Beruflich Dokumente
Kultur Dokumente
Laboratory of Experimental Internal Medicine and 2Department of Intensive Care Medicine, C3-329,
Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Introduction
Diffuse panbronchiolitis (DPB) is a condition of unknown
aetiology, usually diagnosed between the second and fifth decade. DPB is an important cause of progressive obstructive lung
disease in the Far East (mainly in Japan and Korea), but a rare
disease in non-Asian populations. The onset of DPB resembles
bronchial asthma, chronic bronchitis, and pulmonary emphysema, because it is clinically manifested by common symptoms
such as dyspnoea, cough, sputum, coarse crackles and wheeze.
The chest radiograph often shows hyperinflation. Pulmonary
function tests show decreased vital capacity (VC), and forced
expiratory volume in 1 s (FEV1). Lung histology reveals a cellular bronchiolitis, mononuclear cell proliferation and foamy
macrophages involving the bronchiolar walls, adjacent alveolar
ducts and alveoli. Narrowing and constriction of respiratory
bronchioles may develop in advanced stages. Advanced disease
is associated with chronic mucoid Pseudomonas aeruginosa
infection. Death is usually secondary to respiratory failure
and/or P. aeruginosa pneumonia. For a long time, the long-term
..........................................................................................................................................................................................................................................................................................................................................................................................................................
21
JAC vol.54 no.1 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
No. of patients
Takeda et al.
Yamamoto et al.12a
1989
1990
12
101
long-term CLR
ERY for >3 months
Nagai et al.13a
1991
19
Ichikawa et al.14a
1992
Akira et al.4
Therapy
Non-clinical findings
11
improvement in symptoms
improvement in dyspnoea,
amount of sputum
16 patients improved, with less
sputum production and less dyspnoea
improvement in pulmonary function
1993
19
NA
Kadota et al.15a
1993
19 (?)
long-term ERY
NA
Oda et al.16
1994
13
Kusano et al.5a
Fujii et al.17
1995
1995
?
28
long-term RXM
ERY 600 mg/day
for >12 months
NA
reduced sputum volume, improved
VC%, FEV1 and ABA
Kobayashi et al.20a
1995
60
Mukae et al.18
1995
33
Tamaoki et al.19
1995
31
Kadota et al.21
1996
Sakito et al.22
1996
?
improvement in CXR-findings, ABA,
ESR, cold coagulation titre
16 patients showed improvement
in CXR-findings
neutrophil and the neutrophil-derived
elastolytic-like activity in
BALF decreased
decreased areas of high attenuation,
no changes in peripheral areas on
CT scan
reduced BALF neutrophil cell count,
reduced neutrophil chemotactic activity
reduced BALF total cell count,
reduced BALF neutrophil cell count,
reduced neutrophil chemotactic activity
reduced BALF neutrophil cell count
reduced BALF total cell count,
reduced BALF neutrophil cell count in
pts in whom P. aeruginosa cleared
improvement in ESR, cold coagulation titre
Shirai et al.58a
1997
22
Review
Clinical symptoms
11a
Author
Only studies with an abstract in PubMed are listed; ?, unclear or not available; pts, patients; CLR, clarithromycin; ERY, erythromycin; RXM, roxithromycin; AZM, azithromycin; NA, not applicable;
ABA, arterial blood gas analysis; BALF, bronchoalveolar lavage fluid; FVC, forced vital capacity; PaO2, arterial oxygen tension.
a
Only abstract available.
2003
Kadota et al.6
10
2003
Hiratsuka et al.25
33
498
(see text for details)
Therapy
No. of patients
Year of
publication
Author
Table 1. (Continued)
Search results
A search of the PubMed (National Library of Medicine, USA at
www.pubmed.org) for unlimited citations using the words DPB
OR diffuse panbronchiolitis found a total of 708 publications.
At the end of March 2004, a limited search using the items
macrolides AND DPB OR diffuse panbronchiolitis found 164
papers; a limited search using the items erythromycin OR azithromycin OR clarithromycin AND DPB OR diffuse panbronchiolitis listed 154 papers. Limiting these searches for
human and clinical trial, listed 10 identical papers. Only
seven papers were about macrolide therapy in DPB patients, and
only three of them were in the English language.4 6 The reference lists of these publications, and several reviews on this
topic,7 9 were used to find additional papers on macrolide
therapy in DPB. This resulted in identification of 17 additional
papers.1,10 25
A search of the PubMed database for unlimited citations
using the words CF OR cystic fibrosis found a total of 31 600
publications. At the end of March 2004, using limited search
items macrolides AND CF OR cystic fibrosis identified 325
papers; for a limited search using the items erythromycin OR
azithromycin OR clarithromycin AND CF OR cystic fibrosis
125 papers were listed. Limiting these searches for human and
clinical trial, listed eight and 14 papers, respectively. Finally,
after carefully reading the abstracts, only five papers were about
macrolide therapy in CF patients, and only three of them were in
the English language.26 28 Reviews on the topic of macrolide
therapy in chronic lung disease2,3,29 identified two additional
papers.30,31
Clinical symptoms
Non-clinical findings
Review
Review
Table 2. Studies on macrolides in cystic fibrosis
No. of
patients
Jaffe et al.30
1998
Ordonez et al.31
2001
10
Wolter et al.26
2002
60
Equi et al.27
2002
41
Saiman et al.28
2003
185
Therapy
Clinical symptoms
improvement in
FVC% and FEV1
no changes in
VC% and FEV1
improved QOL,
less antimicrobial courses,
better VC% and FEV1
no change in exercise
tolerance or subjective
well-being, modest response in
FEV1, fewer antimicrobial courses
better FEV1, less risk of
experiencing an exacerbation
Non-clinical findings
NA
no changes in BALF
neutrophil cell count
decline in CRP
no change in sputum
bacterial densities,
and inflammatory
markers
AZM, azithromycin; CLR, clarithromycin; NA, not applicable; QOL, quality of life; FVC, forced vital capacity; BALF, bronchoalveolar lavage fluid;
CRP, C-reactive protein.
24
Year of
publication
Author
Review
administration of 5 mg erythromycin per animal 2 h before intratracheal injection of IL-8 or LPS. However, administration of
erythromycin for 1 week did not alter the intrapulmonary neutrophil cell accumulation. In another animal model, LPS-induced
vascular leakage and neutrophil cell accumulation in rat trachea,
both roxithromycin and erythromycin reduced neutrophil cell
accumulation.43
Long-term macrolide treatment of patients with DPB gave
lower neutrophil cell counts in bronchoalveolar lavage fluids in
numerous studies.5,14 17,21 23,25 Although attenuation of inflammation by macrolides was not demonstrated in patients with CF,
it must be mentioned that Ordonez et al.31 gave a short course of
therapy at a high dose. Therefore extrapolation of results from
this study may be difficult especially as the macrolides can
initially increase the inflammatory response.
The mechanisms underlying the effects of macrolides on neutrophil cell functions are largely unclear. It has been suggested
that inhibition of activation of protein kinase A is responsible
for the inhibition of oxidant production.36 Another study suggests
that macrolides influence the phospholipase D phosphatidate
phosphohydrolase transduction pathway, which is essential for
neutrophil cell degranulation.44
Review
an experimental murine model of chronic P. aeruginosa pneumonia.57
In clinical studies focusing on cytokine levels in lung fluids,
long-term macrolide therapy resulted in reduced IL-1b and IL-8
in patients with DPB.21,22,58 There are no data available on the
effects of maintenance macrolide therapy on cytokine production
in patients with CF.
Studies on the mechanisms underlying the effect of macrolides
on cytokine production have produced inconsistent data. Since
macrolide antibiotics exhibit their antimicrobial activity by
interfering with the protein production of microorganisms, interference with protein production may be one mechanism by which
cytokine production is influenced by macrolide antibiotics. Inhibition of cytokine production may also result from a modulation
of gene expression. Indeed, clarithromycin inhibited TNFmediated IL-8 gene expression by human bronchial epithelial
cells.59 Similarly, erythromycin inhibited the transcriptional
activity of nuclear factor kB (NFkB) in T cells,60 and clarithromycin inhibited the activation of NFkB by TNF and staphylococcal
enterotoxin A.61 In airway epithelial cells, erythromycin increases
cAMP levels.62 Elevation of cAMP has a marked effect on cytokine production induced by LPS, which includes inhibition of
TNF and up-regulation of IL-6 and IL-10.63,64 Hence, a possible
increase in cellular cAMP levels by erythromycin would only
partly explain the inhibitory effects of macrolides on cytokine
production.
Conclusions
References
1. Kudoh, S., Azuma, A., Yamamoto, M. et al. (1998). Improvement
of survival in patients with diffuse panbronchiolitis treated with lowdose erythromycin. American Journal of Respiratory and Critical Care
Medicine 157, 1829 32.
2. Schoni, M. H. (2003). Macrolide antibiotic therapy in patients
with cystic fibrosis. Swiss Medical Weekly 133, 297 301.
3. Spencer, H. & Jaffe, A. (2003). Newer therapies for cystic
fibrosis. Current Paediatrics 13, 259 63.
4. Akira, M., Higashihara, T., Sakatani, M. et al. (1993). Diffuse
panbronchiolitis: follow-up CT examination. Radiology 189, 559 62.
5. Kusano, S., Kadota, J., Kohno, S. et al. (1995). Effect of
roxithromycin on peripheral neutrophil adhesion molecules in patients
with chronic lower respiratory tract disease. Respiration 62, 217 22.
6. Kadota, J., Mukae, H., Ishii, H. et al. (2003). Long-term efficacy
and safety of clarithromycin treatment in patients with diffuse
panbronchiolitis. Respiratory Medicine 97, 844 50.
7. Labro, M. T. (1998). Anti-inflammatory activity of macrolides: a
new therapeutic potential? Journal of Antimicrobial Chemotherapy 41,
3746.
8. Labro, M. T. & Abdelghaffar, H. (2001). Immunomodulation by
macrolide antibiotics. Journal of Chemotherapy 13, 3 8.
9. Labro, M. T. (2002). Antibiotics as anti-inflammatory agents.
Current Opinion in Investigational Drugs 3, 61 8.
10. Kudoh, S., Uetake, T., Hagiwara, K. et al. (1987). Clinical effects
of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 25, 632 42.
11. Takeda, H., Miura, H., Kawahira, M. et al. (1989). Long-term
administration study on TE-031 (A-56268) in the treatment of diffuse
panbronchiolitis. Kansenshogaku Zasshi 63, 71 8.
12. Yamamoto, M., Kondo, A., Tamura, M. et al. (1990). Long-term
therapeutic effects of erythromycin and new quinolone antibacterial
agents on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi
28, 130513.
13. Nagai, H., Shishido, H., Yoneda, R. et al. (1991). Long-term lowdose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration 58, 1459.
14. Ichikawa, Y., Ninomiya, H., Koga, H. et al. (1992). Erythromycin
reduces neutrophils and neutrophil-derived elastolytic-like activity in
26
In conclusion, in nearly all reports, long-term low-dose macrolide therapy resulted in, sometimes dramatic, improvements in
pulmonary function in patients with DPB. Before introduction of
maintenance macrolide therapy, the 10-year survival rate was
below 50%. After introduction of macrolide therapy, the 10-year
survival rate improved impressively, and is now above 90%.
Although almost all studies were not randomized controlled
trials, data presented in the peer-reviewed journals are convincing enough to justify recommendations for the general use of
long-term macrolide therapy in DPB.
Similar to DPB, there seems to be some role for macrolides
in the treatment of CF. However, data presented in peerreviewed journals are sparse, and there seems to be considerable
variation in response. At present, it is recommended to use maintenance macrolide therapy for individual patients who do not
respond to conventional therapy.3
Review
27
Review
28
49. Schultz, M. J., Speelman, P., van der Poll, T. et al. (2001).
Erythromycin inhibits Pseudomonas aeruginosa induced tumor necrosis factor-a production in human whole blood. Journal of Antimicrobial
Chemotherapy 48, 2758.
50. Khair, O.A., Devalia, J. L., Abdelaziz, M. M. et al. (1995). Effect
of erythromycin on Haemophilus influenzae endotoxin-induced release
of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells.
European Respiratory Journal 8, 1451 7.
51. Morikawa, K., Watabe, H., Araake, M. et al. (1996). Modulatory
effect of antibiotics on cytokine production by human monocytes
in vitro. Antimicrobial Agents and Chemotherapy 40, 136670.
52. Hirakata, Y., Kaku, M., Mizukane, R. et al. (1992). Potential
effects of erythromycin on host defense systems and virulence of
Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy
36, 19227.
53. Kita, E., Sawaki, M., Nishikawa, F. et al. (1990). Enhanced
interleukin production after long-term administration of erythromycin
stearate. Pharmacology 41, 177 83.
54. Kita, E., Sawaki, M., Mikasa, K. et al. (1993). Alterations of
host response by a long-term treatment of roxithromycin. Journal of
Antimicrobial Chemotherapy 32, 28594.
55. Konno, S., Adachi, M., Asano, K. et al. (1992). Influences of
roxithromycin on cell-mediated immune responses. Life Sciences 51,
L107 12.
56. Yanagihara, K., Tomono, K., Kuroki, M. et al. (2000). Intrapulmonary concentrations of inflammatory cytokines in a mouse model of
chronic respiratory infection caused by Pseudomonas aeruginosa.
Clinical and Experimental Immunology 122, 6771.
57. Yanagihara, K., Tomono, K., Imamura, Y. et al. (2002). Effect of
clarithromycin on chronic respiratory infection caused by Pseudomonas
aeruginosa with biofilm formation in an experimental murine model.
Journal of Antimicrobial Chemotherapy 49, 86770.
58. Shirai, R., Abe, K., Yoshinaga, M. et al. (1997). Analysis of cases
allowed to cease erythromycin therapy for diffuse panbronchiolitis
comparative study between patients with cessation of the therapy and
patients continuing the therapy. Kansenshogaku Zasshi 71, 115561.
59. Abe, S., Nakamura, H., Inoue, S. et al. (2000). Interleukin-8
gene repression by clarithromycin is mediated by the activator