BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear.
OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma.
METHODS: We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677).
RESULTS: Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma.
CONCLUSIONS: Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.
| Discipline Area | Score |
|---|---|
| Allergy and Immunology |  |
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Pediatrics (General) | |
| Respirology/Pulmonology |  |
The effect size of the intervention was not large, and most participants had moderate or severe asthma. This suggests a role for macrolides as a second-line therapy for moderately severe asthma that is not well controlled with standard therapies.
It will good to assess the relevance of it once we see the guideline statements.
As a pediatrician, I am uncertain about the relevance of this issue to my routine clinical practice, particularly given that the discussion concerns long-term (12-26 wks in 3 pediatric studies) macrolide use.
This systematic review of RCTs found that macrolides reduce asthma exacerbations and improve asthma control. Many of the individual trials found significant differences on their own, and the review includes only 2 new trials done in the past decade. Most clinicians likely know this already.
I am a pediatrician and in addition to working in primary care, I am a member of a community-based PROA (Antibiotic Stewardship Programs). The conclusion regarding clinical implications seems extremely risky as it is currently expressed, like a slogan, without any restrictions based on asthma type or severity. It only states that it prevents severe exacerbations and likely improves quality of life. After reviewing the studies and forest plot diagrams, the effect doesn't appear to be anything to celebrate. Furthermore, azithromycin is a "watch" antibiotic according to the WHO's AWaRe classification (antibiotics with a higher potential for generating resistance or broad-spectrum antibiotics, indicated for a limited group of infections), and here they are extending its use chronically to a population highly vulnerable to severe respiratory infections. Finally, although it is mentioned in the discussion, this "major side effect" is omitted from the conclusions regarding side effects (antibiotic resistance is, after all, one of the top 10 public health problems). "Long-term exposure to macrolides... demonstrated an increase in the colonization of oropharyngeal streptococci resistant to azithromycin and erythromycin... presence of azithromycin-resistant Haemophilus influenzae and Pseudomonas aeruginosa after treatment. 49 These results are consistent with a recent Cochrane review that also found the presence of macrolide-resistant bacteria immediately after antibiotic use..." // ORIGINAL COMMENT TRANSLATED BY AI: Soy pediatra y además de trabajar en Atención Primaria soy miembro de grupos PROA comunitarios "Programas de Optimización de Uso de los Antibióticos" y la conclusión en implicaciones clínicas me parece sumamente arriesgada tal como está expresada, como un eslogan, sin hacer restricciones por tipo de asma ni gravedad del asma, solo figura que evita exacerbaciones graves y probable mejoría de la calidad de vida. Después de ver los estudios y los diagramas forestplot no parece que el efecto sea para aplaudir. Además la azitromicina es un antibiótico "watch" de la clasificación AWaRe de la OMS (Antibióticos con un mayor potencial de generar resistencias o de amplio espectro, indicados para un grupo limitado de infecciones.) y aquí lo hacen extendible de forma crónica a una población muy vulnerable a infecciones respiratorias graves. Y por último, aunque se menciona en la discusión, en los efectos secundarios de las conclusiones se omite este "gran efecto secundario" (no en vano la resistencia a los antibióticos es uno de los 10 problemas más importantes de salud pública).
"La exposición a largo plazo a los macrólidos ...... demostró un aumento en la colonización de estreptococos orofaríngeos resistentes a la azitromicina y la eritromicina...presencia de Haemophilus influenzae y Pseudomonas aeruginosa resistentes a la azitromicina después del tratamiento. 49 Estos resultados concuerdan con una revisión Cochrane reciente que también halló la presencia de bacterias resistentes a macrólidos inmediatamente después del uso del antibiótico..."
