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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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An association has been reported between chronic infection with
Chlamydia pneumoniae and the severity of asthma, and uncontrolled observations have suggested that treatment with antibiotics active against C. pneumoniae leads to an improvement in
asthma control. We studied the effect of roxithromycin in subjects
with asthma and immunoglobulin G (IgG) antibodies to C. pneumoniae 
1:64 and/or IgA antibodies 1:16. A total of 232 subjects, from Australia, New Zealand, Italy, or Argentina, were randomized to 6 wk of treatment with roxithromycin 150 mg twice a
day or placebo. At the end of 6 wk, the increase from baseline in
evening peak expiratory flow (PEF) was 15 L/min with roxithromycin and 3 L/min with placebo (p = 0.02). With morning PEF, the
increase was 14 L/min with roxithromycin and 8 L/min with placebo (NS). In the Australasian population, the increase in morning
PEF was 18 L/min and 4 L/min, respectively (p = 0.04). At 3 mo
and 6 mo after the end of treatment, differences between the two
groups were smaller and not significant. Six weeks of treatment
with roxithromycin led to improvements in asthma control but the
benefit was not sustained. Further studies are necessary to determine whether the lack of sustained benefit is due to failure to
eradicate C. pneumoniae.
Keywords: asthma; Chlamydia pneumoniae; roxithromycin; randomized, controlled trial
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chlamydia pneumoniae is an intracellular pathogen and a common cause of respiratory tract infections including sinusitis, bronchitis, and pneumonia (1). There is increasing evidence that infection with C. pneumoniae is also associated with a number of chronic diseases. An association between atherosclerosis and infection with C. pneumoniae (2) has been reported, and infection with C. pneumoniae may influence the presentation of asthma (3).
Serological evidence of infection with C. pneumoniae is not
associated with an increase in the prevalence of mild asthma in children or young adults (4). There is, however, evidence that infection with C. pneumoniae may influence the severity of
asthma. We have described an association between high titers
of immunoglobulin G and A (IgG and IgA) antibodies to C. pneumoniae and an increase in the severity of asthma (5).
Cook and coworkers reported that subjects with severe
chronic asthma were significantly more likely to have IgG antibody titers 1:64 or IgA antibody titers 1:8 than subjects
admitted to hospital with diseases other than asthma or
chronic obstructive pulmonary disease (6). Cunningham and
coworkers studied a cohort of children with asthma who were followed over the course of a year (7). Polymerase chain reaction (PCR) for C. pneumoniae and secretory IgA to C. pneumoniae were measured in nasopharyngeal aspirates from the
children. Of the children, 28% had a positive PCR for C. pneumoniae when they were well. There was no increase in the
proportion of children with a positive PCR during exacerbations of asthma, but secretory IgA antibodies to C. pneumoniae were more than seven times higher in subjects who reported four or more exacerbations during the study compared
with those who reported only one exacerbation. Infection of
monocytes (8) and epithelial cells (9) with C. pneumoniae
leads to increased formation of pro-inflammatory cytokines
including interleukin-1 (IL-1), tumor necrosis factor-
(TNF-),
granulocyte-macrophage colony-stimulating factor (GM-CSF), and RANTES. These observations provide an explanation for
how chronic infection with C. pneumoniae could lead to an increase in the severity of asthma.
If infection with C. pneumoniae influences the severity of asthma, then antibiotic treatment directed against C. pneumoniae might lead to an improvement in asthma control. In an uncontrolled study, Hahn treated 46 subjects with adult onset asthma, who were seropositive for C. pneumoniae, with doxycycline, erythromycin, or clarithromycin for 3-9 wk (10). Half of these subjects had resolution of their asthma or a major improvement in their symptoms. In another uncontrolled study, 12 children with asthma, who were culture positive for C. pneumoniae, were treated with clarithromycin or erythromycin (11). Nine of these subjects improved following treatment. Both of these studies can be criticized because of their open uncontrolled design. We have conducted a multicenter, randomized, double-blind, placebo-controlled study of treatment with roxithromycin 150 mg twice a day for 6 wk in subjects with asthma and high titers of IgG and/or IgA antibodies to C. pneumoniae.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The Chlamydia pneumoniae, Asthma, Roxithromycin, Multinational (CARM) study was a multicenter, randomized, double-blind, placebo-controlled study conducted in Australia, New Zealand, Italy, and Argentina. The majority of subjects were recruited from the general population after the study was publicized on television and in newspapers. A smaller proportion of the subjects was identified from outpatient clinics.
Subjects were eligible for the study if they were 18-60 yr of age,
had a physician diagnosis of asthma, a forced expiratory volume in 1 s
(FEV1) 50% of predicted, and either 15% increase in FEV1 following inhaled salbutamol or 15% diurnal variation in peak expiratory flow (PEF) on 7 of 14 d during the run-in period. They also
needed to have IgG titers to C. pneumoniae 1:64 and/or IgA titers
1:16 and a daytime symptom score of 2 or nighttime symptom
score of 1 (Table 1), on 7 of the 14 days of the run-in period.
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Subjects were not eligible if they had been on treatment with any
macrolide, quinolone, or tetracycline in the 4 wk before study entry or for
more than 3 wk in the preceding 4 mo. Other medicines that were not
permitted were ergot alkaloids, terfenadine, or astemizole. They were
also excluded if they had a smoking history of 20 pack-years, bronchiectasis, any other serious systemic diseases, hypersensitivity to macrolides or any significant change in asthma medication in the previous
month including a course of oral corticosteroids. Treatments for asthma
other than oral corticosteroids were permitted if the dose had not
changed in the previous month. In addition, they were not eligible if
they had a respiratory tract infection (with increased cough and increased volume and/or purulence of sputum) during the run-in or if
they had abnormal liver function tests (aspartate aminotransferase [AST]
or alanine aminotransferase [ALT] two or more times the upper limit
of normal, alkaline phosphatase 1.25 times the upper limit of normal, or total bilirubin more than the upper limit of normal) or serum
creatinine > 200 µmol/L.
The study involved a 2-wk run-in period, a 6-wk treatment period, and 24 wk of follow-up. Subjects attended for eight visits over the course of the study. Blood was drawn for C. pneumoniae serology at the initial screening visit. Antibodies to C. pneumoniae were measured using the microimmunofluoresence technique (LabSystems, Helsinki, Finland). A single laboratory measured the samples in each country.
Subjects who had IgG titers to C. pneumoniae 1:64 or IgA titers
1:16 were eligible to enter the run-in period. Subjects had to enter
the run-in period within 10 wk of the screening visit. Serology from visits other the screening visit was performed at a central laboratory (Institute of Respiratory Diseases, Milan, Italy). FEV1, vital capacity (VC),
and bronchodilator reversibility to inhaled salbutamol were measured
at the beginning of the run-in period. Subjects were then given a Wright
minipeak flow meter and a diary card and were asked to record their
PEF and symptom scores twice daily for 2 wk (Table 1). Three measurements of PEF were taken each morning on waking and each
evening with the best of the three readings being recorded on the diary
card. Subjects who met all the eligibility criteria were randomized to
treatment with roxithromycin 150 mg twice a day or matching placebo
for 6 wk. Subjects continued to record PEF, the use of rescue (bronchodilator) medicine, and symptom scores in the morning and evening
during the 6 wk of treatment and for the subsequent 24 wk.
The Asthma Quality of Life Questionnaire (AQLQ) (12) was administered at randomization, during treatment (Weeks 2 and 6) and at 12 and 24 wk after the end of treatment. C. pneumoniae serology was measured at the same time points. Spirometry was measured at these visits and at 6 wk after the end of treatment. Skin prick tests for the following allergens were performed at the randomization visit: grass pollen mix, cat dander, D. pteronyssinus, D. farinae, and mold mix. Compliance was assessed using diary cards, direct questioning, and counts of returned pills.
The primary endpoints were
- Change in mean morning PEF.
- Change in the symptom scores.
Secondary endpoints included
- Change in evening PEF.
- Change in FEV1.
- Change in use of inhaled
2-agonists.
Permission to conduct the study was obtained from the ethics committee of each participating institution, and all the subjects gave written, informed consent.
Sample Size
The sample size was based on an estimated effect size of 20 L/min in the morning PEF and a standard deviation in the effect size of 45 L/min. This gave a desired sample size of 106 patients in each group to give 90% power to detect the effect size of 20 L/min at the 0.05 level of significance.
Statistical Analysis
The analysis was on an intention to treat basis. The repeated measures obtained from the study were analyzed using the SAS procedure PROC MIXED. The treatment factor was regarded as fixed and the subjects as the random factor. In addition, because observations close together in time are likely to have higher correlations than those far apart in time, an autoregressive covariance was specified of order 1 (usually denoted AR [1]). The effect of missing values in PROC MIXED is to eliminate incomplete multivariate observations from the model. For each time point, the analysis used the diary card values from the previous 2 wk.
Post-hoc comparisons were performed using contrasts of interest with Bonferroni adjustments to the significance levels when appropriate to allow for multiple testing. In addition to the main parametric analysis, comparisons between groups were made using chi-squared tests, two-way analysis of variance, and t tests. A two sample F test for comparing rates based on an underlying Poisson analysis was used for comparison of adverse event rates. Overall, significance levels of 0.05 were used throughout to define significant differences.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A total of 860 subjects were screened for the study of whom 232 were randomized to treatment. Of the subjects, 68.6% came from Australia and New Zealand, 19.8% from Argentina, and 11.6% from Italy. Twelve patients who were randomized to treatment withdrew from the study within a few days of randomization without recording any diary card data. A thirteenth subject was withdrawn because of nausea and vomiting and did not record any diary card data after the first 10 d of treatment. This left 219 evaluable subjects in the intention to treat population, of whom 105 were treated with roxithromycin and 114 were treated with placebo. There were no significant differences between the two groups with respect to age, sex, smoking history, age of onset of asthma, baseline lung function, symptom scores, the proportion of subjects with positive skin tests for aeroallergens, or the treatment for asthma on entry to the study (Tables 2 and 3). There were, however, marked differences between the countries at baseline for all of the markers of asthma severity (Table 4). For example, in the Australasian population, the mean FEV1 was 75.9% of predicted compared with 91.7% in the Italian subjects (p < 0.0001). In view of this, a separate analysis was conducted for Australasia, in addition to the overall intention to treat analysis.
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The distributions of titers to C. pneumoniae in the intention to treat population are shown in Table 2.
Peak Expiratory Flow
The effects of treatment on morning PEF are shown in Figure 1A. From baseline to the end of the 6-wk treatment period, there was an increase in the mean morning PEF of 8 L/min in the placebo group compared with 14 L/min in the roxithromycin group. Although the morning PEF continued to improve in both groups over the next 6 mo, the difference between the two groups decreased. Six months after the end of treatment, the improvement over baseline was 21 L/min in the placebo group compared with 18 L/min in the roxithromycin group. The differences between the two groups were not significant at any time point.
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In the Australasian population, the mean morning PEF increased by 4 L/min in the placebo group compared with an increase of 18 L/min in the roxithromycin group at the end of treatment (Figure 1B). Six months after the end of treatment, the values for the mean morning PEF had increased by 16 L/min and 15 L/min in the placebo and roxithromycin groups, respectively. There was a significant effect of treatment on morning PEF at the end of treatment (p = 0.04) but not at subsequent time points.
The changes with treatment for the evening PEF are shown in Figure 2A. The largest difference between the two treatment groups was seen at the end of treatment when the increase in the mean evening PEF compared with baseline was 3 L/min with placebo and 15 L/min with roxithromycin. Three months after the end of treatment the improvement in the mean evening PEF was 8 L/min for placebo and 13 L/min for roxithromycin. At 6 mo the values were 18 and 20 L/min, respectively. The effect of roxithromycin on evening PEF was significant at the end of treatment (p = 0.02) but not at later time points.
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In the Australasian population, at the end of 6 wk treatment, the mean evening PEF had increased by 1 L/min in the placebo group and by 19 L/min in the roxithromycin group (p = 0.01) (Figure 2B). Six months after the end of treatment, the change from baseline was 9 L/min with placebo and 19 L/min with roxithromycin.
Symptom Scores
At the end of treatment, the daytime symptom score had improved by 18% with placebo and 29% with roxithromycin (Figure 3A). Six months after the end of treatment, the improvement in the daytime symptom score was 35% with placebo and 47% with roxithromycin. In the Australasian population, the improvement with placebo was 18% at end of treatment and 35% at 6 mo after the end of treatment compared with 28% and 52% with roxithromycin (Figure 3B). The effect of roxithromycin on the daytime symptom score was not significant.
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In the placebo group, the nighttime symptom score improved by 12.5% from baseline to the end of treatment. Six months after the end of treatment, the improvement from baseline was 25%. This compared with improvements of 25% and 37.5%, respectively, with roxithromycin (Figure 4A). In the Australasian population, the nighttime symptom score improved by 10% at the end of treatment and 27% at 6 mo with placebo compared with 26% and 41% with roxithromycin (Figure 4B). In neither analysis was the effect of treatment on nighttime symptom scores significant.
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Other Endpoints
There was no difference in FEV1 between roxithromycin and placebo measured at clinic visits or in the number of puffs of rescue medication used either during the daytime or nighttime.
In the placebo group, the geometric mean titers for IgG antibodies to C. pneumoniae were 109.2 at baseline and 131.6 at 6 mo after the end of treatment compared with values of 96.3 and 114.6, respectively, for roxithromycin. There was no significant difference between the groups.
Although changes in the AQLQ score favored treatment with roxithromycin over placebo, the differences were not significant. With placebo, the change from baseline in the AQLQ score was 0.39 points at the end of treatment, 0.44 points at 3 mo after the end of treatment, and 0.40 points at 6 mo after the end of treatment. The values for roxithromycin were 0.48 points, 0.58 points, and 0.56 points.
Adverse Events
During the 6 wk of treatment with roxithromycin or placebo, there were 400 adverse events reported in 157 of the 232 patients. There were no significant differences between the number of adverse events reported for placebo (184) and roxithromycin (216). The commonest adverse events were exacerbation of asthma, headache, rhinitis, infection, and flu syndrome, and these were equally distributed between the two groups. Adverse events that were reported as possibly related to study medicine included diarrhea (10 reports with placebo and six with roxithromycin), nausea (five reports with placebo and 13 with roxithromycin), and changes in liver function tests (one patient on placebo and six patients on roxithromycin). In only two of these subjects did a change in transaminases or bilirubin result in a value outside the normal range. In one subject on roxithromycin, the ALT increased from 18 U/L at baseline to 91 U/L 2 wk into treatment. The patient remained on treatment and when the ALT was checked again at the end of treatment, the value was within the normal range at 11 U/L. In a second subject on roxithromycin, the AST increased from 18 U/L at baseline to 112 U/L at the end of treatment. One week later, the AST was again within the normal range at 30 U/L.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, 6 wk of treatment with roxithromycin led to significant improvement in evening PEF at the end of treatment, but the difference between the groups diminished thereafter. Although there was a trend for improvements in the symptom score, this was not significant.
A significant improvement was seen in the evening PEF at the end of treatment in the overall intention to treat population and a significant improvement in the morning PEF was seen in the Australasian population. The sample size for this study was based on an estimated increase in morning PEF of 20 L/min with a standard deviation of 45 L/min. Retrospectively, we found that the effect size was 15 L/min with a standard deviation of approximately 50 L/min. Using these figures, we calculate that a sample size of 238 in each group would have been necessary for 90% power at the 0.05 significance level.
The clinical significance of a change in PEF of 10-20 L/min can be debated, but this is comparable to the changes seen in other clinical trials where patients, who have had asthma that was not controlled on treatment on inhaled steroids, had an increase in the dose of inhaled steroid or an additional medication was added in. Fabbri and coworkers compared the effects of fluticasone propionate 1.5 mg/d with beclomethasone dipropionate 1.5 mg/d in moderate to severe asthma (13). Fluticasone propionate is twice as potent as beclomethasone, but the increase in morning PEFR with fluticasone propionate was only 15 L/min greater than that with beclomethasone dipropionate. Laviolette and coworkers studied the efficacy of adding in montelukast 10 mg/d in patients whose asthma was not controlled on beclomethasone 200 µg twice a day (14). The addition of montelukast led to an improvement in morning PEF of 10 L/min.
The treatment with roxithromycin was well tolerated. One potential concern with prolonged treatment with macrolide antibiotics is the risk of hepatitis, but only two patients had a greater than 3-fold elevation in transaminases. Neither of these episodes was symptomatic, and, in both cases, the changes resolved uneventfully.
There are number of potential explanations for the benefit that was seen with roxithromycin. Antiinflammatory effects have been reported in vitro with roxithromycin and other macrolide antibiotics (15). Roxithromycin inhibits the neutrophil oxidant burst (16, 17) and reduces the formation of cytokines including IL-6, IL-8, and GM-CSF (18) from airway epithelial cells and of IL-5 from splenocytes (19). In animal models, roxithromycin inhibits the formation of edema in the rat paw in response to carageenin (20) or poly-L-arginine (21). If roxithromycin is useful in the treatment of asthma because of an antiinflammatory action, it should be effective in unselected patients with asthma regardless of whether they have evidence of infection with C. pneumoniae. Previous studies on the use of macrolides for the treatment of asthma are of interest in this regard.
Reports of the use of the macrolide antibiotic, troleandomycin (TAO), for the treatment of asthma stretch back 40 years. In 1959, Kaplan and Goldin reported that TAO was effective in the treatment of asthma (22). In a randomized, controlled trial, Itkin and Menzel confirmed that TAO led to an improvement in symptoms and lung function in patients with asthma who were on treatment with oral corticosteroids (23). A similar improvement was not seen with other antibiotics. The observation that TAO inhibited the metabolism of methylprednisolone provided an explanation for these reports (24). There have, however, been case reports of patients treated with macrolide antibiotics whose asthma improved, although they were not on treatment with oral corticosteroids (25, 26). These reports raise the possibility that TAO might have antiinflammatory actions independent of its effect on steroid metabolism. This question was addressed by Nelson and coworkers, who conducted one of the few double-blind studies on the steroid-sparing effects of troleandomycin (27). They found a greater reduction in the dose of methylprednisolone with TAO than with placebo, but this difference was not significant. They certainly did not see the 2-fold greater reduction in the dose of methylprednisolone with TAO that would be predicted from the effect of TAO on the clearance of methylprednisolone. In a previous study, we examined the effect of roxithromycin in subjects with asthma who were not on treatment with oral corticosteroids (28). In this double-blind, placebo-controlled study the subjects fared less well during 1 mo of treatment with roxithromycin than they did during the month of treatment with placebo. These studies suggest that treatment with macrolides is not beneficial in unselected patients with asthma.
Kraft and coworkers have studied 39 subjects with asthma in a randomized trial of treatment with clarithromycin or placebo for 6 wk (29). Bronchial biopsies and bronchoalveolar lavage were performed prior to treatment. Subjects who were PCR positive for C. pneumoniae or Mycoplasma pneumoniae had a significant improvement in FEV1 in response to clarithromycin unlike those who were PCR negative. Taken together, these studies are consistent with the argument that the benefits of macrolide antibiotics in asthma are not due just to their antiinflammatory properties.
If the benefit of treatment with macrolide antibiotics is due to their antimicrobial activity rather than to any antiinflammatory activity, it does not explain why a significant effect on PEF was seen only at the end of treatment and not at subsequent time points. There are two possible explanations for this. Three months after the end of treatment, the change from baseline in PEF was still greater in the roxithromycin group, although the difference between the two groups diminished over time and was no longer significant. The study may have lacked the power to detect a difference 3 mo after the end of treatment. The main problem, however, may be the difficulty in eradicating an intracellular pathogen such as C. pneumoniae with a single antibiotic. Hammerschlag and her colleagues described three patients who remained culture positive for C. pneumoniae over an 11-mo period despite treatment with either one or two courses of tetracycline or doxycycline of 10-21 d duration (30). Wolf and Malinverni innoculated mice with C. pneumoniae and treated the pneumonitis with azithromycin alone or in combination with rifampicin for 3 d. Following treatment, C. pneumoniae DNA was detected in 12 of 13 lungs treated with azithromycin alone but in only 6 of 16 lungs treated with the combination of azithromycin and rifampicin (31). In our study, treatment with roxithromycin may have suppressed infection with C. pneumoniae rather than eradicating it. This would explain why the greatest benefit was seen at the end of treatment and why the differences between the two groups diminished thereafter.
In this study we used serology, which is an indirect measure of chronic infection with C. pneumoniae. In future studies it may be more appropriate to use PCR to identify infection in sputum or bronchial biopsies. This approach could also be used to identify the success of treatments aimed at eradicating C. pneumoniae. Indeed, if C. pneumoniae is to be successfully eradicated, it may be necessary to treat with two or more antibiotics active against C. pneumoniae and to continue treatment for a longer period.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Peter Black, Department of Medicine, Auckland Hospital, Private Bag 92024, Auckland, New Zealand. E-mail:pn.black{at}auckland.ac.nz
(Received in original form November 10, 2000 and in revised form April 5, 2001).
Acknowledgments: Study coordination and monitoring: S. Hopkins, H. Ormandy, S. Culhane, J. Flynn, C. Ryan (Aventis Pharma). The following centers and investigators took part in the study. Australia: Concord Repatriation Hospital, Sydney (M. Peters). Flinders Medical Centre, Adelaide (J. Alpers). Fremantle Hospital, Fremantle (P. Bremner). John Hunter Hospital, Newcastle. (P. Gibson). Mater Medical Centre, Brisbane (S. Bowler). Princess Alexandra Hospital, Brisbane (C. Mitchell). Queen Elizabeth Hospital, Adelaide (R. Ruffin). Royal Adelaide Hospital, Adelaide (R. Scicchitano). Royal Melbourne Hospital, Melbourne (A. Rubinfeld). Royal Prince Alfred Hospital, Sydney (C. Jenkins). Sir Charles Gairdner Hospital, Perth (M. Phillips). St. Vincent's Hospital, Melbourne (J. Burdon). Westmead Hospital, Sydney. (C. Katelaris). New Zealand: Auckland Hospital, Auckland (P. Black). Christchurch Hospital, Christchurch (I. Town). Waikato Hospital, Hamilton (G. Mills). Italy: Istitutio Malattie Respiratorie, Università di Milano, Milano (L. Allegra, F. Blasi). Sevizio di Pneumologia, Ospedale di Seregno (S. Damato). Unità didattico-assistenziale di Pneumologia, Ospedale S. Paolo, Milano (S. Centanni). Servizio di Pneumologia, Bussolengo, Verona (R. Dal Negro). Argentina: Hospital del Torax Antonia Cetrangolo, Buenos Aires (Dolman). Catedra de Neumonotisiologia del Hospital Muniz (Abate), Buenos Aires. Santoria "La Sagraga Familia," Buenos Aires (Saenz). Hospital de Clinicas Neumonotisiologia, Buenos Aires. Hospital Aleman, Capita Federal (Gene).
This study was supported by Aventis Pharma.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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