Wingrave  published one of the first studies on nasal irrigation, ‘The Nature of Discharges and Douches’, popularizing this type of treatment in the twentieth century. Figure 1 demonstrates the popularity of nasal irrigation with topical saline as a common adjunct in the treatment regimen for relieving the symptoms of upper respiratory tract infections, including chronic rhinosinusitis (CRS).
Topical antibiotics first appeared as a treatment for respiratory conditions decades ago when aerosol penicillin was applied topically to cystic fibrosis patients. Antibiotics, like β lactams, polymyxin, and aminoglycosides, improved the sinonasal symptoms of cystic fibrosis patients [2–5]. After multiple studies with cystic fibrosis patients, topical antibiotics were used in the treatment of various respiratory conditions, such as pulmonary aspergillosis , Pneumocystis carinii pneumonia , recurrent staphylococcal infection, rhinoscleroma, and atrophic rhinitis . Corticosteroids are very popular in the treatment of CRS. Intranasal corticosteroids are seen as the ‘first-line treatment’ in nasal polyps among adult patients and have been given a ‘Grade A recommendation’ .
Antifungals emerged approximately the same time corticosteroids became accepted as a treatment for CRS. In 1983, the first study was published to propose that finding Aspergillus in the nasal mucus of a patient constituted a new form of CRS: allergic Aspergillus sinusitis . In 1989, allergic fungal sinusitis was an acceptable term to describe CRS with fungal organisms detected in the nasal mucosa .
Nasal irrigation with topical saline is a popular supplement in the treatment regimen for upper respiratory tract infections, including CRS. In fact, 87% of patients have used nasal irrigation with saline to relieve sinonasal symptoms . Theoretically, nasal irrigation with saline solution can improve symptoms of CRS, especially after functional endoscopic sinus surgery. Nasal irrigation can reduce inflammation, increase mucociliary clearance, decrease swelling in the mucosa, and physically remove mucus and blood from the airway. Although Pinto et al. showed there were no improvements in sinonasal symptoms after using isotonic and hypertonic saline after endoscopic sinus surgery (ESS) in a randomized clinical trial, four randomized controlled trials with larger sample sizes found significant improvements in nasal discharge, edema in the nasal mucosa, medication use, symptoms frequencies, Sino-Nasal Outcome Test (SNOT-20) scores, and rhinosinusitis outcome measures, after administering the saline solution at a higher dosage , conducting a longer follow-up period , or using large volume, low-positive pressure devices, such as the bulb syringe or the Neti-pot, instead of the nasal spray, to distribute the saline solution in the nasal cavity [16,17].
Although the benefits of saline nasal irrigation are supported by these multiple studies, there have been debates whether to use isotonic saline or hypertonic saline to most effectively treat CRS. Although hypertonic saline solution has shown positive benefits when utilized by cystic fibrosis and asthma patients , hypertonic saline solution has been shown to reduce ciliary beat frequency at 0.9% concentration, elicit reversible absolute ciliostasis at 7% concentration, and irreversible complete ciliostasis at 14.4%, in a cryopreserved mucosa of the sphenoid sinus, indicating the high extracellular concentration of sodium may interfere with the activity of the calcium channels associated with the beating of the cilia . One prospective controlled clinical study with 211 CRS patients  and one randomized trial with 70 CRS patients  showed the use of hypertonic saline solution significantly reduced the use of antibiotics and nasal spray, and improved sinonasal symptoms and overall quality of life. In fact a literature review of eight randomized clinical trials , and two more recently published randomized clinical trials with at least 60 CRS patients each, showed that hypertonic solution had superior results in improving nasal congestion, rhinorrhea, cough, headache and insomnia , and saccharine clearance  than isotonic saline. It is unclear whether isotonic or hypertonic saline is a better option for saline irrigation. On the basis of symptom score and quality of life, hypertonic saline may be a better initial choice; however, if local adverse effects develop, transition to an isotonic solution would be recommended.
Although nasal irrigation can be beneficial, contamination seen in the nasal irrigation delivery devices might perpetuate CRS among patients through backwash. With more than 70% of patients not regularly cleaning the sinus rinse bottles according to the instructions, contaminated sinus irrigation delivery devices is a substantial threat in reversing the benefits seen with nasal irrigation . To combat the problem, one-way valve sinus rinse bottles were designed to eliminate backwash. However, two prospective uncontrolled studies published in 2011 showed the one-way sinus rinse bottles were ineffective in preventing bacterial growth on the delivery devices [25▪,26▪].
The bacteria often associated with CRS are not only present on the sinus valve bottles but also in various stages of biofilms. In a prospective uncontrolled study published in 2009, Welch et al. took culture swabs of the irrigation bottles used twice a day for 1, 2, and 4 weeks after ESS in 20 patients. Twenty-five percent at the end of 2 weeks, 45% at the end of 4 weeks, and 97% of all 43 bottles at the end of 4 weeks had bacterial growth. Staphlyococcus aureus was the most commonly seen bacteria. Bacteria in various stages in the formation of biofilms were found on the bottles.
Regardless of the contamination found in alarmingly high rates in the irrigation bottles, nasal irrigation still improves the quality of life of CRS patients, as seen through increased SNOT and Visual Analog Scale (VAS) scores . Furthermore, higher rates of contamination on nasal irrigation bottles did not show any significant relationship with higher infection rates after ESS in 20 CRS patients . The contamination risks of nasal irrigation delivery devices were not substantial enough to discourage the recommendation of saline solution nasal irrigation to CRS patients.
Multiple lower level studies have shown the benefits of using topical antibiotics in CRS patients: improvement in symptoms and decrease in inflammatory mediators (IL-1 and IL-6) with 2 ml of fosfomycin sodium three times per day for 4 weeks , improvement in endoscopic sinus scores, VAS and SNOT-20 scores with 0.05% mupirocin two times per day for 3 weeks , and improvement in nasal obstruction, facial pain, and rhinorrhea after the use of various topical antibiotics (cefurozime, levofloxacin, ciprofloxin, and tobramycin) . Lim et al. 2008 showed more significant benefits when the topical antibiotic was culture-directed or administered through a nebulizer instead of a nasal spray.
Although several lower level studies showed the positive benefits of topical antibiotics in the overall symptoms and inflammation in CRS patients, higher level studies that compared antibiotics with saline solution failed to report any additional benefit to the use of topical antibiotics in the treatment of CRS. In a 2011 meta-analysis of four prospective, double blinded, randomized trials, Woodhouse and Cleveland [33▪▪] showed there was no statistically significant difference between nebulized saline and nebulized antibiotics in CRS patients, although both treatment options showed significant improvements in symptoms. In another systematic review of the literature from 1949 to 2007 that looked at 14 high-level studies, only one showed that topical antibiotics had superior results in treating CRS compared with the saline solution . There is conflicting evidence regarding the use of topical antibiotic therapy. There are, however, enough studies demonstrating efficacy that topical antibiotic therapy should be considered an option in the treatment of refractory CRS, but not a first-line therapy. Although it appears topical antibiotic therapy is efficacious, to what degree is this medication entering the sinuses.
In a 1989 experimental study, Saijo et al. determined the distribution of topical medications in the sinus model was affected by three factors: particle size, pressure gradient, and diameter of the sinus ostium . There has been a large debate on the optimal size of a particle for distribution in the sinuses, ranging from 0.67 to 0.99 micron, and 5.63 micron . Consequently, controlling the sinus ostium size through surgery seems to be the better option in increasing the distribution of topical medication. Particles cannot penetrate the maxillary sinuses with the sinus ostium diameter being less than 1 mm. Therefore, surgery, which can increase the diameter of the entrance, can also increase the distribution of the topical treatments .
Although the distribution of the topical antibiotics in the sinuses is severely limited by the type of delivery device, the history of surgery, and the human anatomy, there is still some concern over the risks that accompany the systemic absorption of topical antibiotics. Systemic absorption has been seen in other topical antibiotics that were administered on the skin. There are only two studies that explored the systemic absorption of topical antibiotics administered in the nasal cavity with conflicting conclusions. In a retrospective review study of 12 post-ESS CRS patients, serum gentamicin levels were elevated in 10 of 12 patients. An average of 7 dB hearing loss was also observed in the right ear at 8000 Hz after using nasal irrigation with a gentamicin solution twice a day (30 cc of 80 mg/l solution) for 3 to 15 weeks . However, in one prospective case series with 20 patients that required sinus surgery, serum levels of gentamicin were too low to cause any therapeutic effects 30 min after irrigating their sinuses with gentamicin solution during surgery . A likely explanation for this difference is that in the former study, the duration of irrigation was much longer, suggesting that topical antibiotic therapy should not be given for an indefinite period, but rather for a finite duration.
Although the studies that observe the impact of nasal steroids on patients with CRS without nasal polyps are few in number, they all show the benefits of using topical steroids in the treatment regimen for CRS. Patients with CRS without nasal polyps showed significant improvements in symptoms and endoscopic scores after taking 400 μg of beclomethasone dipropionate once per day for 12 weeks  and patients showed significantly more healing after ESS when taking 6 months of mometasone furoate nasal spray (200 μg) twice a day . In one meta-analysis, combined symptom scores improved significantly in the 10 included studies. Snidvongs et al.[41▪▪] caution, however, that there were adverse effects associated with using nasal steroids: minor epistaxis and headache. In addition, four of the 10 studies were funded by pharmaceutical companies, creating a bias.
Multiple studies have shown the positive benefits of budesonide. All of the high-level studies showed that the use of budesonide had shown significant improvements in combined symptom scores, polyp size and peak nasal inspiratory flow with minimal side effects compared with the placebo [42–44]. With such promising results seen in high-level studies, budesonide has been studied in the irrigation form in patients with CRS. When budesonide (1 mg) or betamethasone (1 mg) was delivered to the nasal cavity through a 240 ml squeeze bottle daily in 111 CRS patients that were eligible for ESS, overall symptoms scores, SNOT 22 scores, and endoscopy scores all significantly improved, especially in patients who exhibited high tissue eosinophilia [45▪▪].
However, these two studies did not have a control group of using saline only for irrigation; the benefits observed in these two studies may have been secondary to the act of irrigating the nose with saline solution and not necessarily the addition of budesonide. One high-level study did not see any additional benefits of including budesonide in the saline solution used for nasal irrigation compared with using only saline. In one randomized double-blinded controlled study, 60 patients were assigned to three treatment groups: saline irrigations (240 ml per day), budesonide nasal spray (64 μg per nostril two times per day), and saline irrigations with 2 ml of 0.5 mg/ml budesonide (1000 μg budesonide per day). There were no statistically significant differences between the three treatment groups in SNOT, Lund Mackay computed tomography (CT) scores, and endoscopic scores at 6 months and 1 year after treatment [46▪▪].
Another steroid considered for the treatment of CRS with nasal polyps is mometasone furoate. Doses of 200 μg once per day have shown significant improvements in polyp size, congestion, peak nasal inspiratory flow, and quality of life among nasal polyp patients compared with the placebo with adverse effects, such as the most common complaint, epistaxis , upper respiratory tract infection , headache, nausea, anterior rhinorrhea, nasal congestion, sneezing, and skin irritation . Two high-level studies showed increasing the dose of mometasone furoate to 200 μg two times per day can provide statistically significant additional benefits compared with administering the nasal steroid only 200 μg one time per day, although there is also an increase in the number of adverse effects . In addition to treating nasal polyps and improving symptoms of CRS, one study showed that mometasone furoate can also be considered for postoperative treatment to reduce the possibility of repeat surgery for nasal polyps .
Although corticosteroids show positive benefits in many high-level studies as a topical medication for the treatment of CRS with tolerable side effects, there is a possibility that these corticosteroids will be absorbed into the vasculature of the nose . The nasal cavity has an area of approximately 180 cm2 in which the corticosteroids can be absorbed  and suppress the hypothalamic-pituitary adrenal (HPA) axis through decreasing ACTH levels and consequently inhibiting the adrenal glands ability to produce cortisol. Despite the rapid response of the body to restore equilibrium when administered one dose of corticosteroids, patients’ adrenal glands are at a risk for degeneration if they are exposed to corticosteroids for extended periods .
Budesonide is one of the few intranasal steroids that studies have tested for systemic absorption among CRS patients. There are many factors that can be controlled to limit the possible systemic absorption of intranasal steroids; one of the most important factors is the delivery device used to administer the corticosteroids. In a randomized, open cross over study with 16 healthy controls, systemic absorption of budesonide was tested in three treatments: pressurized aerosol (800 μg), aqueous pump spray (400 μg), and powder (800 μg). The powdered form had the highest blood concentration 10 h after treatment, followed by the aqueous pump spray, and then the pressurized aerosols . In a retrospective chart review of 18 CRS with nasal polyps patients, there were no significant changes in morning cortisol levels when patients added budesonide to their saline solution nasal irrigation . Another study that prescribed 10 post-ESS CRS patients nasal irrigation with budesonide (0.5 mg/2 ml) in saline (250 ml) solution twice a day for 3 months had normal average serum cortisol and 24 h urinary cortisol levels after treatment . Intranasal mometasone at 200 μg per day for 5 days had no significant impact on measurements of the HPA axis, bone, and blood in multiple separate studies [57–59].
Despite several studies stating that there is no significant change in the concentration of cortisol in the blood after the administration of topical steroids, plasma cortisol levels is not the most dependable measure of observing the systemic absorption of corticosteroids because the baseline measurement broadly differs between individuals, which makes assigning the ‘normal’ range very difficult. Plasma cortisol levels also fluctuate during the day, ranging from 570 nmol/l in the morning to 100 nmol/l at night . Therefore, although there are many studies that do not demonstrate a suppression of the HPA axis with the use of intranasal corticosteroids, long-term studies that explore more accurate measurements of the activity of the adrenal gland are required to determine the possibility of the systemic absorption of intranasal steroids.
Two studies have demonstrated the low occurrence rate of fungal organisms among CRS patients. In a clinical prospective cross-sectional study of 62 CRS post-ESS patients, only one patient showed fungus growth in his or her culture swabs of the maxillary sinus (1.6%) . Another clinical prospective study with 41 CRS patients showed fungal growth in the culture swabs of the maxillary/ethmoid sinus secretions of only one patient out of the 41 CRS patients (2.4%) . However, both studies were criticized for using silicofluoride dye to detect fungal growth instead of the PCR sequencing, which may have been more sensitive to fungal organisms and consequently produce higher rates of fungal organisms among CRS patients . The rates of occurrence were not drastically improved when the PCR was used; only three tissue samples and two brush samples swabbed from the middle meatus showed fungal growth among 30 patients with CRS .
In addition, the rates of fungal organisms in the sinuses of healthy controls were similar to the CRS patients when the occurrence did actually manage to exceed more than one patient in the entire sample size. Three studies ranging from 108 CRS with nasal polyps patients to 210 CRS patients have shown comparable rates of fungal growth between CRS patients and the healthy controls: 63.0% of CRS patients versus 62.2% of healthy controls , 14% of CRS patients versus 12% of healthy controls , and 96% of the CRS patients versus 100% of the healthy controls .
Despite the multiple studies that have shown nonsignificant presence of fungal organisms in CRS patients or similar rates of occurrence between CRS patients and healthy controls, there are several studies that do recommend antifungal as a topical treatment to CRS. Lower level studies have shown that amphotericin B has been associated with lower reoccurrence of nasal polyps , especially when administered with lysine acetylsalicylate , improvement in symptoms and CT scans when delivered through a bulb syringe , and endoscopic scores . In fact, when amphotericin B was included in the solution used for nasal irrigation (20 ml 1 : 1000 AmB suspension in each nostril, two times per day, 4 weeks), 39% of the CRS patients resolved their nasal polyps at the end of treatment .
However, antifungals showed no effect or a negative effect when the studies included a control group. For example, topical amphotericin B had no effect on inflammatory markers; in fact, the placebo had higher levels of wound recovery . Another low-level study also showed amphotericin B spray was not effective in treating nasal polyps . One double blinded, randomized clinical trial showed that antifungals showed no benefits over the control and had higher rates of adverse effects than the control . Another double blinded randomized multicenter study showed there were no significant differences in symptoms scores between the CRS patients that used amphotericin B (25 ml two times per day for 3 months) and the placebo . Three meta-analyses also agreed that although topical antifungals did show improvements in radiographic measurements , they did not show any improvements in symptoms while displaying a higher rate of adverse effects [78▪▪,79▪▪]. When compared with saline in 76 CRS with nasal polyps patients, amphotericin (200 μl per nostril four times per day 8 weeks) did not show any additional benefits . Another study with 70 CRS patients confirmed that amphotericin (20 mg in 500 ml of normal saline) did not show any additional benefits compared with saline nasal irrigation . When a different antifungal was used and taken orally, terbinafine (625 mg per day) did not show any benefits compared with the control even if the CRS patient was positive for fungal presence .
A literature review criticized seven of these studies that investigated the effect of antifungal on the progression of CRS for not being strong enough (only one of the three double blinded placebo-controlled studies was multicenter), and for having a wide range of duration (4 weeks to 80 weeks), delivery devices, dosage, and frequencies of the dosages. In addition, none of the researchers had checked if the amphotericin B was stored properly, and therefore was stable at the time of treatment. However, when Shin et al. did correct for these faults seen in other studies in their own double blinded, prospective, randomized placebo-controlled clinical trial, amphotericin B (5 mg/ml spray for 12 months) showed no additional benefits among 33 CRS with nasal polyps patients. On the basis of the review of the literature, the use of antifungal therapy, both topical and systemic, in the management of CRS is not supported by the literature.
Topical therapy has become an important tool in the treatment armamentarium for CRS. On the basis of a review of the literature, nasal saline irrigation and topical steroid sprays are supported by the most evidence. Topical antibiotics, antifungals, and corticosteroid irrigations, however, demonstrate efficacy in only lower level studies and have an unknown systemic absorption and side effect profile. For this reason, they should only be used when traditional treatment (oral antibiotics, saline, steroid sprays) has failed. Further studies are needed to explore the long-term effects of these medications in the topical form.
Conflicts of interest
Both authors do not have any conflicts of interest to report with respect to the content of this article.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 88).
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