Nasal irrigation with corticosteroids in Brazil: the clinical response of 1% compounded budesonide drops and betamethasone cream

Highlights • Nasal irrigation with corticosteroids is effective in chronic rhinosinusitis.• Irrigation with corticosteroids is more effective in patients with nasal polyps and previous sinus surgery.• 1% compounded budesonide drops are better than betamethasone cream.• Higher doses of compounded 1% budesonide drops are more effective than lower ones.


Introduction
There is an increasing perception that chronic rhinosinusitis (CRS) is not a single disease that can be classified solely by the presence or absence of nasal polyps (CRSwNP and CRSnNP, respectively), 1 but rather as an umbrella term that encompasses several different diseases, with distinct pathophysiological mechanisms, leading to chronic inflammation and similar symptoms. 2 Therefore, their therapeutic results can also be very different, ranging widely from poor response to the cure. The focus of CRS treatment is to control inflammation and reduce infectious exacerbations. 1 To achieve clinical disease control, multiple therapeutic strategies may be required, especially topical therapies and surgical interventions. 3 Systemic corticosteroids (CS) should not be routinely used in CRS management, due to unwanted side effects. 3,4 Topical corticosteroid nasal spray (CSNS) therapy and nasal lavage with saline solution have their benefits well established in the literature. 3,4 Despite the high level of recommendation for CSNS use in the treatment of CRS, 1,3,4 it is known that this treatment can have failures, which is why high-volume corticosteroid nasal irrigation (CSNI) started to be recommended, aiming to increase sinus penetration and, consequently, increase the drug concentration in the diseased mucosa. 5 CSNI has shown to be effective in postsurgical patients, in whom the drainage ostia have been enlarged and in those with difficult-to-treat CRS. 2,5---7 It is known that, even in individuals not submitted to surgery (and without polyps), nasal irrigation has greater sinus penetration than nasal sprays, 8 although less than operated sinuses. 9 In Brazil, alternatives are used to optimize the cost of CSNI, such as 0.5 mg/g betamethasone cream or 1% compounded budesonide drops, 2 to be mixed with saline solution and applied to the nasal cavity. 2 These alternatives allowed the popularization of CSNI in our population. There are no robust data on the effectiveness of these alternative CSNI modalities, highlighting the need to evaluate these methods.
The aim of this study was to evaluate the clinical response of nasal irrigation with 1% compounded budesonide drops or betamethasone cream in comparison to nasal sprays and the influence factors in patients with CRS treated at an outpatient clinic specialized in Rhinology.

Ethical considerations
This study was approved by the Research Ethics Committee of our institution under number 1166/2017. Written free and informed consent was obtained from all patients who agreed to participate.

Study population
All electronic medical records of patients treated in Rhinology Section of Sao Paulo Hospital (HU-HSP), Federal University of Sao Paulo (UNIFESP) -Escola Paulista de Medicina (EPM) between January 2013 and December 2019 were evaluated, and 378 treated patients with a confirmed diagnosis of CRS were selected. Of these, 257 patients had nasal topical corticosteroid treatment cycles with complete preand post-evaluation data and were included in this study, 205 patients with CRSwNP and 52 with CRSnNP.

Inclusion criteria
• Aged >18 years; • Confirmed diagnosis of CRS according to the American Academy of Rhinology criteria 3 ; • Treatment cycles between 3 and 6 months of CSNI or CSNS; • Complete subjective and objective evaluation data, preand post-treatment cycle, between January 2013 and December 2019.

Exclusion criteria
Use of oral, intramuscular or intravenous corticosteroids during the studied cycle.

Study design
A retrospective observational study (historical cohort) was carried out with two groups: CSNI and CSNS. The CSNI group had 108 patients who were submitted to at least one treatment cycle with CSNI (totaling 292 treatment cycles with complete data), which were compared to 149 patients who only underwent treatment cycles with CSNS (totaling 300 treatment cycles with complete data) in the CSNS group.
The treatment cycle was defined as a period of 3---6 months with topical nasal treatment with CS, with subjective and objective assessment at the beginning and at the end of this period recorded in electronic medical records. Patients in the CSNS group were treated with nasal CS in commercial spray formulations; while those in the CSNI group were treated with 1% compounded budesonide drops (each drop presented 500 g of budesonide) or betamethasone cream (0.5 mg/g betamethasone) that were diluted in 250 mL of alkaline homemade saline solution (250 mL of water + 1 level teaspoon of table salt + 1 level teaspoon of sodium bicarbonate).
Epidemiological data such as gender and age were collected; associated diseases such as asthma, acetylsalicylic acid (ASA) intolerance, non-steroidal anti-inflammatory (NSAID) intolerance, dipyrone intolerance, NSAIDexacerbated respiratory disease (N-ERD), allergic fungal rhinosinusitis (AFRS); history such as current smoking, former smoking and previous endoscopic sinus surgery (ESS) for CRS; main complaint; and details on the topical therapy used (drug, dose, volume, time of use, adverse events).
The subjective assessment of symptom improvement during the cycle was followed by the investigation of adverse events, CRS exacerbations, need for surgery after the treatment, and systemic medications used.
The patients' objective clinical evaluation was performed with the 22-item SinoNasal Outcome Test test (SNOT)-22 10 and the Lund---Kennedy Endoscopic Score (LKES) 11 applied pre-and post-treatment.
Sub-analyses were performed separating patients with CRSwNP and CRSnNP, previously submitted to ESS and those not submitted to ESS, in addition to sub-analyses comparing the alternative CSNI therapies (1% compounded budesonide drops and betamethasone cream).

Statistical analysis
Continuous variables were represented by mean and standard deviation. Categorical variables were represented by absolute frequencies (n) and percentages (%). Data distribution was analyzed using the Kolmogorov---Smirnov test. The Z-score was used to normalize the non-parametric distribution data. The comparison of continuous data was performed using Student's t test. Pearson's Chi-Square Test or Fisher's Exact Test was used to compare the frequency between   The initial patient assessment showed that the CRSnNP group had higher mean SNOT-22 scores than the CRSwNP group (39.5 vs. 29.6 points; p = 0.0003*). The questions with the greatest impact on the quality of life in the CRSnNP group were number 5 (Postnasal discharge; 2.53), number 1 (Need to ''blow'' nose; 2.32) and number 22 (Blockage/congestion of nose; 2.29), while in the CRSwNP group we identified number 21 (Sense of taste/smell; 2.54), number 5 (Postnasal discharge; 2.14) and number 1 (Need to ''blow'' the nose; 1.77). All questions showed an uneven distribution between the groups, except for questions 2, 3, 7 and 18.
The patients' initial mean LKES was 4.7 with a standard deviation (SD) of 3.1. The CRSwNP group had higher scores, partly due to the presence of polyps that increase the LKES (5.0 vs. 3.0; p < 0.0001*). However, even removing the values of polyps in the LKES, CRSwNP patients have significantly higher scores than CRSnNP (3.5 vs. 3.0; p = 0.04*). Patients with CRSwNP had a higher proportion of grade 2 (polypoid) edema (31.4% vs. 13.1%; p < 0.0001*); while those with CRSnNP showed a higher proportion of grade 2 (purulent) secretion (23.8% vs. 11.5%; p < 0.0001*). The pre-treatment impact of the disease (CRSwNP and CRSnNP) measured by the SNOT-22 and by the LKES can be analyzed in Table 2.

Comparison of CSNI vs. CSNS on the total sample
Considering now the treatment cycles, 592 cycles were counted, being 292 of CSNI and 300 of CSNS. In the 292 cycles of CSNI, the most often used corticosteroid was 1% compounded budesonide drops (51% of the cycles), followed by betamethasone cream (49%). The most often used daily dose of 1% compounded budesonide drops was 1000 g (48.3%), followed by 500 g (44.3%), diluted in 250 mL of saline solution. For the cream, 0.5 mg of betamethasone dipropionate (0.5 mg/g) was used, diluted in this same daily volume of saline solution. All patients used a syringe as an irrigation device. In the 300 cycles of CSNS, the most often used drug was budesonide (90% of the cycles), most of which (68.7%) at a dose of 400 g per day. In addition, 89.7% of the CSNS cycles were accompanied by nasal irrigation with saline solution concomitantly.
There were only 103 cycles of treatments in patients with CRSnNP (49 cycles of CSNI and 54 of CSNS), with no difference regarding patient characteristics between the cycles, except for more patients with previous ESS in the CSNI group (75.5% vs. 53.7%; p = 0.02*). There were also no differences regarding the results between the cycles.
Considering only CRSwNP patients undergoing treatment with CSNI, which accounted for the largest number of CSNI cycles (83.2% ---243 cycles, with 119 cycles of 1% compounded budesonide drops vs. 124 cycles of betamethasone cream), this pattern was maintained, with improvement in LKES only in the group treated with 1% compounded budesonide drops (5.6---5.1; p = 0.02*) with fewer adverse events (0.0% vs. 4.8%; p = 0.03*). The same results were found when considering patients with previous ESS who underwent treat-

Discussion
The present study is a pioneer investigation in demonstrating the clinical response of CSNI therapies used in Brazil (such as 1% compounded budesonide drops and betametha-   In summary, both CSNI and CSNS promoted improvement in the nasal endoscopy, with high rates of subjective improvement and low rates of adverse events and exacerbations in the overall sample and in the CRSwNP sample. There was no improvement with CSNI or CSNS in the CRSnNP group. A previous ESS was the best scenario for CSNI use, which showed better results than CSNS, both in the nasal endoscopy and in subjective improvement and exacerbations. And patients who were never submitted to the surgical procedure was the only scenario in which CSNS showed better results than CSNI regarding the nasal endoscopy improvement. Among the CSNI therapies, 1% compounded budesonide drops showed better results than betamethasone cream, with the 1000 g dose showing better results than the 500 g dose. The treatment of CRS aims to maintain disease control, which presupposes maintaining symptoms at levels that do not cause discomfort to the patient and nasal endoscopy results showing a mucosa close to a healthy status. 1 Nasal obstruction is usually the most prevalent CRS symptom, with a great impact on quality of life, 12 data corroborated in the present study, since in both CRSwNP and CRSnNP groups, nasal obstruction was the most prevalent main symptom. Hyposmia as main symptom was more prevalent in CRSwNP, whereas rhinorrhea and facial pain were more prevalent in CRSnNP, which comprise exactly the pattern of symptoms expected in these diseases, as well as the predominance of asthma, ASA intolerance, dipyrone intolerance, and N-ERD found in CRSwNP. 13 SNOT-22 scores were higher in CRSnNP than in CRSwNP, also in agreement with the literature. 10 Our patients undergoing CSNI had a more co morbid history, such as intolerance to dipyrone, N-ERD, current smoking and previous ESS. These features are known to be associated with a greater degree of inflammation, with a negative influence on clinical disease control, requiring a more effective clinical treatment. 6 Our CRS treatment protocol uses a step-by-step algorithm, in which the modalities are used according to patient evolution. Thus, the topical nasal treatment can be initiated with CSNS and intensified to CSNI if clinical control has not been achieved. This would explain the treatment cycles of the CSNI group being applied in potentially more severe patients. Both CSNI and CSNS seemed to be effective in improving LKES in most settings, although recent studies have shown better results with CSNI than CSNS. 5---7 However, this does not invalidate the treatment of CRS with CSNS, which is already well established and shows a high level of evidence and recommendation. 1,3 In the present study, treatment with CSNS showed 76.7% of subjective improvement in our patients and fewer adverse events than CSNI, in addition to a low rate of exacerbations (10.7%) and need for surgical procedure after treatment (12.0%). This highlights the need to individualize topical therapy to the degree of disease inflammation: patients with less inflammation could benefit from CSNS, while those with more inflammation might need CSNI. The unrestricted use of CSNI in all CRS patients, from our point of view, may not be cost-effective, as the therapy has higher doses of CS, more adverse events, greater difficulty in preparation and greater chance of non-adherence. 14 On the other hand, patients with CRS and more inflammation would clearly benefit more from CSNI, 6 which was corroborated in the present study, with patients with CRSwNP showing better outcomes at CSNI than those with CRSnNP.
Treatment with CSNI showed its greatest advantage over CSNS in the group with a previous ESS, where there was an improvement in the LKES and more evident results in rates of subjective improvement and exacerbations in relation to CSNS. These results are in agreement with the literature, as it is already known that there is greater penetration of the high-volume solution into the operated sinuses and a greater concentration of the medication in contact with the mucosa, promoting better disease control. 9,15 On the other hand, in patients who were never submitted to the surgical procedure, CSNS showed better results than CSNI in relation to LKES, showing its efficacy as a nasal treatment, and not exactly sinus treatment, as the spray does not penetrate the sinuses. 9,15,16 The present study is also an unprecedented one in comparing the results of the modalities of CSNI used in our country, 1% compounded budesonide drops and betamethasone cream. The 1% compounded budesonide drops were more effective than betamethasone cream, with fewer adverse events. This 1% budesonide formulation is a liquid one, prepared in 5% glycerin, allowing the easier dilution in saline solution than a dermatological cream, such as betamethasone. Probably, this more homogeneous dilution than that of the cream formulation allows a greater contact of the drug with the affected mucosa, with a higher concentration of the drug, achieving more significant results. Furthermore, the analysis of the doses of 1% compounded budesonide drops showed that higher doses (1000 g) had better results than lower ones (500 g). This finding is supported by CSNI studies using higher doses of CS, 5---7 showing that the amount of the drug plays a role in CSNI, and not just to greater sinus penetration due to the high volume.
The SNOT-22 questionnaire is a quality-of-life assessment parameter that often changes after nasal endoscopy. 2 For this reason, we believe that our results were more significant in the endoscopic assessment than in the symptom assessment. Because our CRS treatment protocol adjusts topical therapy modalities, more patients with difficult-to-treat disease may have been selected in the CSNI group, which is a possible selection bias in our study. Retrospective studies lack the accuracy of the data, but we believe this bias was well circumvented by the fact that our institution's electronic medical records include mandatory fields containing the data used in this research. Finally, the lack of randomization does not allow robust data in the direct comparisons between treatment modalities.

Conclusion
Nasal irrigation with high-volume corticosteroids with 1% compounded budesonide drops or betamethasone cream was effective in improving the nasal endoscopic condition in patients with chronic rhinosinusitis, especially in the presence of nasal polyps and in those previously submitted to ESS, in addition to promoting a higher rate of subjective improvement and lower rate of exacerbation than the use of corticosteroid nasal spray in previously operated patients. However, nasal irrigation with high-volume corticosteroids showed more adverse events than corticosteroid nasal spray use.
The use of 1% compounded budesonide drops for nasal irrigation showed better results in the nasal endoscopy with fewer adverse events than betamethasone cream. Moreover, higher doses of 1% compounded budesonide drops (1000 g) were more effective than lower doses (500 g).
Finally, corticosteroid nasal spray use was also effective in improving nasal endoscopy in patients with chronic rhinosinusitis with nasal polyps and was more effective than nasal irrigation with high-volume corticosteroid in improving nasal endoscopy in patients who were not previously submitted to surgery.