Applying lessons learned in the treatment of diffuse panbronchiolitis to other chronic inflammatory diseases

Applying Lessons Learned in the Treatment of Diffuse Panbronchiolitis to Other Chronic Inflammatory Diseases Shoji Kudoh, MD, PhD

In addition to having antibacterial effects, macrolides modulate inflammatory responses. Their effectiveness in treating chronic inflammatory airway disease is well documented in patients with diffuse panbronchiolitis (DPB), a chronic condition characterized by inflammation of the airways that, if left untreated, progressively leads to respiratory failure and death. Long-term treatment with certain macrolides has dramatically improved the survival of patients with DPB. The mechanisms of action for the anti-inflammatory properties of macrolides are still being studied. The effects of macrolides on inflammation include decreasing chemotaxis of neutrophils to the respiratory tract and inhibiting the expression of adhesion molecules, with decreased infiltration of neutrophils into the respiratory epithelium. Macrolides also inhibit expression of transcription factors and formation of proinflammatory cytokines, and directly and indirectly block mucus secretion. Even with long-term use, macrolides are safe and well tolerated. The effectiveness of macrolides for treating DPB has led to interest in their use in treating other chronic inflammatory airway diseases. As discussed in this article, because of the similarities between the clinical presentation of cystic fibrosis and chronic bronchitis and DPB, the effects of macrolides in patients with these diseases are currently being studied with particular interest. Am J Med. 2004;117(9A): 12S–19S. © 2004 by Elsevier Inc.

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iffuse panbronchiolitis (DPB) is a chronic disease of the airways involving diffuse inflammation of the respiratory bronchioles. DPB occurs primarily in East Asia, with few cases identified in the Western world.1–3 Although the etiology is still unknown, both genetic and environmental factors contribute to the pathogenesis of DPB.4 –7 Before the introduction of therapy with macrolide antibiotics, the prognosis of patients with DPB was poor. Historically, half of all patients with DPB developed diffuse bronchiectasis, progressive respiratory failure, and ultimately died within 5 years of diagnosis, often as a result of infection.8 The survival rate following infection with Pseudomonas aeruginosa was only about 8%. However, the introduction of long-term treatment with lowdose macrolide antibiotics has dramatically altered disease progression and survival for these patients. In addition to their antimicrobial properties, the immunomodulatory properties of the 14-member ring macrolides, such as erythromycin and clarithromycin, are well established. These drugs reduce inflammation in patients with DPB. The 15-member ring macrolides, such as azithromycin, may also possess these properties, but the 16-member ring macrolides do not have these antiinflammatory effects. These drugs reduce the inflammatory response by decreasing the recruitment and infiltration of neutrophils into the airway, inhibiting expression of transcription factors and, subsequently, expression of proinflammatory cytokines and chemokines, as well as decreasing mucus secretion.9,10 Because of these immunomodulatory effects, there is significant interest in the efficacy of macrolides in the treatment of other chronic inflammatory diseases of the airways such as cystic fibrosis and chronic obstructive pulmonary disease (COPD) or chronic bronchitis, which have clinical and pathologic features similar to those of DPB.11 This review discusses DPB, the effectiveness of macrolides in treating this disease, and the evidence for the efficacy of macrolides in the treatment of cystic fibrosis and chronic bronchitis.

DIFFUSE PANBRONCHIOLITIS

From Nippon Medical School, Tokyo, Japan. Requests for reprints should be addressed to Shoji Kudoh, MD, PhD, Nippon Medical School, 1-1-5 Sendagi, Bumkyo-ku, Tokyo, Japan. 12S

© 2004 by Elsevier Inc. All rights reserved.

Clinical Presentation and Diagnosis of DPB Common signs and symptoms of DPB include productive cough, dyspnea with exertion, airflow limitations, chronic sinusitis, weight loss, and chronic infection with 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.024

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Table 1. Diagnostic Criteria for Diffuse Panbronchiolitis (DPB) Criteria

Indications

Major 1. Symptoms 2. Past history or current coexistence of chronic paranasal sinusitis 3. Chest x-ray findings

Chronic cough, sputum, and dyspnea on exertion

Bilateral fine nodular shadows, mainly in the lower lung fields, often with hyperinflation of the lungs on a plain chest x-ray film or centrilobular micronodules on chest CT images

Minor 4. Physical signs 5. Pulmonary function tests and arterial blood gas analysis 6. Elevated titers of cold hemagglutinin 7. Surgical biopsies

Coarse crackles on auscultation of the chest FEV1/FVC ⬍70% and PaO2 ⬍80 mm Hg ⱖ64⫻ Show thickness of the wall of the respiratory bronchiole, with infiltration of lymphocytes, plasma cells, and foamy histiocytes expanded into the peribronchiolar area. DPB also includes patients with bronchiectasis considered to be in different stages of DPB

CT ⫽ computed tomography; FEV1/FVC ⫽ ratio of forced expiratory volume in 1 second to forced vital capacity, expressed as a percentage; PaO2 ⫽ arterial oxygen pressure.

organisms such as P aeruginosa. Many patients have concomitant paranasal sinusitis; pansinusitis and underdevelopment of the frontal sinus also sometimes occur. Chest examination may show decreased breath sounds and coarse crackles. The pathologic features of DPB include a thickening of the wall of the respiratory bronchiole with infiltration of lymphocytes, plasma cells, and histiocytes. In the advanced stage of disease, respiratory bronchioli are frequently narrowed by infiltration of inflammatory cells, proliferation of lymphoid follicles, accumulation of foamy macrophages within the walls, and secondary ectasia of peripheral bronchi.12–15 Pulmonary function tests initially show mixed obstructive impairment. Patients have an increased residual volume and an increased ratio of residual volume to total lung capacity with increasing restriction as the disease progresses. Hypoxemia is common and appears early in the disease course, with hypercapnea occurring in the terminal stages of disease.12 The most characteristic laboratory abnormality in patients with DPB, particularly in Japanese patients, is a persistent elevation of cold hemagglutinin titer. Additional laboratory abnormalities include positive rheumatoid factor and antinuclear antibody titers, increased serum immunoglobulin A, and sputum cultures positive for Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, or Staphylococcus aureus. Chronic infection with Pseudomonas species such as P aeruginosa may be present.16 Chest x-ray may show diffuse, small nodular shadows in the lower lung fields and hyperinflation of the lung. High-resolution computed tomography (HRCT) may be useful to identify small nodular opacities distributed

around the ends of bronchovascular branches and in centrilobular regions, indicating inflammation of respiratory bronchioles. The diagnostic criteria for DPB are summarized in Table 1 . Treatment of DPB In 1984, we first reported the effectiveness of erythromycin therapy (600 mg/day for ⱖ6 months) in patients diagnosed with DPB.17 Subsequently, several trials and case studies have shown the efficacy of macrolide therapy for the treatment of DPB.7,18 –24 Clinical experience with macrolides in the treatment of patients with DPB is summarized in Table 2.18,20,22,24 –26 A retrospective, multicenter trial demonstrated the effectiveness of erythromycin therapy in 52 patients with DPB.24 Patients received erythromycin (600 mg/day) for a mean of 20 months. The volume of produced sputum was markedly reduced in 86% of patients who received erythromycin. Dyspnea on exertion and cold hemagglutinin titers improved significantly. Pulmonary function measures such as arterial oxygen pressure (PaO2), percent vital capacity, and forced expiratory volume in 1 second (FEV1) were increased significantly, whereas residual volume was significantly reduced.24 A randomized, placebo-controlled, double-blind, multicenter study of erythromycin for the treatment of patients with DPB was conducted in 73 patients. Erythromycin (200 mg) was administered 3 times a day for 3 months. Effectiveness of erythromycin was determined based on changes in dyspnea on exertion, chest x-ray findings, PaO2, FEV1, C-reactive protein, and sputum volume. The response rate was 72% among patients receiving erythromycin compared with 25% in patients re-

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Study

Macrolide

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24

Daily Dosage (mg)

Patients (N)

Duration of Treatment

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Kudoh et al

Erythromycin

600

52

Mean 20 mo

Yamamoto et al25

Erythromycin

600

73

3 mo

Kadota et al20

Clarithromycin

200

10

4y

Ichikawa et al18

Erythromycin

600

18

3 mo

Fujii et al26

Erythromycin

600

28

1–12 mo

Shirai et al22

Erythromycin Roxithromycin Clarithromycin

400–600 150–300 200–400

34

⬎2 mo

Results Pulmonary function: improvement in FEV1, FEV1%, %VC, PaO2, RV/TLC Sputum volume: reduced in 86% of patients Reduced cold hemagglutinin Overall clinical response rate: erythromycin, 72%; placebo, 25% Decreased radiographic evidence of disease: erythromycin, 54.5%; placebo, 15.8% Decreased sputum volume: erythromycin, 59.4%; placebo, 14.3% Decreased cough: erythromycin, 15.6%; placebo, 2.6% Pulmonary function: significant improvement at 3 mo in FEV1, VC, %VC, and PaO2, and at 6 mo in FEV1% Sputum culture: negative for bacteria at 6 months in most patients Pulmonary function: increased FEV1, FVC, and PaO2 Decreased radiographic evidence of disease: improvement in extent of small nodular opacities, severity of periairway thickening, and extent of mucus plugging Increased pulmonary function and arterial blood gas pressure independent of Pseudomonas aeruginosa infection Decreased total cell count and percentage of neutrophils in BALF from patients with DPB Overall clinical response rate: erythromycin, 79%; roxithromycin, 86%; clarithromycin, 67%

BALF ⫽ bronchoalveolar lavage fluid; FEV1 ⫽ forced expiratory volume in 1 second; PaO2 ⫽ arterial pressure of oxygen; RV/TLC ⫽ residual volume/total lung capacity; VC ⫽ vital capacity.

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Table 2. Clinical Experience with Macrolides in Patients with Diffuse Panbronchiolitis (DPB)

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ceiving placebo. Cough (P ⬍0.05), small nodular opacities by chest x-ray (P ⬍0.01), and sputum volume (P ⬍0.001) were significantly improved in these patients.25 The long-term effectiveness and safety of clarithromycin was evaluated in 10 patients with DPB who received clarithromycin (200 mg) once daily for 4 years.20 Pulmonary function, blood gas analysis, comprehensive improvement, and cultures of sputum were evaluated. Pulmonary function improved significantly within 6 months of beginning clarithromycin, and the effect was maintained for the duration of the study period. Likewise, sputum cultures from most patients were negative for bacteria within 6 months of beginning therapy. Furthermore, clarithromycin was well tolerated and no side effects were reported during the study period. Treatment with macrolides significantly improved lesions in the lung. The extent of small nodular opacities, mucoid impaction, and peribronchiolar thickening assessed by HRCT were significantly reduced after treatment with erythromycin (600 mg/day) for about 3 months in 18 patients with DPB.27 Reduced lesions in the lungs correlated with improvements in forced vital capacity (FVC), FEV1, and PaO2. Although the optimum duration for treating patients with macrolides is not clear, there is significantly less improvement in pulmonary function with 1-year versus 2-year treatment for advanced cases of DPB.16, 27 A guideline for macrolide treatment of DPB proposed by the Research Group of Ministry of Health, Labor, and Welfare (RGMHLW) of Japan recommends continued macrolide therapy for advanced disease ⱖ2 years. The effectiveness of macrolide therapy in patients with DPB is not related to the antimicrobial properties of the drug.26 In 16 patients with DPB and P aeruginosa infection in the airway and 12 patients with DPB without P aeruginosa infection, erythromycin improved pulmonary function and PaO2, and also reduced the total cell count and percent neutrophils in bronchoalveolar lavage fluid.26 Overall, the most dramatic effect of macrolides in patients with diffuse panbronchiolitis has been on survival. A retrospective study by the RGMHLW of Japan showed that before the use of macrolides, the 5-year survival rate for patients with DPB was 63% in the 1970s and 72% from 1980 to 1984.8 Prognosis of DPB was especially poor in elderly patients. However, after the introduction of erythromycin therapy in 1985, the 5-year survival rate increased to 92%. Based on these data, therapeutic guidelines were developed for the treatment of DPB. Erythromycin treatment is first-line therapy for patients with DPB, and is typically followed by treatment with clarithromycin for patients with a poor response to erythromycin (Figure 1).28 To maximize clinical effectiveness, macrolide therapy should be started soon after diagnosis. The effectiveness

of therapy is generally apparent within 2 to 3 months of initiating therapy, and patients should receive ⱖ6 months of therapy before the effectiveness of treatment is evaluated. After 2 years of treatment, macrolide therapy can be stopped if the symptoms and clinical findings have improved and are stable, but it should be continued in patients with advanced disease with extensive bronchiectasis and respiratory failure. Therapy is reinitiated upon reappearance of symptoms. Mechanisms of Action Factors contributing to the effectiveness of macrolides as anti-inflammatory agents for the treatment of DPB are unclear. However, it is unlikely that the efficacy of macrolides in this disease is due to their antimicrobial properties. Studies show that the effectiveness of macrolides in treating DPB is independent of their ability to treat bacterial infections and improve symptoms in patients with P aeruginosa infection. The dose of drug used is lower than the maximum inhibitory concentration for most bacteria that commonly cause respiratory infections or colonize the respiratory tract. Most research has focused on the role of neutrophils, epithelial cells, lymphocytes, and macrophages in chronic inflammation of the airways. Macrolides inhibit the cycle of chronic airway infection through their anti-inflammatory effects on these cells and inactivation of bacterial toxicity (Figure 2). Many studies show that macrolides inhibit neutrophil accumulation to the inflammatory site through inhibition of neutrophil adhesion, inhibition of proinflammatory cytokines such as interleukin (IL)-8 from the epithelial cells and neutrophils, and inhibition of mucus hypersecretion.9,10,19,29 –33 (For a review of studies on the immunomodulatory effects of these drugs, see the article by Tamaoki and coworkers elsewhere in this supplement.34) These actions may result in reduction of inflammatory mediators such as superoxides and neutrophil elastase.30,35,37 Macrolides inhibit the release of proinflammatory cytokines through the inhibition of transcription factors nuclear factor–␬B and activator protein–1.38,39 These immunomodulatory effects are correlated with improvements in pulmonary function in patients with DPB.19,29,40,41 A novel action of macrolides is modulation of bacterial function. Macrolides inhibit biofilm formation through suppression of quorum sensing in bacteria.42 The longterm use of the 14- and 15-member macrolides in patients with DPB changes the bacterial composition of the sputum, with a decrease in P aeruginosa and an increase in normal respiratory flora.24 Cystic Fibrosis Cystic fibrosis is a common hereditary disease in the Western world, with an incidence of 1 in 2,500.43 The clinical and pathologic characteristics of cystic fibrosis are remarkably similar to DPB, although no direct evidence

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Figure 1. Therapeutic guidelines for the treatment of diffuse panbronchiolitis. Guidelines shown represent a partial modification of the Report of Diffuse Parenchymal Lung Disease Research Committee, Japanese Ministry of Health and Welfare.28

Figure 2. Mechanisms of action of macrolide therapy for the treatment of diffuse panbronchiolitis. EM ⫽ erythromycin.

links the 2 diseases genetically.44 Patients with cystic fibrosis typically have thick secretions, plugging of the airways, and chronic inflammation of the airways. Progressive lung disease is the primary cause of morbidity and mortality in these individuals.45 Patients with cystic fi16S November 8, 2004

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brosis often develop chronic infection of the airways, usually owing to P aeruginosa, which leads to an inflammatory response that may eventually result in respiratory failure. Only a few randomized, double-blind, placebocontrolled clinical trials have studied the effectiveness of Volume 117 (9A)

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macrolides for the treatment of cystic fibrosis. Most of these trials have shown a clinical benefit for these patients and are summarized below. The effectiveness of azithromycin in the treatment of cystic fibrosis was reported in an open pilot study of 7 children (mean age, 12.1 years) having end-stage cystic fibrosis or chronic airflow limitation that was unresponsive to conventional therapy.46 Patients received azithromycin for ⬎3 months. The average predicted FVC increased from 62.8 to 70.3 (11.3%; P ⬍0.03); FEV1 increased from 47.5 to 49.5 (11%; P ⬍0.03). With these promising data, a subsequent randomized, double-blind, placebo-controlled crossover study was conducted in 41 children with cystic fibrosis.47 In this study, patients received either azithromycin or placebo for 6 months. The primary outcome measure was the median relative difference in FEV1. Secondary outcome measures included FVC, sputum cultures, sputum concentrations of IL-8, concentrations of neutrophil elastase, exercise testing, quality of life, antibiotic use, and pulmonary exacerbation rates. FEV1 improved by 5.4% between the fourth and sixth months of therapy. Children who received azithromycin showed improved pulmonary function compared with placebo recipients. A randomized, double-blind, placebo-controlled study showed that azithromycin was effective for treating adults with cystic fibrosis.48 In this study, 60 cystic fibrosis patients (mean age, 27.9 years) received either azithromycin (250 mg/day) or placebo for 3 months. Improvement in pulmonary function was measured by spirometry, weight, and quality-of-life assessments. Compared with placebo, treatment with azithromycin significantly improved FEV1 by 3.6% and improved percent predicted FVC by 5.7% by the end of the study period. Patients reported an increased quality of life and had fewer acute respiratory exacerbations. Wolter and colleagues48 suggested that the improvement in pulmonary function after treatment with azithromycin was smaller in these older patients compared with improvements in children in previous studies; this discrepancy was likely due to greater severity of the disease in the older individuals. Because the clinical benefit may be a result of the antiinflammatory properties of the macrolides, a greater benefit may be seen in children with cystic fibrosis whose disease has a greater inflammatory component compared with adults who have more scarring of airways. In a large multicenter, randomized, controlled clinical trial, 185 patients with cystic fibrosis (aged ⱖ6 years) who were chronically infected with P aeruginosa received either 250 mg azithromycin 3 times a week for 168 days or placebo.49 Primary outcome measures included safety as well as change in FEV1 from baseline to the end of the study. Secondary outcome measures included changes in FVC, rate of pulmonary exacerbations, weight gain, and quality of life. Patients receiving azithromycin had im-

proved pulmonary function, with a 4.4% increase over baseline values compared with a 1.8% decrease in patients receiving placebo. This effect was sustained throughout the study, but FEV1 returned to baseline 4 weeks after the end of the study. Improvements in FVC were also observed in patients receiving azithromycin. Patients receiving azithromycin had fewer pulmonary exacerbations, a higher weight gain, and an improved quality of life. Treatment with azithromycin was well tolerated in this study. These collective data suggest that the use of macrolides for the management of cystic fibrosis may provide a clinical benefit to patients. It should be noted that although a pilot study of 10 cystic fibrosis patients treated with clarithromycin 500 mg twice daily for 6 weeks did not show a change in FEV1, FVC, or measures of inflammation, that study was underpowered and of insufficient duration to draw conclusions.50 Additional studies are needed to understand the mechanism by which macrolides exert their effect in patients with cystic fibrosis. COPD/Chronic Bronchitis Chronic bronchitis is a disease that occurs commonly in smokers and is characterized clinically by chronic cough, sputum, and dyspnea.51 Continuous exposure to airway irritants causes chronic inflammation and hypersecretion of mucus. Patients with chronic bronchitis have increased proinflammatory cytokines in sputum, including IL-8, tumor necrosis factor–␣, and IL-1␤.52 Increased mucus secretion leads not only to a chronic productive cough but also to recurrent infection. Patients with chronic bronchitis have progressive worsening of pulmonary function, airway thickening, decreased lung elasticity, and an increase in acute exacerbations. Given the similarities between patients with chronic bronchitis and DPB in clinical symptoms and molecular changes in the airway, prospective, randomized, double-blind clinical trials are needed to determine whether macrolides will have the same effect on neutrophils, proinflammatory cytokines, and mucus in patients with chronic bronchitis. Macrolides may also have other benefits in patients with chronic bronchitis. Acute exacerbations in patients with chronic bronchitis are frequently viral. In a study of 109 patients with COPD, patients receiving placebo had more acute exacerbations (relative risk [RR], 4.7) and more common colds (RR, 9.3) compared with patients taking erythromycin.53 Erythromycin also inhibits rhinoviral infection of human tracheal epithelial cells in vitro.54 Future studies will elucidate the role of macrolides in chronic bronchitis.

CONCLUSION Since the discovery of the anti-inflammatory properties of macrolides, there has been extensive research on their possible clinical benefits and their mechanism of action

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for the treatment of chronic inflammatory diseases of the airways. The clinical effects of long-term treatment with the 14-member ring macrolides have been studied most thoroughly in DPB, a chronic, progressive, inflammatory disease of the lower airways. Patients with DPB who receive macrolides have decreased shortness of breath and sputum, with improved FEV1 and PaO2. Patients also have improvements in nodular lung lesions as identified by chest x-ray or HRCT. The necessary duration of treatment is still not known. These clinical benefits are likely due to numerous molecular changes that occur in the respiratory tract. Macrolides inhibit recruitment and infiltration of neutrophils by expression of transcription factors and, subsequently, proinflammatory cytokines like IL-8. This decrease in inflammation is the primary reason for the decrease in infections, decrease in sputum, and decreased shortness of breath in these patients. Most dramatically, macrolide therapy has changed DPB into a disease with 5-year survival rates of ⬎95%. Given the effectiveness of macrolide therapy in patients with DPB, as well as the similarities in pathogenesis among DPB, cystic fibrosis, and chronic bronchitis, it is reasonable to test macrolides in patients with these diseases. Preliminary studies demonstrate that children with cystic fibrosis benefit from macrolide therapy, showing improvement in pulmonary function. Further studies may lead to a greater understanding of why the effects on pulmonary function are greater in children with cystic fibrosis as compared with adults. There are no randomized prospective trials in patients with chronic bronchitis, but it is anticipated that, given the similarities to DPB, these patients may have decreased sputum and fewer exacerbations.

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November 8, 2004

THE AMERICAN JOURNAL OF MEDICINE威

Volume 117 (9A)

19S