S D Greenberg, J Z Ainsworth
Comparative morphology of chronic bronchitis and chronic sinusitis, with discussion of "Sinobronchial" syndrome.
South Med J. 1966 Jan;59(1):64-74.
Abstract/Text
Katsunori Yanagihara, Kazunori Tomono, Yoshifumi Imamura, Yukihiro Kaneko, Misuzu Kuroki, Toyomitsu Sawai, Yoshitsugu Miyazaki, Yoichi Hirakata, Hiroshi Mukae, Jun-Ichi Kadota, Shigeru Kohno
Effect of clarithromycin on chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation in an experimental murine model.
J Antimicrob Chemother. 2002 May;49(5):867-70.
Abstract/Text
Fourteen-membered macrolides (e.g. clarithromycin and erythromycin), but not 16-membered macrolides (e.g. josamycin), are effective in diffuse panbronchiolitis. However, there are no studies that have compared the effects of 14- and 16-membered macrolide antibiotics on biofilm formation. Treatment with high-dose clarithromycin (100 mg/kg) resulted in a significant decrease in the number of viable bacteria in an experimental murine model. Josamycin at a dose of up to 100 mg/kg had no effect on the number of viable bacteria in the lung. Our results may explain, at least in part, the clinical efficacy of 14-membered macrolide antibiotics in patients with chronic pneumonia caused by Pseudomonas aeruginosa.
日本呼吸器学会呼吸器感染症に関するガイドライン作成委員会編：日本呼吸器学会「呼吸器感染症に関するガイドライン」成人気道感染症診療の基本的考え方． 2003．.
Masanori Asada, Motoki Yoshida, Yukimasa Hatachi, Takahiko Sasaki, Hiroyasu Yasuda, Xue Deng, Hidekazu Nishimura, Hiroshi Kubo, Ryoichi Nagatomi, Mutsuo Yamaya
l-carbocisteine inhibits respiratory syncytial virus infection in human tracheal epithelial cells.
Respir Physiol Neurobiol. 2012 Jan 15;180(1):112-8. doi: 10.1016/j.resp.2011.10.017. Epub 2011 Nov 7.
Abstract/Text
To examine the effects of l-carbocisteine on airway infection with respiratory syncytial (RS) virus, human tracheal epithelial cells were pretreated with l-carbocisteine and infected with RS virus. Viral titer, virus RNA, and pro-inflammatory cytokine secretion, including interleukin (IL)-1 and IL-6, increased with time after infection. l-carbocisteine reduced the viral titer in the supernatant fluids, the amount of RS virus RNA, RS virus infection susceptibility, and the concentration of pro-inflammatory cytokines induced by virus infection. l-carbocisteine reduced the expression of intercellular adhesion molecule (ICAM)-1, an RS virus receptor, on the cells. However, l-carbocisteine had no effects on the expression of heparan sulfate, a glycosaminoglycan that binds to the RS virus attachment protein, or on the amount of intracellular activated-RhoA, isoform A of the Ras-homologous family, that binds to the RS virus fusion protein. These findings suggest that l-carbocisteine may inhibit RS virus infection by reducing the expression of ICAM-1. It may also modulate airway inflammation during RS virus infection.
Copyright © 2011 Elsevier B.V. All rights reserved.
Mutsuo Yamaya, Hidekazu Nishimura, Kyoko Shinya, Yukimasa Hatachi, Takahiko Sasaki, Hiroyasu Yasuda, Motoki Yoshida, Masanori Asada, Naoya Fujino, Takaya Suzuki, Xue Deng, Hiroshi Kubo, Ryoichi Nagatomi
Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells.
Am J Physiol Lung Cell Mol Physiol. 2010 Aug;299(2):L160-8. doi: 10.1152/ajplung.00376.2009. Epub 2010 Jun 11.
Abstract/Text
Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H(3)N(2)). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an alpha2,6-linkage (SAalpha2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAalpha2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-kappaB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-kappaB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.
H Yasuda, M Yamaya, T Sasaki, D Inoue, K Nakayama, M Yamada, M Asada, M Yoshida, T Suzuki, H Nishimura, H Sasaki
Carbocisteine inhibits rhinovirus infection in human tracheal epithelial cells.
Eur Respir J. 2006 Jul;28(1):51-8. doi: 10.1183/09031936.06.00058505. Epub 2006 Mar 1.
Abstract/Text
The aim of the study was to examine the effects of a mucolytic drug, carbocisteine, on rhinovirus (RV) infection in the airways. Human tracheal epithelial cells were infected with a major-group RV, RV14. RV14 infection increased virus titres and the cytokine content of supernatants. Carbocisteine reduced supernatant virus titres, the amount of RV14 RNA in cells, cell susceptibility to RV infection and supernatant cytokine concentrations, including interleukin (IL)-6 and IL-8, after RV14 infection. Carbocisteine reduced the expression of mRNA encoding intercellular adhesion molecule (ICAM)-1, the receptor for the major group of RVs. It also reduced the supernatant concentration of a soluble form of ICAM-1, the number and fluorescence intensity of acidic endosomes in the cells before RV infection, and nuclear factor-kappaB activation by RV14. Carbocisteine also reduced the supernatant virus titres of the minor group RV, RV2, although carbocisteine did not reduce the expression of mRNA encoding a low density lipoprotein receptor, the receptor for RV2. These results suggest that carbocisteine inhibits rhinovirus 2 infection by blocking rhinovirus RNA entry into the endosomes, and inhibits rhinovirus 14 infection by the same mechanism as well as by reducing intercellular adhesion molecule-1 levels. Carbocisteine may modulate airway inflammation by reducing the production of cytokines in rhinovirus infection.
Jin-Ping Zheng, Jian Kang, Shao-Guang Huang, Ping Chen, Wan-Zen Yao, Lan Yang, Chun-Xue Bai, Chang-Zheng Wang, Chen Wang, Bao-Yuan Chen, Yi Shi, Chun-Tao Liu, Ping Chen, Qiang Li, Zhen-Shan Wang, Yi-Jiang Huang, Zhi-Yang Luo, Fei-Peng Chen, Jian-Zhang Yuan, Ben-Tong Yuan, Hui-Ping Qian, Rong-Chang Zhi, Nan-Shan Zhong
Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.
Lancet. 2008 Jun 14;371(9629):2013-8. doi: 10.1016/S0140-6736(08)60869-7.
Abstract/Text
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD.
METHODS: We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233.
FINDINGS: 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated.
INTERPRETATION: Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.
Patrick Waller, Samy Suissa
Carbocisteine for acute exacerbations of COPD.
Lancet. 2008 Nov 8;372(9650):1630; author reply 1631-2. doi: 10.1016/S0140-6736(08)61681-5.
Abstract/Text
Hiroyasu Yasuda, Mutsuo Yamaya, Takahiko Sasaki, Daisuke Inoue, Katsutoshi Nakayama, Naoki Tomita, Motoki Yoshida, Hidetada Sasaki
Carbocisteine reduces frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease.
J Am Geriatr Soc. 2006 Feb;54(2):378-80. doi: 10.1111/j.1532-5415.2005.00592_9.x.
Abstract/Text
Fumito Okada, Yumiko Ando, Sachie Yoshitake, Shinji Yotsumoto, Shunro Matsumoto, Masaki Wakisaka, Toru Maeda, Hiromu Mori
Pulmonary CT findings in 320 carriers of human T-lymphotropic virus type 1.
Radiology. 2006 Aug;240(2):559-64. doi: 10.1148/radiol.2402050886.
Abstract/Text
PURPOSE: To retrospectively evaluate pulmonary computed tomographic (CT) findings in human T-lymphotropic virus type 1 (HTLV-1) carriers, who were characterized by means of polyclonal integration of proviral DNA.
MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was waived. Chest CT scans obtained between January 1996 and October 2004 in 320 (154 men, 166 women; age range, 31-86 years; mean, 64 years) patients with HTLV-1 were retrospectively evaluated by three chest radiologists. Parenchymal abnormalities (ground-glass opacity, consolidation, centrilobular nodules, thickening of bronchovascular bundles, interlobular septal thickening, and bronchiectasis) were evaluated, along with enlarged lymph nodes and pleural effusion. In 58 patients who underwent surgical biopsy or transbronchial biopsy, comparison of CT images with the actual specimens was performed by a pathologist and three chest radiologists.
RESULTS: On CT scans, abnormal findings were seen in 98 (30.1%) patients and consisted of centrilobular nodules (n = 95), thickening of bronchovascular bundles (n = 55), ground-glass opacity (n = 51), bronchiectasis (n = 50), interlobular septal thickening (n = 28), and consolidation (n = 5). These abnormalities were predominantly seen in the peripheral lung parenchyma (n = 70). Pathologically, these findings corresponded to lymphocytic infiltration along respiratory bronchioles and bronchovascular bundles. Pleural effusion and enlarged lymph nodes were found in two and five patients, respectively.
CONCLUSION: CT findings in patients with HTLV-1 consisted mainly of centrilobular nodules, ground-glass opacity, and thickening of the bronchovascular bundles in the peripheral lung. These CT findings are considered suggestive of thoracic involvement in patients with HTLV-1.
RSNA, 2006
Jun-ichi Kadota, Hiroshi Mukae, Takeshi Fujii, Masafumi Seki, Kazunori Tomono, Shigeru Kohno
Clinical similarities and differences between human T-cell lymphotropic virus type 1-associated bronchiolitis and diffuse panbronchiolitis.
Chest. 2004 Apr;125(4):1239-47.
Abstract/Text
STUDY OBJECTIVES: Human T-cell lymphotropic virus type 1 (HTLV-1)-associated bronchiolitis and diffuse panbronchiolitis might overlap. We examined whether these conditions can be differentiated by comparing their clinical features and the effect of long-term macrolide treatment.
PATIENTS AND METHODS: Fifty-eight Japanese patients, including 15 with HTLV-1-associated bronchiolitis and 43 with diffuse panbronchiolitis. Both conditions were clinically compared using the clinical criteria for diffuse panbronchiolitis, including findings from CT scans and BAL fluid testing. Pulmonary function, blood gas levels, and cold hemagglutinin (CHA) levels were assessed before and after long-term treatment with macrolides. Interleukin-2 receptor (IL-2R) expression in T cells obtained from the BAL fluid of patients with HTLV-1-associated bronchiolitis or diffuse panbronchiolitis was analyzed by flow cytometry.
RESULTS: Clinical, laboratory, radiologic, and bacterial features were strikingly similar in both groups, except for the fact that patients with HTLV-1-associated bronchiolitis had a higher ratio of IL-2R-positive cells in the BAL fluid. The histopathologic features were also similar. Long-term treatment with macrolides improved PaO(2), FEV(1), and CHA in patients with HTLV-1-associated bronchiolitis to a lesser extent than in those with diffuse panbronchiolitis, and PaO(2) and FEV(1) in the group of patients with HTLV-1-associated bronchiolitis who had high IL-2R levels did not respond after therapy.
CONCLUSIONS: These findings showed that the clinicopathologic features of the two conditions are quite similar, suggesting that diffuse panbronchiolitis is a chronic pulmonary manifestation of HTLV-1 infection. However, HTLV-1-associated bronchiolitis might be associated with conditions that are distinct from those of diffuse panbronchiolitis based on the different responses to macrolide treatment and the difference in the number of activated T cells bearing IL-2R in the lungs.
Kristin L Nichol, James D Nordin, David B Nelson, John P Mullooly, Eelko Hak
Effectiveness of influenza vaccine in the community-dwelling elderly.
N Engl J Med. 2007 Oct 4;357(14):1373-81. doi: 10.1056/NEJMoa070844.
Abstract/Text
BACKGROUND: Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results.
METHODS: Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding.
RESULTS: There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death.
CONCLUSIONS: During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.
Copyright 2007 Massachusetts Medical Society.
日本呼吸器学会呼吸器感染症に関するガイドライン作成委員会編：日本呼吸器学会「呼吸器感染症に関するガイドライン」成人気道感染症診療の基本的考え方．2003年．.
Lisa Saiman, Bruce C Marshall, Nicole Mayer-Hamblett, Jane L Burns, Alexandra L Quittner, Debra A Cibene, Sarah Coquillette, Ann Yunker Fieberg, Frank J Accurso, Preston W Campbell, Macrolide Study Group
Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
JAMA. 2003 Oct 1;290(13):1749-56. doi: 10.1001/jama.290.13.1749.
Abstract/Text
CONTEXT: Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.
OBJECTIVE: To determine if an association between azithromycin use and pulmonary function exists in patients with CF.
DESIGN AND SETTING: A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.
PARTICIPANTS: Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.
INTERVENTION: The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.
MAIN OUTCOME MEASURES: Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.
RESULTS: The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).
CONCLUSION: Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.
Yoshihiro Yamamoto, Koichi Izumikawa, Naoki Hosogaya, Yoshitomo Morinaga, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Yuji Ishimatu, Hiroshi Kakeya, Katsunori Yanagihara, Akira Yasuoka, Shigeru Kohno
A case of refractory chronic respiratory tract infection due to Pseudomonas aeruginosa successfully controlled by combination of clarithromycin and azithromycin.
Intern Med. 2012;51(11):1383-6. Epub 2012 Jun 1.
Abstract/Text
The prognosis of patients with chronic respiratory tract infections, especially diffuse panbronchiolitis, is remarkably improved by long-term administration of low-dose macrolides. However, in some cases, patients are refractory to macrolide treatment and show a low or no response; therefore, new treatment strategies are required. Here we present a patient refractory to either single low-dose clarithromycin or azithromycin but responded remarkably to the combination usage of both macrolides.
Conroy Wong, Lata Jayaram, Noel Karalus, Tam Eaton, Cecilia Tong, Hans Hockey, David Milne, Wendy Fergusson, Christine Tuffery, Paul Sexton, Louanne Storey, Toni Ashton
Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
Lancet. 2012 Aug 18;380(9842):660-7. doi: 10.1016/S0140-6736(12)60953-2.
Abstract/Text
BACKGROUND: Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis.
METHODS: We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493.
FINDINGS: 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108).
INTERPRETATION: Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year.
FUNDING: Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.
Copyright © 2012 Elsevier Ltd. All rights reserved.
B W Ramsey, M S Pepe, J M Quan, K L Otto, A B Montgomery, J Williams-Warren, M Vasiljev-K, D Borowitz, C M Bowman, B C Marshall, S Marshall, A L Smith
Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
N Engl J Med. 1999 Jan 7;340(1):23-30. doi: 10.1056/NEJM199901073400104.
Abstract/Text
BACKGROUND AND METHODS: We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization.
RESULTS: The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group.
CONCLUSIONS: In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.
J Kadota, H Mukae, H Ishii, T Nagata, H Kaida, K Tomono, S Kohno
Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis.
Respir Med. 2003 Jul;97(7):844-50.
Abstract/Text
Diffuse panbronchiolitis (DPB) can now be cured with long-term erythromycin treatment. Our group conducted a prospective open trial of long-term treatment with a macrolide antibiotic, clarithromycin. We studied ten patients who were treated for 4 years with oral clarithromycin (200 mg once a day). Pulmonary function test, blood gas analysis, comprehensive improvement score, and bacterial culture of sputum were examined at 3, 6, 12 months, and at 2, 3, 4 years after the initiation of the therapy. Pulmonary function improved in most of the patients within 6 months: the forced expiratory volume in one second showed a maximal increase from a mean (SE) value of 1.74 (0.12) l at baseline to 2.31 (0.22) l at 6 months (P < 0.01) and the volume (l) of forced vital capacity also showed a maximal increase within 6 months. The partial pressure of arterial oxygen at rest significantly increased at 3-6 months. The comprehensive improvement score also reached maximum within 6 months in nine of the patients. The majority of patients have developed sputum culture in which bacteria were negative within 6 months after the therapy. All of the patients maintained a stable condition with continued therapy, and no side effects of clarithromycin were observed during the study. This prospective study demonstrated that 6-month treatment with clarithromycin might be necessary to improve the clinical conditions of patients with DPB and the drug could be safely used for a long term.
Jun-ichi Kadota, Hiroshi Mukae, Syunji Mizunoe, Kenji Kishi, Issei Tokimatsu, Hiroyuki Nagai, Kazunori Tomono, Shigeru Kohno, Masaru Nasu
Long-term macrolide antibiotic therapy in the treatment of chronic small airway disease clinically mimicking diffuse panbronchiolitis.
Intern Med. 2005 Mar;44(3):200-6.
Abstract/Text
OBJECTIVE: In the current studies, we investigated the clinical effects of long-term macrolide antibiotic therapy for patients with chronic small airway disease (CAD) that clinically and radiologically mimics but is pathologically distinct from diffuse panbronchiolitis (DPB).
PATIENTS AND METHODS: Twenty-one Japanese patients were selected on the basis of clinical criteria for DPB and were categorized as DPB or CAD following histological evaluation of surgical lung biopsies. All patients received long-term macrolide therapy, and therapeutic results were compared for the DPB and CAD groups.
RESULTS: Clinical, laboratory, radiological, and bacterial features, as well as neutrophilia in bronchoalveolar lavage fluid were strikingly similar in both groups. Long-term treatment with macrolides improved the clinical symptoms and PaO(2) in both groups. There was a significant improvement in forced expiratory volume in one second (FEV(1)), vital capacity (VC), and %VC in patients with DPB but not in patients with CAD. Neutrophilia in bronchoalveolar lavage fluid was also reduced following therapy in DPB patients but was refractory in CAD patients.
CONCLUSION: Based on the different responses to macrolides, CAD might be associated with conditions distinct from those of DPB. Nevertheless, low-dose macrolide therapy may be applied in CAD to achieve clinical improvement, such as in respiratory symptoms and PaO(2).
Eva Polverino, Pieter C Goeminne, Melissa J McDonnell, Stefano Aliberti, Sara E Marshall, Michael R Loebinger, Marlene Murris, Rafael Cantón, Antoni Torres, Katerina Dimakou, Anthony De Soyza, Adam T Hill, Charles S Haworth, Montserrat Vendrell, Felix C Ringshausen, Dragan Subotic, Robert Wilson, Jordi Vilaró, Bjorn Stallberg, Tobias Welte, Gernot Rohde, Francesco Blasi, Stuart Elborn, Marta Almagro, Alan Timothy, Thomas Ruddy, Thomy Tonia, David Rigau, James D Chalmers
European Respiratory Society guidelines for the management of adult bronchiectasis.
Eur Respir J. 2017 Sep;50(3). doi: 10.1183/13993003.00629-2017. Epub 2017 Sep 9.
Abstract/Text
Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.
Copyright ©ERS 2017.
James D Chalmers, Wim Boersma, Mike Lonergan, Lata Jayaram, Megan L Crichton, Noel Karalus, Steven L Taylor, Megan L Martin, Lucy D Burr, Conroy Wong, Josje Altenburg
Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis.
Lancet Respir Med. 2019 Oct;7(10):845-854. doi: 10.1016/S2213-2600(19)30191-2. Epub 2019 Aug 9.
Abstract/Text
BACKGROUND: Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended.
METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV1. IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV1, and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV1 percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908.
FINDINGS: Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV1 (67 mL at 1 year, -22 to 112; p=0·14). Effect estimates in prespecified subgroup analyses revealed a reduced frequency of exacerbations in all prespecified subgroups, including a high level of benefit in patients with P aeruginosa infection (IRR 0·36, 0·18-0·72; p=0·0044) and in patients with one to two exacerbations per year (0·37, 0·16-0·88; p=0·025). Studies were rated as low risk of bias across all domains.
INTERPRETATION: Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account.
FUNDING: European Respiratory Society.
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