Pilot study of budesonide inhalant suspension irrigations for chronic eosinophilic sinusitis

To the Editor:

Chronic sinusitis (CS) is often associated with nasal polyposis (NP). CS represents several disease processes including chronic hyperplastic eosinophilic sinusitis (CHES).1 Many immune and pathological features of CHES are shared with asthma, suggesting that these are similar disease processes involving the upper and lower airways. Historically, patients with CS were approached as having a chronic infectious disorder, and treatment consisted of antibiotics and surgery to promote drainage. Often these approaches proved unsatisfactory for patients with CHES.2 Given the marked eosinophilia and pathological similarity of CHES to asthma,3 corticosteroids could be used as a treatment for this disorder. Systemic corticosteroids shrink hyperplastic tissue and associated NP, reduce symptoms, and restore the senses of smell and taste.4 However, their side-effect profile has precluded long-term use.

It has been suggested that topical intranasal corticosteroids would prove effective for eosinophilic forms of CS, given their utility for asthma and allergic rhinitis, while maintaining a minimal risk profile. Although intranasal corticosteroids reduce NP,5 they have never been shown to improve the sinusitis component of this disorder, likely reflecting their inability to access the sinus cavity. Saline irrigations have proven to be an effective method of addressing sinus disease,6 likely through their ability to lavage the nasal and sinus cavities. It has been speculated that the addition of a corticosteroid such as budesonide inhalation suspension (Pulmicort respules; Astra Zeneca, Wilmington, De), a medication already approved for asthma, to the lavage fluid would more effectively treat sinus inflammation. This study was performed to obtain pilot data documenting objective and subjective evidence for improvement in patients who used this approach for a period of ≥3 months. For information regarding the study design, see Methods in the Online Repository at www.jacionline.org.

Patients with CHES or aspirin-exacerbated respiratory disease having failed to respond to previous medical therapy and having been treated with budesonide nasal irrigation for ≥3 months were recruited. A total of 8 subjects were enrolled (see this article's Table E1 in the Online Repository at www.jacionline.org). All subjects had allergy as defined by a positive skin prick test (≥5-mm wheal) to at least 1 aeroallergen, 4 subjects were classified as having aspirin-exacerbated respiratory disease, and all but 1 had physician-diagnosed asthma. None of the subjects took oral steroids during treatment with budesonide, and 5 were on montelukast, with 2 also taking zileuton.

Our primary outcome measure for sinus improvement was the change in CT score. The median CT score before treatment was 15 (maximum, 30), which improved to 5 (P < .05) after treatment (Fig 1). By using our visual analog scale (see this article's Fig E1 in the Online Repository at www.jacionline.org), we calculated scores for each of 16 sinus symptoms on a scale of 0 to 6, with 6 being severe and 0 none (maximum, 96). After budesonide treatment, subjects' sinus scores decreased (mean ± SD) from 43.1 ± 5.4 to 20.1 ± 3.0 (P < .02; Fig 2). Sense of smell was separately examined (0, none, to 6, complete) because of its particular impact on quality of life. Subjects reported a significant improvement in their sense of smell (mean ± SD) (see this article's Fig E2 in the Online Repository at www.jacionline.org), from 1.1 ± 0.7 to 3.6 ± 0.8 (P < .05). Other sinus measures displayed similar improvement. Of the 6 subjects who had prerhinoscopy and postrhinoscopy, 5 showed improvement after treatment, and 3 of 4 subjects had complete resolution of NP (see this article's Fig E3 and Table E2 in the Online Repository at www.jacionline.org).

View Large Image Download to PowerPoint

Fig 1. Change in CT score after budesonide nasal irrigation. Each dot represents an individual with a line connecting the prebudesonide and postbudesonide CT scores. The bold lines to the side of the data points indicate the median, with the interquartile range and inner fence indicated with a box and whisker plot, respectively (P < .05 for prebudesonide compared with postbudesonide sinus score).

View Large Image Download to PowerPoint

Fig 2. Self-assessed change in sinus symptom score after budesonide nasal irrigation. Each dot represents an individual, with a line connecting the prebudesonide and postbudesonide sinus scores. Lines to the side of the data points indicate the mean ± SEM (P < .01 for prebudesonide compared with postbudesonide sinus score).

It has been suggested that improvements in upper respiratory disease can lead to improvements in lower respiratory symptoms. The asthma visual analog scale (see this article's Fig E4 in the Online Repository at www.jacionline.org) was converted to a scale ranging from 0 to 6 and scored (maximum, 36). Of the 7 patients in the study with asthma, there was a trend toward a decrease in the asthma score (mean ± SD) from 15.3 ± 2.9 pretreatment to 11.4 ± 2.2 posttreatment (Table E2). Using the National Institutes of Health definition of asthma control,7 3 of 4 subjects who had poorly controlled disease at the beginning of the study improved to well controlled (Table E2). The remaining 3 patients with asthma had well controlled disease throughout the study.

The current study suggests that the addition of budesonide suspension to nasal saline irrigations produces a significant improvement in sinus symptoms including sense of smell. It is possible, given the construct of the study's methodology, that the findings may overestimate the true benefit of this therapy, especially with regard to recall bias. However, previous works have indicated that patients are able to recall symptoms of smell accurately.8 The lack of a control group makes it difficult to determine what role a placebo effect and the natural course of the disease may have played. That being noted, the cohort was one of patients who remained symptomatic on previous therapy and for whom the addition of budesonide irrigations to the sinus regimen represented the only change.

Subjective improvements were corroborated by objective findings on CT scans and nasal endoscopy. CT scanning is validated for accurately quantifying the extent of mucosal inflammation/hypertrophy within the sinuses. Previous studies have shown that, at least in the short term, radiographic findings of CS are stable. The significant improvement in CT scores is therefore compelling. The complete regression of polyps observed in 3 of 4 patients with NPs before initiation of therapy is consistent with reports of the ability of intranasal corticosteroids to reduce polyposis5 and is indicative of the role that corticosteroid irrigations may play in the management of this disease.

Modest trends toward improvement in asthma symptom scores were also observed. A lack of significance in the pilot data was likely driven by the inclusion of patients with well controlled asthma; however, 3 of 4 subjects who did not have controlled disease at baseline did show improvement. Given the low probability that topical corticosteroids in the upper airway would access the bronchial airway, improvement in asthma more likely reflects 1 or more of the indirect pathways by which reduced sinusitis has been proposed to affect asthma positively.9 Although it remains possible that improvement in asthma symptoms could reflect systemic absorption of the steroid, especially considering the high dose of budesonide used in this study (500 μg twice a day), the nature of sinus irrigations is that most of the sinus irrigant does not remain. As such, likely <50 μg of budesonide remains in the sinuses, a dose equivalent to rhinitis therapy. Absorption from the sinuses is not likely to be dissimilar to that from the airways. These studies provide support for the unified airway concept.

This study supports the concept that addition of budesonide inhalation suspension to standard nasal saline irrigation produces subjective and objective benefit in eosinophilic sinus disease. It is hoped that these data will support enthusiasm for performing a double-blind, placebo-controlled study of budesonide inhalation suspension in nasal saline washes in CS.