Manuka honey versus saline sinus irrigation in the treatment of cystic fibrosis-associated chronic rhinosinusitis: A randomised pilot trial

Abstract

Objectives:

Manuka honey attacks biofilms, which contribute to bacterial persistence in cystic fibrosis sinusitis. The primary objective was to determine feasibility of investigating manuka honey as an irrigation treatment for cystic fibrosis sinusitis and secondarily to assess the treatment’s preliminary effectiveness.

Design:

Prospective, single-blinded (clinician only), randomised, parallel two-arm pilot trial.

Setting:

Tertiary rhinology clinic.

Participants:

Subjects had recalcitrant cystic fibrosis sinusitis and previous sinus surgery. They received manuka honey or saline sinus irrigations twice daily for 30 days.

Main Outcome Measures:

Main outcomes were recruitment/retention rates and tolerability. Preliminary effectiveness was assessed based on quality-of-life Sinonasal Outcome Test-22 and Lund-Kennedy endoscopic change scores and post-treatment culture negativity.

Results:

Over 10 months, 13 subjects were enrolled, and 77% (10/13) were included in the analysis. Manuka honey irrigations were well-tolerated. The quality-of-life change score was clinically significant for manuka honey (−9 [−14,−6]) but not saline (−5 [−9,−1]), although the difference was not statistically significant (P = .29). Lund-Kennedy endoscopic change score was significantly better for manuka honey (−3 [−5,−3]) versus saline (0 [0,0]) (P = .006). There was no difference in post-treatment culture negativity between manuka honey (1/5, 20%) and saline (0/5, 0%) (P = 1.00).

Conclusions:

Manuka honey irrigations were well tolerated, and retention rates were high. Preliminary data showed that manuka honey achieved a clinically important difference in quality-of-life score and a significantly better endoscopic outcome. Microbiological control was difficult to achieve. A future definitive trial would require multi-institutional recruitment.

1 |. INTRODUCTION

Impaired mucociliary clearance contributes to frequent bouts of chronic rhinosinusitis (CRS) in nearly all patients with cystic fibrosis (CF).¹ Chronic bacterial infection, commonly with Staphylococcus aureus and Pseudomonas aeruginosa, exacerbates already impaired mucociliary clearance. Both bacteria also have a propensity to form biofilms, which protect them from environmental stresses and attack—including antibiotics.^2,3 CF-CRS can also contribute to pulmonary exacerbations, a major cause of morbidity in patients with CF.^4,5

Much of the CF literature has focused on topical antibiotics, such as tobramycin that target Pseudomonas aeruginosa, in nebulised form to reach the lower airway.⁶ There is a need for alternative topical anti-infective therapies to treat CF-CRS that have a broad microbiological profile, less propensity for development of resistant strains, and the ability to inhibit biofilm-forming bacteria. High-volume irrigation provides better topical penetration to the sinuses than other delivery methods.⁷ Patients should also have undergone endoscopic sinus surgery (ESS), which opens the sinuses and thereby improves topical treatment penetration.^1,8

Manuka honey has long been used in the treatment of chronic wounds, which are abundant with biofilm-forming bacteria. Manuka honey offers several advantages over traditional topical antibiotics, making it an intriguing topical therapy for CF-CRS: (a) natural, non-toxic product with decreased likelihood of side effects and allergic reactions and favourably associated with antioxidant and anti-inflammatory effects; (b) availability over-the-counter; (c) antibacterial effect against a wide range of bacteria; and (d) decreased propensity for the development of resistant bacteria.^9–13

This is a pilot trial for a future definitive trial evaluating the effectiveness of manuka honey sinus irrigations compared to saline controls for subjects with a CF-CRS exacerbation and prior sinus surgery. The primary objective was to determine feasibility, specifically recruitment/retention rates and treatment tolerability, and secondarily to provide preliminary effectiveness data for effect size estimates.

2 |. MATERIALS AND METHODS

2.1 |. Ethical considerations

Our local institutional review board granted ethics approval for this study. Written informed consent was obtained to participate.

2.2 |. Participants

This was a prospective, single-blinded (clinician only), randomised, parallel two-arm pilot trial conducted at a tertiary rhinology clinic. The CONSORT statement for reporting randomised pilot trials was followed where applicable.¹⁴ Subjects were not blinded as they compounded the sinus irrigations themselves. Patients with CF were approached for this study between November 2015 and August 2016 and considered for inclusion if they met diagnostic criteria for CRS, had undergone ESS > 6 weeks prior to enrolment and had purulent discharge on endoscopy.¹⁵ Exclusion criteria were age <18 years, terminal illness, primary immunodeficiency, severe or emergent complications from CRS, presence of a sinus tumour, unwillingness to stop topical antibiotic sinus irrigations if receiving them and allergy to honey.

2.3 |. Randomisation and intervention

Randomisation was performed to receive either 10% (v/v) manuka honey (MEDIHONEY^®; Derma Sciences; Princeton, NJ) (MH) or saline (SAL) control sinus irrigations for 30 days. Prior to the start of the study, an electronic random number generator tool (Sealed Envelope Ltd; London, UK) generated a blocked (sets of 6) randomisation list. When a new subject was enrolled, the member of the research team (VSL, PLP) communicating with the subject was informed of the next assigned irrigation treatment on the list.

Subjects were provided with supplies and instructions to make the assigned irrigation treatment at home (Table 1) and instructed to irrigate with ½ of the bottle twice daily for 30 days. If subjects were on systemic corticosteroids or antibiotics for pulmonary sequelae related to their CF, these were continued. If subjects were on high-volume topical budesonide sinus irrigations due to the presence of polyps on endoscopy, this was also continued.^4,16 No subjects, however, were started on topical steroids during the trial.

TABLE 1.

Recipe for irrigation treatments

Treatment	Supplies	Instructions
10% Manuka honey	2 rinse bottlesa Buffered salt packeta Manuka honey pasteb Syringe	Mix 24 mL manuka honey paste (measured using syringe) with buffered salt packet and 240 mL of waterc in rinse bottle
Saline control	2 rinse bottlesa Buffered salt packeta	Mix buffered salt packet with 240 mL of waterc in rinse bottle

^aNeilMed Pharmaceuticals (Santa Rosa, CA). Subjects were instructed to clean the rinse bottle at the end of each day, and use one bottle for 15 d and a new bottle for the next 15 d.

^bMEDIHONEY^®, Derma Sciences (Princeton, NJ).

^cPreviously boiled or distilled.

2.4 |. Primary feasibility outcomes

Main feasibility outcomes were recruitment/retention and treatment tolerability. Discomfort associated with sinus irrigations was assessed using a visual analog scale (VAS, continuous scale comprised of a 100 mm horizontal line bounded by no [0] to worst imaginable pain [100]). Subjects also completed a compliance diary to evaluate if they were performing the irrigations per the instructed schedule.

2.5 |. Secondary effectiveness outcomes

Preliminary effectiveness for proposed outcome measures was also assessed secondarily. Sinusitis-related quality of life was quantified using the Sinonasal Outcome Test-22 score (SNOT-22) change score. The SNOT-22 consists of 22 items, each scored from 0 to 5; total score recorded as the sum of all items.¹⁷ Endoscopic evaluation was measured using Lund-Kennedy endoscopic score change from baseline. The Lund-Kennedy endoscopic score consists of 10 items, each scored from 0 to 2 with the total score recorded as the sum of all items, 0–20.¹⁸ Microbiological control was evaluated using post-treatment culture negativity, defined as “negative” if no bacterial pathogen was identified on post-treatment culture. Cultures were collected with a sterile culture swab (Becton, Dickinson and Company, Franklin Lakes, NJ) or Xomed Sinus Secretion Collector (Medtronic-Xomed, Jacksonville, FL).

2.6 |. Sample size

Since this was a pilot trial, a sample size calculation was not performed. It was concluded after 13 subjects enrolled, as recruitment occurred at the same time as a definitive trial of subjects who did not have CF and that trial concluded having achieved target sample size.¹⁹ It was also felt that this was a sufficient sample to inform about the feasibility of a definitive trial.

2.7 |. Data collection

Clinic visit at time of enrolment was defined as the baseline time point. Descriptive characteristics were recorded, including demographics, Lund-Mackay CT score, relevant comorbidities and concurrent therapies.¹⁸ In addition, subjects completed a SNOT-22 questionnaire.¹⁷ A member of the research team (GED, IMH) blinded to the assigned irrigation treatment determined the Lund-Kennedy endoscopic score.¹⁸ An endoscopy was performed, an endoscopically collected sinus culture obtained and culture result recorded.

Following 30 days of treatment, subjects returned to the clinic for post-treatment assessment. Subjects were asked to complete a VAS form describing tolerability of the irrigation and to bring in their compliance diaries, and the results were recorded. The SNOT-22 score, Lund-Kennedy endoscopic score and culture result were recorded in an analogous fashion.^17,18

2.8 |. Statistical analysis

Statistical analyses were performed using Stata/IC 13.1 software (StataCorp LP, College Station, TX). Distribution and summary statistics were evaluated. To assess for inadequate randomisation of known confounders and the need for adjusted analyses of preliminary effectiveness data, Fisher’s exact test for binary variables and a Mann-Whitney U test for continuous variables were performed to evaluate for any significant differences in descriptive characteristics between treatment groups that would need to be adjusted for. A P-value < .10 was used to determine significance and need for adjustment.

Unadjusted comparisons for SNOT-22 score and Lund-Kennedy endoscopic score changes from baseline between the treatment groups were performed using a Mann-Whitney U test. Comparisons for post-treatment culture negativity were performed using Fisher’s exact test. Median and interquartile range are presented unless otherwise specified. A P-value < .05 was considered significant.

3 |. RESULTS

3.1 |. Participant flow, recruitment and retention

A total of 13 subjects were approached and randomised in this study (Figure 1), consistent with a 100% (13/13) recruitment rate. In the MH group (n = 6), 1 subject was lost to follow-up. In the SAL group (n = 7), 2 subjects requested switching to a culture-directed topical antibiotic (tobramycin) due to worsening symptoms. Therefore, there was a 77% (10/13) retention (completed the assigned treatment) rate and 92% (12/13) follow-up rate.

FIGURE 1.

Participant flow. MH, manuka honey, SAL, saline

For the secondary effectiveness outcome analyses, as the 2 treatment discontinuations were subjects that switched to topical antibiotic irrigations rather than simply stopping the assigned treatment, an intention-to-treat analysis was deemed unfavourable as the outcome data would not solely reflect MH. Therefore, these subjects in addition to the one lost to follow-up were excluded, and a per-protocol analysis was performed.

3.2 |. Descriptive characteristics

Table 2 shows descriptive characteristics and p-values evaluating for significant differences between treatment groups.Of note, in the SAL group, 2 subjects had a prior lung transplant, had depression or were on systemic corticosteroids. There were, however, no differences between treatment groups that reached significance for any of the descriptive characteristics. Unadjusted analyses of outcome measures were therefore performed.

TABLE 2.

Baseline patient demographics and clinical data (n = 10)

	MH (n = 5)	SAL (n = 5)	P-value
Age (y)	34 (26–36)	33 (32–40)	.46
Female	3 (60%)	3 (60%)	1.00
Caucasian	5 (100%)	5 (100%)	1.00
Lund-Mackay CT scorea	14 (14–14)	18 (15–20)	.14
Nasal polyposis	3 (60%)	3 (60%)	1.00
Concomitant asthma	0 (0%)	0 (0%)	1.00
Inhalant allergies	2 (40%)	2 (40%)	1.00
Current smoker	0 (0%)	0 (0%)	1.00
Depression	0 (0%)	2 (40%)	.44
Prior lung transplant	0 (0%)	2 (40%)	.44
Systemic antibiotics	4 (80%)	5 (100%)	1.00
Delta F508 heterozygosity	2 (20%)	2b	.46
Systemic corticosteroids	0 (0%)	2 (40%)	.44
Topical steroid sinus irrigations	3 (60%)	3 (60%)	1.00
CFTR modulators	2 (20%)c	0b	.21
Time to follow-up (d)	35 (35–43)	32 (29–33)	.12

Note: Median (interquartile range) or number (%) of patients is presented.

Abbreviations: MH, manuka honey, SAL, saline.

^aRadiologic grading of sinus systems, consisting of 6 items for each nasal cavity, each scored from 0–2; total score recorded as sum of all items, 0–24. Scan closest to treatment period used.

^b2 patients in the SAL group did not have data available.

^c2 patients in the MH group were on lumacaftor/ivacaftor.

3.3 |. Treatment tolerability and compliance

VAS scores were similar in both treatment groups (MH 15 [13,16] vs. SAL 12 [5,12]), indicating irrigations were well-tolerated. One subject experienced mild stinging with the MH irrigation, but this did not preclude performing the irrigation. No serious adverse effects were reported. There was also high per cent compliance in both treatment groups (MH 90 [82,100] vs. SAL 100 [100,100]).

3.4 |. Secondary effectiveness outcome measures

A SNOT-22 score with a negative change value represents an improvement, and a more negative value is a better response. A change of −9 is considered a clinically significant improvement.¹⁷ SNOT-22 score change from baseline was better in the MH(−9[−14,−6]) group compared to the SAL (−5[−9,−1]) group, but the difference between groups was not statistically significant(P = .29; Figure 2). The MH group, however, did achieve a clinically significant improvement whereas the SAL group did not. Assuming 8% loss to follow-up, a power of 0.80, significance level of 0.05 and standard deviation of 7 for both groups based on trial data, the estimated sample size to achieve statistical significance for the change of −4 in the preliminary data are 54 subjects per group. The SNOT-22 does have a minimal clinically important difference of −9.¹⁷ Under the same assumptions, the estimated sample size to achieve statistical significance for a clinically significant change of −9 is 12 subjects per group.

FIGURE 2.

Box plot comparison of SNOT-22 score change from baseline (P = .29). Dotted line indicates change of −9, considered a clinically significant improvement. MH, manuka honey; SAL, saline; SNOT-22, Sinonasal Outcome Test-22

A Lund-Kennedy endoscopic change score with a negative value represents an improvement. Lund-Kennedy endoscopic score change from baseline improved in the MH (−3 [−5,−3]) group and was unchanged in the SAL (0 [0,0]) group, and this difference was statistically significant (P = .006; Figure 3). Improvement in the “crusting” subcategory in the MH compared to SAL cohort was most responsible for this difference. Assuming a power of 0.80, significance level of 0.05, and standard deviation of 2 for the MH group and 1 for the SAL group based on trial data, the estimated sample size to achieve statistical significance for the change of −3 in the preliminary data is 7 subjects per group.

FIGURE 3.

Box plot comparison of Lund-Kennedy endoscopic score change from baseline (P = .006). Dotted line indicates change of 0, below which is considered an improvement. MH, manuka honey, SAL, saline

A higher post-treatment culture negativity rate is a better response. There was no difference in post-treatment culture negativity between manuka honey (1/5, 20%) compared to saline (0/5, 0%) (P = 1.00). Table 3 shows the pre- and post-treatment culture results by type of bacterial species for the MH and SAL groups. In the MH group, 2 subjects had Pseudomonas aeruginosa on pre- but not post-treatment culture. In the SAL group, 1 subject had Corynebacterium on pre- but not post-treatment culture. There were no significant differences in culture negativity between MH and SAL controls. Assuming a power of 0.80 and significance level of 0.05, the estimated sample size to achieve statistical significance for the 20% difference in the preliminary data is 67 subjects per group.

TABLE 3.

Pre- and post-treatment culture results by bacterial species

	MH (n = 5)		SAL (n = 5)
	Pre	Post	Pre	Post
Pseudomonas	3 (60%)	1 (20%)	3 (60%)	3 (60%)
Staphylococcus	2 (40%)	2 (40%)	3 (60%)	3 (60%)
Other gram + speciesa	0 (0%)	2 (40%)	1 (20%)	0 (0%)
Other gram - speciesb	2 (40%)	2 (40%)	0 (0%)	1 (20%)

^aStreptococcus, Corynebacterium.

^bStenotrophomonas, Achromobacter, Escherichia, Pantoea.

4 |. DISCUSSION

Though our clinic is a major tertiary rhinology referral centre, recruitment was challenging, with only 13 adult subjects recruited over a 10-month period, partially due to the uncommonness of CF and the requirement of active purulence in surgically opened sinuses in this patient population. Power analyses identified a need for up to 67 subjects per group to ensure sufficient sample size to address all the proposed outcome measures, with the culture negativity rate requiring the greatest number of participants. The recruitment rate and target sample size highlight the need for any future definitive trial to be multi-institutional.

All patients approached participated in the study. CF-related sinus disease is particularly challenging to treat, and this finding may highlight a particular willingness in this population to explore novel treatment options. Subject retention was also high with only 1 subject lost to follow-up. These patients typically have longstanding familiarity with the medical system, potentially contributing to high retention rates.

Overall, manuka honey sinus irrigations were well-tolerated at the 10% (v/v) concentration with high subject compliance, and no serious adverse effects were reported. The 10% (v/v) concentration of MEDIHONEY^® used in our study was carefully chosen.¹⁹ It needed to be above the minimum inhibitory concentration, but below the upper limit of tolerability and the level at which histological epithelial injury occurs, as ascertained by in vitro and unpublished data (N. Sorrel, personal communication, 28 July 2014; E. Leon, personal communication, 16 July 2014).^9,10,20,21 Only a couple other studies have evaluated manuka honey for nasal use and none in the CF-CRS population.^22–25

This trial does provide data on preliminary effectiveness of manuka honey sinus irrigations in post-ESS subjects with CF-CRS. Subjects receiving manuka honey sinus irrigations achieved a clinically significant improvement in SNOT-22 score whereas subjects receiving saline sinus irrigations did not. In addition, subjects irrigating with manuka honey showed significant improvement in Lund-Kennedy endoscopic scores compared to saline.

Consistent with the refractory nature of CF-CRS, this study found only 1 of the 10 subjects, in the manuka honey group, achieved post-treatment culture negativity. Patients have poor ciliary mucus clearance and develop a thick stagnant mucus layer related to defective CFTR transport. Bacteria can penetrate deep into this layer where the environment is more hypoxic and form biofilms.⁴ Perhaps our results would have been more successful if the topical therapy was used during sinus surgery or after thorough endoscopic debridement. Interestingly, after analysing the pre- and post-treatment culture results by bacterial species, this study found that 2 subjects in the manuka honey group had Pseudomonas aeruginosa on pre- but not post-treatment culture. These results should be interpreted cautiously but may suggest that manuka honey may have some effectiveness against Pseudomonas aeruginosa. This observation was also made in our parallel previously published randomised controlled trial of manuka honey versus saline sinus irrigations in non-CF subjects.¹⁹

Our study has some important limitations. Foremost, it is a pilot trial with a primary objective of evaluating feasibility of a future definitive trial. Thus, the preliminary effectiveness data should be interpreted cautiously as it was not appropriately powered. It is worth noting, however, that the manuka honey group experienced improvement in two of the three outcome measures compared to the saline group. Viewed in this context, manuka honey shows promise as a topical therapy for CF-CRS, worthy of further investigation and larger studies that will need to be multi-institutional to achieve adequate sample sizes. There is also the risk of inadequate randomisation and residual confounding related to unknown confounders in such a small sample size. Furthermore, it was not possible to blind subjects as irrigations were self-compounded. Future studies should attempt to incorporate patient blinding to eliminate bias in the self-reported SNOT-22 score, potentially by using standard clover honey as a control. The culture negativity outcome measure may also be susceptible to sampling error. Finally, the outcome measures were only assessed after 1 month and immediately after completion of treatment.

5 |. CONCLUSIONS

Preliminary effectiveness data support that manuka honey may have promise as a treatment for CF-CRS. Manuka honey sinus irrigations were well-tolerated with high treatment compliance. A future definitive trial should be multi-institutional to achieve necessary sample sizes, attempt subject blinding and employ longer follow-up intervals to truly evaluate treatment impact.

Key points.

• Manuka honey irrigations were well-tolerated.

• Manuka honey irrigations achieved a clinically important difference in quality-of-life score.

• There was a statistically significant improvement in endoscopic findings on manuka honey compared to saline irrigations for cystic fibrosis sinusitis.

• Post-treatment culture negativity was difficult to achieve on manuka honey or saline irrigations for cystic fibrosis sinusitis.

• Manuka honey may have promise as a treatment for cystic fibrosis sinusitis, with a future definitive trial requiring multi-institutional recruitment to achieve necessary sample sizes.