Introduction
Chronic rhinosinusitis is defined as common nasal co-morbidity which manifests with a wide range of symptoms, such as nasal obstruction, nasal discharge, facial pressure, facial pain and hyposmia.Reference Fokkens, Lund, Hopkins, Hellings, Kern and Reitsma1 These symptoms may range from mild to moderate or severe, affecting the quality of life and physical and mental health of patients.Reference Moss, Kjos, Karnezis and Lebovits2
Chronic rhinosinusitis is classically classified according to the phenotype, based on the presence or absence of nasal polyps, into chronic rhinosinusitis with nasal polyps and chronic rhinosinusitis without nasal polyps.Reference Hansen and Alanin3
Yet, the new European Position Paper on Rhinosinusitis and Nasal Polyps 2020 classified primary chronic rhinosinusitis into ‘type 2’ and ‘non-type 2’ according to the endotype predominance.Reference Fokkens, Lund, Hopkins, Hellings, Kern and Reitsma1 Type 2 chronic rhinosinusitis is characterised by high local serum immunoglobulin E (IgE) and elevated blood and/ or tissue eosinophils, most patients of chronic rhinosinusitis with nasal polyps are type 2.
The prevalence of chronic rhinosinusitis with nasal polyps is estimated to be 1–4 per cent of the adult population equally among almost all races and social classes.Reference Dingsør, Kramer, Olsholt and Søderstrøm4,Reference Rimmer, Fokkens, Chong and Hopkins5
The management of chronic rhinosinusitis with nasal polyps is an obstacle in rhinology that hinges on medical and endoscopic surgery approaches. Treatment aims to reduce the size and number of polyps, thus creating space for airflow, consequently improving the sense of smell and decreasing the burden of the disease.Reference Kirtsreesakul, Wongsritrang and Ruttanaphol6 Steroids (either topical ‘spray or drops’ or systemic) are still the mainstay in the treatment of nasal polyps.Reference Hopkins, Slack, Lund, Brown, Copley and Browne7
Refractory cases revert to surgery, Hopkins et al. reported that 50 per cent of patients in the UK population with chronic rhinosinusitis with nasal polyps underwent endoscopic surgery at some point,Reference Hopkins, Slack, Lund, Brown, Copley and Browne7 and a large comprehensive study addressing long-term follow up reported that the risk of revision surgery is 18.6 per cent.Reference Loftus, Soler, Koochakzadeh, Desiato, Yoo and Nguyen8
Intralesional polyp steroid injection has been carried out for decades. Many authors concluded that polyp steroid injection has comparable results with systemic steroids with minimal side effects.Reference Rimmer, Fokkens, Chong and Hopkins5 Kang et al. proved that budesonide nasal wash is safe and effective in reducing the need for systemic steroid intake after sinus surgery, but there was a limitation concerning the appropriate dosing of budesonide and frequency of irrigation.Reference Kang, Chung, Cho, Lee, Kim and Jeong9
Our study aims to investigate whether polyp injection is a more effective method of budesonide delivery and less dependent on subjective compliance rather than irrigation and if it has comparable results with oral systemic steroids on polyps.
Materials and methods
Study population and ethics
This study was held in the Otolaryngology Department of Kafrelsheikh University hospitals where 90 patients with chronic rhinosinusitis with nasal polyps who were enrolled in this prospective randomised clinical trial (NCT number is NCT05474924) sought help at our out-patient clinics over a 15-month period from August 2021 to October 2022. The university ethical committee approved this study (MKSU 50-7-7). We used the ‘Consolidated Standards of Reporting Trials’ checklist when writing our report.Reference Schulz, Altman and Moher10 Patients were diagnosed with chronic rhinosinusitis with nasal polyps according to the criteria of the European Position Paper on Rhinosinusitis and Nasal Polyps 2020Reference Fokkens, Lund, Hopkins, Hellings, Kern and Reitsma1 and according to nasal endoscopic examination with evident polyps. Formal consent was signed by the patients to share and publish their data in this research.
Inclusion criteria
Included patients were those with type 2 chronic rhinosinusitis with nasal polyps, indicated by elevated serum IgE and high absolute eosinophilia, with any grade of nasal polyps, whose ages were between 18 and 60 years old who did not have any contraindications of systemic steroids such as glaucoma, peptic ulcer, acute psychosis, chronic infections, severe osteoporosis, severe hypertension, uncontrolled diabetes mellitus (HbA1c > 8) or history of thromboembolic events.Reference Kapucu, Cekin, Erkul, Cincik, Gungor and Berber11
Exclusion criteria
All patients with cystic fibrosis, ciliary dyskinesia, antrochoanal polyp, fungal sinusitis, unilateral nasal polyps, nasal tumours, patients with previous nasal surgery and patients who took systemic steroids in the last six months before our study were excluded.
All the patients’ complete histories were evaluated in addition to a questionnaire regarding the exclusion criteria. All patients had complete blood count with differential, serum morning cortisol level, random blood glucose, serum creatinine, lipid profile and blood pressure measurement before the start of the study.
Study design
We used Microsoft Excel to generate numbers and randomly allocate our subjects into one of three groups with a ratio of 1:1:1 where numbers were handed to patients by a separate clerk to ensure all patients had an equal chance to be included in any group. Patients were randomly assigned to one of three groups.
Group A
Group A patients received oral prednisolone 1 mg/kg/d (maximum 60 mg/d) in two divided doses for 3 days, then tapering the dose by 5 mg/day for 2 weeks. Patients were prescribed omeprazole 20 mg protective against the gastrointestinal effects of steroids.
Group B
Group B patients received endoscopic intrapolyp steroid injection once weekly for five consecutive weeks, using the following technique: (1) two nasal packs were soaked in xylometazoline hydrochloride 0.1 per cent ‘Otrivin adult nasal drops’ with one pack applied in each nostril for 5 minutes before injection; (2) then using a 175 mm long 0° 4 mm nasal rigid endoscope, patients received intrapolyp budesonide injection using a 0.5 mg/2 ml budesonide vial (one vial), 1 ml for each nasal cavity using (1 cc 28 gauge 0.5 inch) needle sterile syringe (referred to as diabetic or insulin style syringe) for each cavity. Injections were carefully distributed into all visible and accessible polyps (usually 2–3 polyps at each side) starting from the posterior to the most-anterior polyp using the endoscope at more than one depot site, injected into the polyp tissue avoiding the visible vessels. No local anaesthesia was used before injections; patients came back to the clinic weekly to complete a series of five injections. All patients were injected by the same otolaryngologist (IG) who wasn't responsible for the follow-up evaluation to avoid any bias.
Group C
Group C patients underwent budesonide nasal wash, through a 250 ml squeeze bottle filled with normal saline. One vial of 0.5 mg/2 ml budesonide was added to the saline solution and half the amount used for each nasal cavity. Patients gargled with antiseptic solution to minimise the risk of oral candidiasis. Patients carried out the wash twice daily for the one-month duration.Reference Kang, Chung, Cho, Lee, Kim and Jeong9 Patients were instructed to irrigate with normal saline each time just prior to using budesonide irrigation.
Sino-Nasal Outcome Test 22
We used the Arabic-validated version of the 22-item Sino-Nasal Outcome Test (SNOT-22) as a subjective method to assess the patient's quality of life (QoL) and the severity of the disease before and after treatment. Patients filled out the questionnaire before the start of the trial, one week after completion, and at three months after treatment.Reference Hopkins, Gillett, Slack, Lund and Browne12,Reference Asiri and Alokby13 Questionnaires were distributed and collected from the patients by a third party nurse, and the data entry was carried out by a separate clerk.
Lund–Mackay Score
We used the Lund–Mackay computed tomography (CT) score as a tool for the radiological evaluation of patients with nasal polyps where each sinus was solitarily assigned a score (0–2), where the osteomeatal complex was given a score of only 0 or 2, each side was evaluated on its own and the sum of all sinuses was calculated. A combined score of 24 was the maximum. We asked the patients for a CT scan before starting the treatment and three months after the completion of each treatment protocol.Reference Hopkins, Browne, Slack, Lund and Brown14
Total nasal polyp score (endoscopic grading)
Total nasal polyp score was used for the clinical assessment of nasal polyps, where polyp size was evaluated through endoscopy and given a score from 0 (small) to 3 (large). Total nasal polyp score was calculated as the sum of the score on each side, and patients were assessed on regular visits before receiving treatment, one week after treatment, and after three months.Reference Kırıs, Muderris, Yalçıner, Bercin, Sevil and Gul15
Total serum IgE, absolute eosinophilic count and morning cortisol level
Serum IgE and absolute eosinophilic count of patients in all groups were measured before the start, one week after course completion, and after three months of receiving treatment. We also measured the morning plasma cortisol level for patients before and after one month of receiving treatment.
The study was single blinded. The two senior authors (SE, AE) who did the follow-up assessment in two separate settings were not aware of the technique used in each patient, but the patients were arranged by the nature of the technique. The patients of each group were given different appointments to avoid their interaction so that every patient was only aware of their treatment protocol.
All the patients were informed of the nature and the purpose of the study as well as the possible risks and benefits in simple plain language. Patients also were informed about the off-label use of budesonide, and we were available to answer any of their questions. We emphasised that participation was voluntary and that withdrawal was possible at any time. Patients were offered full insurance in case major adverse effects were to happen. All participants signed a written informed consent.
Statistical analysis
Data analysis was performed using the software SPSS (Statistical Package for the Social Sciences) version 26. Categorical variables were described using their absolute frequencies and were compared using the chi-square test, and Monte Carlo tests when appropriate. To compare ordinal data between two groups, chi-square for the trend test was used. The Shapiro–Wilk test was used to verify assumptions for use in parametric tests. Quantitative variables were described using their means and standard deviations or median and interquartile range according to the type of data. To compare quantitative data between two groups, the Kruskal Wallis test (for non-normally distributed data) and the one-way analysis of variance test (for normally distributed data) were used. When the difference was significant, pairwise comparison and Fisher's least significant difference comparison were used to detect the difference between every two individual groups. To compare the same variable in one group over two points of time, paired-sample t-tests (for normally distributed data) and Wilcoxon signed rank tests (for non-normally distributed data) were used. The level of statistical significance was set at p < 0.05. A highly significant difference was present if p ≤ 0.001. The values, calculated at the end of the study based on the SNOT-22 score one week after treatment and based on IgE one week after treatment, are 0.998 and 0.985, respectively. Values for endoscopic grading three months after treatment and based on eosinophilic count one week after treatment are 0.988 and 0.942, respectively.
Results
The study included 90 patients who were equally distributed randomly into three groups. There was no significant differences regarding age, sex, or the co-morbidities diabetes, bronchial asthma or hypertension between patients within each group (Table 1). There were no missed cases reported during the follow-up period.
Comparison of baseline data among the studied groups
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; χ2 = chi-square test values; MC = Monte Carlo test; *p < 0.05 is statistically significant; SD = standard deviation
All 30 patients within the injection group received all five injections at weekly intervals, so a total of 150 intrapolyp injections were completed within our study. There were no visual complications recorded within the injection group. There was no need for anterior nasal packing for controlling epistaxis following injection procedure and any incident of minor bleeding was well controlled using cotton pads soaked with decongestant drops. There were no noticeable systemic side effects in patients who received oral steroids. Some patients within the irrigation group reported minor discomfort regarding the aftertaste of budesonide wash which didn't affect their adherence to the treatment.
Lund–Mackay CT
There was no statistically significant difference regarding the Lund–Mackay CT score between patients within the three groups before receiving treatment. In contrast, there was significant decrease within each group before treatment and three months after completing treatment (p < 0.001), (p < 0.001), (p = 0.035), respectively. The Fisher's least significant difference comparison indicated a significant difference between every two individual groups with a remarkable decrease in groups A and B (p1 = 0.042), (p2 < 0.001) and (p3 < 0.001), respectively (Table 2).
Comparison of Lund–Mackay CT scores before treatment and three months after treatment among the studied groups
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; F = one way ANOVA test; *p < 0.05 is statistically significant Fisher's least significant difference (LSD); p1 = difference between groups A and B; p2 = difference between groups B and C; p3 = difference between groups A and C; pt = paired sample t-test; SD = standard deviation
SNOT-22 score
SNOT-22 score difference was not statistically significant between the three groups before treatment. There was a statistically significant difference in SNOT-22 scores between the studied groups one week after treatment and after three months. Fisher's least significant difference comparison was significant between group C and each other group one week after treatment (p2 < 0.001) and (p3 < 0.001), indicating significant decrease in groups A and B. There was a significant difference in Fisher's least significant difference values between each other group after three months (p1 = 0.001), (p2 = 0.004) and (p3 < 0.001) (decrease in group A > B > C).
There was a statistically significant decrease in SNOT-22 within each group on comparing the before-treatment value with one week after-treatment value (p < 0.001). On comparing values of SNOT-22 one week after treatment and values after three months, there was significant change only in groups A and B (p = 0.007) and (p = 0.004), respectively (Table 3).
Comparison of SNOT-22 scores before, immediately after and three months after treatment among the studied groups
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; F = one way ANOVA test; *p < 0.05 is statistically significant; **p ≤ 0.001 is statistically highly significant; p1 = difference between groups A and B; p2 = difference between groups B and C; p3 = difference between groups A and C; p4§ = paired sample t-test difference between before treatment and one week after within each group; p5§ = difference between one week after treatment and after three months within each group; SD = standard deviation; LSD = Fisher's least significant difference
Endoscopic polyp grading (total nasal polyp score)
There was no statistically significant difference in endoscopic grading between the studied groups before receiving treatment. However, there was a statistically significant difference in endoscopic grading between the studied groups one week after completing treatment and after three months. A chi-square for trend analysis for every two groups indicated that the difference was significant between group C and group A (p3 = 0.01) one week after treatment, while the difference was significant between group C and each other group after three months (p2 = 0.004) and (p3 < 0.001).
There was statistically significant improvement in endoscopic grading within each group on comparing the before-treatment values with the one week after-treatment values (p < 0.001). On comparing endoscopic grading one week after treatment and values after three months, there was significant change (decrease) in grading only in group B (p = 0.033) while both groups A and C showed non-significant change (Table 4).
Comparison of endoscopic grading values before, immediately after, and three months after treatment among the studied groups
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; χ2 = chi-square test values; chi-square test *p < 0.05 is statistically significant, **p ≤ 0.001 is statistically highly significant; p1 = difference between groups A and B; p2 = difference between groups B and C; p3 = difference between groups A and C; χ2§ = chi-square for trend test; p4‡ = Wilcoxon signed rank test difference between before treatment and one week after within each group; p5‡ = difference between one week after treatment and after three months within each group
Serum IgE and absolute eosinophilic count
There was no statistically significant difference between the studied groups regarding IgE and absolute eosinophilic count levels before treatment. There was a statistically significant difference in IgE levels between the studied groups one week after treatment and after three months. On doing a pairwise comparison, the difference was a significant difference between group A (systemic) and each other group (p1 < 0.001) and (p3 < 0.001). There was a statistically significant decrease in IgE within each group on comparing before treatment to values one week after treatment (p < 0.001). Comparing values of IgE one week after treatment and values after three months, there was a significant decrease in both groups A (p = 0.014) and B (p = 0.003) but group C showed a non-significant increase (Figure 1).
Multiple line graph showing the change in serum immunoglobulin E (IgE) before and after treatment among the studied groups. Group A = systemic steroids, Group B = injection,Group C = nasal wash.
Multiple line graph showing the change in serum eosinophilic count before and after treatment among the studied groups. Group A = systemic steroids, Group B = injection, Group C = nasal wash.
There was a statistically significant difference in eosinophilic count between the studied groups one week after treatment and after three months. Fisher's least significant difference values indicated a significant difference between group A (systemic) and each other group (p1 < 0.001) and (p3 < 0.001). There was a statistically significant decrease in eosinophilic count within each group on comparing the before-treatment values with the values one week after treatment (p < 0.001), but the comparison of values one week after treatment and after three months indicated a significant decrease in groups A (p < 0.001) and B (p = 0.029) but group C showed a significant increase (p = 0.005) (Table 5, Figure 2).
Comparison between the studied groups regarding eosinophilic count before, 1 week after treatment and 3 months after treatment
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; χ2 = chi-square test values; F = one way ANOVA test; *p < 0.05 is statistically significant, **p ≤ 0.001 is statistically highly significant; p1 = difference between groups A and B; p2 = difference between groups B and C; p3 = difference between groups A and C; p4§ = paired sample t-test difference between before treatment and one week after treatment within each group; p5§ = difference between one week after and after three months within each group; SD = standard deviation; LSD = Fisher's least significant difference
Morning cortisol level
There was no statistically significant difference in morning cortisol levels between the studied groups before starting treatment. There was a statistically significant difference in morning cortisol levels between the studied groups one month after treatment. Fisher's least significant difference comparison indicated a significant difference between groups A and B (p1 = 0.01). There was only a statistically significant decrease in morning cortisol within group A when comparing before-treatment values and values after one month of treatment (p < 0.001) (Table 6).
Comparison of morning cortisol levels before treatment and one month after treatment among the studied groups.
Group A = patients receiving systemic treatment; Group B = patients receiving injections; Group C = patients receiving nasal-wash technique; F = one way ANOVA test; *p < 0.05 is statistically significant, **p ≤ 0.001 is statistically highly significant; p1 = difference between groups A and B; p2 = difference between groups B and C; p3 = difference between groups A and C; p4§ = paired sample t-test difference between before treatment and one month after treatment within each group; SD = standard deviation; LSD = Fisher's least significant difference
Discussion
Chronic rhinosinusitis is one of the most common chronic disorders in the practice of otorhinolaryngology.Reference Hamilos16 It is characterised by inflammation of the mucosa of the nose and the paranasal sinuses lasting for at least 12 consecutive weeks which can be accompanied by nasal polyps.Reference McCormick, Thompson, Cho, Woodworth and Grayson17 The apparent role of the inflammatory process in chronic rhinosinusitis with nasal polyps is evident and postulates the use of anti-inflammatory agents in the treatment of chronic rhinosinusitis.Reference Chin and Harvey18 For years, steroids anecdotally have been the mainstay treatment in dealing with chronic rhinosinusitis with nasal polyps apart from the method of delivery.Reference Huang, Chen, Huang, Wang, Li and Chen19 According to Alobid and Mullol, the use of short-term oral steroids is beneficial in patients with nasal polyposis.Reference Alobid and Mullol20 Topical steroid delivery is undoubtedly the first line of treatment prescribed for nasal polyposis. Most patients are offered long-term intranasal topical steroids to control the disease.Reference Joe, Thambi and Huang21
Recently there has been a breakthrough by introducing biological treatment in the management of chronic rhinosinusitis with nasal polyps. In 2019, dupilumab was approved by the United States Food and Drug Administration (FDA) as the first biologic agent to be indicated for chronic rhinosinusitis with nasal polyps.22,Reference Gevaert, Van Bruaene, Cattaert, Van Steen, Van Zele and Acke23 Although biologic agents are promising medical modalities, their cost effectiveness in the treatment of chronic rhinosinusitis with nasal polyps is still a great limiting factor that has to be addressed carefully according to the European Position Paper on Rhinosinusitis and Nasal Polyps recommendations,Reference Fokkens, Lund, Hopkins, Hellings, Kern and Reitsma1 so steroids are no doubt still the most feasible and effective medical treatment for chronic rhinosinusitis with nasal polyps.
Some patients require repeated courses of oral steroids over a short period of time, which predisposes them to several adverse effects as noted previously. For some specific patients, it is better to avoid the risk of these adverse effects in patients at risk for osteoporosis, pre-diabetic patients or immunosuppressed patients.Reference Snidvongs, Pratt, Chin, Sacks, Earls and Harvey24 Therefore topical steroids are the first pillar in the algorithm of managing chronic rhinosinusitis with nasal polyps.Reference Wall and Shure25 Topical steroids are delivered in a handful of ways, including via topical sprays, washing and irrigation, nasal drops and intranasal steroid injection.
Intranasal steroid injections were first reported in 1952.Reference Wall and Shure25 A major step backward occurred when Hager and Heise reported the first case of permanent vision loss following intranasal steroid injection.Reference Hager and Heise26 In 1981, Mabry reviewed the literature for similar cases of visual complications following intranasal (intraturbinate and intrapolyp) steroid injections and reported 10 additional cases.Reference Mabry27 Mabry's theory was that retrograde diffusion of steroid particles into ethmoidal circulation lead to retinal embolisation or vasospasm. So guidelines advise using small particle-sized steroids preceded by the application of local vasoconstrictors and using narrow-gauge needles.Reference Moss, Kjos, Karnezis and Lebovits2,Reference Antunes and Becker28 Becker et al. published their 30-year experience of steroid intrapolyp injection and concluded that injection of polyps has a protective effect against surgery (e.g. surgery no longer needed or postponed) and improved patients’ QoL. They used triamcinolone acetate and recommended the use of its injection as an adjuvant method to oral and topical steroids based on its safety, fewer complications and no evident adrenal suppression. It also has been reported that injections have a greater effect on polyp size than topical steroids due to the high concentration of steroids within the polyp structure.Reference Becker, Rasamny, Han, Patrie and Gross29 Kapucu et al. carried out a randomised clinical trial on 48 patients (mean age 32.2 years old) comparing the influence of oral, intrapolyp and topical steroids on the apoptosis of nasal polyps and concluded that there was no significant difference between the apoptotic index of oral and intrapolyp delivery.Reference Kapucu, Cekin, Erkul, Cincik, Gungor and Berber11
Kırıs et al. conducted their trial on 90 patients (mean age 40.9 years old) and, like most other authors, used triamcinolone acetonide for intrapolyp injection. They concluded that it was a safe and effective method for the treatment of nasal polyps and had comparable results to oral steroids.Reference Kırıs, Muderris, Yalçıner, Bercin, Sevil and Gul15
Budesonide is a trending promising drug in the management of chronic rhinosinusitis with nasal polyps. Kang et al. concluded that budesonide nasal irrigation was superior to saline irrigation in asthmatic patients of chronic rhinosinusitis after functional endoscopic sinus surgery (FESS) in improving patients’ QoL and preventing recurrence.Reference Kang, Chung, Cho, Lee, Kim and Jeong9 Pynnonen et al. proved the higher efficacy of nasal irrigation compared to nasal sprays, which may be due to higher pressures and larger volumes delivered by irrigation.Reference Pynnonen, Mukerji, Kim, Adams and Terrell30 Shah et al. reported better sensory attributes with budesonide nasal spray compared to fluticasone propinate nasal spray, which indicated better tolerance and more compliance.Reference Shah, Miller, Pethick, Uryniak, Jones and O'Dowd31
Neubauer et al. reported that patients treated with budesonide (i.e. received budesonide respules irrigation twice daily) after FESS for chronic rhinosinusitis with nasal polyps showed greater improvement in SNOT-22 scores and Lund–Kennedy scores compared to treatment with fluticasone and saline.Reference Neubauer, Schwam and Manes32
Xu et al.Reference Xu, Luo, Xu, Deng, Gao and Jiang33 conducted a randomised clinical trial on 127 patients with chronic rhinosinusitis with nasal polyps comparing oral steroid to budesonide nasal drops to budesonide nasal spray. They confirmed that budesonide suspension delivery as nasal drops provided a high dose of local glucocorticoids results that are comparable to oral steroid in terms of total nasal symptoms, SNOT-22, and total nasal polyp scores, and superior to budesonide nasal wash.
In our study, we used budesonide for intrapolyp injection in patients with chronic rhinosinusitis with nasal polyps. Budesonide is a synthetic, locally potent glucocorticoid that is metabolised rapidly by the liver into a negligible glucocorticoid.Reference Edsbäcker and Andersson34 Budesonide has been widely and safely used as a nasal spray for the treatment of allergic rhinitis and recently for chronic rhinosinusitis with nasal polyps.Reference Li, Li, Xu, Zhang, Wang and Wang35
Although budesonide use in chronic rhinosinusitis is still considered an off-label drug, it has been used safely as oral forms in patients with inflammatory bowel diseases and is well tolerated with fewer side effects than other systemic steroids as prednisone.Reference Baker36–Reference Iborra, Alvarez-Sotomayor and Nos38 Sun et al.Reference Sun, Zhao and Liu39 conducted a randomised clinical trial on 90 patients with sudden sensorineural hearing loss who underwent intratympanic injection of budesonide versus dexamethasone versus the control group. They reported that budesonide intratympanic injection was a safe method and as effective as dexamethasone in treating refractory sensorineural hearing loss, with no evidence suggesting that budesonide has major systemic side effects that would outweigh its benefits.
We conducted our trial on 90 patients (47 females, 43 males) with chronic rhinosinusitis with nasal polyps. The mean age in group A (systemic steroids group) was 39.23 years old, the mean age in group B (injection group) was 39.23 years old, and the mean age in group C (nasal-wash group) was 42.97 years old. We aimed to find out the best way to deliver budesonide in cases of chronic rhinosinusitis with nasal polyps via wash or injection and to assess the role of budesonide injection to control systemic inflammatory process in chronic rhinosinusitis through inducing a detrimental change in the eosinophil count and IgE level. There were no missed cases, the visits were regular, well scheduled by our team, patients were offered completely free non-time-consuming office-based procedures as well as follow-up visits.
Regarding SNOT-22 scores, budesonide intrapolyp injection revealed comparable results to oral steroids one week after the end of weekly injections and three months later, though budesonide wash improved patients' subjective symptoms but was not as potent as an injection or oral steroid.
As for endoscopic polyp grading (total nasal polyp score), patients within the three groups showed improvement regarding polyp size one week after completing their course of treatment, with greater improvement within oral and injection groups and less improvement within the nasal-wash group. The difference between the oral and injection groups was statistically non-significant, but there was a statistically significant difference between both groups and the group of patients that used budesonide wash. When comparing the results between patients within the same groups three months later there was a statistically significant decrease within the injection group, which indicates the lasting effect of injection on polyp size. This finding is compatible with those of Kırıs et al.,Reference Kırıs, Muderris, Yalçıner, Bercin, Sevil and Gul15 who postulated that the depot nature of the suspension used in injecting the polyps seems to last for eight weeks after a single injection. In contrast, the oral-steroid and nasal-wash groups seem to have non-significant changes.
We found no studies comparing the effect of oral steroids to intrapolyp injection on serum IgE and absolute eosinophilic count. We found that serum IgE was significantly decreased within all patients when compared to its level before treatment. The decrease is remarkable within the systemic group, followed by the intrapolyp-injection group while the least difference occurs within the nasal-wash group.
On comparing these values with values within the same groups three months later there was a significant decrease within the systemic and injection groups which showed the prolonged systemic anti-inflammatory effect of both techniques, while values showed an insignificant increase within patients of the nasal-wash group.
Serum absolute eosinophilic count showed a significant decrease in all groups. When comparing values between each group one week after treatment the decrease was significant within the systemic group only. On comparing the values after three months there was a significant decrease within the systemic and injection groups only while the nasal-wash group showed significant increase in the eosinophilic count values indicating a fading therapeutic effect. A systemic meta-analysis showed that the use of budesonide in eosinophilic oesophagitis significantly reduced the eosinophilic count versus the control group.Reference Liu, Xiao, Liu and Tan40 Finally, we measured the plasma morning cortisol level before starting treatment for all patients and one month after they completed their treatment to assess the effect of different steroids on the hypothalamic-pituitary axis.
Sachanandani et al.Reference Sachanandani, Piccirillo, Kramper, Thawley and Vlahiotis41 showed that budesonide respules as a nasal wash do not affect the hypothalamic-pituitary axis. When the mean values within the three groups were compared, we found that there was only a significant decrease in the morning cortisol value within the oral steroid group while the other two groups showed a non-significant difference.
To the best of our knowledge, our prospective trial was the first to assess the usage of budesonide in intrapolyp injection. We found it has comparable results with oral steroids as a substitute to those who are subjected to repeated courses of oral steroid every year.
Our study had some limitations. This was a single-centre study, which means the generalisability may not be optimal. Another limitation is that budesonide has not yet been approved by the FDA for chronic rhinosinusitis with nasal polyps despite being widely used as a nasal spray for chronic rhinosinusitis with nasal polyps and showing acceptable results. In addition, intrapolyp injection has not been approved by the FDA, although there have been multiple studies suggesting its safety and efficacy.Reference Moss, Kjos, Karnezis and Lebovits2,Reference Kirtsreesakul, Wongsritrang and Ruttanaphol6,Reference Kapucu, Cekin, Erkul, Cincik, Gungor and Berber11 Additional studies will be needed to evaluate the long-term efficacy of budesonide as an injection agent, as well as the probability of the emergence of late side effects. We also have not tried budesonide intrapolyp injection for non-eosinophilic nasal polyps. Further studies will be needed to determine which agent is superior as an intrapolyp injection.
Conclusion
Intrapolyp steroid injection appears to be an effective and safe method for treatment of chronic rhinosinusitis with nasal polyps. Budesonide is an effective agent used in injection with no documented systemic or visual side effects. It has comparable results with oral steroids with fewer side effects and no suppression of the hypothalamic-pituitary axis. Budesonide is recommended in cases where systemic steroid side effects are intolerable or when repeated short courses of steroids are needed. Budesonide also can be used as a nasal wash. With proper irrigation technique budesonide can achieve admissible results in cases with nasal polyps, but it is less potent than intrapolyp injection.
Ethical approval statement
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research editorial boards and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Data availability statement
The data used and/or analysed during the current study are available from the corresponding author upon reasonable request.
Competing interests
None declared.
Authors' contributions
SE, final revision, methodology; HL, methodology, idea formulation; IG, data collection, review writing and editing the final draft; ME, data collection and revision; MMA, data collection; AE, methodology and final revision.
