Low-concentration hypochlorous acid nasal irrigation for chronic sinonasal symptoms: a prospective randomized placebo-controlled study

Myeong Sang Yu1 Bo-Hyung Kim1 Sung-Ho Kang1 Dae Jun Lim1

Received: 26 September 2016/Accepted: 10 November 2016/Published online: 17 November 2016

Springer-Verlag Berlin Heidelberg 2016

Abstract Low-concentration hypochlorous acid (HOCl) is an endogenous antibacterial and antiviral agent. The purpose of this study was to evaluate the effectiveness of HOCl irrigation in patients with chronic rhinosinusitis (CRS) refractory to medical therapy. Forty-three adult patients (mean age 45.5 years) were enrolled in this study. They were randomly chosen to receive nasal irrigation with either low-concentration HOCl generated by a Salicid device (n = 21), or a placebo (saline; n = 22) for 8 weeks. The outcome measures were scores on the 20-Item SinoNasal Outcome Test (SNOT-20), rhinosinusitis disability index (RSDI), nasal endoscopic score, and bacterial cultures. The SNOT-20 scores were significantly lower in the HOCl group than in the placebo group after 2 weeks of treatment (p\0.05) and remained lower after 4 weeks of treatment. With respect to the RSDI scores, there was a significant improvement in the HOCl group at 1 week after treatment and in both groups at 2 weeks after treatment (p\0.05). There were no significant differences in the endoscopic scores between the two groups after the treatment. The bacterial culture rates were lower in the HOCl group than in the placebo group after 4 weeks of treatment, but this was not significant (p[0.05). Our results showed that low-concentration HOCl irrigation resulted in a greater improvement in CRS symptoms as compared to saline irrigation.

& Myeong Sang Yu

1 Chungju Hospital, Konkuk University School of Medicine,

Chungcheongbuk-do 380-704, South Korea

Keywords Hypochlorous acid  Chronic rhinosinusitis

Nasal irrigation  Placebo controlled  Double blind method

Introduction

Chronic rhinosinusitis (CRS) is a common inflammatory condition with significant morbidity and refractory symptoms such as rhinorrhea, nasal obstruction, cough, and post nasal dripping [1, 2]. Since the exact cause of CRS is still unclear, traditional treatments for CRS, including antibiotics and surgery, are not universally successful in controlling patient complaints [3]. Therefore, various adjunct therapies, including nasal irrigation with or without drugs, topical steroid, steam inhalation, and leukotriene antagonists have been attempted to control the chronic sinonasal symptoms [4–8].

Nasal saline irrigation is a simple and inexpensive method that is believed to alleviate the sinus and nasal symptoms of CRS. This method increases the mucociliary clearance by facilitating the removal of nasal discharge, and reduces mucosal inflammation by decreasing the number of bacteria, allergen, or fungi [9–12]. Many studies evaluating the efficacy of saline irrigation have indicated a clear improvement in the quality of life of patients undergoing treatment for various diseases, including rhinosinusitis and allergic rhinitis, and in the postoperative care of patients who have undergone endoscopic sinus surgery [13–15]. However, saline irrigation may be less effective for uncontrolled rhinosinusitis because saline irrigation by itself lacks an antibacterial effect and mucin is hydrophobic [16, 17].

Hypochlorous acid (HOCl) is a weak acid that forms when chlorine dissolves in water, which is used as a bleach, a deodorant, and a disinfectant. Low concentrations of HOCl have been shown to have antibacterial, antifungal, and antiviral effects without toxicity to the nasal mucosa [16, 18, 19], indicating that it can be used effectively for nasal irrigation. Therefore, we hypothesized that low-concentration HOCl nasal irrigation would be more beneficial to CRS patients because of its bactericidal effects, and it may be used as an alternative adjunctive therapy in CRS patients. The purpose of this study was to investigate the efficacy of low-concentration HOCl nasal irrigation in the reduction of typical CRS symptoms refractory to medical therapy.

Materials and methods

Subjects

A total of 105 potential participants with CRS were assessed for eligibility, and 43 patients were included in the analysis. The participants were recruited from among the patients visiting the otolaryngology clinic of the Konkuk University Chungju Hospital between November 2011 and March 2015. Participants were deemed eligible if they were adults who self-reported one or more of the following symptoms: nasal obstruction, nasal dryness or crusting, mucopurulent nasal discharge, or postnasal drip. The inclusion criteria were: (1) age C16 years, (2) typical nasal symptoms for C12 weeks, (3) nasal endoscopy that showed mucosal swelling or purulent discharge, (4) positive findings on sinus X-ray films, (5) CRS refractory to medical therapy[2 months, and (6) follow-up duration C4 weeks.

The exclusion criteria were: (1) age\16 years, (2) history of sinus surgery, (3) imbibed antibiotics within 1 week before enrolling in the study, and (4) a bleeding tendency.

A total of 105 patients were assessed for eligibility, 50 patients were enrolled, and 43 were included in the final analysis. Out of the 50 enrolled patients, seven did not complete the follow-up or performed the nasal irrigation inconsistently, and were thus excluded (Fig. 1).

Study design

This was a prospective, randomized, double-blind, placebo-controlled trial comparing low-concentration HOCl nasal irrigation with a placebo. Informed consent was obtained from all patients and this study was approved by the Institutional Review Board of the Konkuk University Chungju Hospital. All participants were divided into a HOCl or placebo group, according to a computer-generated randomization that was prepared by the nursing staff. Patients were blinded to the assignment.

The 21 patients in the HOCl group received nasal irrigation two times daily with 30 mL of low-concentration HOCl that was generated as previously described [16, 18] using a Salicid device (Dolki Korea, Wonju, South Korea) in conjunction with Salicid packets containing 315 mg of NaCl. One Salicid packet was added to the test device, which contained 35 mL of tap water at pH 7.0, yielding a 0.85% (w/v) NaCl solution. The 22 patients in the placebo group also received normal saline administered by sham Salicid equipment. The patients were blinded to the sham allocation and were trained to perform the nasal irrigation using the same method.

Outcome assessment

All patients were asked to complete the 20-item Sino-Nasal Outcome Test (SNOT-20), and the rhinosinusitis disability index (RSDI) questionnaire. These tests are validated, selfadministered, quality of life instruments specific to patients with symptoms of rhinosinusitis [20, 21]. The patients filled out the questionnaires before, and at 1, 2, 4, and 8 weeks after enrollment.

Bilateral assessment of the nasal cavity with sinonasal endoscopy was also performed by three independent physicians who were blinded to the group information. The endoscopicfindingswerequantifiedusingtheLund-Kennedy(score range 0–20) scoring system [22]. The endoscopic findings, including edema, discharge, polyps, crusting, and scarring, weregradedfromzero(normal)totwo(severelydiseased).The scores from each group were averaged and analyzed. The changes in the SNOT-20, RSDI, and endoscopic score before the treatment, and at 1, 2, 4, and 8 weeks after the treatment were compared for the HOCl and placebo groups.

The bacterial culture was done on the day before and 4 weeks after the treatment. The nasal swab specimens for bacterial cultures were taken endoscopically from the bilateral middle meatus.

Statistical analysis

The baseline characteristics were compared between the two study groups using a Chi-square test for the categorical variables and a 2-sample t test for the continuous variables. Friedman tests were utilized to compare the SNOT-20, RDSI, and endoscopic scores within each group. Mann– Whitney U tests were utilized to compare the outcomes between the two groups at each follow-up point. McNemar’s tests were utilized to compare the bacterial culture rates before and after treatment for each group. All collected data were presented as mean ± standard deviation. The statistical analyses were performed using SPSS for Windows, Version 20.0 (IBM, North Castle, NY, USA). The level of significance was set at p\0.05.

Fig. 1 CONSORT diagram of the randomized controlled trial. A total of 105 potential subjects were screened, and 43 subjects successfully completed the study. Subjects were randomly assigned to the hypochlorous acid (HOCl) or placebo group

Results

Patient demographics

This study included 24 male and 19 female patients, with a mean age of 45.5 years (range 16–72 years). The HOCl group (n = 21) consisted of 10 male and 11 female patients. The mean age of the HOCl group was

48.2 ± 15.3 years. The placebo group (n = 22) consisted of 14 male and 8 female patients. The mean age of the placebo group was 43.6 ± 13.9 years. There was no significant difference between the two groups regarding age, sex, or symptom characteristics. The mean follow-up period was 9.1 months (range 6–29 months).

Subjective outcome measurement

There were no significant differences in either the SNOT20 or RSDI scores between both groups at baseline before the treatment. During the follow-up period, there was a significant improvement in the mean SNOT-20 scores in both groups at 1 week after treatment (p\0.05). The mean SNOT-20 scores at 2 and 4 weeks after treatment were significantly lower in the HOCl group compared with the placebo group (p\0.05; Fig. 2). With respect to the RSDI scores, there was a significant improvement in the HOCl group at 1 week after treatment and in both groups at 2 weeks after treatment (p\0.05). However, there were no significant differences in the RSDI scores between the two groups after the treatment (Fig. 3).

Objective outcome measurement

The endoscopic scores were significantly improved in both groups at 2 weeks after treatment. However, there were no significant differences in the endoscopic scores between the groups at any follow-up duration (Fig. 4).

Bacteria were recovered from 36 of 42 nasal swab specimens (85.7%) in the HOCl group and 36 of 44

(81.8%) specimens in the placebo group before treatment,

Fig. 2 Changes in the SNOT-20 score after treatment in the placebo group at 2 and 4 weeks after treatment (c). HOCl hypochlorhypochlorous acid (a) and placebo groups (b). The SNOT-20 scores ous acid, *p\0.05 were significantly lower for the HOCl group compared with the

Fig. 3 Changes in the RSDI score after treatment in the hypochlorous acid (a) and placebo groups (b). The RSDI scores were significantly improved in the HOCl group at 1 week after treatment,

Fig. 4 Changes in the Lund–Kennedy endoscopic score after treatment in the hypochlorous acid (HOCl) and placebo groups. The endoscopic scores were significantly improved in both groups at

2 weeks after treatment. *p\0.05

and 28 of 42 (66.7%) specimens in the HOCl group and 34 of 44 (77.3%) in the placebo group at 4 weeks after treatment (Table 1). In both groups, the bacterial culture rates were reduced at 4 weeks after treatment, but the change was not statistically significant (p = 0.129 and 0.365, respectively) and no significant differences were observed between the HOCl and placebo groups.

and in both groups at 2 weeks after treatment. There were no significant differences in the RSDI scores between the two groups after the treatment (c). HOCl hypochlorous acid, *p\0.05

Table 1 Bacteriologies before and after treatment

HOCl group                  Placebo group

Adverse effect

An independent investigator evaluated nasal cavities of all patients at each follow-up visit, and no adverse events were observed. No patients in either the HOCl or the placebo group reported any significant uncomfortable symptoms or feelings that accompanied the daily nasal irrigation. Two patients dropped out during the study because they caught a common cold and wanted to quit the study.

Discussion

The present study analyzed the efficacy of nasal irrigation using low-concentration HOCl for the patients with CRS refractory to medical therapy. We found a significant improvement in the RSDI and SNOT-20 scores within the HOCl group, and significantly lower SNOT-20 scores in the HOCl group than in the placebo group after 2 and 4 weeks of treatment. Furthermore, the bacterial culture rates were lower in the HOCl group than in the placebo group after 4 weeks of treatment, although the difference was not statistically significant. This finding suggests that low concentration of HOCl nasal irrigation can be used as an adjunct therapyinpatientswithCRSrefractorytomedicaltreatment. Inaddition, there were nosignificant complicationsresulting from the HOCl nasal irrigation. To our knowledge, this is the first randomized controlled trial to elucidate the efficacy of low-concentration HOCl nasal irrigation in adult patients with CRS refractory to medical treatment.

CRS is a common inflammatory condition defined by persistent symptomatic inflammation of the sinonasal cavities, such as nasal obstruction, nasal discharge, olfactory disturbance, and facial pain. It accounts for 1–2% of total physician visits and is associated with large health care expenditures for both pediatric and adult populations [23–25]. The appropriate application of medical therapies for chronic sinusitis is necessary to optimize patient quality of life (QoL) and daily functioning, and minimize the risk of acute inflammatory exacerbations [4]. The typical multiple courses of systemic oral antibiotics may have associated side effects, negatively affect QoL, are costly, and may lead to the development of resistant organisms [26]. Therefore, topical therapeutic strategies, such as nasal saline irrigation, might be preferable for the treatment of CRS. Intranasal saline irrigation is a simple, inexpensive, and generally well-tolerated treatment with very few side effects or risks. Many clinical trials have indicated the efficacy of nasal saline irrigation in the treatment of several diseases, including rhinosinusitis and allergic rhinitis, and in the postoperative care of patients who have undergone endoscopic sinus surgery [13–15]. Many studies evaluating the efficacy of saline irrigation for alleviating chronic nasal symptoms have demonstrated a clear improvement in patient QoL [1, 3, 27, 28]. The benefits derived from nasal saline irrigation are likely due to local effects, including the removal of debris from the nasal cavity while promoting sinus drainage, decreased edema of the nasal mucosa, and a reduction in mucosal inflammation by decreasing the amount of inflammatory mediators, bacteria, and allergens via the mechanical lavage action of saline irrigation [3, 29–32]. However, intranasal saline irrigation by itself lacks antibacterial activity. It may be less effective for uncontrolled CRS because mucin is hydrophobic and negatively charged [17]. Therefore, nasal irrigation containing antibacterial agents may be more useful for the treatment of CRS.

HOCl is a weak acid that is used as a bleach, an oxidizer, a deodorant, and a disinfectant [33]. Low concentrations of HOCl have been shown to have antibacterial effects, and an antiviral effect against the influenza virus, suggesting that such solutions might be effective nasal irrigants. Although HOCl has germicidal activity, the mechanism by which HOCl acts is still unclear [34]. Chlorine is thought to act as a disinfectant by inhibiting key enzymatic reactions within cells and by denaturing proteins [35, 36].

In previous reports, low-concentration (3.5 ppm) free chlorine and hypochlorous acid (HOCl) generated through the electrolysis of a salt solution using a Salicid device demonstrated bactericidal, fungicidal, and antiviral activity without toxicity to the nasal mucosa [18, 19]. This lowconcentration HOCl had excellent bactericidal and fungicidal activity against Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenza, Klebsiella pneumoniae, Rhizopus oryzae, Candida albicans, and Aspergillus fumigatus [19]. In addition, low-concentration HOCl generated by a Salicid device also inhibited the human rhinovirus-induced secretion of interleukin-6 and interleukin8, and viral replication in human nasal epithelial cells [18]. Because of these effects nasal irrigation with low-concentration HOCl was suggested as an effective adjuvant therapy for CRS. Recently, Cho et al. [16] reported that nasal irrigation with low-concentration HOCl produced by a Salicid device was an effective adjuvant therapy, compared to isotonic normal saline for pediatric sinusitis, and no adverse events were observed. In our study, an improvement in the symptoms of sinusitis with HOCl nasal irrigation was also observed in adult patients. Although the bacterial culture rate was not significantly different before and after the HOCl nasal irrigation in patients, low-concentration HOCl irrigation likely sterilizes bacterial pathogens in the nasal cavity to alleviate sinus infections.

Several limitations of our study need to be acknowledged. First, this study has a relatively small number of participants. However, this study is a randomized, placebocontrolled, double-blind study designed to minimize the number of variables that might complicate the main treatment comparison. Second, the duration of follow-up was relatively short. A longer follow-up period would make for an interesting subsequent study, especially to determine whether the effect of HOCl on the sinonasal mucosa is real and sustainable over the longer term. In addition, our study made no attempt to compare radiological findings before and after treatment. Paranasal sinus x-ray images or computed tomography scans can show the effects of HOCl irrigation on CRS patients more objectively. Therefore, further evaluations comparing the radiological findings before and after HOCl treatment are warranted.

Conclusion

Our results showed that low-concentration HOCl irrigation resulted in a greater improvement of symptoms of chronic sinusitis as compared to saline irrigation in adult patients. Therefore, we suggest that low-concentration HOCl nasal irrigation can be a useful adjuvant therapy for CRS.

Acknowledgements This paper was supported by Konkuk University.

Compliance with ethical standards

Conflict of interest All of authors declare that they have no conflict of interest.

Ethical approval The protocol of the study was reviewed and approved by our institutional review board. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent Informed consent was obtained from all individual participants included in the study.

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