Allergic Fungal Rhinosinusitis and the Unified Airway: the Role of Antifungal Therapy in AFRS.

Allergic fungal sinusitis (AFS) or rhinosinusitis (AFRS) is a form of polypoid chronic rhinosinusitis that is believed to be due to hypersensitivity to fungal antigens. The disease is characterized by type 1 hypersensitivity to fungal allergens, dramatically elevated total serum IgE, accumulation of thick eosinophil-laden mucin with non-invasive fungal hyphae within the paranasal sinuses, nasal polyposis, and sinus bony remodeling. Because of many clinicopathologic similarities to allergic bronchopulmonary aspergillosis (ABPA), these conditions can be considered analogous examples of disease in the unified airway. However, these conditions rarely occur together and their treatment differs. The treatment of AFRS relies upon surgical removal of fungal hyphae in eosinophilic mucin, while antifungal therapy is used to clear fungi from the airways in ABPA. Several uncontrolled studies suggest there may be some benefit to antifungal agents in AFRS, but randomized trials of topical and systemic antifungal therapies have not shown beneficial results in chronic rhinosinusitis (CRS). Antifungal treatment within the sinonasal cavities does not appear to be an effective approach for most chronic sinusitis, and antifungal therapy for AFRS is unproven.

Human IgA-inducing protein from dendritic cells induces IgA production by naive IgD+ B cells.

Over the last several years, there has been a great deal of progress in characterizing the role of dendritic cells (DCs) in the activation and modulation of B cells. DC-secreted chemokines can induce B cell trafficking to the lymph nodes. DC-produced survival factors such as B cell-activating factor of the TNF family and a proliferation-inducing ligand have been shown to be essential for B cell maturation, but have also been implicated in class-switch recombination and B cell lymphoma survival. Recently added to this list of DC-derived factors effecting B cells is IgA-inducing protein (IGIP). In this study, we characterize production of IGIP by human DCs, and examine its capacity to induce IgA class switching and differentiation of naive B cells in vitro. Monocyte-derived DCs were cultured in vitro with TLR agonists (TLR3, 4, 5, and 9) and other factors, including CD40 ligand, GM-CSF, and IL-4 as well as the neuropeptide vasoactive intestinal peptide. Under in vitro stimulation with vasoactive intestinal peptide and CD40L, IGIP mRNA expression could be up-regulated as much as 35-fold above nonstimulated samples within 12-48 h. Naive B cells cultured with exogenous recombinant human IGIP produced IgA in greater quantities than nonstimulated controls. Finally, we demonstrate that IGIP stimulation drives the production of mu-alpha switch circles from IgM(+)IgD(+) naive human B cells, indicating its role as an IgA switch factor.

Targeted Molecular Therapies in Allergy and Rhinology.

Biologic agents, monoclonal antibodies that target highly-specific molecular pathways of inflammation, are becoming integrated into care pathways for multiple disorders that are relevant in otolaryngology and allergy. These conditions share common inflammatory mechanisms of so-called Type 2 inflammation with dysregulation of immunoglobulin E production and eosinophil and mast cell degranulation leading to tissue damage. Biologic agents are now available for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, eosinophilic granulomatosis with polyangiitis (EGPA), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). This paper summarizes the diagnosis and management of these conditions and critically reviews the clinical trial data that has led to regulatory approval of biologic agents for these conditions.

Rhinosinusitis and comorbidities.

A variety of systemic conditions impact the incidence, severity, prognosis, and treatment approach in patients with chronic rhinosinusitis (CRS). The controversy surrounding the impact of allergic rhinitis on CRS continues, but it is reasonable to consider and treat allergic sources of inflammation in any patient with CRS. CRS is more severe in patients with aspirin sensitivity but improves--at least temporarily--to the same degree as in non-aspirin-sensitive patients, given appropriate therapy. Polypoid rhinosinusitis in cystic fibrosis patients is characterized by compromised mucociliary clearance and infection with staphylococcal and pseudomonal organisms. Affected individuals require frequent antibiotic treatment, saline lavage, and repeated surgeries. Rhinosinusitis is among the most common infectious complications of humoral immunodeficiency, which is not uncommon in patients with refractory CRS. The treatment approach in immunodeficiency includes aggressive antibiotic treatment and intravenous immunoglobulin. Specific diagnosis of comorbid systemic conditions with CRS will facilitate appropriate management.

Intravenous vs oral acetaminophen in sinus surgery: A randomized clinical trial.

BACKGROUND: Multimodal perioperative analgesia including acetaminophen is recommended by current guidelines. The comparative efficacy of intravenous vs oral acetaminophen in sinus surgery is unknown. We aimed to determine whether intravenous or oral acetaminophen results in superior postoperative analgesia following sinus surgery. METHODS: This was a prospective randomized trial with blinded endpoint assessments conducted at a single large academic medical center. Subjects undergoing functional endoscopic sinus surgery were randomized to intravenous vs oral acetaminophen in addition to standard anesthetic and surgical care. The primary outcome was visual analogue scale pain score at 1 hour postoperatively. RESULTS: One hundred and ten adult patients were randomized; 9 were excluded from the data analysis. Fifty patients were assigned to intravenous acetaminophen and 51 to oral acetaminophen. Postoperative pain scores at 1 hour (primary endpoint) were not significantly different between the intravenous and oral acetaminophen groups. Similarly, there was no significant difference in pain scores at 24 hours postoperatively. Finally, there was no significant difference in postoperative opioid usage in the postanesthesia care unit or over the first 24 hours postoperatively. CONCLUSIONS: This is the first comparative efficacy trial of oral vs intravenous acetaminophen in sinus surgery. There was no significant difference in pain scores at 1 or 24 hours postoperatively, and no difference in postoperative opioid use. Intravenous acetaminophen offers no apparent advantage over oral acetaminophen in patients undergoing sinus surgery. LEVEL OF EVIDENCE: 1b.

Asthma and rhinitis: comorbidities.

The connection between asthma and rhinitis is not a new discovery. Significant progress has been made in understanding the relationship of these two conditions, however, and the implications of the asthma-rhinitis link make it increasingly important. Patients who have asthma and rhinitis tend to have more severe disease with higher treatment costs. Treatment of rhinitis may improve asthma control, and early treatment of allergies may prevent the development of asthma. This article more fully explores the epidemiologic, pathophysiologic, and clinical relationships between asthma and rhinitis.

Maxillary sinus melanoma as the presenting feature of Carney complex.

We present a case of a large maxillary sinus tumor in a 6-year-old boy, immunohistologically indistinguishable from a malignant melanoma, that led to the diagnosis of Carney complex. The Carney complex is an autosomal dominant disorder characterized by mucocutaneous pigmented lesions and neoplasia of multiple endocrine glands and is usually due to an inactivating mutation of the gene for the protein kinase A regulatory subunit 1A. The Carney complex has characteristic head and neck manifestations that can point to the diagnosis of this potentially lethal condition.

Bevacizumab for Epistaxis in Hereditary Hemorrhagic Telangiectasia: An Evidence-based Review.

Objective Epistaxis is a primary complaint in 90% to 96% of patients with hereditary hemorrhagic telangiectasia (HHT). Numerous surgical and medical treatments aim to decrease the frequency and severity of epistaxis in this patient population. Bevacizumab is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, an angiogenic factor elevated in HHT. It has been used in several forms to treat epistaxis in HHT but thus far, evidence-based recommendations are limited. Study Design Systematic review with evidence-based recommendations. Methods A systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using Embase, MEDLINE, MEDLINE In-Process/Epub, and Cochrane databases. English language abstracts were reviewed for relevance. Results Eleven manuscripts met inclusion criteria and were analyzed. Submucosal injection, submucosal injection plus laser coagulation, intravenous (IV), and topical formulations of bevacizumab were evaluated for their therapeutic impact on epistaxis in patients with HHT. Three randomized controlled trials failed to show topical bevacizumab to be more effective in controlling epistaxis than saline or other moisturizers. Conclusions The use of submucosal and IV bevacizumab shows promise, but further study is necessary to determine the true efficacy in the treatment of epistaxis as only grade C level exists currently. Based on the available literature, the use of topical bevacizumab is not recommended (grade B).

Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder resulting in vascular dysplasia and formation of arteriovenous malformations. Recurrent epistaxis is a hallmark of the disease. An array of medical therapies are used in this patient population, but robust evidence-based recommendations regarding the medical treatment of epistaxis are lacking. This systematic review was performed to look at the current literature and make meaningful evidence-based recommendations. METHODS: A search of the Ovid MEDLINE, Embase, and Cochrane databases was conducted by a research librarian. Abstracts in the English language and published in a peer-review journal were reviewed for relevance and inclusion. PRISMA guidelines were followed. RESULTS: Eighteen studies met the inclusion criteria. In a few small studies, thalidomide was shown to consistently improve severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion. Tranexamic acid appeared to only impact the epistaxis severity score and not other clinical outcomes. Selective estrogen modulators (SERMs), propranolol, rose geranium oil, and N-acetylcysteine, have demonstrated promising efficacy in small trials. CONCLUSION: Appropriate medical therapies for epistaxis outcomes in HHT remain undefined, and there is no "gold standard." Many of the studies are small and the data reported are heterogeneous, and therefore the ability to make strong evidence-based recommendations is limited. However, many different medications appear to be promising options.

Allergic fungal rhinosinusitis: diagnosis and management.

PURPOSE OF REVIEW: The proper diagnosis and treatment of allergic fungal rhinosinusitis remain controversial. We discuss recent additions to the literature regarding diagnosis and treatment of this condition. RECENT FINDINGS: There is considerable overlap in the clinical features of allergic fungal rhinosinusitis and other forms of eosinophilic mucin chronic rhinosinusitis. Type 1 hypersensitivity and characteristic computed tomographic findings may have predictive value for a final diagnosis of allergic fungal rhinosinusitis, patients with which are more likely to have bony erosion than patients with other forms of chronic rhinosinusitis. The decreases in orbital volume associated with expansive allergic fungal rhinosinusitis disease may spontaneously improve after successful treatment. Most patients have detectable fungal-specific IgE in their so-called allergic mucin. Elevated levels of fungal-specific IgG3 are a consistent finding in patients with allergic fungal rhinosinusitis and eosinophilic mucin chronic rhinosinusitis. Antifungal treatment is still considered a treatment option, but further study is needed. SUMMARY: Type 1 hypersensitivity to fungal antigens helps to distinguish allergic fungal rhinosinusitis from other forms of eosinophilic mucin chronic rhinosinusitis. Bony erosion and orbital expansion giving rise to proptosis are prominent features of allergic fungal rhinosinusitis. Advances in medical treatment will require prospective and controlled trials.

The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients.

OBJECTIVE: To compare the effect of two saline nasal sprays on nasal patency and mucociliary clearance in patients with rhinosinusitis. STUDY DESIGN: Randomized double-blind trial. SUBJECTS AND METHODS: Eighty patients with rhinosinusitis at a tertiary care academic center had nasal patency and mucociliary clearance measured. Each patient was then treated with either physiological or hypertonic saline. Nasal patency and mucociliary clearance measurements were repeated after treatment. Subjective evaluation was also performed. RESULTS: Both solutions improved saccharine clearance times (P < 0.0001). Buffered physiological saline significantly affected nasal airway patency (P = 0.006). Both solutions improved symptoms of nasal stuffiness (P < 0.0001) and nasal obstruction (P < 0.0001). Buffered hypertonic saline caused increased nasal burning/irritation compared with buffered physiological saline (P < 0.0001). CONCLUSIONS: Buffered physiological and buffered hypertonic saline nasal sprays both improve mucociliary clearance, which is beneficial for treatment of rhinosinusitis. Additionally, buffered physiological saline improves nasal airway patency, whereas buffered hypertonic saline has no effect. Both solutions provide symptomatic relief, but buffered hypertonic saline is more irritating.

Comparison of intradermal dilutional testing, skin prick testing, and modified quantitative testing for common allergens.

OBJECTIVES: To compare and correlate wheal size using the Multi-Test II applicator with the endpoint obtained by intradermal dilutional testing (IDT) for 5 common allergens. To examine the safety of modified quantitative testing (MQT) for determining immunotherapy starting doses. STUDY DESIGN: Prospective comparative clinical study. SUBJECTS AND METHODS: A total of 134 subjects were simultaneously skin tested for immediate hypersensitivity using the Multi-Test II device and IDT. RESULTS: There was a 77% concordance between results from IDT and results from MQT. When there was a difference, MQT predicted a safer endpoint for starting immunotherapy in all but 2 cases. CONCLUSION: Wheal size by SPT is predictive of endpoint by IDT. MQT is nearly as effective as formal IDT in determining endpoint. SIGNIFICANCE: Modified quantitative testing appears to be a safe alternative to IDT for determining starting doses for immunotherapy.

Executive summary: asthma and the unified airway.

Asthma is a common comorbid disorder that will be seen by otolaryngologists in their treatment of patients with rhinitis, rhinosinusitis, and otitis media. Among otolaryngologists, however, a diagnosis of asthma is infrequently considered in this patient population. Otolaryngologists, however, may be in an important position to recognize this potential diagnosis and provide treatment or appropriate referral. To further develop this relationship among upper and lower airway inflammation, and to provide important information to otolaryngologists regarding this relationship, a multidisciplinary workgroup was impaneled by the American Academy of Otolaryngologic Allergy in August 2006. The full report of this meeting is published separately as a Supplement to Otolaryngology-Head and Neck Surgery. This Executive Summary provides a brief synopsis of that document, with a focus on comorbid respiratory inflammation for otolaryngologists. In the treatment of their patients with allergic rhinitis and rhinosinusitis, otolaryngologists must be aware of the possible presence of asthma so that appropriate treatment and/or referral can be initiated. The impact of this practice will allow more comprehensive treatment of patients with upper and lower airway disease, and will improve patient symptoms, function, and quality of life.

Asthma and the unified airway.

Inflammatory processes of the upper and lower airway commonly co-exist. Patients with upper respiratory illnesses such as allergic rhinitis and acute and chronic rhinosinusitis often present to both otolaryngologists and primary care physicians for treatment of their symptoms of nasal and sinus disease. These patients often have concurrent lower respiratory illnesses such as asthma that may be contributing to their overall symptoms and quality of life. Unfortunately, asthma frequently remains undiagnosed in this population. It was the objective of this paper to examine the relationship between upper respiratory illnesses such as rhinitis and rhinosinusitis and lower respiratory illnesses such as asthma, and to provide a framework for primary care and specialty physicians to approach these illnesses as a spectrum of inflammatory disease. The present manuscript was developed by a multidisciplinary workgroup sponsored by the American Academy of Otolaryngic Allergy. Health care providers in various specialties contributed to the manuscript through preparation of written materials and through participation in a panel discussion held in August 2006. Each author was tasked with reviewing a specific content area and preparing a written summary for inclusion in this final document. Respiratory inflammation commonly affects both the upper and lower respiratory tracts, often concurrently. Physicians who are treating patients with symptoms of allergic rhinitis and rhinosinusitis must be vigilant to the presence of asthma among these patients. Appropriate diagnostic methods should be used to identify individuals with concurrent respiratory illnesses, and comprehensive treatment should be instituted to reduce symptoms and improve quality of life.

Advancing otolaryngology education in the new millennium.

Just as the practice of otolaryngology has changed over the years, so too the educational enterprise that supports the growth and development of the field continues to evolve. Changes in otolaryngology education have been driven by multiple internal and external factors. These changes need to be understood, and a proactive, cooperative approach by the members of this specialty is required to help shape the future in a way that will ultimately benefit both patients and the specialty itself. Rapid growth in the clinical sciences, accelerating technologic developments, and expanding quality improvement initiatives mandate that modern otolaryngologist-head and neck surgeons actively engage in continuing education. As described in many of the articles in this issue of the Otolaryngologic Clinics of North America, the resident in otolaryngology is graduating into a career of lifelong learning.

Fellowship training in otolaryngology-head and neck surgery.

Fellowship training in otolaryngology-head and neck surgery is a relatively new phenomenon that reflects the increasing complexity of clinical medicine. Despite an expansion of fellowship opportunities over the last three decades, there is still incomplete regulation and standardization of fellowship training. Approximately one third of residency graduates obtain some form of fellowship training. This article describes the fellowship opportunities that are currently available within the field of otolaryngology. Fellowship training serves as an avenue to gain further credentials and certification, although only the fields of neurotology, pediatric otolaryngology, and sleep medicine are accredited by the ACGME.

The prevalence of colonization with drug-resistant pneumococci among adult workers in children's daycare.

We conducted a study to determine if employment at a children's daycare facility increases an adult's risk of carrying Streptococcus pneumoniae in general and antibiotic-resistant S pneumoniae in particular From January through March 2003, we obtained nasopharyngeal and oropharyngeal specimens from 63 adult workers at 6 daycare facilities and 65 similarly aged controls; all but 2 controls were nonclinical employees at our tertiary care center. Culture and sensitivity data were obtained from all specimens, and written questionnaires were used to gather information on each daycare worker, control, and daycare center. The vaccination records of children at 5 of the 6 daycare centers were reviewed. Odds ratios with 95% confidence intervals were calculated to compare the rates of colonization with S. pneumoniae in the daycare workers and controls. Multinomial logistic regression analysis was used to compare different daycare centers and to identify risk factors for S. pneumoniae carriage. Analysis of the results revealed that the prevalence of S. pneumoniae colonization among daycare workers (3/63 [4.76%]) and controls (3/65 [4.62%]) was nearly identical. Whereas no S. pneumoniae isolate from a daycare worker displayed multiple drug resistance, all 3 isolates from the controls did; however this difference was not statistically significant. We conclude that employment at a children's daycare facility in our community did not increase an adult's risk of carrying S. pneumoniae. In fact, daycare workers may be even less likely to carry antibiotic-resistant S. pneumoniae because of the widespread and successful use of the heptavalent pneumococcal vaccine in young children.

Epstein-Barr Virus-Positive Plasma Cell Neoplasm of Nasal Cavity in an Immunocompetent Adult.

This case report describes patient in their 40s with a medical history of sleep apnea and diabetes and no history of immunosuppression who presented with left-sided nasal obstruction for 1 year and was found to have an Epstein-Barr virus­positive plasmacytoma.

Correlation between the number of allergen sensitizations and immunoglobulin E: monosensitization vs polysensitization.

BACKGROUND: The purpose of this study was to determine if total serum immunoglobulin E (IgE) could predict monosensitization compared to polysensitization in patients with allergic rhinitis (AR). METHODS: This was a retrospective study of a cohort of 1073 patients who underwent allergy testing. Differences in total IgE level between unsensitized, monosensitized, and polysensitized subjects were calculated. Pearson correlation coefficient was calculated to determine whether there was a relationship between total IgE level and the number of positive allergen sensitizations. In addition, allergen sensitization class was calculated for each allergen sensitization and totaled for each patient. Pearson correlation coefficient was calculated to determine the relationship between total IgE level and weighted allergen sensitization by class. RESULTS: There were 159 patients who were monosensitized compared to 492 patients who were polysensitized. Of the monosensitized patients, almost 50% (74) were sensitized to one or both dust mites. Total IgE was higher in polysensitized patients compared to monosensitized compared to controls (p < 0.001). Pearson correlation coefficient between total IgE and number of positive allergen sensitizations was 0.465 (p ≤ 0.001). Pearson correlation coefficient between total IgE and allergen class-weighted sensitizations was 0.529 (p ≤ 0.001). CONCLUSION: IgE level can be used to predict monosensitization vs polysensitization. There is a moderate correlation between total IgE sensitization and the number of positive allergen sensitizations, as well as allergen class-weighted sensitizations.

The association of allergic sensitization with radiographic sinus opacification.

BACKGROUND: The relationship between allergic sensitization and radiographic sinus inflammation remains unclear. OBJECTIVES: To determine whether specific allergen sensitization is correlated with sinonasal radiographic opacification. METHODS: Patients with chronic sinonasal symptoms were selected and included if they had allergy testing and a computed tomography (CT) of the paranasal sinuses. Data regarding demographic characteristics, in vitro allergy test results, and comorbidities were collected. CTs were reviewed, and an overall Lund-Mackay score (LMS) was calculated for each patient. A two-sample t-test was used to compare mean LMS between patients who were sensitized and patients who were not sensitized. A multiple linear regression model was used to determine whether a relationship existed among LMS and allergy results, asthma, nasal polyps, immunoglobulin E (IgE) level, medication usage, in-season versus out-of-season CTs, age, and sex. Significance was determined at an alpha level of 0.05. RESULTS: There were 437 patients included, of whom, 251 had positive specific allergen test results and 186 had negative test results. A total of 282 patients had allergic rhinitis symptoms without a documented diagnosis of sinusitis, and 155 carried a diagnosis of chronic rhinosinusitis. The mean LMS did not differ between patients who were sensitized and patients who were not sensitized (5.56 versus 5.28; p = 0.61). Linear regression demonstrated an increase in LMS in patients with asthma (p = 0.02), male sex (p < 0.01), elevated IgE (p < 0.01), a history of anaphylaxis (p = 0.03), and nasal polyps (p < 0.01). There was a statistically significant decrease in LMS in patients with an in-season CT (p = 0.02). CONCLUSIONS: Patients with a positive specific in vitro allergen test result did not have higher overall rates of radiographic sinus inflammation. Asthma, male sex, polyps, elevated IgE, and a history of anaphylaxis were associated with higher LMS.