The document discusses the role of oral mucolytics in the prevention of lower respiratory tract infections (LRTIs) in patients with chronic obstructive pulmonary disease (COPD). It summarizes the findings of clinical trials that show mucolytics reduce exacerbations in COPD patients not treated with inhaled corticosteroids. However, the largest trial (BRONCUS) found no difference in exacerbation rates between N-acetylcysteine and placebo in COPD patients, though a subgroup analysis found fewer exacerbations in patients not on inhaled corticosteroids with N-acetylcysteine. Given most COPD patients are now treated with inhaled corticosteroids, the role of mucolytics in

1. ERS Vienna 2009 Congress
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PG1 – EU GRACE Network Full-day Course:
Vaccination and preventive measures for LRTIs in
the community: what’s new?
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2. Debate: is there a place for oral mucolytics in the prevention of LRTI? – CON
Dr Marc Miravitlles
Servicio de Neumologia
Institut Clínic del Tòrax
Hospital Clinic
Villarroel 170
8036 Barcelona, Spain
marcm@separ.es
Aims
1. Describe the main clinical studies with mucolytics in chronic lung disease in adults and
understand the methodology
2. Compare the results of mucolytics and other drugs in prevention of exacerbations in chronic
bronchitis and COPD
3. Define the role of mucolytics in the contemporary management of COPD
Summary
Obstructive lung diseases, particularly chronic obstructive pulmonary disease (COPD) are one of the
main causes of morbidity and mortality in developed countries. It is estimated that more than 15
million persons in the United States have COPD, and more than 12 million have chronic bronchitis,
with this numbers having grown over recent decades. The age-adjusted mortality rate from COPD
doubled from 1970 to 2002 in the United States, whereas rates from stroke and heart disease decreased
by 63% and 52%, respectively (1).
The chronic and progressive course of COPD is often aggravated by short periods of increasing
symptoms, particularly increasing cough, dyspnea and production of sputum which can become purulent.
Exacerbations have demonstrated to have a negative impact on the quality of life of patients with COPD
(2,3). Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions
and death among patients with chronic lung disease.
There is evidence that these patients with chronic bronchitis and/or COPD have mucociliary
dysfunction with increased sputum production and impaired ability to clear it (4,5). There is evidence
that chronic mucus hypersecretion is associated both with an accelerated decline in FEV1 and
increased mortality in COPD (6,7). It is less clear whether this is due to a causal relationship or
whether mucus hypersecretion is just a marker for more severe disease. However it is not difficult to
imagine how sputum retention may contribute to airflow obstruction and how it might also lead to an
increase in infections because of reduced clearance of microbes. If this was the case, the use of drugs
that may help to eliminate the excessive mucus production should have an impact in bronchial
bacterial colonisation and the development of exacerbations.
Although mechanistic studies of the anti-inflammatory and anti-oxidant actions of mucolytics are of
interest the most important question is whether they influence clinical outcomes in patients with
chronic bronchitis and/or COPD. A recent review was published in the Cochrane Database of
Systematic Reviews (CDSR) in 2006 (8). There were 7335 participants in the 26 studies selected for
inclusion and the primary outcome measure was the number of acute exacerbations which were
defined as an increase in cough and in the volume and/or purulence of sputum.
All of the studies were randomised, double blind and placebo controlled with a parallel group design.
The duration of the studies ranged from 2-36 months. The mean age of the participants in the different
studies ranged from 40 to 67 years. The most studied mucolytic was N-acetylcysteine which
accounted for 13 studies. There were 3 studies with ambroxol. No other mucolytic accounted for more
than two studies. Twenty-one of the studies were conducted in patients with chronic bronchitis
although it is likely that a proportion of these participants in these studies would have also had airflow
obstruction and would have met the definition of COPD. Five studies only enrolled participants who
had a diagnosis of COPD.
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3. There were significantly fewer exacerbations with mucolytics than with placebo. In the most recent
review the weighted mean difference was -0.05 exacerbations per patient per month (95% CI -0.05 to
-0.04, P<0.01) and this represents a 20% reduction in exacerbations.
However, the largest clinical trial with mucolytics, the BRONCUS study, had negative results. It
enrolled 523 patients of whom half were randomised to NAC 600mg once daily (9). The findings
warrant a more detailed discussion for a number of reasons. This was one of the larger studies with
NAC, it enrolled patients with COPD (FEV1 had to be between 40 and 70% of predicted), it measured
quality of life and participants were treated for three years which was long enough to determine if
there was an effect on decline in FEV1 and in frequency of exacerbations. There was however no
difference in the rate of decline in FEV1 with NAC compared with placebo. The exacerbation rates in
BRONCUS did not differ between NAC (1.25 exacerbations per year) and placebo (1.31
exacerbations per year). This would appear to represent a major difference between the results of this
trial and the systematic review but interestingly in a prespecified subgroup analysis the subjects who
were not taking inhaled steroids (ICS) (n=155) had fewer exacerbations with NAC (0.96 exacerbations
per year) than with placebo (1.29 exacerbations per year). In this subgroup analysis the difference was
significant (Hazard Ratio 0.79, 95% CI 0.63 to 0.99, p=0.04). The reduction in exacerbations seen in
patients not taking ICS is comparable to that seen in the meta-analysis. Quality of life was measured
using the St George’s Respiratory Questionnaire or the EuroQoL-5D questionnaire. There were no
significant differences between NAC and placebo with either questionnaire.
Although the results of the BRONCUS study appears to be at odds with the systematic review it is
important to remember that most of the trials reported in the systematic review were conducted at a
time when very few patients with COPD (let alone chronic bronchitis) were on treatment with ICS. It
is possible that NAC acts to reduce exacerbations in a similar way to ICS and the benefit of NAC and
other mucolytics to reduce exacerbations are not observed if the patients are on concomitant treatment
with ICS. Another of the largest studies with mucolytics in COPD observed an increase in the
incidence of patients without exacerbations during a six-month winter period in patients treated
continously with carbocysteine compared to placebo (10). However, no information on concomitant
medication is provided and the groups were disbalanced with respect to severity. Patients in the
carbocysteine arm had amean FEV1 of 4.6 L compared with 3.3 L in the placebo group (10);
therefore, making the interpretation of the results very difficult. In the same line, the results of a recent
large, placebo-controlled trial, with carbocysteine perfomed in China observed a significant reduction
in the frequency of exacerbations in patients treated with the active drug, but only 16.7% of the
participants were concomitantly treated with ICS (11). This is particularly important because in
European countries aproximately 60-70% of COPD patients managed in Primary Care are treated with
ICS (12), and guidelines recommed the use of these drugs in COPD patients with an FEV1<50% (or
60% predicted in the case of salmetrol/fluticasone) and frequent exacerbations (13). In this setting, is
still there a place in therapy for mucolytics?
If mucolytics reduce exacerbations of COPD one would anticipate that their use would also lead to a
reduction in hospitalisations for exacerbations but few of the studies have reported on hospitalisations
and it is not possible to come to a firm conclusion on the basis of the randomised, controlled trials. A
Dutch study has taken another approach to this question. They linked hospital records of admissions
for COPD to a pharmacy database which recorded the outpatient drug use for 450,000 patients in the
Netherlands (14). They identified 1,219 patients who were hospitalised between 1986 and 1989. They
then compared those who received NAC immediately after discharge and those who didn’t. The use of
NAC was associated with a significantly lower risk of rehospitalisation (Relative Risk = 0.67, 95% CI
0.53-0.85). In this population 36% were on treatment with ICS compared with 70% in the BRONCUS
study. Clearly an observational study like this has the potential to be confounded. In fact, a similar
study perfomed in Canada suggested that ICS prevented subsequent hospitalisation (15), but further
analyses demonstrated that the results were affected by the immortal time bias and no effect of ICS on
reduction of hospitalisation existed (16).
Conclusions
The use of mucolytics for the treatment of COPD has been controversial. They are used infrequently
in the United Kingdom, North America and Australasia. Although they are used more often in
continental Europe there is uncertainty about their place in therapy. The GOLD guidelines note that a
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4. reduction in exacerbations has been observed with mucolytics but they did not feel that the evidence
warranted the use of mucolytics as part of the standard management of COPD (13). The BRONCUS
study which is perhaps the best conducted study failed to confirm the effect of NAC on exacerbations.
Nonetheless in the BRONCUS study a reduction in exacerbations was seen in the subgroup of patients
who were not using ICS. In the current situation in which up to 70% of patients with COPD
(particularly those with frequent exacerbations) are treated with ICS (12,17), the role of mucolytics in
the management of COPD is not clear or even unnecesary.
References
1. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States,
1970-2002. JAMA 2005; 294: 1255-1259.
2. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of
exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1998; 157: 1418-1422.
3. Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL, Masa JF, et al. Exacerbations
impair quality of life in patients with chronic obstructive pulmonary disease. A two-year
follow-up study. Thorax 2004; 59: 387-395.
4. Goodman RM, Yergin BM, Landa JF, Golivanux MH.. Relationship of smoking history and
pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-
smokers and patients with chronic bronchitis. Am Rev Respir Dis 1978; 117: 205-14.
5. Santa Cruz R, Landa J. Hirsh J. Tracheal mucous velocity in normal man and patients with
obstructive lung disease. Am Rev Respir Dis 1974; 109: 458-63.
6. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1
decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study
Group. Am J Respir Crit Care Med 1996; 153: 1530-5.
7. Lange P, Nyboe J, Appleyard M, Jensen G, Schnor P. Relation of ventilatory impairment and
of chronic mucus hypersecretion to mortality from chronic obstructive lung disease and all
causes. Thorax 1990; 45: 579-85.
8. Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2006; Jul 19: 3:CD001287.
9. Decramer M, Rutten-van Mölken, Dekhuijzen PNR, Troosters T, van Herwarden C,
Pellegrino R, van Schayk CPO, Oliveri D, Del Donno M, De Backer W, Lankhorst I, Ardia A.
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis
Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.
Lancet 2005; 365: 1552-1560.
10. Allegra L, Cordaro CI, Grassi C. Prevention of acute exacerbations of chronic obstructive
bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-
controlled trial. Respiration 1996; 63: 174-180.
11. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, et al. Effect of carbocisteine on
acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised
placebo-controlled study. Lancet 2008, 371: 2013-2018.
12. Miravitlles M, de la Roza C, Naberan K, Lamban M, Gobartt E, Martín A. Use of spirometry
and patterns of prescribing in COPD in primary care. Respir Med 2007; 101: 1753-1760.
13. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the
diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD
executive summary. Am J Respir Crit Care Med 2007: 176: 532-555.
14. Gerritts CMJM, Herings RMC, Leufkens HGM, Lammers J-W J. N-acetylcysteine reduces the
risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur
Respir J 2003; 21: 795-798.
15. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:
580-584.
16. Suissa S. Inhaled steroids and mortality in COPD: bias from unaccounted immortal time. Eur
Respir J 2004; 23: 391-395.
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5. 17. Miravitlles M, Murio C, Tirado-Conde G, Levy G, Muellerova H, Soriano JB, Ramirez-
Venegas A, Ko FWS, Canelos-Estrella B, Giugno E, Bergna M, Chérrez I, Anzueto A.
Geographic differences in clinical characteristics and management of COPD: the EPOCA
study. Int J COPD 2008; 3: 803-814.
Evaluation
1. Which of the following is false regarding clinical trials with mucolytics:
a. They consistently show a reduction in hospitalisations compared with placebo
b. There is a reduction in exacerbations with mucolytics in patients not treated with
inhaled corticosteroids
c. Mucolytics are well tolerated
d. There is no signficant difference in results between NAC and carbocysteine
2. The BROCHUS trial with NAC versus placebo:
a. Followed more than 500 patients for 4 years
b. Demonstrated a reduction in the rate of decline of FEV1 in patients treated with NAC
c. Did not show any difference in the rate of exacerbations between the 2 treatment arms
d. Patients with concomitant teratment with theophyllines showed a trend towards a
reduction in exacerbations in the NAC arm
3. Which is the role of mucolytics in COPD:
a. Should be used in moderate to severe patients not treated with inhaled corticosteroids
and with frequent exacerbations.
b. Should be used in moderate to severe patients with frequent exacerbations irrespective
of concomitant medication.
c. Should be used in early disease irrespective of the frequency of exacerbations
d. They have no role in COPD treatment
Answers on page 109
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6. Oral mucolytics in COPD:
CON
Marc Miravitlles
Servicio de Neumología
Hospital Clínic. Barcelona
marcm@clinic.ub.es
IJCP 2008;62:585-592
Types of COPD
Chronic cough and
sputum as risk
factors for frequent
exacerbations
Burgel et al. Chest 2009; 135: 975-982
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7. NAC and COPD
Mean epithelial lining fluid and BALF
concentrations in a control group and patients
treated with NAC 600 mg thrice daily for 5 days
Bridgeman et al. Thorax 1994; 49: 670-675
Carbocysteine
in COPD
Small study
Disbalance in groups
No ICS
Very low rate of
exacerbations
Tatsumi et al. JAGS 2007;55:1884-1885
Carbocysteine in COPD
NO TT
with
ICS
Yasuda et al. JAGS 2006;54:378-379
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8. Oral NAC and exacerbations
Prevention of
exacerbations with
NAC compared to
placebo.
Arrows show mean
values
Dekhuijzen. Eur Respir J 2004;23:629-636
Oral NAC and exacerbations
Dekhuijzen. Eur Respir J 2004;23:629-636
Mucolytics and COPD
Poole & Black. BMJ 2001;322:1271-1274
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9. Ambroxol and exacerbations
One-year study on
mild-moderate
COPD.
Never smokers 25%
ICS were forbidden
Malerba et al. Pulm Pharmacol Ther 2004;17:27-34.
Carbocysteine in COPD
Allegra et al. Respiration 1996; 63: 174-180
Carbocysteine in COPD
Allegra et al. Respiration 1996; 63: 174-180
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10. NAC and re-hospitalisation
Risk of
readmission to
hospital for
COPD
according to
treatment with
NAC
Gerrits et al. ERJ 2003; 21: 795-798
Ontario study
Sin & Tu. AJRCCM 2001;164:580-584
Unexposed and immortal time period
Time zero:
Cohort entry
Death
ICS Rx filled
ICS user
0
Death
IMMORTAL
ICS non-user TIME BIAS
0
Suissa et al. Proc Am Thorac Soc 2007;4:535-542
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11. TORCH
Calverley et al NEJM 2007
Mucolytics in LRTI
Cochrane Library 2009, issue 2
Mucolytics in LRTI
Cochrane Library 2009, issue 2
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12. Mucolytics in LRTI
Cochrane Library 2009, issue 2
Mucolytics in LRTI
Cochrane Library 2009, issue 2
Oral NAC and COPD
BRONCHUS study:
523 patients
followed for 3 years
Same decline in
FEV1 in both
groups of treatment.
Decramer et al. Lancet 2005;365:1552-60
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13. Oral NAC and COPD
BRONCHUS study: No effect on HRQL.
Decramer et al. Lancet 2005;365:1552-60
Oral NAC and COPD
Group NAC Placebo RR (95%CI) p
All 693 658 0.99 (0.89-1.1) 0.847
ICS 563 471 1.06 (0.93-1.2) 0.359
No ICS 130 187 0.79 (0.63-0.98) 0.040
No effect on frequency of exacerbations.
Decramer et al. Lancet 2005;365:1552-60
Prevention of exacerbations
with carbocysteine
Zheng et al. Lancet 2008;371:2013-2018
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14. Prevention of exacerbations
with carbocysteine
Ex per pt/yr
Placebo 1.35 (0.06)
Carbocysteine 1.01 (0.06)
Reduction 0.75 (0.62-0.92)
One-year RCT with 709 patients from 22 centres in China.
Mean FEV1=44%, only 15% received ICS and 28% xanthines.
Zheng et al. Lancet 2008;371:2013-2018
Incidence of exacerbations
1,2 UPLIFT TORCH
Exacerbations per patient - year
1.13 Placebo
1,1
- 25 %
1
0,9 0.85 Control
0.85 SFC
0,8 - 14%
0.73 Tiotropium
0,7
0,6
“Floor”
0,5
Miravitlles & Anzueto. Int J COPD 2009;4:185-201
Exacerbations and FEV1
R= -0.256; p<0.001
Miravitlles et al. Int J COPD 2008; 3: 803-814
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15. Tiotropium and E-COPD
P=0.34 P=0.043 P=0.079
AUC of sputum inflammatory markers. RCT of tiotropium
or placebo in 142 pts with mean FEV1=50%.
Reduction of exacerbations of 52% with TIO (p=0.001)
Powrie et al. ERJ 2007;30:472-478
Prevention of E-COPD
Time to event
analysis of
surgical
responders
(improvement
> 200 ml),
nonresponders
and controls
Washko et al. AJRCCM 2008;177:164-169
Forms of COPD
Percentages of
eosinophils and
macrophages in
induced sputum in
COPD patients with
or without chronic
bronchitis
Snoeck-Stroband et al. ERJ 2008;31:70-77
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16. Inhaled corticosteroids in COPD
Ex/yr
2
P=0.02
1,6
Reduction of
1,2
P=0.45 exacerbations
0,8 with Fluticasone.
FEV1<50% (391)
0,4 FEV1>50% (359)
0
>50% <50%
Fluticasona Placebo
Jones et al. ERJ 2003;21:68-73
LABAs and ICs in COPD
Reduction in
frequency of
exacerbations: 35%
Estimated treatment
effect ratio: 0.65
(95%CI= 0.57-0.76)
Kardos et al. AJRCCM 2007;175:144-149.
Tiotropium + combination in COPD
Outcome Tio Tio + Sal Tio + Flu/Sal
Patients with ex. 62.8 64.8 60
-2 (-12 to 9) 2.8 (-8 to 14)
Ex. per patient-year 1.61 1.75 1.37
1.1 (0.8 to 1.3) 0.85 (0.6 to 1.1)
Urgent visits 185 184 149
1.06 (0.9 to 1.3) 0.81 (0.6 to 1.01)
Hospitalizations for COPD 49 38 26
0.83 (0.5 to 1.3) 0.53 (0.3 to 0.8)
All –cause hospitalizations 62 48 41
0.83 (0.6 to 1.2) 0.67 (0.4 to 0.99)
Aaron et al. Ann Intern Med 2007;146:545-555
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17. Treatment of COPD in PC
Miravitlles et al. Respir Med 2007; 101: 1753-1760
Treatment of COPD
Miravitlles et al. Int J COPD 2008; 3: 803-814
Theophylline in COPD
Time to the first
exacerbation.
Theophylline 100
mg/12 h vs placebo.
Frequency of
exacerbations:
T= 0.98 (1.3)
Pla= 2.07 (2.7)
P=0.036
Zhou et al. Respirology 2006;11:603-610
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18. Theophylline
and ICS
Mean levels of
inflammatory markers
in sputum in patients
with exacerbations of
COPD treated with oral
steroids with or without
low-dose theophylline
Cosío et al. Thorax 2009; 64: 424-429
Bronchial colonisation
Relationship
between LABC
and exacerbation
frequency
Patel et al. Thorax 2002;57:759-764
Prevention of exacerbations
with macrolides
Proportion of
patients without
an exacerbation
vs time to the
first exacerbation
in placebo and
macrolide arms
(p=0.02)
Seemungal et al. AJRCCM 2008;178:1139-1147
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19. Bronchial colonisation
119 patients included
Colonized Not colonized
58 61
High bacterial load (≥
Low bacterial load (< 106)
106)
22
36
Miravitlles et al. ERJ 2009 (in press)
Bronchial colonisation
Colonisation at 2 and
8 weeks.
Bottom: persistence
Upper: acquired
*p<0.01
Miravitlles et al. ERJ 2009 (in press)
Secondary
Trial Primary variable:
variables:
•no. of
exacerbations
overview no. of
exacerbations •diff in lung function
•HEOR
•QoL, etc.
Moxi 400mg Pulse Pulse ET FU FU
OD x 5 #2 #6 #1 #3
days
N=1132
Mod-severe CB
stable phase
Placebo Pulse Pulse ET FU FU
OD x 5 #2 #6 #1 #3
days
Screened &
Randomized 8 wks 8 wks 8 wks 8 wks 8 wks
48 week treatment period 24 week follow-up
period
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20. Clinical efficacy
Purulent/muco-purulent sputum
*adjusted for region and pre-therapy %PFEV1
GOLD Guidelines
Rabe et al. AJRCCM 2007;176:532-555
Optimal Pharmacotherapy in COPD
Increasing Disability and Lung Function Impairment
Mild Moderate Severe
Infrequent AECOPD Frequent AECOPD
(< 1/year) (> 1/year)
SABD prn LAAC or LABA+ SABA prn LAAC + ICS/LABA +
persistent persistent disability SABA prn
disability
LAAC + LABA + SABA prn persistent disability
LAAC + SABA prn
persistent disability
or
LAAC + ICS/LABA +
LAAC + ICS/LABA +
LABA + SABA prn SABA prn +/- Theophyline
SABA prn
O’Donnell et al. Can Respir J 2007; 14 (Suppl B): 5-32
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21. Optimal Pharmacotherapy of Moderate
to Severe COPD
Frequent AECOPD
(> 1/year requiring systemic steroids or antibiotics)
Long-acting anticholinergic (LAAC)
+
Inhaled corticosteroid/Long-acting beta-2-agonist
(ICS/LABA)
+
Short-acting beta-2-agonist (SABA) prn
persistent disability
Consider adding Theophylline
Can Respir J 2007;14(Suppl B):3B-32B.
Conclusions
• No changes in mucus viscosity.
• No increase in glutation in BAL.
• No impact in bronchial colonisation.
• Most studies are small, not well
characterised COPD.
• The best study was negative.
• Possible effect in untreated patients (?).
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22. Answers to evaluation questions
Debate: is there a place for oral mucolytics in the prevention of LRTI? – CON
1. b
2. c
3. a
109

23. Faculty disclosure forms
Marc Miravitlles has received honoraria for consultancy and lecturing from Bayer Schering.
Wisia Wedzicha is the advisory board member of GSK, Astra Zeneca, Boehringer Ingelheim, Pfizer
and Novartis. He has received lecture fee from GSK, Astra Zeneca, Boehringer Ingelheim, Pfizer and
Novartis.
111