Pembrolizumab-associated chronic rhinosinusitis: A new endotype and management considerations.

KEY POINTS: Patients treated with pembrolizumab experience an increase in paranasal sinus inflammation Use of topical triamcinolone in carboxymethylcellulose is a treatment option for such patients.

IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

RNA Sequencing and Gene Ontology Analysis in Acute Invasive Fungal Sinusitis.

BACKGROUND: Acute invasive fungal sinusitis (AIFS) is an aggressive and dangerous disease of the paranasal sinuses with high morbidity and mortality. The immune response at the level of the nasal mucosa, the site of entry, has not been previously evaluated. OBJECTIVE: To evaluate differential gene expression in the sinonasal mucosa of AIFS patients as compared to control patients using RNA sequencing. METHODS: Sinonasal tissue samples were prospectively obtained from consenting patients undergoing surgery between November, 2020 and November, 2021. RNA extraction and sequencing were performed and differential expression was analyzed to detect transcriptional differences between patient groups. RESULTS: Tissue samples were collected from 4 patients with active AIFS diagnoses, 2 patients with recovered AIFS, 1 patient with a diagnosis of non-invasive fungal ball, and 4 healthy controls. 255 genes were differentially expressed in AIFS patients as compared to control patients. Specific Gene Ontology (GO) biological processes that were identified as differentially expressed in AIFS patients as compared to controls included the following: 1. GO:0007155 (cell adhesion), 2. GO:0030199 (collagen fibril organization) and 3. GO:0001525 (angiogenesis). CONCLUSION: Transcriptional differences were noted between AIFS and control patients in sinonasal tissue samples. Future work is necessary to determine causes of the differential gene expressions between AIFS and control patients, specifically those who are immunosuppressed, or with preexisting non-invasive forms of fungal sinusitis, to guide treatment and prevention strategies.

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function.

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

Use of computational fluid dynamics (CFD) to model observed nasal nitric oxide levels in human subjects.

BACKGROUND: Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and nasal NO (nNO) levels typically exceed those in exhaled breath (fractional exhaled NO [FeNO]). Elevated concentrations of NO sampled from the nose, in turn, reflect even higher concentrations in the paranasal sinuses, suggesting a "reservoir" role for the latter. However, the dynamics of NO flux within the sinonasal compartment are poorly understood. METHODS: Data from 10 human subjects who had previously undergone both real-time nNO sampling and computed tomography (CT) scanning of the sinuses were analyzed using computational fluid dynamics (CFD) methods. Modeled and observed nNO values during the initial 2-s transient ("spike") during nasal exhalation were then compared. RESULTS: Examining the initial 2-s transient spike for each subject (as well as the pooled group), there was a statistically significant correlation between modeled and observed nNO levels, with r values ranging from 0.43 to 0.89 (p values ranging from <0.05 to <0.0001). Model performance varied between subjects, with weaker correlations evident in those with high background (FeNO) levels. In addition, the CFD simulation suggests that ethmoid sinuses (>60%) and diffusion process (>54%) contributed most to total nasal NO emissions. CONCLUSION: Analysis of this dataset confirms that CFD is a valuable modeling tool for nNO dynamics, and highlights the importance of the ethmoid sinuses, as well as the role of diffusion as an initiating step in sinonasal NO flux. Future model iterations may apply more generally if baseline FeNO is taken into account.

Obstructive Sleep Apnea: A Surgeon's Perspective.

Obstructive sleep apnea (OSA) is a complex medical disorder with significant impact on mortality, quality of life, and long-term cardiovascular outcomes. The apnea-hypopnea index does not correlate well with either quality-of-life measures or health outcomes, so other outcome measures must be evaluated in treatment of OSA. OSA can be successfully treated through behavioral, nonsurgical, and surgical methods with improvements in quality of life, morbidity, and mortality. Surgical intervention should be considered in patients who are noncompliant with or fail positive airway pressure use. As is true with PAP therapy, surgery for OSA improves mortality and symptoms of OSA even when the polysomnogram does not fully normalize.

Computational modeling of nasal nitric oxide flux from the paranasal sinuses: Validation against human experiment.

BACKGROUND: Nitric oxide (NO) is important in respiratory physiology and airway defense. Although the paranasal sinuses are the major source of nasal NO, transport dynamics between the sinuses and nasal cavities are poorly understood. METHODS: Exhaled nasal NO tracings were measured in two non-asthmatic subjects (one with allergic rhinitis, one without) using NO analyzer connected via face mask. We subsequently performed computational fluid dynamics NO emission simulations based on individual CT scans and compared to the experimental data. RESULTS: Simulated exhaled NO tracings match well with experimental data (r > 0.84, p < 0.01) for both subjects, with measured peaks reaching 319.6 ppb in one subject (allergic-rhinitis), and 196.9 ppb in the other. The CFD simulation accurately captured the peak differences, even though the initial sinus NO concentration for both cases was set to the same 9000 ppb based on literature value. Further, the CFD simulation suggests that ethmoid sinuses contributed the most (>67%, other sinuses combined <33%) to total nasal NO emission in both cases and that diffusion contributes more than convective transport. By turning off diffusion (setting NO diffusivity to ~0), the NO emission peaks for both cases were reduced by >70%. CONCLUSION: Historically, nasal NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). Here, we showed that the ethmoid sinuses and diffusive transport dominate the process. These findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.

Septum submucosal glands exhibit aberrant morphology and reduced mucin production in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by significant accumulation and thickening of mucus in the sinonasal cavities. One contributor of aberrant mucus production and impaired mucociliary clearance (MCC) is altered function of the sinonasal submucosal glands (SMGs), yet contributions of SMGs to upper airway disease initiation and progression remain unknown. The objective of this study was to characterize the morphology and secretory cell identities of the nasal septum SMGs in both healthy and CRS adults. METHODS: Biopsies from adult participants with CRS without nasal polyps (CRSsNP, n = 4), CRS with nasal polyps (CRSwNP, n = 8), and non-CRS controls (n = 14) were collected from the posterior septum. Glandular morphology and mucus markers were investigated using histological techniques and high-resolution confocal microscopy. RESULTS: Analysis revealed a significant decrease in gland density in the posterior septum of CRSsNP (28% ± 6.15%) and CRSwNP (23% ± 3.09%) compared to control participants (53% ± 1.59%, p < 0.0001). Further analysis of the CRS SMG secretory function revealed an overall decrease in Mucin 5B+ gland mucus being produced. Dilated and cystic ductal structures filled with inspissated mucus were also common to CRS glands. CONCLUSION: Here, we describe a significant alteration in SMG structure and function in the adult CRS posterior septum suggesting reduced gland contribution to MCC. The SMGs of both the nose and sinuses may represent targets for future therapeutic approaches.

The microbiome in obstructive sleep apnea.

Recent evidence has highlighted important associations between obstructive sleep apnea and the microbiome. Although the intricacies of the pathophysiologic mechanisms are not well understood, available evidence suggests a bidirectional relationship between obstructive sleep apnea and microbiota composition. Sleep fragmentation, intermittent hypoxia, and intermittent hypercapnia all play significant roles in altering the microbiome, and initial evidence has shown that alterations of the microbiota affect sleep patterns. Animal model evidence strongly supports the idea that the microbiome mediates disease states associated with obstructive sleep apnea including hypertension, atherosclerosis, and obesity. While evidence is limited, several studies suggest there may be a role for treatment of obstructive sleep apnea and obstructive sleep apnea-related comorbidities through alteration of the microbiome with probiotics, prebiotics, and microbiota transplantation.

Patient Use of Low-cost Digital Videoscopes and Smartphones for Remote Ear and Oropharyngeal Examinations.

Importance: During the novel coronavirus disease 2019 pandemic, telehealth has become a vital component of health care delivery. For otolaryngology evaluations, examination of the ear and oropharynx is important but difficult to achieve remotely. Objective: To assess the feasibility of patient use of low-cost digital videoscopes and smartphones for examination of the ear and oropharynx. Design, Setting, and Participants: A prospective quality improvement study was conducted in an academic adult otolaryngology clinic including 23 patients who presented for an in-person appointment and owned a smartphone device. The study was conducted from July 1 to 15, 2020. Interventions: Participants were asked to capture pictures and videos of their ear canals and oropharynx with digital videoscopes and their smartphones under real-time guidance over a telehealth platform. They were then surveyed about their experience. Main Outcomes and Measures: The primary outcomes were ratings by health care clinicians and a blinded otolaryngologist reviewer of image acceptability. Secondary outcomes included participant time to image acquisition and willingness to purchase digital videoscopes for telehealth use. Results: Of the 23 participants included, 14 were women (61%); mean age was 50 years (range, 21 to 80 years). Of the images obtained using the digital otoscope ear examination, 95% were considered acceptable by the health care clinicians and 91% were considered acceptable by the blinded reviewer; 16 participants (70%) reported that the otoscope was easy to use. The mean time to acquire images for both ears was 114 seconds (95% CI, 84-145 seconds). Twenty-one participants (91%) were willing to pay for a digital otoscope for telehealth use. For the oropharyngeal examination, a greater proportion of smartphone video examinations were considered acceptable by clinicians (63% acceptability) and the blinded reviewer (55%) compared with the digital endoscope (clinicians, 40%; blinded reviewer, 14%). The mean time required for the oropharyngeal examination smartphone video capture was shorter at 35 seconds compared with both the digital endoscope (difference, -27 seconds; 95% CI, -7 to -47 seconds) and smartphone photo capture (difference, -53 seconds; 95% CI, -20 to -87 seconds). Conclusions and Relevance: Digital otoscopes and smartphones apparently can facilitate remote head and neck physical examination in telehealth. Digital otoscopes were useful for ear examinations, and smartphone videos appeared to be the most useful for oropharyngeal examinations. Further studies are required to determine specific diagnostic capabilities in various telehealth practice settings.

Communication Chaos from Discrepancies in Personal Protective Equipment and Preoperative Guidelines.

OBJECTIVES/HYPOTHESIS: To compare personal protective equipment (PPE) guidelines, specifically respirator use, among international public health agencies, academic hospitals, and otolaryngology-head and neck surgery (OHNS) departments in the United States for the care of coronavirus-19 (COVID-19) patients. STUDY DESIGN: Cross sectional survey. METHODS: Review of publicly available public health and academic hospitals guidelines along with review of communication among otolaryngology departments. RESULTS: Among 114 academic institutions affiliated with OHNS residencies, 20 (17.5%) institutions provided public access to some form of guidance on PPE and 73 (64%) provided information on screening or diagnostic testing. PPE guidelines were uniquely described based on several variables: location of care, COVID-19 status, involvement of aerosol generating or high-risk procedures, and physical distance from the patient. Six hospital guidelines were highlighted. Across these six institutions, there was agreement that N95 respirators were needed for high-risk patients undergoing high-risk procedures. Variations existed among institutions for scenarios with low-risk patients. Definitions of the low-risk patient and high-risk procedures were inconsistent among institutions. Three of the highlighted institutions had OHNS departments recommending higher level of airway protection than the institution. CONCLUSIONS: OHNS departments typically had more stringent PPE guidance than their institution. Discrepancies in communicating PPE use were frequent and provide inconsistent information on how healthcare workers should protect themselves in the COVID-19 pandemic. Identification of these inconsistencies serves as an opportunity to standardize communication and develop evidence-based guidelines. LEVEL OF EVIDENCE: V Laryngoscope, 131:E746-E754, 2021.

Consensus-based perioperative protocols during the COVID-19 pandemic.

OBJECTIVE: During the COVID-19 pandemic, quaternary-care facilities continue to provide care for patients in need of urgent and emergent invasive procedures. Perioperative protocols are needed to streamline care for these patients notwithstanding capacity and resource constraints. METHODS: A multidisciplinary panel was assembled at the University of California, San Francisco, with 26 leaders across 10 academic departments, including 7 department chairpersons, the chief medical officer, the chief operating officer, infection control officers, nursing leaders, and resident house staff champions. An epidemiologist, an ethicist, and a statistician were also consulted. A modified two-round, blinded Delphi method based on 18 agree/disagree statements was used to build consensus. Significant disagreement for each statement was tested using a one-sided exact binomial test against an expected outcome of 95% consensus using a significance threshold of p < 0.05. Final triage protocols were developed with unblinded group-level discussion. RESULTS: Overall, 15 of 18 statements achieved consensus in the first round of the Delphi method; the 3 statements with significant disagreement (p < 0.01) were modified and iteratively resubmitted to the expert panel to achieve consensus. Consensus-based protocols were developed using unblinded multidisciplinary panel discussions. The final algorithms 1) quantified outbreak level, 2) triaged patients based on acuity, 3) provided a checklist for urgent/emergent invasive procedures, and 4) created a novel scoring system for the allocation of personal protective equipment. In particular, the authors modified the American College of Surgeons three-tiered triage system to incorporate more urgent cases, as are often encountered in neurosurgery and spine surgery. CONCLUSIONS: Urgent and emergent invasive procedures need to be performed during the COVID-19 pandemic. The consensus-based protocols in this study may assist healthcare providers to optimize perioperative care during the pandemic.

The Nose and Nasal Breathing in Sleep Apnea.

Assessment of the nose is critical in evaluating obstructive sleep apnea (OSA) because the nose plays an important role in the physiology of sleep by regulating nasal airway resistance and stimulating ventilation. Nasal obstruction is common in sleep apnea, contributes to OSA, and interferes with tolerance of OSA treatment with continuous positive airway pressure (CPAP) or oral appliances. Medical treatment of nasal obstruction and rhinitis with nasal corticosteroid sprays is associated with improved OSA severity and sleep symptoms. Surgery for nasal obstruction, including septoplasty, turbinate reduction, rhinoplasty, and sinus surgery, improves OSA-related quality-of-life measures and CPAP tolerance.

Implementation and Impact of a Hospital-Wide Instrument Set Review: Early Experiences at a Multisite Tertiary Care Academic Institution.

A multidisciplinary team of nurses, sterile processing technicians, and surgeons reviewed 609 otolaryngology-head and neck surgery (OHNS) surgical instrument sets at the study institution's 3 hospitals. Implementation of the 4-phase instrument review resulted in decreased OHNS surgical instrument set types from 261 to 234 sets, and a decreased number of instruments in these sets from 18 952 to 17 084. The instrument set review resulted in an estimated savings of $35 665 in sterile processing costs for the OHNS department. Instrument review applied to all 10 surgical specialties at the institution would result in an estimated annual savings of $425 378. Through effective leadership, multidisciplinary participation of all key stakeholders, and a systematic approach, this study demonstrates that a hospital-wide quality improvement intervention for instrument set optimization can be successfully performed in a large, multisite tertiary care academic hospital.

Postoperative Opioid Use in Sinonasal Surgery.

OBJECTIVE: To survey patients following sinonasal surgery regarding postoperative pain and opioid use. STUDY DESIGN: Patients were surveyed for 4 days following sinus and/or nasal surgery regarding their pain level and use of prescribed opioids. SETTING: Four academic medical centers and 1 private practice institution. SUBJECTS: Consecutive adult patients undergoing sinonasal surgery. RESULTS: A total of 219 subjects met criteria and were included for analysis; 134 patients (61%) took 5 or fewer combination oxycodone (5-mg) and acetaminophen (325-mg) tablets in the first 3 postoperative days, and 196 patients (89.5%) took fewer than 15. Fifty-one patients (23%) consumed no opioid pain medication. Opioid consumption was positively correlated with postoperative pain ( R2 = 0.2, P < .01) but was not correlated with the use of acetaminophen ( R2 = 0.002, P = .48). No significant difference in postoperative pain or opioid consumption was seen with respect to age, sex, specific procedures performed, postoperative steroids, or smoking history. Current smokers reported higher average pain than nonsmokers ( P < .001) and also required more postoperative opioids ( P = .02). CONCLUSIONS: An evidence-based approach to postoperative pain control following sinonasal surgery that reduces the number of unused and potentially diverted opioids is needed. The current study suggests that 15 combination oxycodone (5-mg) and acetaminophen (325-mg) tablets provide sufficient pain control for 90% of patients in the immediate postoperative period following sinonasal surgery, irrespective of the specific procedures performed, use of acetaminophen, or use of systemic steroids. Smoking status may help surgeons predict which patients will require larger opioid prescriptions.

Loss of Microbial Niche Specificity Between the Upper and Lower Airways in Patients With Cystic Fibrosis.

OBJECTIVES/HYPOTHESIS: To determine the relationship between mucosal-associated sinus and bronchial microbiota in cystic fibrosis (CF) patients compared to non-CF patients with chronic rhinosinusitis (CRS). STUDY DESIGN: Case series. METHODS: We examined the microbial composition of 52 paired sinus and bronchial brushings from 26 patients with CRS. Paired airway samples from nine subjects with CF were compared with samples from 17 non-CF-CRS disease control patients. The Illumina MiSeq platform was used to sequence the V4 region of the 16S rRNA gene. Sequences were analyzed using QIIME 1.9.0. RESULTS: CF patients demonstrate increased severity of sinus inflammation (Lund-Mackay score 16.3 vs. 12.4, P = .023) and diminished diversity of microbial communities in both the sinuses (Shannon diversity 0.98 vs. 3.3, P = .009) and lungs (Shannon diversity 2.2 vs. 4.0, P = .042) relative to non-CF-CRS. Non-CF-CRS sinus and lung microbiota were distinct and clustered by niche (sinus vs. lung, P = .004). However, CF airway microbiota demonstrated a loss of niche specificity (sinus vs. lung, P = .492). Two CF patients underwent lung transplantation at 4.5 and 9 months prior to sampling. Sinus and lung samples from these two patients demonstrated distinct microbial communities. CONCLUSIONS: Patients with CF undergoing surgery for CRS exhibit substantial bacterial community collapse in the sinuses and a loss of niche specificity between the upper and lower airways compared to non-CF patients with CRS. These results extend previous studies elucidating the lower airway microbiome in cystic fibrosis and provide support for the concept of microbial translocation in the cystic fibrosis airways. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:544-550, 2019.

Heterogeneity of Microbiota Dysbiosis in Chronic Rhinosinusitis: Potential Clinical Implications and Microbial Community Mechanisms Contributing to Sinonasal Inflammation.

Recent studies leveraging next-generation sequencing and functional approaches to understand the human microbiota have demonstrated the presence of diverse, niche-specific microbial communities at nearly every mucosal surface. These microbes contribute to the development and function of physiologic and immunological features that are key to host health status. Not surprisingly, several chronic inflammatory diseases have been attributed to dysbiosis of microbiota composition or function, including chronic rhinosinusitis (CRS). CRS is a heterogeneous disease characterized by inflammation of the sinonasal cavity and mucosal microbiota dysbiosis. Inflammatory phenotypes and bacterial community compositions vary considerably across individuals with CRS, complicating current studies that seek to address causality of a dysbiotic microbiome as a driver or initiator of persistent sinonasal inflammation. Murine models have provided some experimental evidence that alterations in local microbial communities and microbially-produced metabolites influence health status. In this perspective, we will discuss the clinical implications of distinct microbial compositions and community-level functions in CRS and how mucosal microbiota relate to the diverse inflammatory endotypes that are frequently observed. We will also describe specific microbial interactions that can deterministically shape the pattern of co-colonizers and the resulting metabolic products that drive or exacerbate host inflammation. These findings are discussed in the context of CRS-associated inflammation and in other chronic inflammatory diseases that share features observed in CRS. An improved understanding of CRS patient stratification offers the opportunity to personalize therapeutic regimens and to design novel treatments aimed at manipulation of the disease-associated microbiota to restore sinus health.