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Chronic rhinosinusitis is characterized by persistent locoregional mucosal inflammation of the paranasal sinuses and upper airway that has substantial associated health care costs. Personalized approaches to care that incorporate use of molecular biomarkers, phenotypes, and inflammatory endotypes is a major focus of research at this time, and the concurrent rise of targeted therapeutics and biologic therapies has the potential to rapidly advance care and improve outcomes. Recent findings suggest that improved understanding of chronic rhinosinusitis phenotypic and endotypic heterogeneity, and incorporation of these characteristics into clinical care pathways, may facilitate more effective selection of surgical and/or therapeutic interventions. Ultimately, these personalized approaches have the potential to target specific inflammatory pathways, increase efficacy, reduce costs, and limit side effects. This review summarizes recent advances in the identification and characterization of chronic rhinosinusitis phenotypes, endotypes, and biomarkers and reviews potential implications for targeted therapeutics.

Inflammatory patterns in chronic rhinosinusitis (CRS) may predict disease severity, need for multiple sinus surgeries, and treatment response. This study analyzes nasal mucus inflammatory cytokine patterns in patients with (CRSwNP) and without (CRSsNP) nasal polyposis and their association with revision sinus surgery.A total of 319 CRS patients who underwent sinus surgery were included. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Cytokine expression patterns in patients with 0, 1, and ≥2 previous surgeries were analyzed using Kruskal-Wallis and principal component (PC) regression analyses.There were 122 (38%) patients with CRSsNP and 197 (62%) with CRSwNP. On univariate analysis, interleukin (IL)-1β, IL-6, IL-8, and IL-21 were associated with increasing number of sinus surgeries in CRSsNP, as were IL-2, IL-4, IL-5, IL-6, IL-9, IL-17A, and tumor necrosis factor (TNF)-α in CRSwNP. PC analysis with continuous Poisson regression in CRSwNP demonstrated that high IL-5 and IL-13 and low IL-1β, IL-12, and IL-21 were associated with more prior surgeries. In CRSsNP low IL-13 and high IL-5 and regulated-on-activation, normal T-cell-expressed and secreted (RANTES) were associated with more prior surgeries. Age remained a significant covariate in the full regression model for CRSsNP, but was nonsignificant in CRSwNP.In CRSwNP, elevated IL-5 and IL-13 levels were higher at time of surgery in patients with more prior surgeries. Type 2 cytokines in CRSsNP demonstrated mixed associations with revision surgery. For both phenotypes, IL-10, IL-12, and IL-21 were consistently lower as number of prior surgeries increased, suggesting that treatment-resistant disease may be modulated by impairment in these signaling pathways.

Objectives Iatrogenic injury to the internal carotid artery (ICA) is one of the most catastrophic complications of endoscopic sinus and skull base surgery. Previous research has shown that packing with a crushed muscle graft at the injury site can be an effective management technique to control bleeding and prevent the need for ICA sacrifice. Here, we describe a novel and readily available repair donor site—an autologous lateral tongue muscle patch. Design Three representative cases of a successful repair of ICA injuries using a lateral tongue muscle patch are included in this study. The graft measured approximately 2 × 3 cm and was taken from the lateral intrinsic tongue musculature. We describe the harvest of the graft, its advantages, and the details of operative repair. Results The lateral tongue provides a large and readily accessible source of muscle within the surgical field that can be quickly harvested during an endoscopic procedure. For the first case, an expanding parasellar ICA pseudoaneurysm was managed with a tongue muscle patch and nasal packing. In the second case, a cavernous ICA injury was sustained during craniopharyngioma resection. Case three involved an ICA injury during endonasal debridement of invasive fungal rhinosinusitis. None of the patients required embolization or neurovascular stenting. Postoperative angiograms and serial computed tomography angiograms showed complete resolution of the pseudoaneurysm, and the patients continued to do well at least 1 year after repair. Conclusions Lateral tongue muscle graft is an effective and efficient method to manage ICA injuries during endoscopic endonasal surgery. Advantages include the speed of harvest, donor site being readily accessible in the surgical field, and low donor site morbidity. It should be added to the repertoire of possible donor sites for addressing catastrophic sinonasal bleeding.

Several prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity.

To date, little is known about the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, on the upper respiratory tract (URT) microbiota over time. To fill this knowledge gap, we used 16S ribosomal RNA gene sequencing to characterize the URT microbiota in 48 adults, including (1) 24 participants with mild-to-moderate COVID-19 who had serial mid-turbinate swabs collected up to 21 days after enrolment and (2) 24 asymptomatic, uninfected controls who had mid-turbinate swabs collected at enrolment only. To compare the URT microbiota between groups in a comprehensive manner, different types of statistical analyses that are frequently employed in microbial ecology were used, including ⍺-diversity, β-diversity and differential abundance analyses. Final statistical models included age, sex and the presence of at least one comorbidity as covariates. The median age of all participants was 34.00 (interquartile range=28.75–46.50) years. In comparison to samples from controls, those from participants with COVID-19 had a lower observed species index at day 21 (linear regression coefficient=−13.30; 95 % CI=−21.72 to −4.88; q=0.02). In addition, the Jaccard index was significantly different between samples from participants with COVID-19 and those from controls at all study time points (PERMANOVA q Corynebacterium ASV, Frederiksenia canicola , and one Lactobacillus ASV) were decreased in samples from participants with COVID-19 at all seven study time points, whereas the abundance of one ASV (from the family Neisseriaceae ) was increased in samples from participants with COVID-19 at five (71.43 %) of the seven study time points. Our results suggest that mild-to-moderate COVID-19 can lead to alterations of the URT microbiota that persist for several weeks after the initial infection.

Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.

Little is known about the relationships between symptomatic early-time SARS-CoV-2 viral load and upper airway mucosal gene expression and immune response. To examine the association of symptomatic SARS-CoV-2 early viral load with upper airway mucosal gene expression, we profiled the host mucosal transcriptome from nasopharyngeal swab samples from 68 adults with symptomatic, mild-to-moderate COVID-19. We measured SARS-CoV-2 viral load using qRT-PCR. We then examined the association of SARS-CoV-2 viral load with upper airway mucosal immune response. We detected SARS-CoV-2 in all samples and recovered >80% of the genome from 85% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited co-detection of common respiratory viruses i.e., only the human Rhinovirus (HRV) being identified in 6% of the samples. We observed a significant positive correlation between SARS-CoV-2 viral load and interferon signaling (OAS2, OAS3, IFIT1, UPS18, ISG15, ISG20, IFITM1, and OASL), chemokine signaling (CXCL10 and CXCL11), and adaptive immune system (IFITM1, CD300E, and SIGLEC1) genes in symptomatic, mild-to-moderate COVID-19 adults, when adjusted for age, sex and race. Interestingly, the expression levels of most of these genes plateaued at a CT value of ~25. Overall, our data shows that early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, which potentially could modify COVID-19 outcomes.AUTHOR SUMMARYSeveral prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. However, the relationship between SARS-CoV-2 viral load and airway mucosal gene expression and immune response remains elusive. We profiled the nasal mucosal transcriptome from nasal samples collected from adults infected with SARS-CoV-2 during Spring 2020 with mild-to-moderate symptoms using a comprehensive metatranscriptomics method. We observed a positive correlation between SARS-CoV-2 viral load with interferon signaling, chemokine signaling, and adaptive immune system in adults with COVID-19. Our data suggest that early nasal mucosal immune response to SARS-CoV-2 infection was viral load-dependent and may modify COVID-19 outcomes.

I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.

Chronic rhinosinusitis (CRS) is a heterogeneous disease process with a complex underlying cause. Improved understanding of CRS pathophysiology has facilitated new approaches to management of the patient with CRS that rely on targeting patient-specific characteristics and individual inflammatory pathways. A more personalized approach to care will ultimately incorporate a combination of phenotypic and endotypic classification systems to guide treatment. This review summarizes current evidence with respect to CRS phenotypes and endotypes, as well as the identification of potential biomarkers with potential to guide current and future treatment algorithms.

Chronic invasive fungal sinusitis (CIFS) is a rare, life-threatening infection of the nose and sinuses. This study aims to identify factors that impact survival in 1 of the largest cohorts to date.Pathology records were reviewed for biopsy-proven CIFS from 3 tertiary academic institutions from 1995 to 2016. Variables were analyzed using log-rank survival analysis. Univariate Cox regression was performed at 1 and 12 months.Thirty-eight patients were included. Hematologic malignancy and diabetes were the most common underlying diseases (32% each). Aspergillus was the most common fungus (63%). Greater than 75% of the patients had an absolute neutrophil count (ANC)1000 at the time of diagnosis. Overall survival at 1, 6, and 12 months was 89%, 68%, and 48%, respectively. In univariate analysis, factors associated with worse survival included: ANC500 at 12 months (hazard ratio [HR] 4.8; p = 0.01), ANC1000 at 12 months (HR 5.8; p = 0.001), and recent chemotherapy (HR 4; p = 0.01). The following factor was associated with improved survival in univariate analysis: ANC as a linear variable in the entire cohort (HR 0.7; p = 0.005).We present a multi-institutional case-series of CIFS and long-term follow-up. ANC1000 at time of diagnosis and recent chemotherapy (within 1 month of diagnosis) are associated with poorer survival, whereas a rising ANC1000 is associated with improved survival at 12 months. Further prospective studies are needed to further define factors that affect outcomes.

Importance The opioid epidemic has generated interest in optimizing opioid prescribing after common surgeries. Recent studies have shown a broad range of analgesic prescription patterns following endoscopic sinus surgery (ESS). Objective To compare the efficacy of different analgesic regimens after ESS. Design, Setting, and Participants This multi-institutional, nonblinded randomized clinical trial was conducted at 6 tertiary centers across the US and Canada and included participants who underwent ESS for acute or chronic rhinosinusitis. The study was conducted from March 2019 to March 2020, and the data were analyzed in November to December 2020. Interventions All participants received acetaminophen, 650 mg, as the first-line analgesic. From there, patients were randomized to either oxycodone rescue (oxycodone, 5 mg, as second-line therapy) or ibuprofen rescue (ibuprofen, 600 mg, as second-line therapy, with oxycodone, 5 mg, reserved for breakthrough pain). Main Outcomes and Measures Baseline characteristics and disease severity were collected at enrollment. Medication logs, pain scores, and epistaxis measures were collected until postoperative day 7. The primary outcome was the postoperative visual analog scale score for pain. Brief Pain Inventory Pain Severity and Pain Interference Scores were also collected. Results A total of 118 patients were randomized (62 [52.5%] oxycodone rescue, 56 [47.5%] ibuprofen rescue; mean [SD] age, 46.7 [16.3] years; 44 women [44.0%]; 83 White [83.0%], 7 Black [7.0%], and 7 Asian individuals [7.0%]). After exclusions for loss to follow-up and noncompliance, 51 remained in the oxycodone rescue group and 49 in the ibuprofen rescue group. The groups had similar demographic characteristics and disease severity. Thirty-two (63%) in the oxycodone rescue group had adequate pain management with acetaminophen only, while 19 (37%) consumed at least 1 oxycodone dose. In the ibuprofen rescue group, 18 (16%) required only acetaminophen, 28 (57%) used only acetaminophen and ibuprofen, and the remaining 13 (26%) consumed 1 or more oxycodone doses. The groups had similar average acetaminophen (9.69 vs 7.96 doses; difference, 1.73; 95% CI, –1.37 to 4.83) and oxycodone (1.89 vs 0.77 doses; difference, 1.13; 95% CI, –0.11 to 2.36) use. Both groups had similar postoperative visual analog scale scores. A subanalysis that compared opioids users with nonusers showed clinically significant lower pain scores in nonusers at multiple postoperative points. Conclusions and Relevance In this randomized clinical trial, most patients who underwent ESS could be treated postoperatively using a nonopioid regimen of either acetaminophen alone or acetaminophen and ibuprofen. Ibuprofen as a second-line therapy did not reduce overall narcotic consumption, but the overall narcotic use was low in both groups. Trial Registration ClinicalTrials.gov Identifier:NCT03783702

The nose is the portal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, suggesting the nose as a target for topical antiviral therapies. The purpose of this study was to assess both the in vivo and in vitro efficacy of a detergent-based virucidal agent, Johnson and Johnson's Baby Shampoo (JJ), in SARS-CoV-2-infected subjects.Subjects were randomized into three treatment groups: (1) twice daily nasal irrigation with JJ in hypertonic saline, (2) hypertonic saline alone, and (3) no intervention. Complementary in vitro experiments were performed in cultured human nasal epithelia. The primary outcome measure in the clinical trial was change in SARS-CoV-2 viral load over 21 days. Secondary outcomes included symptom scores and change in daily temperature. Outcome measures for in vitro studies included change in viral titers.Seventy-two subjects completed the clinical study (n = 24 per group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, JJ irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering JJ to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal JJ detergent components rapidly absorbed from nasal surfaces.In this randomized clinical trial of subjects with SARS-CoV-2 infection, a topical detergent-based virucidal agent had no effect on viral load or symptom scores. Complementary in vitro studies confirmed a lack of efficacy, reflective of pharmacokinetic failure and rapid absorption from nasal surfaces.

BACKGROUND Mucus cytokines have been linked to baseline metrics of quality of life and olfactory function in patients with chronic rhinosinusitis (CRS). However, their potential utility in predicting postoperative outcomes has not been assessed. Therefore, in this study we evaluated the role of mucus cytokines in predicting 22-item Sino-Nasal Outcomes Test (SNOT-22) scores after endoscopic sinus surgery (ESS) in a prospective cohort of CRS patients. METHODS One hundred forty-seven patients with CRS electing surgical therapy were enrolled in a longitudinal cohort study. Mucus was collected intraoperatively from the middle meatus and tested for interleukin (IL)-1β, IL-2, -4, -5, -6, -7,- 8, -9, -10, -12, -13, -17A, and -21; tumor necrosis factor (TNF)-α; interferon-γ; eotaxin; and RANTES (regulated-on-activation, normal T-cell expressed and secreted) expression using a multiplex flow-cytometric bead assay. Sixty-two patients were followed postoperatively (average, 10.2 months) with baseline and follow-up SNOT-22 surveys. Stepwise multivariate linear regression was used to model relationships between baseline cytokines, phenotype, and average postoperative SNOT-22 total and domain scores. A machine learning approach using a random forest algorithm was also used to investigate potential nonlinear relationships. RESULTS IL-5 was an independent predictor of postoperative total SNOT-22 improvement (β = -8.8, p < 0.0001), whereas IL-2 levels predicted postoperative worsening (β = 6.97, p = 0.0015). Similar relationships were also seen for postoperative SNOT-22 domain scores. The overall model was also noted to be significant fit for the data (adjusted R2 = 0.398, p < 0.0001). The random forest model similarly identified IL-5, TNF-α, IL-13, and IL-2 as major predictors of postoperative SNOT-22 scores. CONCLUSION Mucus cytokine profiles may help identify CRS patients who are likely to obtain postoperative improvement after ESS.

Background Nasal saline irrigation (NSI) plays an important role in the treatment of chronic rhinosinusitis (CRS). It is a beneficial low-risk treatment that serves an adjunctive function in the medical and surgical management of CRS. NSI is hypothesized to function by thinning mucous, improving mucociliary clearance, decreasing edema, and reducing antigen load in the nasal and sinus cavities. Although its use in CRS is nearly universal, significant variety exists with regard to delivery volume, delivery pressure, frequency of use, duration of use, composition, and hygiene recommendations. Evidence is limited regarding the most optimal methods of NSI delivery. In addition, use of NSI has recently come under increasing scrutiny due to potential associations with cases of primary amebic meningoencephalitis. Methods In this review we provide a clinical update summarizing use of NSI for treatment of CRS, including current recommendations for use, and data regarding overall efficacy, available delivery devices, solution composition, and hygiene. Results Current evidence and recommendations for nasal saline delivery methods, composition, and hygiene are presented. Conclusion The most recent consensus statements and Cochrane Review recommend the use of NSI for CRS based on a preponderance of lower level evidence. A conclusion regarding the optimal method of delivery and solution composition cannot be drawn based on the current literature.

Background It is hypothesized that uncontrolled inflammation is responsible for many of the manifestations and symptoms of chronic rhinosinusitis (CRS). Although earlier work has demonstrated an association between olfactory loss and mucus cytokines, the impact on other symptoms is unknown. In this study we investigated the relationship between cytokines, inflammatory cell counts, and patient-reported outcomes measures to better understand how the inflammatory microenvironment correlates with CRS symptomatology. Methods The 22-item Sino-Nasal Outcome Test (SNOT-22) and 8-item Short Form Health Survey (SF-8) were administered to 76 patients undergoing endoscopic sinus surgery for CRS. Mucus was collected intraoperatively from the middle meatus and tested for 17 cytokines using a multiplex flow cytometric bead assay. Eosinophil/neutrophil counts were obtained from histopathologic slide review. Spearman correlations between cytokines, cell counts, and quality-of-life subdomain scores were assessed without multiple comparisons correction due to the small sample size. Results Interleukin-4 (IL-4) correlated significantly with the Rhinologic domain (Rs = 0.25, p = 0.03), whereas eosinophil and neutrophil counts were inversely correlated with the Extranasal Rhinologic domain (Rs = -0.32, p = 0.01; and Rs = -0.27, p = 0.03). Subgroup analysis for nasal polyposis (CRSwNP) showed significant correlations between IL-6 and Total SF-8 (Rs = 0.35, p = 0.02), General Health (Rs = 0.34, p = 0.03), and Emotional (Rs = 0.47, p = 0.002) scores. In patients without polyps (CRSsNP), IL-21 correlated positively with Extranasal Rhinologic Symptoms domain (Rs = 0.41, p = 0.01). Conclusion This pilot study identifies possible pairwise correlations between mucus cytokine levels and baseline quality-of-life measures that need confirmation in larger, targeted studies. Due to the exploratory methodology, positive results may be spurious and should only be used as a starting point for future confirmatory work.

BACKGROUND Olfactory dysfunction is a common symptom of chronic rhinosinusitis (CRS). We previously identified several cytokines potentially linked to smell loss, potentially supporting an inflammatory etiology for CRS-associated olfactory dysfunction. In the current study we sought to validate patterns of olfactory dysfunction in CRS using hierarchical cluster analysis, machine learning algorithms, and multivariate regression. METHODS CRS patients undergoing functional endoscopic sinus surgery were administered the Smell Identification Test (SIT) preoperatively. Mucus was collected from the middle meatus using an absorbent polyurethane sponge and 17 inflammatory mediators were assessed using a multiplexed flow-cytometric bead assay. Hierarchical cluster analysis was performed to characterize inflammatory patterns and their association with SIT scores. The random forest approach was used to identify cytokines predictive of olfactory function. RESULTS One hundred ten patients were enrolled in the study. Hierarchical cluster analysis identified 5 distinct CRS clusters with statistically significant differences in SIT scores observed between individual clusters (p < 0.001). A majority of anosmic patients were found in a single cluster, which was additionally characterized by nasal polyposis (100%) and a high incidence of allergic fungal rhinosinusitis (50%) and aspirin-exacerbated respiratory disease (AERD) (33%). A random forest approach identified a strong association between olfaction and the cytokines interleukin (IL)-5 and IL-13. Multivariate modeling identified AERD, computed tomography (CT) score, and IL-2 as the variables most predictive of olfactory function. CONCLUSION Olfactory dysfunction is associated with specific CRS endotypes characterized by severe nasal polyposis, tissue eosinophilia, and AERD. Mucus IL-2 levels, CT score, and AERD were independently associated with smell loss.

Sinonasal small cell neuroendocrine carcinoma (SNEC) is an extremely rare and aggressive neoplasm that can arise in the sinonasal region. These tumors are associated with high morbidity and mortality, are difficult to diagnose, and are hard to treat. We describe 2 cases of this poorly understood malignancy and review imaging, pathology, and treatment decisions. A 41-year-old male and a 64-year-old female presented to a tertiary center in 2019 after developing nasal obstruction and were found to have sinonasal masses on imaging. Both biopsies showed strong expression of pancytokeratin with dot-like reactivity and expression of neuroendocrine markers chromogranin and synaptophysin. The findings were diagnostic of SNEC. Staging positron emission tomography/computed tomography and brain MRI were performed, and patients were discussed at a multidisciplinary tumor board. Neither had distant metastatic disease at presentation. One patient had no intracranial or orbital disease and underwent a subtotal endoscopic resection with adjuvant chemoradiation. The other patient demonstrated middle cranial fossa, dural, and orbital involvement as well as cranial nerve V palsy. This patient was treated with induction chemotherapy, followed by concurrent chemoradiation. Both patients are presently alive at 4 months follow-up, but one with persistent local disease and the other distant metastasis. Sinonasal small cell neuroendocrine carcinoma is a rare and poorly understood malignancy with an aggressive clinical course. Continued careful review of pathology and study of molecular features are needed for improved understanding of SNEC, and particularly for head and neck SNEC, to establish a staging system and better formulate treatment protocols.

Background Little is known about the relationships between SARS-CoV-2, the respiratory virus responsible for the ongoing COVID-19 pandemic, and the upper respiratory tract (URT) microbiome. Objective Our objectives were 1) to compare the URT microbiome between SARS-CoV-2-infected and -uninfected adults, and 2) to examine the association of SARS-CoV-2 viral load with the URT microbiome during COVID-19. Methods We characterized the URT microbiome using 16S ribosomal RNA sequencing in 59 adults (38 with confirmed, symptomatic, mild-to-moderate COVID-19 and 21 asymptomatic, uninfected controls). In those with COVID-19, we measured SARS-CoV-2 viral load using quantitative reverse transcription PCR. We then examined the association of SARS-CoV-2 infection status and its viral load with the ⍺-diversity, β-diversity, and abundance of bacterial taxa of the URT microbiome. Our main models were all adjusted for age and sex. Results The observed species index was significantly higher in SARS-CoV-2-infected than in -uninfected adults (β linear regression coefficient=7.53, 95%CI=0.17-14.89, p=0.045). In differential abundance testing, 9 amplicon sequence variants (ASVs) were significantly different in both of our comparisons, with Peptoniphilus lacrimalis, Campylobacter hominis, Prevotella 9 copri, and an Anaerococcus unclassified ASV being more abundant in those with SARS-CoV-2 infection and in those with high viral load during COVID-19, whereas Corynebacterium unclassified, Staphylococcus haemolyticus, Prevotella disiens, and 2 Corynebacterium_1 unclassified ASVs were more abundant in those without SARS-CoV-2 infection and in those with low viral load during COVID-19. Conclusion Our findings suggest complex associations between SARS-CoV-2 and the URT microbiome in adults. Future studies are needed to examine how these viral-bacterial interactions can impact the clinical progression, severity, and recovery of COVID-19., Capsule Summary: In our study, we found substantial differences in the upper respiratory tract microbiome between SARS-CoV-2-infected and -uninfected adults. Furthermore, we show that the SARS-CoV-2 viral load is associated with the upper respiratory tract microbiome during COVID-19.

BACKGROUND Recent advances in molecular biology have enabled the identification of potential inflammatory endotypes of chronic rhinosinusitis (CRS), with prior work suggesting differential short-term surgical outcome trajectories based on cytokine signatures. However, there is a paucity of data assessing long-term treatment failure and need for revision surgery based on inflammatory biomarkers. METHODS Retrospective analysis of prospectively collected cross-sectional data from 231 patients electing surgical therapy for CRS. Intraoperative mucus specimens were quantitatively sampled for inflammatory cytokines using a multiplex flow cytometric bead assay. Univariate Spearman correlations between cytokine levels and prior number of surgeries were assessed. A stepwise adjusted multivariate Poisson regression analysis was used to model patient-reported prior sinus surgery counts as a function of cytokine levels. RESULTS Several cytokines (interleukin [IL]-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, tumor necrosis factor α [TNF-α], interferon γ [IFN-γ], and eotaxin) demonstrated significant positive correlations with number of prior surgeries. However, only higher IL-17A levels were independently associated with a higher number of prior sinus surgeries (β = 0.345, p = 0.0003) after adjusting for the significant covariates of age (β = 0.018, p = 0.0036), Lund-Mackay score (β = -0.046, p = 0.02), history of aspirin-exacerbated respiratory disease (β = 1.01, p < 0.0001) and allergic fungal rhinosinusitis (β = 1.08, p < 0.0001). Higher levels of regulated on activation, normal T-cell expressed and secreted (RANTES) were conversely associated with a lower number of prior surgeries (β = -0.17, p = 0.048). CONCLUSION An IL-17A-predominant cytokine profile is linked to an increased number of prior sinus surgeries. Thus, type 3 inflammatory markers may indicate a particularly difficult-to-treat, recalcitrant CRS endotype.

Early reports have suggested that smell loss may be an early symptom associated with the pandemic known as COVID‐19. The possibility that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) might cause olfactory dysfunction is certainly plausible. Patients presenting to specialized smell clinics are commonly diagnosed with upper respiratory infection (URI)‐associated olfactory loss and most are presumed to be viral related. In acute phases of infection, it is common to experience some smell loss as a result of nasal inflammation, mucosal edema, and obstruction of airflow into the olfactory cleft. In most cases, these episodes of smell loss are self‐limiting and coincide with resolution of URI symptoms. However, in some cases the smell loss persists for months to years and this is presumed to occur through a more direct olfactory insult by the virus. It remains too early to know whether infection with SARS‐CoV‐2 causes persistent olfactory dysfunction. However, given the scale of this pandemic, if SARS‐CoV‐2 does cause chronic olfactory loss in even a small portion of those infected, then the overall population prevalence could be quite large. This review provides a brief, practical overview of viral‐associated olfactory loss, realizing that evidence related to COVID‐19 will likely not be clear for some time. Our goal is to highlight the existence and importance of this condition and provide information geared for both providers and patients. Practical suggestions regarding evaluation and treatment will be provided, realizing that there may be constraints on medical resources and the nature of this pandemic remains dynamic. This article is protected by copyright. All rights reserved

BACKGROUND Convolutional neural networks (CNNs) are advanced artificial intelligence algorithms well suited to image classification tasks with variable features. These have been used to great effect in various real-world applications including handwriting recognition, face detection, image search, and fraud prevention. We sought to retrain a robust CNN with coronal computed tomography (CT) images to classify osteomeatal complex (OMC) occlusion and assess the performance of this technology with rhinologic data. METHODS The Google Inception-V3 CNN trained with 1.28 million images was used as the base model. Preoperative coronal sections through the OMC were obtained from 239 patients enrolled in 2 prospective chronic rhinosinusitis (CRS) outcomes studies, labeled according to OMC status, and mirrored to obtain a set of 956 images. Using this data, the classification layer of Inception-V3 was retrained in Python using a transfer learning method to adapt the CNN to the task of interpreting sinonasal CT images. RESULTS The retrained neural network achieved 85% classification accuracy for OMC occlusion, with a 95% confidence interval for algorithm accuracy of 78% to 92%. Receiver operating characteristic (ROC) curve analysis on the test set confirmed good classification ability of the CNN with an area under the ROC curve (AUC) of 0.87, significantly different than both random guessing and a dominant classifier that predicts the most common class (p < 0.0001). CONCLUSION Current state-of-the-art CNNs may be able to learn clinically relevant information from 2-dimensional sinonasal CT images with minimal supervision. Future work will extend this approach to 3-dimensional images in order to further refine this technology for possible clinical applications.

Background Acute invasive fungal sinusitis (AIFS) is a rare, aggressive infection occurring in immunocompromised patients. In this study we examined factors that affect survival in AIFS, and whether immune-stimulating therapies (IST) improve survival. Methods Pathology records of biopsy-proven AIFS were reviewed from 3 academic institutions from 1995 to 2016. Univariate and multivariate Cox regressions were performed at 1 and 3 months from diagnosis. Results One hundred fourteen patients were included; 45 received IST. In the univariate analysis, the following factors were associated with worse survival: hematologic malignancy (3-month hazard ratio [HR], 3.7; p = 0.01); recent chemotherapy (within 1 month of AIFS diagnosis) (3-month HR, 2.3; p = 0.02); recent bone marrow transplant (BMT) (3-month HR, 2.5; p = 0.02); and infection with atypical fungi (1-month HR, 3.1; p = 0.04). The following were associated with improved survival in univariate analysis: increasing A1c% (1-month HR, 0.7; p = 0.01) and surgical debridement (1-month HR, 0.1; p = 0.001). One third of patients with a hematologic malignancy had an absolute neutrophil count (ANC) >1000 at the time of diagnosis. ANC was not associated with prognosis in these patients. The following were associated with worse survival in multivariate analyses: hematologic malignancy; recent chemotherapy; atypical organisms; and cavernous sinus extension. In multivariate analyses, IST was associated with a 70% reduction in mortality at 1 month (p = 0.02). Conclusion We presented the largest series of AIFS. Further studies are needed to examine the importance of ANC in diagnosis and prognosis. Patients diagnosed with atypical organisms may be at higher risk of death. IST likely improves short-term survival, but prospective studies are needed.

Background Chronic rhinosinusitis (CRS) is a diverse clinical syndrome with a heterogeneous pathophysiology. Early attempts to identify CRS endotypes and biomarkers have largely relied on analysis of surgically obtained tissue, thus limiting their practical utility. This study examined the ability of mucus T helper 2 (Th2) biomarkers to predict CRS disease severity and clinical characteristics. Methods CRS (n = 90) and healthy control subjects (n = 17) were prospectively enrolled prior to surgical intervention and mucus levels of interleukin (IL)-4, IL-5, and IL-13 were determined using a multiplex cytometric bead assay. Data for relevant cytokines was then scaled, normalized, and later combined to develop standardized metrics indicative of Th2-associated inflammation. Th2-high and Th2-low subgroups were consequently identified and validated against factors associated with disease severity and clinical outcomes. Results Mucus levels of IL-5 and IL-13 were elevated in CRS subjects compared to controls, while no significant difference was noted for IL-4. IL-5 and IL-13 high CRS were associated with worse objective measures of disease severity and greater rates of revision surgery. Similar relationships were noted for both cytokines when CRS with nasal polyps (CRSwNP) patients were analyzed separately. Th2-high CRS and Th2-low CRS were then categorized using a scaled IL-5/IL-13 metric. Th2-high CRS was characterized by an increased number of subjects with nasal polyps and comorbid asthma, and worse symptom and computed tomography (CT) scores. Conclusion The Th2-associated cytokines, IL-5 and IL-13, are detectable in sinonasal mucus and their levels can be used to define Th2-high and Th2-low CRS. Identification of Th2-high and Th2-low endotypes using mucus-based biomarkers could facilitate stratification of CRS subgroups and guide personalized therapies.

Background The supraglottic airway (SGA) represents an alternative to endotracheal intubation (endotracheal tube [ETT]) in many types of ambulatory surgery. Adoption of the SGA has progressed slowly in sinonasal surgery due to concerns about airway protection. The purpose of this study was to compare quality of life measures and indices of airway protection between patients undergoing sinonasal surgery who were ventilated via an SGA or ETT. Methods Patients undergoing outpatient sinonasal surgery were enrolled into a randomized, single-blind study in which patients would be ventilated with either an SGA or ETT. At the first postoperative visit, a symptom severity and quality of life questionnaire was completed. Additional objective metrics were extracted from the anesthesia record. Results A total of 102 patients were enrolled; 49 assigned to the SGA group and 53 assigned to the ETT group. No significant differences in swallowing function or cough were identified. SGA patients reported more difficulty returning to a normal diet (p = 0.03) with a trend toward reduced throat pain (p = 0.07) and improved phonation (p = 0.06). No significant difference in perioperative oxygen desaturations, emesis, recovery time, or airway blood penetration were identified. Conclusion While the use of the SGA results in patient diet modification postoperatively, it may also be associated with a reduction in throat pain and dysphonia. SGA use had no appreciable effect on postanesthesia recovery times, oxygen desaturations, or emesis. Use of the SGA in sinonasal surgery appears to be a safe and reliable option for airway management in selected adult patients undergoing routine ambulatory sinonasal surgery.

OBJECTIVES/HYPOTHESIS The etiology of chronic rhinosinusitis (CRS)-associated olfactory loss is unclear, but may result from inflammatory changes in the olfactory epithelium that result in signaling dysfunction or loss of olfactory neurons. Several proinflammatory cytokines have been associated with CRS, but their expression within the olfactory cleft microenvironment and association with olfactory function is unknown. STUDY DESIGN Prospective case-control study. METHODS Mucus was collected from the olfactory cleft and middle meatus of 31 CRS without nasal polyps subjects, 36 CRS with nasal polyps (CRSwNP) subjects, and 12 healthy controls. Olfactory function was assessed using the validated Smell Identification Test (SIT). Site-specific levels of 14 cytokines/chemokines (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, tumor necrosis factor-α, Eotaxin, RANTES [regulated on activation, normal T cell expressed and secreted]) were assessed using a multiplex flow cytometric bead assay and correlated with SIT scores. RESULTS Mucus cytokine levels in the olfactory cleft were strongly or moderately correlated with levels in the middle meatus for all but one measured inflammatory mediators. SIT scores were inversely correlated with levels of IL-2 (P = .006), IL-5 (P

Background Olfactory dysfunction is 1 of the hallmark symptoms of chronic rhinosinusitis (CRS). Eosinophilic inflammation has been implicated as a potential causative factor. However, prior studies have been limited by retrospective study designs, concomitant use of systemic corticosteroids, and other confounding factors. Methods CRS and healthy non-CRS control subjects undergoing endoscopic sinus or skull-base surgery were prospectively enrolled and completed olfactory testing utilizing the 40-item Smell Identification Test (SIT) immediately prior to surgery. Histopathological evaluation of tissue excised from the ethmoid bulla was performed by a pathologist in a blinded fashion. Disease severity and patient-reported outcomes were measured via the Lund-Mackay computed tomography (CT) grading system and 22-item Sino-Nasal Outcome Test (SNOT-22), respectively. The associations between olfactory function, tissue eosinophilia, and disease severity were analyzed using Spearman rank order correlation and multiple linear regression. Results Twenty-seven (27) subjects with CRS without nasal polyps (CRSsNP), 32 subjects with CRS with nasal polyps (CRSwNP), and 10 healthy non-CRS controls were enrolled. CRSwNP was associated with higher mean tissue eosinophil counts (71.6 vs 28.1 eosinophils/high-power field [HPF], p < 0.05) and lower age/sex-adjusted SIT scores (−17.4 vs −6.2, p < 0.001) when compared to CRSsNP. SIT scores were strongly negatively correlated with tissue eosinophil counts in CRSwNP (r = −0.60, p = 0.0003), but not CRSsNP (r = 0.16, p = 0.42). The correlation between olfactory function and tissue eosinophilia in CRSwNP persisted after adjusting for disease severity. Conclusion Tissue eosinophilia is associated with olfactory loss in CRSwNP, independent of disease severity. These results suggest a possible role for eosinophils or eosinophil-associated cytokines in CRS-associated olfactory loss.

Background Abnormal mucus composition and bacterial biofilms are thought to contribute to the pathophysiology of rhinosinusitis. Addition of a mucoactive surfactant to saline irrigation solution has been hypothesized to address these factors. We evaluated the safety and tolerability of a reformulated surfactant in a sample of normal subjects. Methods A total of 33 volunteers were randomly assigned to receive either surfactant solution or buffered saline at baseline in a controlled crossover study design. Each subject underwent rhinoscopic exam and in-office smell testing via the 40-question smell identification test (SIT). Those with non-normosmic results or active rhinitis symptoms were excluded. Subjects were instructed to irrigate twice daily with the selected solution for 1 week while keeping a daily diary. For week 2, treatment was stopped. During week 3, each group switched to the other treatment. Exam, SIT, and degree of congestion were assessed after each phase. Results Use of surfactant led to a marginal reduction in mean SIT score of 1.5 points, which was statistically significant (p = 0.012). A clinically meaningful reduction in SIT score, defined as ≥4 points, was observed in 18% (6/33) of subjects after surfactant vs 3% (1/33) after saline (p = 0.046). During the surfactant phase, moderate or severe congestion was reported in 29% (8/28) of subjects completing the diary. In contrast, only 6% (2/32) of subjects reported moderate congestion after the saline phase (p = 0.021). Conclusion In normal volunteers, surfactant nasal irrigation may be associated with tolerability issues due to congestion. A subset may experience reduction in olfactory acuity that appears reversible.

Background The clinical association between cystic fibrosis (CF) and chronic rhinosinusitis (CRS) is well known. Studies have identified several non-CF transmembrane conductance regulator single nucleotide polymorphisms (SNPs) associated with disease severity in CF patients. We hypothesized that prevalence of these SNPs would be different between CRS patients and age/gender-matched non-CRS controls. Methods This is a targeted SNP study of 1231 CRS patients identified through a large university hospital database who were compared with 8796 age- and gender-matched controls without a history of rhinitis, sinusitis, allergies, or asthma. Prevalence of 5 relevant SNPs was compared between groups, with p < 0.05 considered significant. Stratification by race and gender was performed among groups when statistically appropriate. Results CRS patients exhibited a statistically significant (p = 0.036) lower prevalence of rs12883884 (associated with an ion transporter) compared with controls. This association was lost when patients were stratified by race. CRS patients manifested a greater prevalence of rs1403543 (chromosome 23) in both Caucasian and African American subgroups (p = 0.036 and p = 0.026, respectively). Statistical significance disappeared among Caucasians when stratified by gender, but persisted among African American women (p = 0.047). rs12188164 and rs12793173 were both more prevalent in African Americans with CRS than controls (p = 0.042 and p = 0.020, respectively). A trend was also observed for decreased prevalence of rs12883884 in CRS patients compared with controls in the African American subgroup (p = 0.086). Conclusion The identified SNPs were differentially prevalent in CRS compared with control groups, with some variability as a function of race and gender. Further research is required to confirm these findings and elucidate clinical significance.

Background Patient-specific and disease-specific factors shape the course of chronic rhinosinusitis (CRS) and its response to treatment, with optimal management involving interventions tailored to these factors. Recent evidence suggests CRS inflammatory signatures depend on age. The objective of this study was to determine whether age also influences quality-of-life (QOL) and postoperative outcomes. Methods Retrospective analysis of prospectively collected QOL data from 403 adults with medically refractory CRS who underwent functional endoscopic sinus surgery (FESS) at a tertiary care medical center between 2014 and 2018 was undertaken. Total and subdomain scores from the 22-item Sino-Nasal Outcome Test (SNOT-22) and the Short Form 8 Health Survey (SF-8) measure of general health completed at preoperative and postoperative visits were reviewed. Results Patients were divided into young (18 to 39 years, n = 100), middle-aged (40 to 59 years, n = 172), and elderly (≥60 years, n = 131) groups. Baseline total SNOT-22 scores differed between groups (p = 0.01), with middle-aged patients having the highest symptom burden and elderly patients having the lowest. Similar patterns were observed for SNOT-22 subdomains. Elderly patients reported smaller improvements and were less likely to achieve a minimally important clinical difference. CRS patients had worse SF-8 scores compared to the general population, and elderly patients were the least likely to match population norms following surgery. Age was an independent predictor of QOL outcomes after FESS. Conclusion Age may play a significant role in CRS pathophysiology, symptom burden, and surgical outcomes. Elderly patients report smaller improvements in disease-specific and general health QOL after surgery. CRS management in the elderly population should incorporate age-dependent differences in symptom burden and expectations into treatment algorithms.