseline features of patients with seasonal influenza A according to their use of clarithromycin.
Male gender Age (years) Vaccination for flu within a year Underlying disease bronchial asthma allergic rhinitis Period from the onset of pyrexia until visit (day) Body temperature on visit ( C) Max body temperature ( C) Symptoms on visit cough sputum sore throat nasal secretions general malaise Anti-influenza drug oseltamivir zanamivir laninamivir Concomitant drug acetoaminophen NSAIDs dextromethorphan carbocystein Development of pneumonia
CAM () (n Z 67)
CAM (þ) (n Z 74)
p-value
30 (45) 33.0 (23.0e44.0) 9 (13)
31 (42) 29.0 (23.8e39.2) 20 (27)
0.73 0.43 0.04
10 6 0.88 37.9 38.4
11 2 0.77 37.9 38.4
(15) (3) (0.48e1.09) (37.4e40.7) (38.0e39.1)
0.99 0.11 0.91 0.78 0.59
(95) (81) (82) (85) (99)
0.8 0.12 0.23 0.28 0.5
64 (96) 2 (3) 1 (1)
67 (90) 5 (7) 2 (3)
0.23 0.3 0.62
21 3 0 0 1
18 5 1 2 1
0.35 0.56 0.34 0.18 0.94
64 60 60 61 65
(15) (9) (0.50e1.00) (37.6e38.5) (38.0e39.0) (96) (90) (90) (91) (97)
(31) (4) (0) (0) (1)
70 60 61 63 73
(24) (7) (1) (3) (1)
Data are the medians (interquartile range) or numbers (%) of patients. CAM; clarithromycin, NSAIDs; nonsteroidal anti-inflammatory drugs.
with a combination of oseltamivir and CAM (n Z 12), in comparison to the group treated with oseltamivir (n Z 14), despite the fact that the investigation was of a small population, like our study. This study also showed that CAM boosted the mucosal antiviral secretory IgA responses in children with influenza, resulting in a decrease
Table 2
of respiratory symptoms. Mucus formation, a significant cause of morbidity in patients with chronic airway inflammation, is directly inhibited by macrolides, and is suppressed by decreased inflammation in the airway.3,4 Macrolides also inhibit the production of many proinflammatory cytokines in the lungs of patients with airway
The outcomes of patients with seasonal influenza A according to their use of clarithromycin.
Period from the onset of pyrexia until pyretolysis Period from the visit hospital until pyretolysisa Duration of cough Duration of sputum Duration of sore throat Duration of nasal secretions Duration of general malaise
a
Duration of cough in patients with severe cough from the onset of pyrexia Duration of sputum in patients with a lot of sputum from the onset of pyrexia Duration of nasal secretions in patients with a lot of nasal secretions from the onset of pyrexia Duration of cough in patients without cough at the onset of pyrexia
CAM () (n Z 67)
CAM (þ) (n Z 74)
1.83 1.04 5.56 5.13 3.67 4.21 2.67 CAM 5.33
1.88 1.04 6.00 5.56 4.04 4.88 2.75 CAM 6.48
(1.29e2.54) (0.58e1.70) (4.40e6.93) (3.94e6.47) (2.26e5.56) (2.42e5.48) (1.88e4.00) () (3.50e6.33) (n Z 23)
p-value
(1.47e2.54) (0.68e1.75) (5.17e7.25) (4.35e6.63) (2.56e5.73) (2.96e6.25) (1.77e3.46) (þ) (5.33e7.50) (n Z 36)
0.88 0.77 0.21 0.29 0.64 0.13 0.97
5.50 (4.44e6.50) (n Z 9)
6.25 (5.33e7.54) (n Z 13)
0.15
4.42 (3.16e6.06) (n Z 14)
6.04 (3.63e7.58) (n Z 19)
0.23
5.50 (1.85e6.77) (n Z 13)
2.0 (0e5.54) (n Z 13)
Data are the median (interquartile range) days. CAM; clarithromycin. a Body temperature <37.5 C.
0.05
<0.05
Letter to the Editor diseases.4,5 In addition, experimental studies have demonstrated that macrolides show inhibitory effects on influenza virus infection.6e9 These inhibitory actions are suggested to result in improved pulmonary functions, fewer airway infections, and perhaps in a decreased prevalence of cough. The suppression of cough due to influenza infection may contribute to preventing the spread of infection, since cough is a means of viral transmission. This study showed that the effects of using CAM in combination with antiviral drugs were limited in nonelderly and non-immunosuppressed adults with seasonal influenza A infection. Based on these results, physicians are therefore recommended to refrain from using macrolide concurrently with antiviral drugs in patients presenting with influenza, especially for healthy adults. However, further studies targeting a large cohort of elderly subjects or immunosuppressed patients, is needed to further evaluate the effects of macrolides in patients with influenza.
Acknowledgments The authors thank Drs. A. Kinoshita (Akeno-Chuo Hospital); Y. Gendo (Gendo-Naika Hospital); Y. Awaya (Yahata Municipal Hospital); T. Kawajiri (Kurate Municipal Hospital); Y. Nikaido (Nikaido Clinic); N. Inoue (Kyushu Rosai Hospital); H. Obata (Saiseikai Shimonoseki General Hospital); H. Fujii (Oita Sanai Medical Center); J. Murakami (Goto-J Respiratory and Allergy Clinic); and A. Yokoyama, H. Kushima, S. Otani, R. Shirai (Oita University Faculty of Medicine), for the patient enrollment.
References 1. Viasus D, Pano-Pardo JR, Cordero E, Campins A, LopezMedrano F, Villoslada A, et al. Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia. J Infect 2011;62(3):193e9. 2. Sawabuchi T, Suzuki S, Iwase K, Ito C, Mizuno D, Togari H, et al. Boost of mucosal secretory immunoglobulin A response by clarithromycin in paediatric influenza. Respirology 2009;14(8):1173e9. 3. Kadota J, Sakito O, Kohno S, Sawa H, Mukae H, Oda H, et al. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis 1993;147(1):153e9. 4. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med 2004; 117(Suppl. 9A):5Se11S. 5. Ichiyama T, Nishikawa M, Yoshitomi T, Hasegawa S, Matsubara T, Hayashi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother 2001;45(1):44e7. 6. Yamaya M, Shinya K, Hatachi Y, Kubo H, Asada M, Yasuda H, et al. Clarithromycin inhibits type a seasonal influenza virus
345 infection in human airway epithelial cells. J Pharmacol Exp Ther 2010;333(1):81e90. 7. Sato K, Suga M, Akaike T, Fujii S, Muranaka H, Doi T, et al. Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice. Am J Respir Crit Care Med 1998;157(3 Pt 1): 853e7. 8. Tsurita M, Kurokawa M, Imakita M, Fukuda Y, Watanabe Y, Shiraki K. Early augmentation of interleukin (IL)-12 level in the airway of mice administered orally with clarithromycin or intranasally with IL-12 results in alleviation of influenza infection. J Pharmacol Exp Ther 2001;298(1):362e8. 9. Miyamoto D, Hasegawa S, Sriwilaijaroen N, Yingsakmongkon S, Hiramatsu H, Takahashi T, et al. Clarithromycin inhibits progeny virus production from human influenza virus-infected host cells. Biol Pharm Bull 2008;31(2):217e22.
Hiroshi Ishii*,a Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan E-mail address: [email protected] Kosaku Komiyaa Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan Eiji Yamagataa Goto-J Respiratory and Allergy Clinic, Oita, Japan Kazuhiro Yateraa Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka, Japan Yasuo Chojina Department of Respiratory Medicine, Hagiwara Central Hospital, Fukuoka, Japan Hidehiko Yamamotoa Department of Respiratory Medicine, Iizuka Hospital, Fukuoka, Japan Hiroshi Mukaea Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka, Japan Jun-ichi Kadotaa Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan Accepted 3 December 2011 Available online 8 December 2011
* Corresponding author. Tel.: þ81 97 549 4411; fax: þ81 97 549 4245. a These authors contributed equally to this work.
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Clarithromycin has limited effects in non-elderly, non-severe patients with seasonal influenza virus A infection
Dear Editor, We read with interest the paper by Viasus and colleagues concerning the role of immunomodulatory therapies (corticosteroids, macrolides and statins) in severe cases with pandemic influenza A (H1N1) 2009.1 They concluded that these therapies used upon hospital admission did not prevent the development of severe disease in adults complicated by pneumonia.1 However, no study has determined the clinical role of immunomodulatory medicine in mild cases of influenza, including during pandemic influenza A 2009 virus infection. In Japan, since April 1st 2011, the pandemic influenza A (H1N1) 2009 has been simply called influenza 2009, and that in the 2010/2011 season has been regarded as the usual seasonal influenza. We examined the effect of concurrent therapy using the 14-member macrolide clarithromycin (CAM) and neuraminidase inhibitors in non-severe patients infected influenza A virus on an outpatient clinic basis. Open-label prospective cohort study was carried out at thirteen hospitals. The study was approved by the institutional Ethics Committee, Oita University Hospital. Written informed consent was obtained from all patients before enrollment. All non-immunosuppressed adults, who visited hospital with influenza A virus infection from December 2010 to March 2011, were included (Table 1). All patients in this study had an influenza-like illness with laboratory-confirmed influenza A virus infection. In addition to patients who showed signs of pneumonia at the time of their visit, patients with comorbid chronic diseases such as diabetes mellitus, COPD, and diseases that required treatment with an oral corticosteroid or immunosuppressant were excluded from this study. Patients diagnosed with influenza A infection were divided in a random manner by attending physicians into two groups: patients who were treated with an oral neuraminidase inhibitor at the regular dose for an adult for 5 days and those who were treated with a combination of the inhibitor and CAM at 400 mg/day for 5 days. Although the physicians had sole discretion regarding the selection of
the treatment regimen, this study was not able to be randomized because such a randomized-controlled trial at this time was deemed to be ethically unacceptable. Antipyretics were used on an as-needed basis. All patients were followed for 5e7 days, and their compliance with treatment was verified. The clinical manifestations of influenza, including body temperature, cough, sputum, sore throat, nasal secretions, and general malaise (Tables 1 and 2), were recorded. The clinical episodes of a total of 141 outpatients with influenza A, including 67 patients treated with a neuraminidase inhibitor alone and 74 treated with combination therapy, were analyzed. The prevalence of disease signs/ symptoms on the hospital visit, and concomitant drug use were similar between the two groups, except for the history of vaccination for the flu within a year (Table 1). At the time of the hospital visit, a cough was present in 96% and 95% of patients in each group. However, 13 patients in each group did not have cough at the time of onset of pyrexia, as shown in Table 2. Table 2 compares the duration of disease manifestations within the period of one week. There was no significant increase in the efficacy of treatment on the duration of disease signs/symptoms when CAM was added, as indicated by the analysis of the whole patient population. However, as shown in the lower half of Table 2, a subdivision analysis according to symptoms at the time of onset of pyrexia revealed that the duration of cough in patients without cough at the onset of pyrexia was significantly shortened by the combined treatment. There were two patients, one each in each group, who developed pneumonia, but no other cases of severe disease related to influenza were seen in the entire subject population. Although the study by Viasus et al.1 showed that the use of immunomodulatory therapies did not prevent the development of severe disease in adult patients with pandemic influenza A 2009 complicated by pneumonia, there is a possibility that their study subjects could have included patients who did not receive prompt treatment because all of the subjects already showed pneumonia on admission. Nevertheless, according to their report, patients who received macrolides developed severe disease less often, although it was not statistically significant in a multivariate analysis.1 According to a retrospective study2 of children with influenza in 2005e2007, a significant decrease in the prevalence of cough was recorded in the group treated
0163-4453/$36 ª 2011 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2011.12.002
344 Table 1
Letter to the Editor Baseline features of patients with seasonal influenza A according to their use of clarithromycin.
Male gender Age (years) Vaccination for flu within a year Underlying disease bronchial asthma allergic rhinitis Period from the onset of pyrexia until visit (day) Body temperature on visit ( C) Max body temperature ( C) Symptoms on visit cough sputum sore throat nasal secretions general malaise Anti-influenza drug oseltamivir zanamivir laninamivir Concomitant drug acetoaminophen NSAIDs dextromethorphan carbocystein Development of pneumonia
CAM () (n Z 67)
CAM (þ) (n Z 74)
p-value
30 (45) 33.0 (23.0e44.0) 9 (13)
31 (42) 29.0 (23.8e39.2) 20 (27)
0.73 0.43 0.04
10 6 0.88 37.9 38.4
11 2 0.77 37.9 38.4
(15) (3) (0.48e1.09) (37.4e40.7) (38.0e39.1)
0.99 0.11 0.91 0.78 0.59
(95) (81) (82) (85) (99)
0.8 0.12 0.23 0.28 0.5
64 (96) 2 (3) 1 (1)
67 (90) 5 (7) 2 (3)
0.23 0.3 0.62
21 3 0 0 1
18 5 1 2 1
0.35 0.56 0.34 0.18 0.94
64 60 60 61 65
(15) (9) (0.50e1.00) (37.6e38.5) (38.0e39.0) (96) (90) (90) (91) (97)
(31) (4) (0) (0) (1)
70 60 61 63 73
(24) (7) (1) (3) (1)
Data are the medians (interquartile range) or numbers (%) of patients. CAM; clarithromycin, NSAIDs; nonsteroidal anti-inflammatory drugs.
with a combination of oseltamivir and CAM (n Z 12), in comparison to the group treated with oseltamivir (n Z 14), despite the fact that the investigation was of a small population, like our study. This study also showed that CAM boosted the mucosal antiviral secretory IgA responses in children with influenza, resulting in a decrease
Table 2
of respiratory symptoms. Mucus formation, a significant cause of morbidity in patients with chronic airway inflammation, is directly inhibited by macrolides, and is suppressed by decreased inflammation in the airway.3,4 Macrolides also inhibit the production of many proinflammatory cytokines in the lungs of patients with airway
The outcomes of patients with seasonal influenza A according to their use of clarithromycin.
Period from the onset of pyrexia until pyretolysis Period from the visit hospital until pyretolysisa Duration of cough Duration of sputum Duration of sore throat Duration of nasal secretions Duration of general malaise
a
Duration of cough in patients with severe cough from the onset of pyrexia Duration of sputum in patients with a lot of sputum from the onset of pyrexia Duration of nasal secretions in patients with a lot of nasal secretions from the onset of pyrexia Duration of cough in patients without cough at the onset of pyrexia
CAM () (n Z 67)
CAM (þ) (n Z 74)
1.83 1.04 5.56 5.13 3.67 4.21 2.67 CAM 5.33
1.88 1.04 6.00 5.56 4.04 4.88 2.75 CAM 6.48
(1.29e2.54) (0.58e1.70) (4.40e6.93) (3.94e6.47) (2.26e5.56) (2.42e5.48) (1.88e4.00) () (3.50e6.33) (n Z 23)
p-value
(1.47e2.54) (0.68e1.75) (5.17e7.25) (4.35e6.63) (2.56e5.73) (2.96e6.25) (1.77e3.46) (þ) (5.33e7.50) (n Z 36)
0.88 0.77 0.21 0.29 0.64 0.13 0.97
5.50 (4.44e6.50) (n Z 9)
6.25 (5.33e7.54) (n Z 13)
0.15
4.42 (3.16e6.06) (n Z 14)
6.04 (3.63e7.58) (n Z 19)
0.23
5.50 (1.85e6.77) (n Z 13)
2.0 (0e5.54) (n Z 13)
Data are the median (interquartile range) days. CAM; clarithromycin. a Body temperature <37.5 C.
0.05
<0.05
Letter to the Editor diseases.4,5 In addition, experimental studies have demonstrated that macrolides show inhibitory effects on influenza virus infection.6e9 These inhibitory actions are suggested to result in improved pulmonary functions, fewer airway infections, and perhaps in a decreased prevalence of cough. The suppression of cough due to influenza infection may contribute to preventing the spread of infection, since cough is a means of viral transmission. This study showed that the effects of using CAM in combination with antiviral drugs were limited in nonelderly and non-immunosuppressed adults with seasonal influenza A infection. Based on these results, physicians are therefore recommended to refrain from using macrolide concurrently with antiviral drugs in patients presenting with influenza, especially for healthy adults. However, further studies targeting a large cohort of elderly subjects or immunosuppressed patients, is needed to further evaluate the effects of macrolides in patients with influenza.
Acknowledgments The authors thank Drs. A. Kinoshita (Akeno-Chuo Hospital); Y. Gendo (Gendo-Naika Hospital); Y. Awaya (Yahata Municipal Hospital); T. Kawajiri (Kurate Municipal Hospital); Y. Nikaido (Nikaido Clinic); N. Inoue (Kyushu Rosai Hospital); H. Obata (Saiseikai Shimonoseki General Hospital); H. Fujii (Oita Sanai Medical Center); J. Murakami (Goto-J Respiratory and Allergy Clinic); and A. Yokoyama, H. Kushima, S. Otani, R. Shirai (Oita University Faculty of Medicine), for the patient enrollment.
References 1. Viasus D, Pano-Pardo JR, Cordero E, Campins A, LopezMedrano F, Villoslada A, et al. Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia. J Infect 2011;62(3):193e9. 2. Sawabuchi T, Suzuki S, Iwase K, Ito C, Mizuno D, Togari H, et al. Boost of mucosal secretory immunoglobulin A response by clarithromycin in paediatric influenza. Respirology 2009;14(8):1173e9. 3. Kadota J, Sakito O, Kohno S, Sawa H, Mukae H, Oda H, et al. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis 1993;147(1):153e9. 4. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med 2004; 117(Suppl. 9A):5Se11S. 5. Ichiyama T, Nishikawa M, Yoshitomi T, Hasegawa S, Matsubara T, Hayashi T, et al. Clarithromycin inhibits NF-kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother 2001;45(1):44e7. 6. Yamaya M, Shinya K, Hatachi Y, Kubo H, Asada M, Yasuda H, et al. Clarithromycin inhibits type a seasonal influenza virus
345 infection in human airway epithelial cells. J Pharmacol Exp Ther 2010;333(1):81e90. 7. Sato K, Suga M, Akaike T, Fujii S, Muranaka H, Doi T, et al. Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice. Am J Respir Crit Care Med 1998;157(3 Pt 1): 853e7. 8. Tsurita M, Kurokawa M, Imakita M, Fukuda Y, Watanabe Y, Shiraki K. Early augmentation of interleukin (IL)-12 level in the airway of mice administered orally with clarithromycin or intranasally with IL-12 results in alleviation of influenza infection. J Pharmacol Exp Ther 2001;298(1):362e8. 9. Miyamoto D, Hasegawa S, Sriwilaijaroen N, Yingsakmongkon S, Hiramatsu H, Takahashi T, et al. Clarithromycin inhibits progeny virus production from human influenza virus-infected host cells. Biol Pharm Bull 2008;31(2):217e22.
Hiroshi Ishii*,a Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan E-mail address: [email protected] Kosaku Komiyaa Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan Eiji Yamagataa Goto-J Respiratory and Allergy Clinic, Oita, Japan Kazuhiro Yateraa Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka, Japan Yasuo Chojina Department of Respiratory Medicine, Hagiwara Central Hospital, Fukuoka, Japan Hidehiko Yamamotoa Department of Respiratory Medicine, Iizuka Hospital, Fukuoka, Japan Hiroshi Mukaea Department of Respiratory Medicine, University of Occupational and Environmental Health, Fukuoka, Japan Jun-ichi Kadotaa Department of Internal Medicine 2, Oita University Faculty of Medicine, 1-1 Idaigaoka Yufu, Oita 879-5593, Japan Accepted 3 December 2011 Available online 8 December 2011
* Corresponding author. Tel.: þ81 97 549 4411; fax: þ81 97 549 4245. a These authors contributed equally to this work.