Biologic Therapies across Nasal Polyp Subtypes.

Chronic rhinosinusitis with nasal polyposis is a common inflammatory condition, with subtypes like aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease sharing a common type 2 inflammatory pathway. Respiratory biologic therapies have been developed that target type 2 inflammation. In this article, we discuss the use of respiratory biologic therapies for nasal polyposis in general, as well as within the various subtypes of nasal polyps. Further, we discuss future roles of novel biologic therapies targeting type 2 inflammation in nasal polyposis.

Efficacy of EDS-FLU for Chronic Rhinosinusitis: Two Randomized Controlled Trials (ReOpen1 and ReOpen2).

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. OBJECTIVE: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). METHODS: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24. RESULTS: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids. CONCLUSIONS: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.

Allergy and Asthma Prevalence and Management Across Nasal Polyp Subtypes.

Allergy and asthma prevalence vary across different subsets of chronic rhinosinusitis with nasal polyposis. In this article, the authors investigate the management of allergy and asthma within populations of patients with aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease. Topical steroids, nasal rinses, and endoscopic sinus surgery are frequently employed in the management of nasal polyposis. Further, other causes of upper and lower airway inflammation like allergy and asthma should be considered in the overall treatment plan in order to optimize outcomes.

Inflammatory characteristics of central compartment atopic disease.

BACKGROUND: Central compartment atopic disease (CCAD) is an emerging phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP) characterized by prominent central nasal inflammatory changes. This study compares the inflammatory characteristics of CCAD relative to other phenotypes of CRSwNP. METHODS: A cross-sectional analysis of data from a prospective clinical study was performed on patients with CRSwNP who were undergoing endoscopic sinus surgery (ESS). Patients with CCAD, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and non-typed CRSwNP (CRSwNP NOS) were included and mucus cytokine levels and demographic data were analyzed for each group. Chi-squared/Mann-Whitney U tests and partial least squares discriminant analysis (PLS-DA) were performed for comparison and classification. RESULTS: A total of 253 patients were analyzed (CRSwNP, n = 137; AFRS, n = 50; AERD, n = 42; CCAD, n = 24). Patients with CCAD were the least likely to have comorbid asthma (p = 0.0004). The incidence of allergic rhinitis in CCAD patients did not vary significantly compared to patients with AFRS and AERD, but was higher compared to patients with CRSwNP NOS (p = 0.04). On univariate analysis, CCAD was characterized by less inflammatory burden, with reduced levels of interleukin 6 (IL-6), IL-8, interferon gamma (IFN-γ), and eotaxin relative to other groups and significantly lower type 2 cytokines (IL-5, IL-13) relative to both AERD and AFRS. These findings were supported by multivariate PLS-DA, which clustered CCAD patients into a relatively homogenous low-inflammatory cytokine profile. CONCLUSIONS: CCAD has unique endotypic features compared to other patients with CRSwNP. The lower inflammatory burden may be reflective of a less severe variant of CRSwNP.

Determinants of physician assessment of chronic rhinosinusitis disease control using EPOS 2020 criteria and the importance of incorporating patient perspectives of disease control.

BACKGROUND: We identify chronic rhinosinusitis (CRS) manifestations associated with how rhinologists assess CRS control, with a focus on patient perspectives (patient-reported CRS control). METHODS: Fifteen rhinologists were provided with real-world data from 200 CRS patients. Participating rhinologists first classified patients' CRS control as "controlled," "partly controlled," and "uncontrolled" using seven CRS manifestations reflecting European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) CRS control criteria (nasal obstruction, drainage, impaired smell, facial pain/pressure, sleep disturbance, use of systemic antibiotics/corticosteroids in past 6 months, and nasal endoscopy findings) and patient-reported CRS control. They then classified patients' CRS control without knowledge of patient-reported CRS control. Interrater reliability and agreement of rhinologist-assessed CRS control with patient-reported CRS control and EPOS guidelines were determined. RESULTS: CRS control classification with and without knowledge of patient-reported CRS control was highly consistent across rhinologists (κw  = 0.758). Rhinologist-assessed CRS control agreed with patient-reported CRS control significantly better when rhinologists had knowledge of patient-reported CRS control (κw  = 0.736 vs. κw  = 0.554, p < 0.001). Patient-reported CRS control, nasal obstruction, drainage, and endoscopy findings were most strongly associated with rhinologists' assessment of CRS control. Rhinologists' CRS control assessments weakly agreed with EPOS CRS control guidelines with (κw  = 0.529) and without (κw  = 0.538) patient-reported CRS control. Rhinologists classified CRS as more controlled than EPOS guidelines in almost 50% of cases. CONCLUSIONS: This study directly demonstrates the importance of patient-reported CRS control as a dominant influence on rhinologists' CRS control assessment. Knowledge of patient-reported CRS control may better align rhinologists' CRS control assessments and treatment decisions with patients' perspectives.

Single-cell analysis of human nasal mucosal IgE antibody secreting cells reveals a newly minted phenotype.

Immunoglobulin (Ig) E is central to the pathogenesis of allergic conditions, including allergic fungal rhinosinusitis. However, little is known about IgE antibody secreting cells (ASCs). We performed single-cell RNA sequencing from cluster of differentiation (CD)19+ and CD19- ASCs of nasal polyps from patients with allergic fungal rhinosinusitis (n = 3). Nasal polyps were highly enriched in CD19+ ASCs. Class-switched IgG and IgA ASCs were dominant (95.8%), whereas IgE ASCs were rare (2%) and found only in the CD19+ compartment. Through Ig gene repertoire analysis, IgE ASCs shared clones with IgD-CD27- "double-negative" B cells, IgD+CD27+ unswitched memory B cells, and IgD-CD27+ switched memory B cells, suggesting ontogeny from both IgD+ and memory B cells. Transcriptionally, mucosal IgE ASCs upregulate pathways related to antigen presentation, chemotaxis, B cell receptor stimulation, and survival compared with non-IgE ASCs. Additionally, IgE ASCs have a higher expression of genes encoding lysosomal-associated protein transmembrane 5 (LAPTM5) and CD23, as well as upregulation of CD74 (receptor for macrophage inhibitory factor), store-operated Calcium entry-associated regulatory factor (SARAF), and B cell activating factor receptor (BAFFR), which resemble an early minted ASC phenotype. Overall, these findings reinforce the paradigm that human ex vivo mucosal IgE ASCs have a more immature plasma cell phenotype than other class-switched mucosal ASCs and suggest unique functional roles for mucosal IgE ASCs in concert with Ig secretion.

Trends Following Implementation of an Otolaryngology Hospitalist Model in a Tertiary Care Setting.

OBJECTIVES: The otolaryngology hospitalist (OH) model is an emerging paradigm for inpatient and acute patient care. This study presents encounter volume before and after the implementation of an OH service. Postimplementation trends are evaluated. STUDY DESIGN: Retrospective administrative and clinical database review. SETTING: Tertiary care university hospital. METHODS: This review includes 2 distinct time frames (2008-2012, 2014-2018), representing periods before and after OH implementation. The number of billed patient encounters is compared between these 2 periods using the hospital data warehouse. Additional data is evaluated for the postimplementation period, using a clinical database. Encounter type, the reason for consultation, procedures, and requesting service/location are described. RESULTS: After the OH implementation, there was a 451% increase in evaluation and management encounters submitted for billing. Since the OH model inception, there was an overall increase in encounters (849-910), procedures performed (319-345), and operative cases (46-54) per year. Each inpatient consultation request generates one or more procedures on average. Common reasons for consultation include sinonasal pathology (20.3%), dysphonia/dysphagia (17.5%), and airway evaluation (15%). Critical Care (24%), Emergency Medicine (21%), and Hospital Medicine (21%) requested most of the Otolaryngology consults. Most consults were seen on the inpatient medical/surgical floor (46%), with the ICU (27%) and the Emergency Department (22%) being the next most common locations. CONCLUSIONS: The OH model is an evolving paradigm that is viable and offers timely, specialized care for patients in a hospital or acute care setting.

Hemostasis in endoscopic sinus and skull base surgery.

PURPOSE OF REVIEW: Bleeding during endoscopic endonasal procedures can quickly obscure critical anatomic landmarks. This increases both the difficulty of the surgical procedure and the risk of complications faced by the patient. As the indications for surgical management of sinonasal pathology grow, it is important to review techniques to minimize bleeding and facilitate safe surgery. RECENT FINDINGS: Evidence continues to accumulate for best practices in the surgical management of sinonasal disease. Recently, international guidelines have attempted to summarize this body of evidence, lending further support to several interventions which have been advocated as methods to decrease bleeding during endoscopic endonasal surgery. Additional studies have specifically investigated the safety of certain commonly employed techniques. The utility of preoperative corticosteroid therapy and the use of total intravenous anesthetic techniques in increasingly validated. Further evidence supports the safety of reverse Trendelenburg positioning for surgical management of inflammatory disease. SUMMARY: Recent wide scale systematic review of the literature regarding perioperative and intraoperative management of hemostasis has reinforced the utility of certain interventions, while others remain ambiguous.

Diagnosis, Prognosticators, and Management of Acute Invasive Fungal Rhinosinusitis: Multidisciplinary Consensus Statement and Evidence-Based Review with Recommendations.

BACKGROUND: Acute invasive fungal sinusitis (AIFS) is an aggressive disease that requires prompt diagnosis and multidisciplinary treatment given its rapid progression. However, there is currently no consensus on diagnosis, prognosis, and management strategies for AIFS, with multiple modalities routinely employed. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on AIFS, summarize the existing evidence, and provide recommendations on the management of AIFS. METHODS: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through January 2022. Studies evaluating management for orbital, non-sinonasal head and neck, and intracranial manifestations of AIFS were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on management principles for AIFS were generated. RESULTS: A review and evaluation of published literature was performed on 12 topics surrounding AIFS (signs and symptoms, laboratory and microbiology diagnostics, endoscopy, imaging, pathology, surgery, medical therapy, management of extrasinus extension, reversing immunosuppression, and outcomes and survival). The aggregate quality of evidence was varied across reviewed domains. CONCLUSION: Based on the currently available evidence, judicious utilization of a combination of history and physical examination, laboratory and histopathologic techniques, and endoscopy provide the cornerstone for accurate diagnosis of AIFS. In addition, AIFS is optimally managed by a multidisciplinary team via a combination of surgery (including resection whenever possible), antifungal therapy, and correcting sources of immunosuppression. Higher quality (i.e., prospective) studies are needed to better define the roles of each modality and determine diagnosis and treatment algorithms.

Management paradigms for chronic rhinosinusitis in individuals with asthma: An evidence-based review with recommendations.

BACKGROUND: Despite the significant morbidity associated with chronic rhinosinusitis (CRS) in individuals with asthma (CRSwA), there is a paucity of codified, evidence-based management strategies for CRS in this population. METHODS: Using PubMed, Embase, and Cochrane Review Databases, a systematic review was performed covering management strategies for CRSwA. A total of 5903 articles were screened, and 70 were included for full-text analysis. After application of exclusion criteria, 53 articles comprised the qualitative synthesis. The level of evidence was graded and benefit-harm assessments, as well as value judgment and recommendations, were provided RESULTS: Strong evidence confirms the benefit of oral and topical medications on sinonasal-specific outcomes in individuals with CRSwA; there is low-grade evidence demonstrating that these agents improve lung function and/or asthma control. Moderate to strong evidence suggests that endoscopic sinus surgery (ESS) improves both sinonasal- and asthma-specific quality of life. Although there is insufficient to low evidence to indicate that ESS improves pulmonary function in this population, data indicate a positive impact of this intervention on asthma control. Biologic medications strongly improve both subjective and objective sinonasal- and asthma-specific outcomes. CONCLUSION: Evidence supports managing CRS in individuals with CRSwA in a stepwise fashion, starting with traditional nonbiologic oral and topical medication, and escalating to second-line treatments, such as ESS and biologics. Optimal treatment of individuals who have CRSwA often requires concurrent, directed management of asthma, as not all CRS interventions impact asthma status.

Unified Airway Disease: Examining Prevalence and Treatment of Upper Airway Eosinophilic Disease with Comorbid Asthma.

The "unified airway" describes the concept that inflammation affects upper and lower airways by similar mechanisms; this often manifests as rhinitis, rhinosinusitis, and/or nasal polyposis in the upper airway with associated asthma or bronchial inflammation in the lower airways. The relationships between eosinophilic diseases of the upper and lower airways are highlighted by examining their prevalence and treatment regimens along with the synergistic effects of treatment on upper and lower airway symptoms. It is important to recognize the interrelatedness of upper and lower airway eosinophilic disease to assess and manage patients accurately and holistically.

Pituitary Gland Surgical Emergencies: The Role of Endoscopic Intervention.

True pituitary surgical emergencies are rare. These events can occur throughout the perioperative period and are broadly categorized by the timing of occurrence. Acute indications for emergent pituitary surgery include pituitary apoplexy, vision loss, and severe Cushing presentation. Emergencies may also occur intraoperatively, secondary to bleeding. Postoperative emergencies include epistaxis, pneumocephalus, and intracranial bleeding. Cerebrospinal fluid (CSF) leak occurs in about 37.4% of transsphenoidal sellar surgery, yet postoperative CSF leaks are less frequent at approximately 2.6%. As they occur often during pituitary surgery, CSF leaks alone are generally not considered a true surgical emergency unless associated with symptomatic tension pneumocephalus.

A Prospective Analysis of Systemic and Local Aeroallergen Sensitivity in Central Compartment Atopic Disease.

OBJECTIVE: To compare systemic allergen sensitivity and local allergen sensitivity in the sinonasal tissue of patients with a recently identified subtype of chronic rhinosinusitis strongly associated with allergy: central compartment atopic disease (CCAD). STUDY DESIGN: Prospective cohort study. SETTING: Academic tertiary care rhinology clinic. METHODS: Fifteen participants with endoscopic and radiographic evidence of CCAD underwent systemic allergy testing with skin testing and measurement of serum specific immunoglobulin E (sIgE) to 15 regionally common aeroallergens. Local allergen sensitivity was determined by measuring sIgE to these same 15 allergens in their sinonasal tissue. sIgE testing was performed by ImmunoCAP assay. RESULTS: Of the 15 participants, 14 were sensitive to at least 1 allergen locally in the central compartment and systemically on skin or serum testing. Among all participants, 4 were sensitive to allergens on central compartment sIgE testing that they were not sensitive to on skin and serum sIgE testing (range, 1-8 discordant allergens). Comparisons between local and systemic aeroallergen sensitivity results showed statistically significant correlations (P < .05) ranging from weak to strong. CONCLUSION: Systemic allergy testing is recommended in the initial workup for CCAD. Local allergen sensitivities may be present in a subset of patients with CCAD. Further study of the clinical significance of these sensitivities should be undertaken in CCAD, with evaluation of the role of medical therapies and allergen immunotherapy in the treatment of CCAD.

Intermediate Invasive Fungal Sinusitis, a Distinct Entity From Acute Fulminant and Chronic Invasive Fungal Sinusitis.

BACKGROUND: The current classification system of invasive fungal sinusitis (IFS) includes acute (aIFS) and chronic (cIFS) phenotypes. Both phenotypes display histopathologic evidence of tissue necrosis, but differ by presence of angioinvasion, extent of necrosis, and disease progression. aIFS is defined by a rapid onset of symptoms, while cIFS slowly progresses over ≥12 weeks. However, a subset of IFS patients do not fit into the clinical presentation and histopathologic characteristics of either aIFS or cIFS. OBJECTIVES: To investigate the demographic, clinical, and histopathologic characteristics of a distinct subset of IFS. METHODS: Retrospective review of patients with IFS from a single tertiary-care institution (2010-2020). Patients with symptoms for ≤4 weeks were classified as aIFS if they displayed endoscopic evidence of mucosal necrosis or fungal angioinvasion on pathology. Patients with slowly progressive IFS for ≥12 weeks were classified as cIFS. Patients with symptom duration between 4 and 12 weeks with evidence of invasive fungal disease were classified as a new entity and were further investigated. RESULTS: Of the 8 patients identified, 50% were immunosuppressed at presentation. The mean symptom duration prior to presentation was 50.5 days (SD 16.8), and common symptoms included facial pain (100%), vision change (87.5%), and blindness (37.5%). Two patients (25%) died of their disease. Sites of fungal involvement confirmed by histopathology included sphenoid (62.5%) and ethmoid sinuses (12.5%), orbital apex (25%), optic nerve (12.5%), pterygopalatine fossa (12.5%), and clivus (12.5%). Fungal elements but without obvious angioinvasion, were identified in all specimens, and fungus balls (50%), granulomas (37.5%), and giant cells (25%) were also observed on histopathology. CT and MRI radiographic imaging showed findings consistent with orbital, intracranial, or skull base involvement in all patients. CONCLUSION: We propose intermediate IFS as a new subgroup of patients with IFS who do not fit into the standard classification of aIFS or cIFS.

Inhalation and deposition of spherical and pollen particles after middle turbinate resection in a human nasal cavity.

Middle turbinate resection significantly alters the anatomy and redistributes the inhaled air. The superior half of the main nasal cavity is opened up, increasing accessibility to the region. This is expected to increase inhalation dosimetry to the region during exposure to airborne particles. This study investigated the influence of middle turbinate resection on the deposition of inhaled pollutants that cover spherical and non-spherical particles (e.g. pollen). A computational model of the nasal cavity from CT scans, and its corresponding post-operative model with virtual surgery performed was created. Two constant flow rates of 5 L/min, and 15 L/min were simulated under a laminar flow field. Inhaled particles including pollen (non-spherical), and a spherical particle with reference density of 1000 kg/m3 were introduced in the surrounding atmosphere. The effect of surgery was most prominent in the less patent cavity side, since the change in anatomy was proportionally greater relative to the original airway space. The left cavity produced an increase in particle deposition at a flow rate of 15 L/min. The main particle deposition mechanisms were inertial impaction, and to a lesser degree gravitational sedimentation. The results are expected to provide insight into inhalation efficiency of different aerosol types, and the likelihood of deposition in different nasal cavity surfaces.

Biologics for chronic rhinosinusitis with nasal polyps: Economics and ethics.

Biologics have recently been approved for use in chronic rhinosinusitis with nasal polyps patients. While effective in controlling disease on subjective and objective short-term outcome measures, limited data suggest that biologics have the potential to be used long term. The current wholesale acquisition costs for biologics are quite high. Widespread, prolonged use of these medications may create a large burden to our healthcare system. Cost-effectiveness analyses, particularly for specific patient cohorts, are needed to determine appropriate use of these medications. The ethics of patient preference of various treatment options, counseling regarding side effect profiles, and healthcare economics also need to be addressed.

Central compartment atopic disease: outcomes compared with other subtypes of chronic rhinosinusitis with nasal polyps.

BACKGROUND: Central compartment atopic disease (CCAD) is a variant of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) characterized by polypoid changes of the superior nasal septum, middle (MT), and/or superior turbinates (ST). This study evaluates surgical outcomes in patients with CCAD compared with other CRSwNP subtypes. METHODS: Retrospective analysis was performed at Emory University from May 2012 to November 2019. Patients undergoing primary endoscopic sinus surgery (ESS) for CCAD, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and CRSwNP not otherwise specified (CRSwNP NOS) were included consecutively, beginning with the earliest date of CCAD patient. Outcome measures included polyp recurrence, revision ESS, oral steroid use, and oral antibiotic use. Pearson chi-square and univariate analysis of variance (ANOVA) were performed for group comparisons. RESULTS: Data was collected for 132 patients (CCAD = 38, AERD = 20, AFRS = 37, CRSwNP NOS = 37; 58 females, mean age 42.9 years [range, 13-85 years]). CCAD patients demonstrated polyp recurrence less frequently than expected, whereas AFRS patients had polyp recurrence more frequently than expected (p = 0.003; phi 0.32). CCAD patients underwent revision ESS less frequently than expected; AFRS and CRSwNP NOS underwent revision ESS more frequently than expected (p = 0.03; phi 0.26). CRSwNP NOS patients received more total antibiotic courses than those with CCAD (p = 0.01; eta-squared 0.09) and more courses of antibiotics per month than those with AFRS (p = 0.03; eta-squared 0.07). There was no significant difference in follow-up measures across groups (number of visits, total months, or visits per month). CONCLUSION: Rates of polyp recurrence and revision ESS were significantly lower in CCAD patients compared with patients with other CRSwNP subtypes, suggesting durable benefit of ESS and postoperative medical therapy in CCAD patients.

Biologics in Otolaryngology: Past, Present, and Future.

Biologics have been widely adopted in multiple subspecialties of otolaryngology. This article provides an overview of past, present, and future uses of biologics in otolaryngology with emphasis on allergic rhinitis, chronic rhinosinusitis with polyposis, head and neck squamous cell carcinoma, salivary and skull base tumors, hearing loss, and other otologic disorders.

Gender and authorship trends in rhinology, allergy, and skull-base literature from 2008 to 2018.

BACKGROUND: A recent analysis suggested potential narrowing of the gender gap in research productivity in the field of rhinology. This analysis did not, however, provide insight into how the genders are represented in the rhinologic literature. This study aimed to evaluate 11 years of literature to evaluate for gender differences in authorship position, collaborations, category and content of research, citations, and funding to gain perspective on how gender and authorship has changed over time. METHODS: Authorship data for all articles on rhinologic subject matter published between January 1, 2008 and December 31, 2018 in four otolaryngology journals was collected. The gender of authors was determined by protocol. Category and content of research and funding status/source were additionally obtained. RESULTS: Data were collected from 2666 articles. Gender of 14,510 authors was determined. Female authors accounted for 23% of the overall authors and male authors accounted for 77%. Female first authorship increased significantly over time, but there was no change in female senior authorship. The percentage of female authors steadily increased over time, whereas male authorship decreased slightly. Mixed gender teams were shown to be increasing in frequency. Women published more than expected in basic science and allergy and less than expected in skull base. On funded studies, women were significantly underrepresented as senior authors. CONCLUSION: This study represents the first assessment of gender differences in the rhinology literature. Areas where female representation can improve include senior authorship, increased involvement in skull base publications, and increased funding.