Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force9s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4–5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.

https://erj.ersjournals.com/content/erj/55/1/1900588.full.pdf

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

Background: Macrolides have immunomodulatory properties. However, the mechanisms underlying the non-antimicrobial effects of macrolides are not well understood. Objectives: To systematically review the current evidence of immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extend of their influence on the innate and adaptive immune system. Methods: A systematic literature search was performed in MEDLINE using the OVID interface from 1946 to December 2016 according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Original articles reporting the influence of four macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin) on immunological markers in humans were included. Results: We identified 22 randomised, controlled trials, 16 prospective cohort studies and 8 case-control studies reporting on 47 different immunological markers (186 measurements) in 1777 patients. The most frequently reported outcomes were a decrease in the number of neutrophils, concentration of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumour necrosis factor-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function compared to eosinophils was more frequently reported. A decrease of T-helper (Th)2 cell cytokines (IL-4, IL-5, IL-6) was more frequently reported than a decrease of Th1 cytokines (IL-2, INF-gamma). Conclusion: Macrolides influence a broad range of immunological mechanisms resulting in immunomodulatory effects. To further optimise the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly also comparing different macrolides and dose effect relationships.

/pdf/the-immunomodulatory-effects-of-macrolides-a-systematic-1s15opkev2.pdf

The Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying Mechanisms.

Background The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared with control subjects, but the effects of clinical characteristics on the microbial community composition and structure are not clear. Objectives We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic persistent asthma, including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia. Methods DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic patients and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was used to compare the relative abundance of bacterial genera with clinical characteristics. Results Differential feature selection analysis revealed significant differences in microbial diversity between brush and lavage samples from asthmatic patients and control subjects. Lactobacillus, Pseudomonas, and Rickettsia species were significantly enriched in samples from asthmatic patients, whereas Prevotella, Streptococcus, and Veillonella species were enriched in brush samples from control subjects. Generalized linear models on brush samples demonstrated oral corticosteroid use as an important factor affecting the relative abundance of the taxa that were significantly enriched in asthmatic patients. In addition, bacterial α-diversity in brush samples from asthmatic patients was correlated with FEV1 and the proportion of lavage eosinophils. Conclusion The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of nonasthmatic control subjects and influenced by worsening airflow obstruction and corticosteroid use.

https://www.jacionline.org/article/S0091-6749(15)01563-8/pdf

Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways.

© 2019 The Cochrane Collaboration. Background: Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment-specific, rather than disease-specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. Objectives: To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. Selection criteria: We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. Data collection and analysis: Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide-resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta-analysis when three or more included studies reported a specific adverse event. Main results: We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin. Most studies (89%) reported some adverse events or at least stated that no adverse events were observed. Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low-quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low-quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate-quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate-quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate-quality evidence) were also reported more often in participants taking macrolides compared to placebo. The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000. The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting. There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration. Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; I2 = 46%; low-quality evidence). Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; I2 = 0%; low-quality evidence). We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low-quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low-quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low-quality evidence) compared to placebo. We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo. Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate-quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate-quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate-quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non-significant. There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; I2 = 11%; low-quality evidence). Only 24 studies (13%) provided useful data on macrolide-resistant bacteria. Macrolide-resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent. Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. Authors' conclusions: The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance.

/pdf/adverse-events-in-people-taking-macrolide-antibiotics-versus-apvsdqqzz4.pdf

Adverse events in people taking macrolide antibiotics versus placebo for any indication.

Background: Macrolides have antimicrobial and anti-inflammatory properties that may be useful in the treatment of chronic asthma. Methods: We performed a randomized, placebo-controlled, double-blinded effectiveness trial of 12 weekly doses of adjunctive azithromycin, with follow-up to 1 year after randomization, in adults with persistent asthma. Measurements included overall asthma symptoms, asthma quality of life (AQL), and asthma control. Eligible subjects who declined to participate in randomization were offered enrollment into a parallel open-label (OL) azithromycin treatment arm. Results: Of 304 adult asthma patients screened, 97 (32%) were enrolled: 38 were randomized to azithromycin, 37 were randomized to placebo, and 22 opted in as OL subjects. OL subjects had higher rates of severe persistent asthma compared with randomized subjects (32% vs 8%, respectively; P = .012). At 1 year, compared with the placebo arm, subjects randomized to azithromycin were more likely to have an AQL score ≥1 unit increase compared with baseline, but this difference was not statistically significant (36% vs 21% for placebo; P = .335). Compared with placebo, OL subjects had significant improvements in overall asthma symptoms from baseline (P = .0196), AQL (P = .0006), and asthma control (P = .0148). Conclusions: Adults with asthma who were randomized to azithromycin did not show statistically significant improvement in asthma outcomes, although the study was underpowered to detect clinical improvement in 15% (number needed to treat = 7). Adults with severe persistent asthma who elected OL treatment documented clinical improvements in asthma symptoms, AQL, and asthma control that persisted after completion of OL azithromycin (number needed to treat = 2).

/pdf/azithromycin-for-bronchial-asthma-in-adults-an-effectiveness-21f71m3lsz.pdf

Azithromycin for bronchial asthma in adults: an effectiveness trial.

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Azithromycin for bronchial asthma in adults: an effectiveness trial.