INTRODUCTION
Chronic rhinosinusitis (CRS) is characterized by persistent inflammation of the sinus mucosa and is prevalent worldwide. Persistent CRS can significantly decrease quality of life. CRS frequently necessitates endoscopic sinus surgery (ESS), making postoperative care crucial [1].
Poor treatment of recalcitrant CRS is often associated with bacterial biofilms, and the use of inappropriate antibiotics may exacerbate symptoms. Repeated antibiotic use without effective disruption of biofilms can further contribute to antibiotic resistance. Thus, novel treatments are needed to address the biofilm challenge in recalcitrant CRS [2].
Cleaning the nasal cavity with saline is a traditional method for treating CRS, as it helps remove allergens and contaminated mucus [3]. Saline nasal irrigation or spray increases the moisture of the sol layer and reinforces the gel layer, thereby enhancing mucociliary clearance by thinning thick mucus. In postoperative ESS patients, saline cleaning may promote earlier mucosal wound healing. Moreover, saline irrigation can alleviate CRS symptoms by removing inflammatory materials [3,4].
Manuka (Leptospernum scoparium) honey (MH) has been used to treat wounds for a long time [5]. Although its precise mechanism of action is not fully understood, its high sugar content is thought to contribute to its antibacterial properties. Additionally, MH is characterized by high acidity, high osmolality, low pH, the presence of hydrogen peroxide, and methylglyoxal components, all of which may help reduce bacterial biofilms [6-8]. MH exhibits broad-spectrum antibacterial effects against both Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus [9]. It can increase the sensitivity of resistant bacteria to antibiotics [10] and preserve cilia and mucosa [11]. It exerts anti-oxidative and anti-inflammatory effects [10].
Although no standard concentration of MH for topical use has been established, one report recommends dilution to 16.5% [12]. In an in vivo sheep study, MH augmented with methylglyoxal at concentrations of 0.9 to 1.8 mg/mL was found to be relatively safe for the sinus mucosa and effective against Staphylococcus aureus biofilms [11]. Reported adverse effects are minimal and include mild irritation, stinging, nausea, and a slight burning sensation [13-16]. Importantly, no serious adverse effects have been reported [6,7].
The clinical research on MH remains controversial, with significant heterogeneity among studies. Various clinical investigations have evaluated MH using different regimens and in patients with varying severity of CRS, which may influence the observed effectiveness of both saline and MH. In this report, we performed a meta-analysis of several clinical studies to evaluate the efficacy and safety of topical MH in CRS treatment, with subgroup analyses for each contributing factor. To the best of our knowledge, this is the first meta-analysis in the English literature addressing the use of MH for sinusitis treatment.
METHODS
Search methods
Articles published up to January 2021 were retrieved from PubMed, Embase, OVID, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials. The search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17]. Only original articles published in English were considered. The search employed the keywords “sinusitis,” “rhinitis,” “sinus,” “nasal,” “chronic rhinosinusitis,” “rhinosinusitis,” “recalcitrant chronic rhinosinusitis,” “endoscopic sinus surgery,” “manuka,” and “medihoney.” Institutional review board (The Catholic University of Korea, St. Vincent’s Hospital) approval was not required since the study did not involve any human or animal subjects (exemption number:VC20ZISI0272).
Eligibility criteria
We included randomized trials with either single- or double-blinded designs. Studies involving adults aged 17 years or older diagnosed with CRS and who had recently undergone ESS were eligible.
The experimental groups comprised patients receiving MH via sprays, packing, or irrigation, while the control groups received saline via similar methods. Eligible studies evaluated outcomes such as visual analogue scale (VAS) scores (0–100) for discomfort during sinus irrigations, quality of life measured by the Sinonasal Outcome Test-22 (SNOT-22; 22 items, each scored 0 to 5), the Philpott-Javer endoscopic score (PJ score; a 10-grade system assessing the frontal, ethmoid, maxillary, and sphenoid sinus cavities with a maximum total score of 40 per side) or Lund-Kennedy endoscopic score (LK score; 10 items, each scored from 0 to 2) for grading mucosal inflammation, post-treatment culture negativity (defined as “negative” if no bacterial pathogen was identified), and adverse event reporting. The SNOT-22 questionnaire covers four symptom domains: sleep, nasal, emotional, and otologic/facial pain symptoms [18].
Study records
The search utilized consistent terms. Two authors independently reviewed the titles and abstracts to identify articles reporting on patients with CRS undergoing ESS and treated with MH. The articles were then evaluated against the eligibility criteria, and relevant study details were extracted and analyzed. When information was insufficient or inconsistent, the authors discussed and reviewed the data multiple times to resolve discrepancies.
The extracted data included study type, patient age and number, interventions, comparison groups, follow-up period (minimum 4 weeks after initiation of MH application), outcomes, diagnostic tools, and conclusions.
The quality of the included studies was assessed using the Cochrane Handbook for Systematic Review of Interactions [19]. The risk of bias was assessed based on random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants, personnel, or outcome assessment (performance or detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Studies with clearly described methods were rated as low risk; those without adequate description were rated as high risk, and insufficient information resulted in an unclear risk assessment.
Statistical analysis
The meta-analysis was performed using RevMan Manager (RevMan) version 5.4.1 (The Nordic Cochrane Centre, The Cochrane Collaboration) [20]. The weighted mean difference was presented with a 95% confidence interval (CI). Statistical heterogeneity was assessed using the chi-square test (p-value) and the I2 statistic, with I2 values categorized as low, medium, or high based on thresholds of 40% and 60%. A random-effects model was applied in cases of high heterogeneity, while a fixed-effects model was used for low or medium heterogeneity. A p-value of less than 0.05 was considered statistically significant. For continuous variables, treatment effects were evaluated using either the mean difference or standardized mean difference (SMD) with the standard deviation and 95% CI. When the study populations were heterogeneous, subgroup analyses were performed. Reliable results were then used to draw conclusions.
RESULTS
Selection of studies
A total of 48 studies were identified through title and abstract screening. Of these, 39 studies underwent full-text screening to evaluate eligibility. After full-text review, six studies were selected for qualitative synthesis. Among the 39 studies, 14 were excluded because they were in vitro or animal studies, 13 were excluded as case reports, two were excluded for using a different type of honey (e.g., thyme honey) in the experimental group, and four were excluded for other reasons such as a lack of quantifiable data or absence of a control group.
The remaining six studies satisfied our inclusion criteria [12,13-16,21]. For the meta-analysis, four studies were ultimately included; one study was excluded because it was a clinical trial without peer review [15] and another was excluded due to a different follow-up period [12]. A PRISMA flowchart detailing the study selection process is presented in Fig. 1. Table 1 summarizes the study type, number of patients, patient ages, intervention and control groups, duration of MH treatment, and outcome measurements for each study.
Characteristics of studies
Across the six studies, a total of 196 adult patients aged 17 years or older were evaluated, with 134 patients from four studies included in the meta-analysis. Two studies [13,21] evaluated each nostril of one patient. All studies were randomized, one study was double-blinded [21], and other studies were single-blinded [13,14,16]. Patients were diagnosed with CRS, allergic fungal rhinosinusitis, or cystic fibrosis-associated CRS and underwent ESS (Table 1).
In the control groups, patients or nostrils were treated with normal saline via Merocel, saline sprays, or saline irrigation, while the experimental groups received either 50% MH-soaked Merocel, 50% MH spray, or 10% MH irrigation.
The duration of MH treatment ranged from 4 weeks to 30 days, and the outcome measures varied across studies. Outcomes included VAS scores, SNOT-22 scores, PJ scores or LK scores, post-treatment culture negativity, and adverse event reporting. In particular, changes in the LK score from baseline to post-treatment were used to assess mucosal status. The quality of the four included studies was evaluated for risk of bias (Supplementary Fig. 1 in the online-only Data Supplement).
Subjective symptom score after the use of manuka honey
Two studies (n=52) assessed discomfort associated with sinus irrigations, using a 100-mm VAS (0 representing no pain and 100 representing the worst pain) after ESS in patients treated with saline or MH. The forest plot is presented in Fig. 2A. The meta-analysis revealed no significant difference between VAS scores for saline versus MH (SMD, -0.46; 95% CI, -1.02 to 0.10), with low heterogeneity (I2=7%).
Additionally, two studies (n=52) evaluated changes in the SNOT-22 score from baseline, comparing saline irrigation with 10% MH irrigation.
The corresponding forest plot is shown in Fig. 2B. Although the saline group exhibited slightly greater improvement in SNOT-22 scores than the MH group, the difference was not statistically significant (SMD, -0.03; 95% CI, -0.58 to 0.52), and heterogeneity was low (I2=34%).
Endoscopic status of mucosa after the use of manuka honey
Two studies (n=50) evaluated the endoscopic status of the mucosa after ESS using the Philpott-Javer endoscopic scoring system (range 0 to 40) in patients treated with MH. In these studies, one nostril was treated with normal saline-soaked Merocel packing or the patient’s previous regimen (budesonide or saline irrigation), while the contralateral nostril received treatment with 50% MH-soaked Merocel packing or 50% MH spray.
Rigid nasal endoscopy was used to assess mucosal status, and the forest plot is shown in Fig. 3A. Although the MH-treated nostrils exhibited slightly better mucosal status compared to the control, the difference was not statistically significant (SMD, 0.13; 95% CI, -0.26 to 0.52), and heterogeneity was absent (I2=0%).
In another two studies (n=52), changes in mucosal status from baseline were evaluated using the LK score in patients treated with saline irrigation versus 10% MH irrigation. The forest plot is shown in Fig. 3B. The improvement in LK scores with MH was slightly greater than with saline, but the difference did not reach statistical significance (SMD, 0.59; 95% CI, -0.03 to 1.21).
Culture negativity after the use of manuka honey
Two studies (n=50) evaluated bacterial culture negativity following treatment with 10% MH irrigation compared to saline irrigation. Mucous discharge was directly collected using a swab and endoscopy, and cultures were analyzed for various bacteria including Pseudomonas, Streptococcus, and Haemophilus influenzae, among others.
The forest plot is shown in Fig. 4. Although culture negativity was slightly higher in the MH group compared to the saline group, the difference was not statistically significant (risk ratio, 0.43; 95% CI, 0.16 to 1.15), and heterogeneity was absent (I2 =0%).
Adverse effects after the use of manuka honey
No serious adverse events were reported in any of the studies. Only minor adverse effects, including mild irritation and a stinging sensation, were noted (Table 2).
DISCUSSION
Our results indicate that the efficacy of MH irrigation or spray on endoscopic mucosal status and bacterial culture negativity warrants reconsideration, as no statistically significant benefits were observed.
The SNOT-22 scores, which reflect sinusitis-related quality of life, did not differ significantly between MH and saline groups. This may be attributed to the subjective nature of some SNOT-22 items, which assess functional limitations and emotional factors rather than directly evaluating antibacterial or anti-inflammatory effects. Similarly, the VAS scores for sinus irrigation tolerability did not differ significantly, suggesting that MH is well tolerated.
All six studies, including the two eventually excluded from the meta-analysis, consistently reported MH as a safe material without severe adverse effects. One study demonstrated a significant improvement in symptoms using the SNOT-22 [13], while another reported a significantly improved endoscopic outcome with MH [16]. However, other studies did not show statistically significant effects on the progression of CRS.
The discrepancies between these studies and our findings may be attributed to several limitations. Although the heterogeneity among included studies was low, variations in interventions likely contributed to the lack of statistical significance.
First, longer investigation periods may be necessary; the duration of MH and control treatments was approximately one month, and one study suggested that more than one month of MH use is required to effectively reduce bacterial biofilm [12]. Second, the MH treatment modalities varied, including Merocel packing, irrigation, or spray, with concentrations ranging from 10% to 50% and differing frequencies of daily use. Third, the control treatments also varied, including saline sprays and irrigations. Fourth, concurrent treatments differed among studies; for example, one study administered oral antibiotics and prednisone to all patients, whereas another allowed patients who previously used steroid sprays or oral antibiotics to continue their medications. Fifth, the inclusion of patients with allergic fungal rhinosinusitis and cystic fibrosis-associated CRS in some studies introduced further heterogeneity, potentially affecting the generalizability of the results. Standardizing these conditions might yield different meta-analytic outcomes. Further research under unified conditions is needed to reassess the clinical use of MH.
Unifying these conditions could introduce different results of a meta-analysis. After researching again with unified conditions, the clinical use of MH should be reconsidered.
In conclusion, the potential benefits of topical MH treatment on mucosal status and bacterial culture negativity in the postoperative care of CRS patients following ESS warrant reconsideration, as no significant positive effects were observed. Nonetheless, MH is a natural substance with no serious adverse effects, and evidence suggests it may exert broad effects on biofilms and antibiotic-resistant bacteria. Therefore, the use of MH should be reexamined, and further well-designed trials should be conducted, particularly for patients with recalcitrant CRS.
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