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Diffuse Panbronchiolitis
D i ffu s e P a n b ro n c h i o l i t i s Shoji Kudoh, MD, PhDa,b,*, Naoto Keicho, MD, PhDc KEYWORDS Diffuse panbronchiolitis Chronic airway infection Macrolide antibiotics Asian disease
KEY POINTS This chronic airway disease mainly involves Japanese, Korean, Chinese, and other Asian people. Main symptoms are a large amount of sputum and progressive exertional dyspnea in patients with nonallergic chronic paranasal sinusitis. Centrilobular nodular shadows, frequently with peripheral bronchiectasis, in high-resolution computed tomography (CT) images are characteristic. Long-term treatment with 14-membered or 15-membered ring macrolides is effective.
EPIDEMIOLOGY According to a population-based survey in 1980, the incidence of physician-diagnosed DPB was 11.1 per 100,000 in Japan.5 However, the incidence of disease seems recently to have decreased. The peak of the age distribution is among patients in their 40s to 50s. No sex predominance is noted.
Two-thirds of the patients did not smoke tobacco. There was no history of inhalation of toxic fumes.3 DPB has been also described in other east Asian populations such as the Koreans and Chinese.6,7 A limited number of cases have been reported from outside Asia,8,9 and about half the patients were Asian immigrants in reports from Western countries. Currently, it is reasonable to conclude that DPB is a chronic airway disease predominantly affecting east Asians.
CAUSE Development of DPB in east Asians, including Asian emigrants, indicates that disease susceptibility is possibly determined by a genetic predisposition unique to Asians. Human leukocyte antigen (HLA)-B54, known as an ethnic antigen unique to east Asians, was strongly associated with the disease in Japan.10,11 In contrast, Korean patients with DPB showed a positive association with HLAA11.12 Keicho and colleagues,13 analyzed genetic markers and predicted that the most likely region for the major disease susceptibility gene was between the 2 HLA loci on chromosome 6. They recently cloned 2 novel mucinlike genes designated panbronchiolitis-related mucinlike 1 and 2
a
Japan Anti-Tuberculosis Association, Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8522, Japan Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan c Department of Respiratory Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan * Japan Anti-Tuberculosis Association, Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8522, Japan. E-mail address: [email protected] b
Clin Chest Med 33 (2012) 297–305 doi:10.1016/j.ccm.2012.02.005 0272-5231/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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In the mid1960s, a new disease entity, diffuse panbronchiolitis (DPB), distinct from chronic bronchitis or bronchiectasis, was established from clinicopathologic investigation by Homma and Yamanaka.1 The first comprehensive report of DPB was published in the English language literature in 1983.2 Prognosis of DPB was dismal in the advanced stages after superinfection with Pseudomonas aeruginosa.3 The prognosis of this life-threatening airway disease has improved greatly since the initial success of long-term treatment with low-dose erythromycin was reported by Kudoh and colleagues4 in 1984. The disease is now regarded as curable. Although the cause of the disease is still unknown, recent advances in cellular and molecular biology have helped in the understanding of the mechanisms underlying the efficacy of macrolides.
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Kudoh & Keicho (PBMUCL1 and PBMUCL2) in the candidate region.14
PATHOLOGY Cut surfaces of autopsied lung tissue in DPB are characterized by fine yellowish nodules in the parenchymal area (Fig. 1).15 These nodules consist of thickened walls of the respiratory bronchioles with infiltrations of lymphocytes, plasma cells, and histiocytes. These inflammatory changes extend to the peribronchiolar tissues, whereas alveolar walls are not affected with accumulation of foamy histiocytes in the walls of the respiratory bronchioles adjacent to the alveolar ducts. DPB in the advanced stages is difficult to distinguish from diffuse bronchiectasis because of secondary ectasia of proximal bronchioles.
PATHOGENESIS Lymphocyte Accumulation Around the Small Airway It is important to characterize lymphocyte and macrophage accumulation around respiratory bronchioles to elucidate the pathogenesis of DPB. Sato and colleagues16 showed that bronchus-associated lymphoid tissue hyperplasia is frequently observed in the lung biopsy samples from patients with DPB. Surface immunoglobulin
(Ig) M–positive B lymphocytes are distributed in the follicular area and T lymphocytes, mainly CD41 cells, are located in the parafollicular area. In subsequent studies, it was reported that cytotoxic T cells expressing CD81/CDIIb- were activated, and activated cell numbers correlated with the levels of the chemokine, MIP-1a, in the bronchial fluid.17–19
Neutrophil Accumulation into the Large Airway Neutrophil accumulation in the proximal airway is another important feature of the disease.20 Neutrophil numbers and their elastase activity were significantly elevated in the bronchial fluid from patients with DPB.21 Kadota and colleagues22 also showed that chemotactic activity was significantly increased in the bronchial fluid from patients with DPB. Subsequent investigations clarified that these chemotaxins were interleukin (IL)-8, leukotriene B4 (LTB4), and other chemotactic substances. Leukocyte adherent surface molecule Mac1 of neutrophils in the peripheral blood and bronchial fluid of patients with DPB expressed significantly higher levels. In addition, serum levels of soluble forms of other adhesion molecules, members of the selectin and the immunoglobulin supergene family, were found to be significantly increased in patients with
Fig. 1. Pathologic findings of DPB. Fine yellowish nodules with bronchiectasis are scattered on the cut surface of autopsied lung (A). Respiratory bronchioles with infiltrations of lymphocytes, plasma cells (B), and accumulation of foamy histiocytes (C).
Diffuse Panbronchiolitis DPB.23,24 These results suggest that, in DPB, excessive neutrophil chemotactic factors at the site of inflammation and upregulation of adhesion molecules in the circulation are followed by recruitment of neutrophils into the proximal airway.
DIAGNOSIS Clinical Manifestations More than 80% of patients with DPB have a history or coexistence of chronic paranasal sinusitis. In their second to fifth decade, patients usually present with chronic cough and copious purulent sputum production. Exertional dyspnea develops subsequently. Physical examination of the lungs reveals coarse crackles. In about a half of patients with no intervention, sputum volume is greater than 50 mL/d.3 In a review of 81 histologically proven cases of diffuse panbronchiolitis in 1980, 44% had Haemophilus influenzae in their sputum at presentation and 22% had P aeruginosa.22 Streptococcus pneumoniae and Moraxella catarrhalis have been detected in sputum. The detection rate of P aeruginosa increases, on average, to 60% after 4 years of the disease.
Radiological Manifestations A plain chest radiograph reveals bilateral, diffuse, small nodular shadows in the lower lung field with hyperinflation of the lung. Ring-shaped or tramline shadows suggesting bronchiectasis are frequently noted in advanced cases. High-resolution CT (HRCT) is useful for the detection of characteristic pulmonary lesions associated with DPB (Fig. 2).25,26 Centrilobular nodular opacities, which suggest inflammatory lesions of the peripheral airway, are observed with bronchiectasis.
Pulmonary Functions Pulmonary function measurements show significant airflow limitation that is resistant to bronchodilators.3,27 Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) are less than 70% from the early stages. Vital capacity (VC) decreases and residual volume (RV) increases in advanced stages. However, diffusing capacity (DLco) is not decreased, as distinct from chronic obstructive pulmonary disease (COPD). Arterial blood gas analysis has revealed hypoxemia from the early stage of the disease. Hypercapnia progresses in the advanced stage. In addition, pulmonary hypertension develops and is associated with the development of cor pulmonale.
Laboratory Findings Laboratory findings suggest immunologic abnormalities reflecting chronic bacterial infection.3 The titer of cold hemagglutinin is continuously increased in most Japanese patients with no evidence of mycoplasma infection.28 Serum IgA levels are increased and a positive rheumatoid factor is often observed. Other laboratory abnormalities suggesting nonspecific inflammation include mild neutrophilia, increased erythrocyte sedimentation rate, and positive findings for Creactive protein.
Diagnostic Criteria Diagnostic criteria for DPB proposed29 by a working group of the Ministry of Health and Welfare of Japan are as follows: 1. Persistent cough, sputum, and exertional dyspnea 2. History of, or current, chronic sinusitis 3. Bilateral, diffuse, small nodular shadows on a plain chest radiograph or centrilobular micronodules on chest CT images 4. Coarse crackles 5. FEV1/FVC less than 70% and PaO2 less than 80 mm Hg 6. Titer of cold hemagglutinin equal to or greater than 64. Definite cases should fulfill the first 3 criteria (1–3) and at least 2 other remaining criteria (4–5).
TREATMENT History
Fig. 2. Typical CT findings of DPB. Centrilobular nodular shadows (tree in bud) are diffusely distributed with bronchiectasis.
In the 1970s, none of the medications for DPB was effective in preventing a fatal outcome. Antibiotics such as b-lactams were administered against H influenzae and other bacteria, but failed to change the natural course of the disease. The
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Kudoh & Keicho overall 5-year survival rate of histologically proven cases of DPB was 51% and 8% in advanced DPB with P aeruginosa superinfection.3 In 1984, Kudoh and colleagues4 first reported efficacy of low-dose, long-term erythromycin therapy for DPB, which was discovered from an open trial as a reexamination of the records of a patient with DPB treated by a general physician. After 6 months to 3 years of treatment with erythromycin 600 mg/d, 18 patients with DPB showed improvement in symptoms and clinical parameters of lung function. FEV1 was increased from 1.61 to 2.17 L (P<.01) and PaO2 was increased on average from 65.2 to 75.1 mm Hg (P<.01). Small nodular shadows on chest radiographs disappeared in more than 60% of the cases after therapy (Fig. 3).
Erythromycin Therapy The favorable effect of erythromycin in the treatment of DPB was soon confirmed by others. The beneficial effects of erythromycin was also confirmed in a prospective double-blind, placebocontrolled study conducted by Yamamoto,30 with the support of the Ministry of Health and Welfare of Japan in 1990. In the 1970s, the overall 5-year survival rate of patients with DPB was 63%. Between 1980 and 1984, fluoroquinolones were administered for the treatment of P aeruginosa superinfection and the survival rate was increased to 72%. After 1985, when erythromycin therapy was widespread, the 5-year survival rate was significantly increased to 91% (Fig. 4).31
It seems to have similar beneficial effects to other macrolides on DPB.34 Sixteen-membered ring macrolides (eg, josamycin) have been ineffective against DPB.35 A recent clinical guideline for macrolide therapy for DPB is designated in Box 1.36
POTENTIAL MECHANISM OF ACTION In the treatment of DPB, it seems that bactericidal activity is not a major determinant of the clinical efficacy of 14-membered ring macrolides.4 First, irrespective of bacterial clearance, clinical parameters are significantly improved by the treatment. Second, even in cases with superinfection with P aeruginosa, which is resistant to macrolides, treatment with macrolides is effective. Third, at the recommended dosage, peak levels of macrolides in the sputum and serum are less than the minimum inhibitory concentrations for major pathogenic bacteria colonizing the airway. Moreover, longterm usage of potent antimicrobial agents including fluoroquinolones was less effective than low-dose erythromycin in the treatment of patients with DPB.37 Investigations for the potential mechanisms underlying the effectiveness of macrolide therapy in DPB have commenced. An association for studying novel actions of macrolides was established in Japan and has had annual meetings since 1994, and many clinicians and researchers are studying the mechanism of action of macrolides. Several reviews38–41 are now available on the antiinflammatory effects of macrolides.
Inhibition of Hypersecretion Other Macrolides Recently, 14-membered ring macrolides other than erythromycin have also been used in the treatment of patients with DPB. Clinicians administered clarithromycin and roxithromycin for the treatment of DPB in the 1990s, and obtained similar clinical benefits.32,33 Azithromycin, a 15membered ring macrolide, was in limited use in Japan until it was made freely available in 2001.
Copious sputum production is one of the major characteristics in DPB. The sputum volume is reduced with erythromycin therapy. Goswami and associates42 first reported that erythromycin dose dependently suppressed the secretion of respiratory glycoconjugates from human airway cells in vitro. Tamaoki and colleagues43 measured a short-circuit current representing in vitro ion transport across airway epithelial cells and showed
Fig. 3. CT findings of before (A) and after (B) 3 years of erythromycin therapy.
Diffuse Panbronchiolitis
Fig. 4. Survival curves of DPB by the years of first examination; 5-year survival significantly improved after the first report on erythromycin therapy in 1984.
that erythromycin from the submucosal side suppressed the current in a dose-dependent manner. They showed that the chloride channel was blocked by erythromycin, leading to suppression of water secretion into the airway lumen.
Inhibition of Neutrophil Accumulation As mentioned previously, a large number of neutrophils, frequently reaching 70% to 80% of the total lavage cells, are found in the bronchial fluid in patients with DPB.20 After treatment with
erythromycin, neutrophil numbers and elastase activity in the lower respiratory tract of patients with DPB are decreased.21 Kadota and colleagues22 showed that neutrophil chemotactic activity in the bronchoalveolar lavage fluid is reduced in patients with DPB treated with erythromycin. Oishi and colleagues44 and Sakito and colleagues45 showed that levels of IL-8, a major neutrophil chemoattractant, are decreased in the airways of patients with DPB after erythromycin therapy. Takizawa and colleagues46 reported that erythromycin suppressed the expression of IL-8
Box 1 Guidelines for therapy for DPB One would think that therapy should be started soon if clinical response is better in the early stage Choice of drug: First choice: erythromycin 400–600 mg/d, orally Second choice: clarithromycin 200–400 mg/d or roxithromycin 150–300 mg/d, orally, in the event of poor efficacy or adverse events associated with erythromycin Azithromycin is also acceptable, but 16-membered ring macrolides seem to be ineffective Assessment of response and duration of treatment: Clinical response is usually obvious within 2 or 3 months of commencing therapy; however, treatment should be continued for at least 6 months and the overall response evaluated Therapy should be completed after 2 years when clinical manifestations, radiological findings, and pulmonary function measurements are improved or stable without significant impairment of daily activity Therapy should be restarted if symptoms reappear after cessation of erythromycin treatment. In advanced cases with extensive bronchiectasis or respiratory failure, therapy should be continued for more than 2 years if there is a response to treatment Based on the clinical guidelines on macrolide therapy for diffuse panbronchiolitis (Diffuse Lung Disease Committee of the Ministry of the Health and Welfare in Japan, 200036; revised by the authors).
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Kudoh & Keicho and other inflammatory cytokines from airway epithelial cells in vitro. They subsequently showed that this suppression of inflammatory cytokines was the result of inhibition of the transcription factors nuclear factor (NF)-kB or activator protein-1.47
Inhibition of Lymphocyte Accumulation and Effects on Macrophages It is difficult to obtain tissue samples of respiratory bronchioles from patients with DPB, because surgical lung biopsy is usually not necessary to make a diagnosis for the therapy. There is a lack of information on lymphocytes and macrophages around respiratory bronchioles. As mentioned earlier, an increase in the number of activated CD81 cells is observed in the bronchial fluid of patients with DPB, and these cell numbers decrease after the therapy.18 Keicho and colleagues48,49 showed that erythromycin partially suppresses lymphocyte proliferation when these cells are activated by lectins and antigens. They50 also showed that differentiation of monocyte-derived macrophages was promoted by erythromycin, although the mechanism was unknown. Currently, the mechanism by which macrolide therapy can resolve nodular lesions consisting of lymphocytes and foamy macrophages in patients with DPB remains unknown.
elastase and pyocyanin produced by P aeruginosa.51,52 Mucoid type of P aeruginosa produces alginate, forming a biofilm that makes eradication of the bacteria difficult. Alginate can be disrupted by 14-membered or 15-membered macrolides at sub-MICs. P aeruginosa uses extracellular chemical signals that cue cell-density-dependent gene expression to coordinate biofilm formation. This type of gene regulation has been termed quorum sensing and response.53 In a recent study, Tateda and colleagues54 reported that azithromycin inhibits the quorum-sensing circuitry of P aeruginosa. These anti-Pseudomonas effects of macrolides at sub-MICs may be beneficial for patients infected with P aeruginosa in the advanced stage of chronic lung diseases including cystic fiborosis.55 Fig. 5 shows the change of bacterial species in sputum of patients with DPB before and after treatment. With the conventional therapy, mainly using b-lactam antibiotics, the frequency of isolation of H influenzae declined and the frequency of isolation of P aeruginosa increased after the treatment. Conversely, the isolation of both H influenzae and P aeruginosa declined after erythromycin therapy, whereas the frequency of isolation of only nonpathogenic bacteria increased. This changing to normal flora is considered to be a result of improvement in chronic airway inflammation by erythromycin, as mentioned previously.
Modulation of Bacterial Virulence Many investigators have shown that the macrolides at less than the minimum inhibition concentrations (MICs) exert inhibitory effects on a variety of potential virulence factors such as
RECENT ADVANCEMENTS IN CLINICAL APPLICATIONS OF MACROLIDE THERAPY Recently, 14-membered and 15-membered ring macrolides have been used for many other
Fig. 5. Changes of isolated pathogens from sputum before and after therapy. Comparison between erythromycin and conventional therapy; frequency of pathogenic bacteria including P aeruginosa isolated from sputum decreased, and nonpathogenic bacteria increased (normalization of bacterial flora) after erythromycin therapy. (Data from Nakata K, Inatomi K. The 1981 Annual Report of Interstitial Lung Disease Research Committee, Japanese Ministry of Health and Welfare; 1982. p. 25; and Kudoh S, Yamaguchi T, Kurashima A, et al. The 1988 Annual Report Diffuse Parenchymal Lung Disease Research Committee, Japanese Ministry of Health and Welfare; 1989. p. 175.)
Diffuse Panbronchiolitis diseases. Recent reviews discussed long-term macrolide therapy for chronic inflammatory airway diseases including cystic fibrosis, bronchiectasis, bronchial asthma, COPD and posttransplant obstructive bronchiolitis other than DPB.38,39 Suzuki and colleagues56 first reported that erythromycin inhibits exacerbation of COPD by inhibiting rhinovirus infection to the airway. Seemangal and colleagues57 recently reported that long-term erythromycin therapy was associated with a significant reduction in exacerbations of COPD from a 12-month cohort study. In addition, Albert and colleagues58 reported that azithromycin decreased the frequency of exacerbations and improved quality of life among patients with COPD. Recently, preventive effects for seasonal and swine (H1N1) influenza infection have been discussed.59,60
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SUMMARY More than 40 years have passed since DPB was first described in Japan. Studies on the cause of the disease have progressed in the context of a genetic predisposition unique to Asians. The advent of macrolide therapy has changed the prognosis of DPB, and has clarified various antiinflammatory actions of 14-membered and 15membered ring macrolides and the pathogenesis of airway inflammation in DPB. The beneficial effects are now being applied in other chronic inflammatory diseases.
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ACKNOWLEDGMENTS This work supported by the Japanese Association of Nobel Action of Macrolides.
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37. Yamamoto M, Kondo A, Tamura M, et al. [Long-term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis]. Nihon Kyobu Shikkan Gakkai Zasshi 1990;28(10): 1305–13 [in Japanese]. 38. Crosbie PA, Woodhead MA. Long-term macrolide therapy in chronic inflammatory airway diseases [review]. Eur Respir J 2009;33:171–81. 39. Friedlander AL, Albert RK. Chronic macrolide therapy in inflammatory airways diseases [review]. Chest 2010;138:1202–12. 40. Altenburg J, de Graaff CS, van der Werf TS, et al. Immunomodulatory effects of macrolide antibioticspart1: biological mechanisms [review]. Respiration 2011;81(1):67–74. 41. Altenburg J, de Graaff CS, van der Werf TS, et al. Immunomodulatory effects of macrolide antibioticspart 2: advantages and disadvantages of long-term, low-dose macrolide therapy [review]. Respiration 2011;81(1):75–87. 42. Goswami SK, Kivity S, Marom Z. Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis 1990; 141(1):72–8. 43. Tamaoki J, Isono K, Sakai N, et al. Erythromycin inhibits Cl secretion across canine tracheal epithelial cells. Eur Respir J 1992;5(2):234–8. 44. Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun 1994;62(10): 4145–52. 45. Sakito O, Kadota J, Kohno S, et al. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration 1996;63(1):42–8. 46. Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Crit Care Med 1997;156(1):266–71. 47. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun 2000;267(1):124–8. 48. Keicho N, Kudoh S, Yotsumoto H, et al. Antilymphocytic activity of erythromycin distinct from that of FK506 or cyclosporin A. J Antibiot (Tokyo) 1993; 46(9):1406–13. 49. Morikawa K, Oseko F, Morikawa S, et al. Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro. Antimicrobial Agents Chemother 1994;38(11):2643–7. 50. Keicho N, Kudoh S, Yotsumoto H, et al. Erythromycin promotes monocyte to macrophage differentiation. J Antibiot (Tokyo) 1994;47(1):80–9.
Diffuse Panbronchiolitis 51. Kita E, Sawaki M, Oku D, et al. Suppression of virulence factors of Pseudomonas aeruginosa by erythromycin. J Antimicrob Chemother 1991;27(3):273–84. 52. Sakata K, Yajima H, Tanaka K, et al. Erythromycin inhibits the production of elastase by Pseudomonas aeruginosa without affecting its proliferation in vitro. Am Rev Respir Dis 1993;148(4 Pt 1): 1061–5. 53. Davies DG, Parsek MR, Pearson JP, et al. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 1998;280(5361): 295–8. 54. Tateda K, Comte R, Pechere JC, et al. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrobial Agents Chemother 2001;45(6):1930–3. 55. Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998;351(9100):420.
56. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest 2001;120(3): 730–3. 57. Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139–47. 58. Albert RK, Connett J, Bailey WC. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–98. 59. Yamaya M, Shinya K, Hatachi Y, et al. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J Pharmacol Exp Ther 2010;333(1):81–90. 60. Bermejo-Martin JF, Kelvin DJ, Eiros JM, et al. Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains. J Infect Dev Ctries 2009;3(3):159–61.
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KEY POINTS This chronic airway disease mainly involves Japanese, Korean, Chinese, and other Asian people. Main symptoms are a large amount of sputum and progressive exertional dyspnea in patients with nonallergic chronic paranasal sinusitis. Centrilobular nodular shadows, frequently with peripheral bronchiectasis, in high-resolution computed tomography (CT) images are characteristic. Long-term treatment with 14-membered or 15-membered ring macrolides is effective.
EPIDEMIOLOGY According to a population-based survey in 1980, the incidence of physician-diagnosed DPB was 11.1 per 100,000 in Japan.5 However, the incidence of disease seems recently to have decreased. The peak of the age distribution is among patients in their 40s to 50s. No sex predominance is noted.
Two-thirds of the patients did not smoke tobacco. There was no history of inhalation of toxic fumes.3 DPB has been also described in other east Asian populations such as the Koreans and Chinese.6,7 A limited number of cases have been reported from outside Asia,8,9 and about half the patients were Asian immigrants in reports from Western countries. Currently, it is reasonable to conclude that DPB is a chronic airway disease predominantly affecting east Asians.
CAUSE Development of DPB in east Asians, including Asian emigrants, indicates that disease susceptibility is possibly determined by a genetic predisposition unique to Asians. Human leukocyte antigen (HLA)-B54, known as an ethnic antigen unique to east Asians, was strongly associated with the disease in Japan.10,11 In contrast, Korean patients with DPB showed a positive association with HLAA11.12 Keicho and colleagues,13 analyzed genetic markers and predicted that the most likely region for the major disease susceptibility gene was between the 2 HLA loci on chromosome 6. They recently cloned 2 novel mucinlike genes designated panbronchiolitis-related mucinlike 1 and 2
a
Japan Anti-Tuberculosis Association, Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8522, Japan Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan c Department of Respiratory Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan * Japan Anti-Tuberculosis Association, Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8522, Japan. E-mail address: [email protected] b
Clin Chest Med 33 (2012) 297–305 doi:10.1016/j.ccm.2012.02.005 0272-5231/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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In the mid1960s, a new disease entity, diffuse panbronchiolitis (DPB), distinct from chronic bronchitis or bronchiectasis, was established from clinicopathologic investigation by Homma and Yamanaka.1 The first comprehensive report of DPB was published in the English language literature in 1983.2 Prognosis of DPB was dismal in the advanced stages after superinfection with Pseudomonas aeruginosa.3 The prognosis of this life-threatening airway disease has improved greatly since the initial success of long-term treatment with low-dose erythromycin was reported by Kudoh and colleagues4 in 1984. The disease is now regarded as curable. Although the cause of the disease is still unknown, recent advances in cellular and molecular biology have helped in the understanding of the mechanisms underlying the efficacy of macrolides.
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Kudoh & Keicho (PBMUCL1 and PBMUCL2) in the candidate region.14
PATHOLOGY Cut surfaces of autopsied lung tissue in DPB are characterized by fine yellowish nodules in the parenchymal area (Fig. 1).15 These nodules consist of thickened walls of the respiratory bronchioles with infiltrations of lymphocytes, plasma cells, and histiocytes. These inflammatory changes extend to the peribronchiolar tissues, whereas alveolar walls are not affected with accumulation of foamy histiocytes in the walls of the respiratory bronchioles adjacent to the alveolar ducts. DPB in the advanced stages is difficult to distinguish from diffuse bronchiectasis because of secondary ectasia of proximal bronchioles.
PATHOGENESIS Lymphocyte Accumulation Around the Small Airway It is important to characterize lymphocyte and macrophage accumulation around respiratory bronchioles to elucidate the pathogenesis of DPB. Sato and colleagues16 showed that bronchus-associated lymphoid tissue hyperplasia is frequently observed in the lung biopsy samples from patients with DPB. Surface immunoglobulin
(Ig) M–positive B lymphocytes are distributed in the follicular area and T lymphocytes, mainly CD41 cells, are located in the parafollicular area. In subsequent studies, it was reported that cytotoxic T cells expressing CD81/CDIIb- were activated, and activated cell numbers correlated with the levels of the chemokine, MIP-1a, in the bronchial fluid.17–19
Neutrophil Accumulation into the Large Airway Neutrophil accumulation in the proximal airway is another important feature of the disease.20 Neutrophil numbers and their elastase activity were significantly elevated in the bronchial fluid from patients with DPB.21 Kadota and colleagues22 also showed that chemotactic activity was significantly increased in the bronchial fluid from patients with DPB. Subsequent investigations clarified that these chemotaxins were interleukin (IL)-8, leukotriene B4 (LTB4), and other chemotactic substances. Leukocyte adherent surface molecule Mac1 of neutrophils in the peripheral blood and bronchial fluid of patients with DPB expressed significantly higher levels. In addition, serum levels of soluble forms of other adhesion molecules, members of the selectin and the immunoglobulin supergene family, were found to be significantly increased in patients with
Fig. 1. Pathologic findings of DPB. Fine yellowish nodules with bronchiectasis are scattered on the cut surface of autopsied lung (A). Respiratory bronchioles with infiltrations of lymphocytes, plasma cells (B), and accumulation of foamy histiocytes (C).
Diffuse Panbronchiolitis DPB.23,24 These results suggest that, in DPB, excessive neutrophil chemotactic factors at the site of inflammation and upregulation of adhesion molecules in the circulation are followed by recruitment of neutrophils into the proximal airway.
DIAGNOSIS Clinical Manifestations More than 80% of patients with DPB have a history or coexistence of chronic paranasal sinusitis. In their second to fifth decade, patients usually present with chronic cough and copious purulent sputum production. Exertional dyspnea develops subsequently. Physical examination of the lungs reveals coarse crackles. In about a half of patients with no intervention, sputum volume is greater than 50 mL/d.3 In a review of 81 histologically proven cases of diffuse panbronchiolitis in 1980, 44% had Haemophilus influenzae in their sputum at presentation and 22% had P aeruginosa.22 Streptococcus pneumoniae and Moraxella catarrhalis have been detected in sputum. The detection rate of P aeruginosa increases, on average, to 60% after 4 years of the disease.
Radiological Manifestations A plain chest radiograph reveals bilateral, diffuse, small nodular shadows in the lower lung field with hyperinflation of the lung. Ring-shaped or tramline shadows suggesting bronchiectasis are frequently noted in advanced cases. High-resolution CT (HRCT) is useful for the detection of characteristic pulmonary lesions associated with DPB (Fig. 2).25,26 Centrilobular nodular opacities, which suggest inflammatory lesions of the peripheral airway, are observed with bronchiectasis.
Pulmonary Functions Pulmonary function measurements show significant airflow limitation that is resistant to bronchodilators.3,27 Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) are less than 70% from the early stages. Vital capacity (VC) decreases and residual volume (RV) increases in advanced stages. However, diffusing capacity (DLco) is not decreased, as distinct from chronic obstructive pulmonary disease (COPD). Arterial blood gas analysis has revealed hypoxemia from the early stage of the disease. Hypercapnia progresses in the advanced stage. In addition, pulmonary hypertension develops and is associated with the development of cor pulmonale.
Laboratory Findings Laboratory findings suggest immunologic abnormalities reflecting chronic bacterial infection.3 The titer of cold hemagglutinin is continuously increased in most Japanese patients with no evidence of mycoplasma infection.28 Serum IgA levels are increased and a positive rheumatoid factor is often observed. Other laboratory abnormalities suggesting nonspecific inflammation include mild neutrophilia, increased erythrocyte sedimentation rate, and positive findings for Creactive protein.
Diagnostic Criteria Diagnostic criteria for DPB proposed29 by a working group of the Ministry of Health and Welfare of Japan are as follows: 1. Persistent cough, sputum, and exertional dyspnea 2. History of, or current, chronic sinusitis 3. Bilateral, diffuse, small nodular shadows on a plain chest radiograph or centrilobular micronodules on chest CT images 4. Coarse crackles 5. FEV1/FVC less than 70% and PaO2 less than 80 mm Hg 6. Titer of cold hemagglutinin equal to or greater than 64. Definite cases should fulfill the first 3 criteria (1–3) and at least 2 other remaining criteria (4–5).
TREATMENT History
Fig. 2. Typical CT findings of DPB. Centrilobular nodular shadows (tree in bud) are diffusely distributed with bronchiectasis.
In the 1970s, none of the medications for DPB was effective in preventing a fatal outcome. Antibiotics such as b-lactams were administered against H influenzae and other bacteria, but failed to change the natural course of the disease. The
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Kudoh & Keicho overall 5-year survival rate of histologically proven cases of DPB was 51% and 8% in advanced DPB with P aeruginosa superinfection.3 In 1984, Kudoh and colleagues4 first reported efficacy of low-dose, long-term erythromycin therapy for DPB, which was discovered from an open trial as a reexamination of the records of a patient with DPB treated by a general physician. After 6 months to 3 years of treatment with erythromycin 600 mg/d, 18 patients with DPB showed improvement in symptoms and clinical parameters of lung function. FEV1 was increased from 1.61 to 2.17 L (P<.01) and PaO2 was increased on average from 65.2 to 75.1 mm Hg (P<.01). Small nodular shadows on chest radiographs disappeared in more than 60% of the cases after therapy (Fig. 3).
Erythromycin Therapy The favorable effect of erythromycin in the treatment of DPB was soon confirmed by others. The beneficial effects of erythromycin was also confirmed in a prospective double-blind, placebocontrolled study conducted by Yamamoto,30 with the support of the Ministry of Health and Welfare of Japan in 1990. In the 1970s, the overall 5-year survival rate of patients with DPB was 63%. Between 1980 and 1984, fluoroquinolones were administered for the treatment of P aeruginosa superinfection and the survival rate was increased to 72%. After 1985, when erythromycin therapy was widespread, the 5-year survival rate was significantly increased to 91% (Fig. 4).31
It seems to have similar beneficial effects to other macrolides on DPB.34 Sixteen-membered ring macrolides (eg, josamycin) have been ineffective against DPB.35 A recent clinical guideline for macrolide therapy for DPB is designated in Box 1.36
POTENTIAL MECHANISM OF ACTION In the treatment of DPB, it seems that bactericidal activity is not a major determinant of the clinical efficacy of 14-membered ring macrolides.4 First, irrespective of bacterial clearance, clinical parameters are significantly improved by the treatment. Second, even in cases with superinfection with P aeruginosa, which is resistant to macrolides, treatment with macrolides is effective. Third, at the recommended dosage, peak levels of macrolides in the sputum and serum are less than the minimum inhibitory concentrations for major pathogenic bacteria colonizing the airway. Moreover, longterm usage of potent antimicrobial agents including fluoroquinolones was less effective than low-dose erythromycin in the treatment of patients with DPB.37 Investigations for the potential mechanisms underlying the effectiveness of macrolide therapy in DPB have commenced. An association for studying novel actions of macrolides was established in Japan and has had annual meetings since 1994, and many clinicians and researchers are studying the mechanism of action of macrolides. Several reviews38–41 are now available on the antiinflammatory effects of macrolides.
Inhibition of Hypersecretion Other Macrolides Recently, 14-membered ring macrolides other than erythromycin have also been used in the treatment of patients with DPB. Clinicians administered clarithromycin and roxithromycin for the treatment of DPB in the 1990s, and obtained similar clinical benefits.32,33 Azithromycin, a 15membered ring macrolide, was in limited use in Japan until it was made freely available in 2001.
Copious sputum production is one of the major characteristics in DPB. The sputum volume is reduced with erythromycin therapy. Goswami and associates42 first reported that erythromycin dose dependently suppressed the secretion of respiratory glycoconjugates from human airway cells in vitro. Tamaoki and colleagues43 measured a short-circuit current representing in vitro ion transport across airway epithelial cells and showed
Fig. 3. CT findings of before (A) and after (B) 3 years of erythromycin therapy.
Diffuse Panbronchiolitis
Fig. 4. Survival curves of DPB by the years of first examination; 5-year survival significantly improved after the first report on erythromycin therapy in 1984.
that erythromycin from the submucosal side suppressed the current in a dose-dependent manner. They showed that the chloride channel was blocked by erythromycin, leading to suppression of water secretion into the airway lumen.
Inhibition of Neutrophil Accumulation As mentioned previously, a large number of neutrophils, frequently reaching 70% to 80% of the total lavage cells, are found in the bronchial fluid in patients with DPB.20 After treatment with
erythromycin, neutrophil numbers and elastase activity in the lower respiratory tract of patients with DPB are decreased.21 Kadota and colleagues22 showed that neutrophil chemotactic activity in the bronchoalveolar lavage fluid is reduced in patients with DPB treated with erythromycin. Oishi and colleagues44 and Sakito and colleagues45 showed that levels of IL-8, a major neutrophil chemoattractant, are decreased in the airways of patients with DPB after erythromycin therapy. Takizawa and colleagues46 reported that erythromycin suppressed the expression of IL-8
Box 1 Guidelines for therapy for DPB One would think that therapy should be started soon if clinical response is better in the early stage Choice of drug: First choice: erythromycin 400–600 mg/d, orally Second choice: clarithromycin 200–400 mg/d or roxithromycin 150–300 mg/d, orally, in the event of poor efficacy or adverse events associated with erythromycin Azithromycin is also acceptable, but 16-membered ring macrolides seem to be ineffective Assessment of response and duration of treatment: Clinical response is usually obvious within 2 or 3 months of commencing therapy; however, treatment should be continued for at least 6 months and the overall response evaluated Therapy should be completed after 2 years when clinical manifestations, radiological findings, and pulmonary function measurements are improved or stable without significant impairment of daily activity Therapy should be restarted if symptoms reappear after cessation of erythromycin treatment. In advanced cases with extensive bronchiectasis or respiratory failure, therapy should be continued for more than 2 years if there is a response to treatment Based on the clinical guidelines on macrolide therapy for diffuse panbronchiolitis (Diffuse Lung Disease Committee of the Ministry of the Health and Welfare in Japan, 200036; revised by the authors).
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Kudoh & Keicho and other inflammatory cytokines from airway epithelial cells in vitro. They subsequently showed that this suppression of inflammatory cytokines was the result of inhibition of the transcription factors nuclear factor (NF)-kB or activator protein-1.47
Inhibition of Lymphocyte Accumulation and Effects on Macrophages It is difficult to obtain tissue samples of respiratory bronchioles from patients with DPB, because surgical lung biopsy is usually not necessary to make a diagnosis for the therapy. There is a lack of information on lymphocytes and macrophages around respiratory bronchioles. As mentioned earlier, an increase in the number of activated CD81 cells is observed in the bronchial fluid of patients with DPB, and these cell numbers decrease after the therapy.18 Keicho and colleagues48,49 showed that erythromycin partially suppresses lymphocyte proliferation when these cells are activated by lectins and antigens. They50 also showed that differentiation of monocyte-derived macrophages was promoted by erythromycin, although the mechanism was unknown. Currently, the mechanism by which macrolide therapy can resolve nodular lesions consisting of lymphocytes and foamy macrophages in patients with DPB remains unknown.
elastase and pyocyanin produced by P aeruginosa.51,52 Mucoid type of P aeruginosa produces alginate, forming a biofilm that makes eradication of the bacteria difficult. Alginate can be disrupted by 14-membered or 15-membered macrolides at sub-MICs. P aeruginosa uses extracellular chemical signals that cue cell-density-dependent gene expression to coordinate biofilm formation. This type of gene regulation has been termed quorum sensing and response.53 In a recent study, Tateda and colleagues54 reported that azithromycin inhibits the quorum-sensing circuitry of P aeruginosa. These anti-Pseudomonas effects of macrolides at sub-MICs may be beneficial for patients infected with P aeruginosa in the advanced stage of chronic lung diseases including cystic fiborosis.55 Fig. 5 shows the change of bacterial species in sputum of patients with DPB before and after treatment. With the conventional therapy, mainly using b-lactam antibiotics, the frequency of isolation of H influenzae declined and the frequency of isolation of P aeruginosa increased after the treatment. Conversely, the isolation of both H influenzae and P aeruginosa declined after erythromycin therapy, whereas the frequency of isolation of only nonpathogenic bacteria increased. This changing to normal flora is considered to be a result of improvement in chronic airway inflammation by erythromycin, as mentioned previously.
Modulation of Bacterial Virulence Many investigators have shown that the macrolides at less than the minimum inhibition concentrations (MICs) exert inhibitory effects on a variety of potential virulence factors such as
RECENT ADVANCEMENTS IN CLINICAL APPLICATIONS OF MACROLIDE THERAPY Recently, 14-membered and 15-membered ring macrolides have been used for many other
Fig. 5. Changes of isolated pathogens from sputum before and after therapy. Comparison between erythromycin and conventional therapy; frequency of pathogenic bacteria including P aeruginosa isolated from sputum decreased, and nonpathogenic bacteria increased (normalization of bacterial flora) after erythromycin therapy. (Data from Nakata K, Inatomi K. The 1981 Annual Report of Interstitial Lung Disease Research Committee, Japanese Ministry of Health and Welfare; 1982. p. 25; and Kudoh S, Yamaguchi T, Kurashima A, et al. The 1988 Annual Report Diffuse Parenchymal Lung Disease Research Committee, Japanese Ministry of Health and Welfare; 1989. p. 175.)
Diffuse Panbronchiolitis diseases. Recent reviews discussed long-term macrolide therapy for chronic inflammatory airway diseases including cystic fibrosis, bronchiectasis, bronchial asthma, COPD and posttransplant obstructive bronchiolitis other than DPB.38,39 Suzuki and colleagues56 first reported that erythromycin inhibits exacerbation of COPD by inhibiting rhinovirus infection to the airway. Seemangal and colleagues57 recently reported that long-term erythromycin therapy was associated with a significant reduction in exacerbations of COPD from a 12-month cohort study. In addition, Albert and colleagues58 reported that azithromycin decreased the frequency of exacerbations and improved quality of life among patients with COPD. Recently, preventive effects for seasonal and swine (H1N1) influenza infection have been discussed.59,60
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SUMMARY More than 40 years have passed since DPB was first described in Japan. Studies on the cause of the disease have progressed in the context of a genetic predisposition unique to Asians. The advent of macrolide therapy has changed the prognosis of DPB, and has clarified various antiinflammatory actions of 14-membered and 15membered ring macrolides and the pathogenesis of airway inflammation in DPB. The beneficial effects are now being applied in other chronic inflammatory diseases.
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ACKNOWLEDGMENTS This work supported by the Japanese Association of Nobel Action of Macrolides.
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