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. 2021 Nov 22;11(11):CD002997.
doi: 10.1002/14651858.CD002997.pub5.

Macrolides versus placebo for chronic asthma

Krishna Undela  1 , Lucy Goldsmith  2 , Kayleigh M Kew  3 , Giovanni Ferrara  4
Affiliations

Macrolides versus placebo for chronic asthma

Krishna Undela et al. Cochrane Database Syst Rev. .

Abstract

Background: Asthma is a chronic disease in which inflammation of the airways causes symptomatic wheezing, coughing and difficult breathing. Macrolides are antibiotics with antimicrobial and anti-inflammatory activities that have been explored for the long-term control of asthma symptoms.

Objectives: To assess the effects of macrolides compared with placebo for managing chronic asthma.

Search methods: We searched the Cochrane Airways Group Specialised Register up to March 2021. We also manually searched bibliographies of previously published reviews and conference proceedings and contacted study authors. We included records published in any language in the search.

Selection criteria: We included randomised controlled clinical trials (RCTs) involving both children and adults with asthma treated with macrolides versus placebo for four or more weeks. Primary outcomes were exacerbation requiring hospitalisation, severe exacerbations (exacerbations requiring emergency department (ED) visits or systemic steroids, or both), symptom scales, asthma control questionnaire (ACQ, score from 0 totally controlled, to 6 severely uncontrolled), Asthma Quality of Life Questionnaire (AQLQ, with score from 1 to 7 with higher scores indicating better QoL), rescue medication puffs per day, morning and evening peak expiratory flow (PEF; litres per minutes), forced expiratory volume in one second (FEV1; litres), bronchial hyperresponsiveness, and oral corticosteroid dose. Secondary outcomes were adverse events (including mortality), withdrawal, blood eosinophils, sputum eosinophils, eosinophil cationic protein (ECP) in serum, and ECP in sputum.

Data collection and analysis: Two review authors independently examined all records identified in the searches then reviewed the full text of all potentially relevant articles before extracting data in duplicate from all included studies. As per protocol, we used a fixed-effect model. We conducted a sensitivity analysis for analyses with high heterogeneity (I2 greater than 30%). GRADE was used to assess the certainty of the body of evidence.

Main results: Twenty-five studies met the inclusion criteria, randomising 1973 participants to receive macrolide or placebo for at least four weeks. Most of the included studies reported data from adults (mean age 21 to 61 years) with persistent or severe asthma, while four studies included children. All participants were recruited in outpatient settings. Inclusion criteria, interventions and outcomes were highly variable. The evidence suggests macrolides probably deliver a moderately sized reduction in exacerbations requiring hospitalisations compared to placebo (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.20 to 1.12; studies = 2, participants = 529; moderate-certainty evidence). Macrolides probably reduce exacerbations requiring ED visits and/or treatment with systemic steroids (rate ratio (RaR) 0.65, 95% CI 0.53 to 0.80; studies = 4, participants = 640; moderate-certainty evidence). Macrolides may reduce symptoms (as measured on symptom scales) (standardised mean difference (SMD) -0.46, 95% CI -0.81 to -0.11; studies = 4, participants = 136 ; very low-certainty evidence). Macrolides may result in a little improvement in ACQ (SMD -0.17, 95% CI -0.31 to -0.03; studies = 5, participants = 773; low-certainty evidence). Macrolides may have little to no effect on AQLQ (mean difference (MD) 0.24, 95% CI 0.12 to 0.35; studies = 6, participants = 802; very low-certainty evidence). For both the ACQ and the AQLQ the suggested effect of macrolides versus placebo did not reach a minimal clinically important difference (MCID, 0.5 for ACQ and AQLQ) (ACQ: low-certainty evidence; AQLQ: very low-certainty evidence). Due to high heterogeneity (I2 > 30%), we conducted sensitivity analyses on the above results, which reduced the size of the suggested effects by reducing the weighting on the large, high quality studies. Macrolides may result in a small effect compared to placebo in reducing need for rescue medication (MD -0.43 puffs/day, 95% CI -0.81 to -0.04; studies = 4, participants = 314; low-certainty evidence). Macrolides may increase FEV1, but the effect is almost certainly below a level discernible to patients (MD 0.04 L, 95% CI 0 to 0.08; studies = 10, participants = 1046; low-certainty evidence). It was not possible to pool outcomes for non-specific bronchial hyperresponsiveness or lowest tolerated oral corticosteroid dose (in people requiring oral corticosteroids at baseline). There was no evidence of a difference in severe adverse events (including mortality), although less than half of the studies reported the outcome (OR 0.80, 95% CI 0.49 to 1.31; studies = 8, participants = 854; low-certainty evidence). Reporting of specific adverse effects was too inconsistent across studies for a meaningful analysis.

Authors' conclusions: Existing evidence suggests an effect of macrolides compared with placebo on the rate of exacerbations requiring hospitalisation. Macrolides probably reduce severe exacerbations (requiring ED visit and/or treatment with systemic steroids) and may reduce symptoms. However, we cannot rule out the possibility of other benefits or harms because the evidence is of very low quality due to heterogeneity among patients and interventions, imprecision and reporting biases. The results were mostly driven by a well-designed, well powered RCT, indicating that azithromycin may reduce exacerbation rate and improve symptom scores in severe asthma. The review highlights the need for researchers to report outcomes accurately and according to standard definitions. Macrolides can reduce exacerbation rate in people with severe asthma. Future trials could evaluate if this effect is sustained across all the severe asthma phenotypes, the comparison with newer biological drugs, whether effects persist or wane after treatment cessation and whether effects are associated with infection biomarkers.

Trial registration: ClinicalTrials.gov NCT00760838 NCT02517099.

PubMed Disclaimer

Conflict of interest statement

KU: none.

LG: I was the statistical Editor at Cochrane Airways Group and checked the data and then joined the team after providing extensive help.

KK: I was a paid researcher on a National Institute for Health Research (NIHR) Cochrane Programme Grant until December 2016, during which time I contributed to the first version of this review. The grant was awarded to the Cochrane Airways review group at St George's, University of London, where I continued as an honorary research assistant until April 2017. I am currently an employee of the Cochrane Central Executive Team and my contribution to the update for this review is not subject to any funding.

GF: I received fees for lectures (AstraZeneca) and advisory boards/lectures (Boehringer Ingelheim and Roche) for topics not related to and outside the work of this systematic review and meta‐analysis.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.1 Exacerbation requiring hospitalisation.
5
5
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.2 Severe exacerbations: exacerbations requiring emergency department visits/systemic steroids.
6
6
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.3 Symptom scales.
7
7
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.4 Asthma Control.
8
8
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.5 Asthma Quality of Life Questionnaire (AQLQ).
9
9
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.6 Rescue medication puffs/day.
10
10
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.7 Morning PEF (L/minute).
11
11
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.8 Evening PEF (L/minute).
12
12
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.9 FEV1 (L).
13
13
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.11 Oral corticosteroid dose.
14
14
Forest plot of comparison: 1 Macrolide versus placebo, outcome: 1.12 Serious adverse events (including mortality).
1.1
1.1. Analysis
Comparison 1: Macrolide versus placebo, Outcome 1: Exacerbation requiring hospitalisation
1.2
1.2. Analysis
Comparison 1: Macrolide versus placebo, Outcome 2: Severe exacerbations: exacerbations requiring emergency department visits/systemic steroids
1.3
1.3. Analysis
Comparison 1: Macrolide versus placebo, Outcome 3: Asthma symptom scales
1.4
1.4. Analysis
Comparison 1: Macrolide versus placebo, Outcome 4: Asthma control
1.5
1.5. Analysis
Comparison 1: Macrolide versus placebo, Outcome 5: Asthma Quality of Life Questionnaire (AQLQ)
1.6
1.6. Analysis
Comparison 1: Macrolide versus placebo, Outcome 6: Need for rescue medication puffs/day
1.7
1.7. Analysis
Comparison 1: Macrolide versus placebo, Outcome 7: Morning PEF (L/minute)
1.8
1.8. Analysis
Comparison 1: Macrolide versus placebo, Outcome 8: Evening PEF (L/minute)
1.9
1.9. Analysis
Comparison 1: Macrolide versus placebo, Outcome 9: Forced expiratory volume in 1 second (FEV 1; L)
1.11
1.11. Analysis
Comparison 1: Macrolide versus placebo, Outcome 11: Oral corticosteroid dose
1.12
1.12. Analysis
Comparison 1: Macrolide versus placebo, Outcome 12: Serious adverse events (including mortality)
1.13
1.13. Analysis
Comparison 1: Macrolide versus placebo, Outcome 13: Withdrawal
1.14
1.14. Analysis
Comparison 1: Macrolide versus placebo, Outcome 14: Blood eosinophils
1.15
1.15. Analysis
Comparison 1: Macrolide versus placebo, Outcome 15: Sputum eosinophils
1.16
1.16. Analysis
Comparison 1: Macrolide versus placebo, Outcome 16: Eosinophil cationic protein (ECP) in serum
1.17
1.17. Analysis
Comparison 1: Macrolide versus placebo, Outcome 17: ECP in sputum
2.1
2.1. Analysis
Comparison 2: Sensitivity analysis, Outcome 1: Severe exacerbations: exacerbations requiring emergency department visits/systemic steroids
2.2
2.2. Analysis
Comparison 2: Sensitivity analysis, Outcome 2: Symptom scales
2.3
2.3. Analysis
Comparison 2: Sensitivity analysis, Outcome 3: Asthma control
2.4
2.4. Analysis
Comparison 2: Sensitivity analysis, Outcome 4: Asthma Quality of Life Questionnaire (AQLQ)
2.5
2.5. Analysis
Comparison 2: Sensitivity analysis, Outcome 5: Forced expiratory volume in 1 second (FEV 1; L)
See this image and copyright information in PMC

Update of

References

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Kraft 2002 {published data only}
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Nelson 1993 {published data only}
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Piacentini 2007 {published and unpublished data}
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Shoji 1999 {published data only}
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Simpson 2008 {published and unpublished data}
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Sutherland 2010 {published data only}
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Wan 2016 {published and unpublished data}
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References to studies excluded from this review

Andrade 1983 {published data only}
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Anon 2009 {published data only}
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Bacharier 2015 {published data only}
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Ball 1990 {published data only}
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Cogo 1994 {published data only}
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D'Azevedo Silveira 2016 {published data only}5639760
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Ebling 1984 {published data only}
    1. Ebling WF, Szefler SJ, WJ Jusko. Analysis of cortisol, methylprednisolone, and methylprednisolone hemisuccinate. Absence of effects of troleandomycin on ester hydrolysis. Journal of Chromatography 1984;305(2):271-80. - PubMed
Feldman 1997 {published data only}
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Gong 2016 {published data only}5639762
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Gotfried 2004 {published data only}
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Hueston 1991 {published data only}
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Itkin 1970 {published data only}
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Johnston 2016 {published data only}
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Kaplan 1958 {published data only}
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Koh 1997 {published data only}
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Koutsoubari 2012 {published data only}
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Lee 1998 {published data only}
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Spector 1974 {published data only}
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Stokholm 2016 {published data only}
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Szefler 1980 {published data only}
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Szefler 1982a {published data only}
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Takamura 2001 {published data only}
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Wald 1986 {published data only}
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Zeiger 1980 {published data only}
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References to ongoing studies

NCT02517099 {published data only}
    1. NCT02517099. Preschool wheeze: Inflammation/Infection Guided Management (PrIGMa) [Use of pathological phenotype to determine optimal management for moderate to severe preschool wheeze]. www.clinicaltrials.gov/ct2/show/NCT02517099 (first received 6 August 2015).

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