Abstract
Purpose
1. To assess the efficacy of omalizumab therapy in improving sinonasal outcomes in refractory allergic fungal rhinosinusitis (AFRS) patients with moderate or severe asthma. 2. To determine if omalizumab therapy reduces the usage of corticosteroids or antifungal therapy in AFRS patients
Method: Design
The clinical charts of patients with AFRS with moderate or severe asthma who received at least three subcutaneous injections of omalizumab therapy between 1st January 2012 and 1st May 2014 were retrospectively reviewed. These patients had undergone bilateral functional endoscopic sinus surgery (FESS) and failed adjunct medical treatments (oral or topical corticosteroids and/or antifungal therapy) prior to omalizumab therapy.
Results
Seven patients met the inclusion criteria and were included in this study. The mean age of the patients was 48.14. The average number of subcutaneous omalizumab injections was 7.57 (range 6–11) with a mean dosage of 287 mg (range 225–375 mg). The mean pre-omalizumab treatment Sino-Nasal Outcome Test-22 (SNOT-22) score was 52.14 while the mean post-omalizumab treatment SNOT-22 score was 35.86 (31% improvement). The mean pre-omalizumab therapy Phillpott–Javer endoscopic score (over the last one year before omalizumab therapy) was 36 while the mean post-omalizumab therapy endoscopic score (from the last clinic visit) was 14 (61% improvement). Omalizumab therapy reduced the dependence of AFRS patients on corticosteroid and antifungal treatments.
Conclusion
Omalizumab therapy can be considered as a potential adjunct for the treatment for patients with refractory AFRS with moderate or severe asthma. However, larger prospective studies to confirm the findings of this study will be required.
1
Introduction
Allergic fungal rhinosinusitis (AFRS) is a noninvasive form of fungal rhinosinusitis (FRS) . It accounts for approximately 7% of all chronic sinusitis cases requiring surgery . The hallmark of this disease is the presence of thick peanut butter-like allergic mucin in the sinuses with histological findings of degenerating eosinophils, Charcot–Layden crystals and fungal hyphae without the evidence of sinonasal tissue invasion . The typical AFRS patients are young, immunocompetent adults presenting with symptoms of CRS. The benchmark for the diagnosis of AFRS for many years has been the Bent and Kuhn criteria . These include the presence of type I IgE-mediated hypersensitivity, nasal polyposis, characteristic CT findings (double density sign), eosinophilic or allergic mucin and a positive fungal smear .
Although AFRS has been recognized as an independent subset of CRS for over 30 years, the pathophysiology remains unknown and controversial. In a literature review by Ferguson et al., two popular theories were found . The allergic (immunologic) theory proposed by Manning et al., was derived from the allergic bronchopulmonary aspergillosis (ABPA) model. They believed that an atopic host exposed to fungi resulted in antigenic stimulation by a combination of Gel and Coomb type I and type III hypersensitivity, leading to an intense inflammatory response . The eosinophilic theory was suggested by Ponikou et al. when they demonstrated that eosinophilic chemotaxis in response to extramucosal fungi was the hallmark of the inflammatory reaction in AFRS . The term eosinophilic mucin rhinosinusitis (EMRS) was then coined by Ferguson et al. to describe the non-allergic group of patients who have AFRS-like features in the absence of demonstrable fungal hyphae . Dysregulation of immunologic controls of upper and lower airway eosinophilia was believed to be the underlying mechanism in EMRS.
The first step in the management of AFRS is complete and meticulous functional endoscopic sinus surgery (FESS) to debride and remove all polypoid disease, allergic mucin and fungal debris . The aim of FESS is to restore ventilation, improve drainage of the paranasal sinuses and reduce the antigenic stimulus . Following this, a combination of adjunct medical treatment is often required to keep the disease in a dormant state. These include topical and systemic corticosteroids and antifungal agents, immunotherapy and nasal rinses. Unfortunately, there is a subset of patients who are refractory to these treatments and the search for a salvage therapy continues.
Omalizumab is a humanized monoclonal anti-IgE antibody that has been shown to be an effective adjuvant therapy in severe atopic asthma, allergic rhinitis, CRS with nasal polyposis (CRSwNP) and asthma and ABPA . Omalizumab decreases free IgE levels by binding to free circulating IgE. This process inhibits the binding of IgE to the high-affinity IgE receptors . In addition, omalizumab reduces IgE receptors on mast cells, basophils and dendritic cells . As an increase in local production of IgE is implicated in the pathophysiology of CRSwNP and AFRS omalizumab may have a potential benefit in these patients. Furthermore, given the pathophysiological similarity between ABPA and AFRS and recent case reports and case series demonstrating improvement in the clinical outcome of omalizumab in ABPA patients, the efficacy of omalizumab in patients with AFRS should be explored. Hence in this study, we aim to compare the sinonasal outcomes before and after omalizumab therapy in patients with refractory AFRS and moderate to severe asthma.
2
Methods
The clinical charts of AFRS patients with moderate or severe asthma who had undergone FESS and failed adjunct medical treatments (topical and systemic corticosteroid and oral itraconazole) between January 2012 and February 2013 were retrospectively reviewed at St Paul’s Sinus Centre in Vancouver, Canada. Patients who had received omalizumab during this period were selected for this study. The study received approval from the University of British Columbia Clinical Research Ethics Board. The regimen for medical treatments were as follows: a course of systemic steroid consisted of a tapering dose of oral prednisolone at 40 mg daily for 4 days, followed by 30 mg daily for 4 days, followed by 20 mg daily for 4 days and 10 or 5 mg daily for 1 month; topical steroid used was budesonide respules (0.5 mg/ml × 2 ml) applied through the Mucosal Atomization Device (MAD) in the Mygind position (1 ml in each nostril); oral itraconazole dosage was 100 mg bid for at least 6 weeks duration. The following data were collected form the patients’ charts:
- 1.
Patients’ demographics and baseline characteristics
- 2.
Change in sinonasal symptoms before and after omalizumab therapy (as documented by the SNOT-22 score)
- 3.
Change in endoscopic mucosal disease before and after omalizumab therapy (as documented by the Phillpott-Javer endoscopic staging for AFRS)
- 4.
Change in the frequency and dosage of adjunct medical treatment postsurgery (oral and topical corticosteroids and antifungal agents) before and after omalizumab therapy
- 5.
Documented side effects from omalizumab therapy.
The Philpott–Javer endoscopic staging system ( Fig. 1 ) is a validated system that was derived from modifications made to the Kupferberg endoscopic staging system . Each sinus cavity and the olfactory cleft are scored independently on a scale from 0 to 9 based on the degree of mucosal inflammation. An additional 1-point is allocated for each sinus if allergic mucin is noted grossly. This allows for a maximum score of 10 points per sinus cavity, 50 points for each side of the nose (including the olfactory cleft) and 100 points for the total maximum bilateral score. Such a system is much more sensitive and allows for much better tracking of disease control postoperatively.
2.1
Statistical analysis
Demographic and baseline characteristics were extracted from patient charts and recorded for each subject. Demographic data included age (years), sex, history of smoking and race. Baseline characteristics included presence or absence of asthma, forced expiratory volume in one second (FEV 1 ), immunoglobulin-E level (IU/ml), SNOT-22 and endoscopic score (Philpott–Javer) immediately prior to receiving treatment and current medications. Dosage and frequency of omalizumab injections were dependant on each patient’s weight and IgE level. Subcutaneous dosage of omalizumab ranged from 150 to 375 mg and was offered in either 2 or 4-week intervals. Categorical, explanatory variables were summarized by frequency and absolute proportion. Continuous, explanatory variables were summarized by mean, standard deviation and range. The primary outcome variables were change in SNOT-22, endoscopic mucosal scores and IgE levels evaluated before and after treatment. As the duration of treatment varied among patients included in this case series, the endoscopic score was averaged over each respective follow-up period. The outcome variables were recorded as continuous, numerical outcomes and summarized by mean and standard deviation. The number of injections received and months treated with omalizumab were also reported. Frequency of concurrent medication was recorded and compared to baseline levels as categorical outcome variables. These observations were reported by count and absolute proportion.
2
Methods
The clinical charts of AFRS patients with moderate or severe asthma who had undergone FESS and failed adjunct medical treatments (topical and systemic corticosteroid and oral itraconazole) between January 2012 and February 2013 were retrospectively reviewed at St Paul’s Sinus Centre in Vancouver, Canada. Patients who had received omalizumab during this period were selected for this study. The study received approval from the University of British Columbia Clinical Research Ethics Board. The regimen for medical treatments were as follows: a course of systemic steroid consisted of a tapering dose of oral prednisolone at 40 mg daily for 4 days, followed by 30 mg daily for 4 days, followed by 20 mg daily for 4 days and 10 or 5 mg daily for 1 month; topical steroid used was budesonide respules (0.5 mg/ml × 2 ml) applied through the Mucosal Atomization Device (MAD) in the Mygind position (1 ml in each nostril); oral itraconazole dosage was 100 mg bid for at least 6 weeks duration. The following data were collected form the patients’ charts:
- 1.
Patients’ demographics and baseline characteristics
- 2.
Change in sinonasal symptoms before and after omalizumab therapy (as documented by the SNOT-22 score)
- 3.
Change in endoscopic mucosal disease before and after omalizumab therapy (as documented by the Phillpott-Javer endoscopic staging for AFRS)
- 4.
Change in the frequency and dosage of adjunct medical treatment postsurgery (oral and topical corticosteroids and antifungal agents) before and after omalizumab therapy
- 5.
Documented side effects from omalizumab therapy.
The Philpott–Javer endoscopic staging system ( Fig. 1 ) is a validated system that was derived from modifications made to the Kupferberg endoscopic staging system . Each sinus cavity and the olfactory cleft are scored independently on a scale from 0 to 9 based on the degree of mucosal inflammation. An additional 1-point is allocated for each sinus if allergic mucin is noted grossly. This allows for a maximum score of 10 points per sinus cavity, 50 points for each side of the nose (including the olfactory cleft) and 100 points for the total maximum bilateral score. Such a system is much more sensitive and allows for much better tracking of disease control postoperatively.
