Macrolide antibiotics in the treatment of chronic rhinosinusitis: evidence from a meta-analysis
Original Article

Macrolide antibiotics in the treatment of chronic rhinosinusitis: evidence from a meta-analysis

Shen Shen1#, Hongfei Lou1,2#, Chengshuo Wang1,2, Luo Zhang1,2,3

1Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; 2Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing 100005, China; 3Department of Allergy, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China

Contributions: (I) Conception and design: C Wang, L Zhang; (II) Administrative support: H Lou, C Wang, L Zhang; (III) Provision of study materials: H Lou, C Wang, L Zhang; (IV) Collection and assembly of data: S Shen, H Lou; (V) Data analysis and interpretation: S Shen, H Lou; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to the study.

Correspondence to: Chengshuo Wang, MD, PhD. Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, No. 1, Dongjiaominxiang, Dongcheng District, Beijing 100730, China. Email: wangcs830@126.com; Luo Zhang, MD, PhD. Beijing Institute of Otolaryngology, No. 17, Hougouhutong, Dongcheng District, Beijing 100005, China. Email: dr.luozhang@139.com.

Background: The purpose of this study was to systematically assess the subjective and objective outcomes of macrolide therapy for chronic rhinosinusitis (CRS).

Methods: PubMed, Embase and Cochrane databases were searched for clinical trials detailing the effects of macrolide therapy in patients with CRS and published up to December 2017. Sino-Nasal Outcome Test (SNOT), endoscopic scores and computed tomography scans (CT) scores were assessed by mean difference (MD) or standardized mean difference (SMD) with 95% confidence interval. Subgroup analyses were performed to evaluate the source of heterogeneity according to study design and geographic locations. I2 metric was used to assess the heterogeneity.

Results: Seven randomised clinical trials (RCTs) and four cohort trials meeting pre-determined selection criteria were enrolled in this meta-analysis. Assessment of the findings for SNOT after 12 weeks’ macrolide treatment demonstrated a significant improvement in subgroup of trials in Asian patients (SMD =−0.51; 95% CI: −0.96, −0.02; P=0.04), but not in non-Asians (SMD =−0.01; 95% CI: −0.65, 0.63; P=0.98). At 12 or 24 weeks’ visit no significant difference in SNOT was noted compared with control group, either in RCTs or cohort trials subgroups. However, findings for endoscopic scores were found to be significantly improved compared to placebo in the subgroup of non-RCT studies after 8 weeks (SMD =−0.77; 95% CI: −1.07, −0.46; P<0.00001) and 12 weeks (SMD=−1.40; 95% CI: −1.97, −0.82; P<0.00001) of macrolide therapy. Similarly, findings for CT scores showed significant improvements in CT scores compared to baseline after 12 weeks’ treatment (MD=−5.81; 95% CI: −8.10, −3.52; P<0.00001) in cohort trials.

Conclusions: Macrolide therapy can significantly improve endoscopic and CT scores in CRS patients, compared to baseline. Further well-designed studies are needed to confirm the efficacy and safety of macrolides in CRS treatment.

Keywords: Macrolide antibiotics; chronic rhinosinusitis (CRS); Asian; non-Asian; meta-analysis


Submitted May 22, 2018. Accepted for publication Oct 15, 2018.

doi: 10.21037/jtd.2018.10.41


Introduction

Chronic rhinosinusitis (CRS) is a condition characterised by chronic inflammation of the paranasal sinuses, which shows a high prevalence worldwide and significantly affects patients’ quality of life (1). The treatment of CRS according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012 consists of intranasal or oral corticosteroids, nasal saline irrigation, antibiotics and surgery. The efficacy of antibiotics, however, remains controversial in the treatment of CRS (1).

Of the available antibiotics, the macrolides have been shown to have good bioavailability and tissue penetration, following oral administration (2,3). Since the first demonstration by Kikuchi and colleagues (4) of the effectiveness of long-term treatment with low-dose erythromycin in a cohort of 26 patients with CRS, this macrolide has been recommended in the treatment of CRS in Japan (5), as well as in the treatment of CRS without nasal polyps (CRSsNP) by the EPOS (1). Although the macrolides were widely applied for treating bacterial pathogens in CRS, increasing evidence has demonstrated that the macrolides possessed both anti-inflammatory and immunomodulatory effect (6-10), and lead to the concept of macrolides being immune-modulatory rather than anti-bacterial. However, several studies have shown some macrolides to have no significant benefits compared to placebo in the treatment of CRS (11-13), and therefore a matter of much debate presently. Pynnonen and colleagues (14) have conducted a meta-analysis of studies investigating the outcomes of long-term macrolide therapy for CRS and shown limited evidences to support long-term macrolide therapy. In particular, while studies in patients from Asian countries such as China and Japan have demonstrated macrolide and nasal steroids to provide a similar clinical effect for CRSsNP and both improving symptoms of CRS (13,15,16); some studies in patients from western countries have demonstrated different outcomes (11,17). Indeed, it is as been demonstrated that there was a difference of macrolide efficacy between Asian and western patients due to CRS endotypes (18), possibly as a result of differences in the inflammatory mechanisms in the ethnicity of the patients.

Since the publication of the meta-analysis by Pynnonen and colleagues (14), several studies investigating the curative effects of long-term macrolide therapy for CRS have been published. Thus, we have performed another meta-analysis of all available studies to date to re-evaluate the efficacy of macrolide therapy for CRS with additional objective measurements (endoscopic examination and CT examination) as well as distinguish the possible different curative effect between Asian and Caucasian.


Methods

The study followed recommendations of the Cochrane (http://www.cochrane.org) and the PRISMA 2009 guidelines (http://www.prisma-statement.org).

Search strategy

PubMed, Embase and Cochrane databases were systematically searched by two independent reviewers for appropriate studies published up to December 2017. The search terms were “Macrolide” or “Clarithromycin” or “Erythromycin” or “Roxithromycin” or “Azithromycin” and “Chronic rhinosinusitis”. All published studies were included in the meta-analysis if they met the following criteria: (I) the criteria for diagnosis of CRS employed in all studies were clear and as recommended outline by the Rhinosinusitis Task Force (19) or European position paper on rhinosinusitis and nasal polyps (1); (II) the patients were aged over 14 years old; (III) all patients had received oral macrolide therapy; (IV) outcomes such as Sino-Nasal Outcome Test-20 (SNOT-20), SNOT-22, endoscopic scores, and computed tomography (CT) scan scores were reported; (V) all patients had signed informed consent before participation in the study; and (VI) published in English or Chinese language. Articles published as reviews, and abstracts or reports presented at scientific/medical meetings were excluded.

Data extraction and