Mucosal Gene Expression in Response to SARS-CoV-2 Is Associated with Viral Load.

Little is known about the relationships between symptomatic early severe acute respiratory syndrome coronavirus 2 (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 coronavirus disease 19 (COVID-19). We measured SARS-CoV-2 viral load using reverse transcription-quantitative PCR (RT-qPCR). 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 95% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited codetection of other respiratory viruses, with the human Rhinovirus C being identified in 4 (6%) samples. This limited codetection of other respiratory viral pathogens may be due to the implementation of public health measures, like social distancing and masking practices. 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 adjusting for age, sex, and race. Interestingly, the expression levels of most of these genes plateaued at a cycle threshold (CT) value of ~25. Overall, our data show that the early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, potentially modifying COVID-19 outcomes. IMPORTANCE 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. However, the relationship between SARS-CoV-2 viral load, 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, 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.

Particulate matter exposure is associated with increased inflammatory cytokines and eosinophils in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is thought to result from complex interactions between the host immune system, microbiota, and environmental exposures. Currently, there is limited data regarding the impact of ambient particulate matter ≤2.5 µm in diameter (PM2.5) in the pathogenesis of CRS, despite evidence linking PM2.5 to other respiratory diseases. We hypothesized that PM2.5 may result in differential cytokine patterns that could inform our mechanistic understanding of the effect of environmental factors on CRS. METHODS: We conducted an analysis of data prospectively collected from 308 CRS patients undergoing endoscopic sinus surgery. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Clinical and demographic data including zip codes were extracted and used to obtain tract-level income and rurality measures. A spatiotemporal machine learning model was used to estimate daily PM2.5 levels for the year prior to each patient's surgery date. Spearman correlations and regression analysis were performed to characterize the relationship between mucus cytokines and PM2.5. RESULTS: Several inflammatory cytokines including IL-2, IL-5/IL-13, IL-12, and 21 were significantly correlated with estimated average 6, 9, and 12-month preoperative PM2.5 levels. These relationships were maintained for most cytokines after adjusting for age, income, body mass index, rurality, polyps, asthma, and allergic rhinitis (AR) (p < .05). There were also higher odds of asthma (OR = 1.5, p = .01) and AR (OR = 1.48, p = .03) with increasing 12-month PM2.5 exposure. Higher tissue eosinophil counts were associated with increasing PM2.5 levels across multiple timeframes (p < .05). CONCLUSIONS: Chronic PM2.5 exposure may be an independent risk factor for development of a mixed, type-2 dominant CRS inflammatory response.

Development of parallel forms of a brief smell identification test useful for longitudinal testing.

Although there are numerous brief odor identification tests available for quantifying the ability to smell, none are available in multiple parallel forms that can be longitudinally administered without potential confounding from knowledge of prior test items. Moreover, empirical algorithms for establishing optimal test lengths have not been generally applied. In this study, we employed and compared eight machine learning algorithms to develop a set of four brief parallel smell tests employing items from the University of Pennsylvania Smell Identification Test that optimally differentiated 100 COVID-19 patients from 132 healthy controls. Among the algorithms, linear discriminant analysis (LDA) achieved the best overall performance. The minimum number of odorant test items needed to differentiate smell loss accurately was identified as eight. We validated the sensitivity of the four developed tests, whose means and variances did not differ from one another (Bradley-Blackwood test), by sequential testing an independent group of 32 subjects that included persons with smell dysfunction not due to COVID-19. These eight-item tests clearly differentiated the olfactory compromised subjects from normosmics, with areas under the ROC curve ranging from 0.79 to 0.83. Each test was correlated with the overall UPSIT scores from which they were derived. These brief smell tests can be used separately or sequentially over multiple days in a variety of contexts where longitudinal olfactory testing is needed.

Current insight into treatment of chronic rhinosinusitis: Phenotypes, endotypes, and implications for targeted therapeutics.

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.

SARS-CoV-2 infection and viral load are associated with the upper respiratory tract microbiome.

BACKGROUND: Little is known about the relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the respiratory virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, and the upper respiratory tract (URT) microbiome. OBJECTIVE: We sought to compare the URT microbiome between SARS-CoV-2-infected and -uninfected adults and 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, ß-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 (ß linear regression coefficient = 7.53; 95% CI, 0.17-14.89; P = .045). In differential abundance testing, 9 amplicon sequence variants were significantly different in both of our comparisons, with Peptoniphilus lacrimalis, Campylobacter hominis, Prevotella 9 copri, and an Anaerococcus unclassified amplicon sequence variant 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 amplicon sequence variants were more abundant in those without SARS-CoV-2 infection and in those with low viral load during COVID-19. CONCLUSIONS: 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.

Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Although frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting. OBJECTIVE: We sought to identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist. METHODS: Levels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups, and patterns of inflammation among patients with AERD were determined by hierarchical cluster analysis. RESULTS: AERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ; however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified 3 inflammatory subendotypes of AERD characterized by (1) low inflammatory burden, (2) high type 2 cytokines, and (3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity; however, lipid mediators showed less variability than cytokines. CONCLUSIONS: AERD is associated with elevations in type 2 cytokines (IL-5 and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting subendotypes of the disease. Variability in AERD immune signatures should be further clarified because this may predict clinical response to biologic medications that target type 2 inflammation.

Chronic rhinosinusitis in elderly patients is associated with an exaggerated neutrophilic proinflammatory response to pathogenic bacteria.

BACKGROUND: Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined but might have important ramifications given a rapidly aging US and world population. OBJECTIVE: The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures. METHODS: Levels of 17 mucus cytokines and inflammatory mediators were measured in 147 patients with CRS. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes, as well as to determine whether age was associated with specific immune signatures. RESULTS: A CRS endotype with a proinflammatory neutrophilic immune signature was enriched in older patients. In the overall cohort patients 60 years and older had increased mucus levels of IL-1ß, IL-6, IL-8, and TNF-α when compared with their younger counterparts. Increases in levels of proinflammatory cytokines were associated with both tissue neutrophilia and symptomatic bacterial infection/colonization in aged patients. CONCLUSIONS: Aged patients with CRS have a unique inflammatory signature that corresponds to a neutrophilic proinflammatory response. Neutrophil-driven inflammation in aged patients with CRS might be less likely to respond to corticosteroids and might be closely linked to chronic microbial infection or colonization.

Differential effect of omalizumab on pulmonary function in patients with allergic asthma with and without chronic rhinosinusitis.

BACKGROUND: Omalizumab, an anti-immunoglobulin E monoclonal antibody, is approved by the U.S. Food and Drug Administration for the management of patients with allergic asthma and with refractory disease, and has also proven beneficial in the management of selected patients with chronic rhinosinusitis (CRS). The common airway model indicates that patients with both allergic asthma and CRS may be more challenging to manage clinically. This is the first study to evaluate the response of omalizumab in patients with asthma and CRS versus those with asthma alone. OBJECTIVE: To compare pulmonary function test (PFT) responses in omalizumab-treated patients with asthma with CRS with omalizumab-treated patients with asthma without CRS. METHODS: This was a retrospective case-control study at a tertiary university clinic. Between 2007 and 2014, a total of 259 patients with allergic asthma had been prescribed omalizumab for asthma. Outcome measures were absolute, and the percentage changes in PFT results were compared with the baseline. RESULTS: Overall, 81 patients had serial PFT results available for evaluation, among whom 59 (73%) had CRS. Average treatment duration was 27.2, 27.7, and 25.8 months for the entire sample, for patients with asthma and CRS, and for patients with asthma and without CRS, respectively. Overall, PFT metrics improved across all parameters (forced expiratory volume in 1 second, forced vital capacity, forced expiratory volume in 1 second to forced vital capacity ratio, and forced expiratory flow 25-75%). Significant improvement (p < 0.05, paired t-test) was observed for three of four metrics in patients with comorbid CRS but in none of these parameters in patients without CRS. CONCLUSION: Patients with allergic asthma who were treated with omalizumab manifested some improvement in PFT scores. CRS may add to the overall symptom burden experienced by patients with asthma, especially in those with increasing severity, but comorbid CRS did not adversely impact the therapeutic potential of omalizumab. In fact, the benefit of omalizumab was more likely to be observed in patients with asthma and with CRS than in patients with asthma and without CRS.

Endoscopic Repair of Internal Carotid Artery Injury with a Lateral Tongue Muscle Patch Graft: Novel Technique and Literature Review.

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. Conclusion 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.

Frailty is an independent predictor of postoperative rescue medication use after endoscopic sinus surgery.

INTRODUCTION: The modified five-item frailty index (mFI-5) is a validated risk stratification tool with the ability to predict adverse outcomes following surgery. In this study, we sought to use mFI-5 to assess the potential relationship between unhealthy aging and postoperative endoscopic sinus surgery (ESS) outcomes. METHODS: Patients who underwent sinus surgery at Vanderbilt between 2014 and 2018 were identified and assessed using the mFI-5, which is calculated based on the presence of five comorbidities: diabetes mellitus, hypertension requiring medication, chronic obstructive pulmonary disease, congestive heart failure, and non-independent functional status. Multivariate regression analyses were performed to quantify the association of mFI-5 score on need for rescue oral antibiotics, oral steroids, and antibiotic irrigations within 1 year following ESS, adjusting for relevant potential confounders. RESULTS: Four hundred and three patients met inclusion criteria.  Within 6 months of surgery, 312 (77%) required rescue antibiotics, 243 (60%) required oral corticosteroids (OCS), and 31 (8%) initiated antibiotic irrigations. Increasing mFI-5 scores were significantly associated with higher postoperative use of rescue antibiotics (p < 0.0001), OCS (p = 0.032), and antibiotic irrigation (p < 0.0001). Frailty scores remained as an independent predictor of these outcomes after adjustment for age, polyp status, preoperative sinonasal outcomes test (SNOT-22) score, and revision surgery status. CONCLUSIONS: Modified frailty scores may be a useful clinical tool to predict the need for postoperative rescue medication use after ESS.

Epithelial innate immune response to Pseudomonas aeruginosa-derived flagellin in chronic rhinosinusitis.

BACKGROUND: Pseudomonas aeruginosa is a common colonizing pathogen in the upper respiratory tract and is associated with recalcitrant chronic rhinosinusitis (CRS). Herein we sought to characterize the effect of P. aeruginosa-derived flagellin on human sinonasal epithelial cell (HSNEC) immune responses and determine whether these pathways are disrupted in CRS. METHODS: Air-liquid interface cultures were established from CRS and healthy control donors. Cells were incubated with P. aeruginosa-derived flagellin for 24 hours and transcriptional changes were assessed using whole transcriptome RNA sequencing. Apical and basolateral secretion of the pro-inflammatory cytokines in interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 were measured after stimulation by lipopolysaccharide or flagellin and responses were compared between CRS and healthy control patients. RESULTS: HSNECs were weakly responsive to lipopolysaccharide, whereas flagellin stimulated a profound innate immune response dominated by TNF-α, IL-1ß, and IL-17 signaling and activation of the IL-17C/IL-23 axis. CRS-derived HNSECs showed an altered innate immune response to flagellin, characterized by a profound increase in TNF-α secretion coupled with reduced IL-6 secretion. CONCLUSIONS: Flagellin activates a potent innate immune response in HSNECs characterized by pro-inflammatory mediators and cytokines/chemokines associated with neutrophilic inflammation. HSNECs from CRS patients have a dysregulated innate immune response to flagellin characterized by an imbalance between IL-6 and TNF-α secretion.

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis.

BACKGROUND: 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. METHODS: 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. RESULTS: There were 122 (38%) patients with CRSsNP and 197 (62%) with CRSwNP. On univariate analysis, interleukin (IL)-1ß, 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-1ß, 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. CONCLUSION: 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.

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.

Upper respiratory tract microbiota dynamics following COVID-19 in adults.

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, ß-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<0.05 for all comparisons). The abundance of three amplicon sequence variants (ASVs) (one 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.

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.

Aggressive sinonasal natural killer/T-cell lymphoma with hemophagocytic lymphohistiocytosis.

Extranodal natural killer/T-cell lymphoma of the nasal cavity is a rare malignancy with poor overall prognosis. We report the case of a rapidly fatal natural killer/T-cell lymphoma of the nasal cavity complicated by the concominant development of hemophagocytic lymphohistiocytosis. This disorder is marked by clinical findings such as fever and splenomegaly, a multitude of abnormal laboratory findings, and a profound proliferation of circulating macrophages. Left untreated, multi-organ failure and death are common. Prompt diagnosis is essential to the successful management of this disorder and for subsequent recovery.

Mucocele formation under pedicled nasoseptal flap.

The pedicled nasoseptal flap has become an indispensible tool for the reconstruction of skull base defects. This flap is easily harvested, provides a large surface area of vascularized tissue, and has few reported complications. We describe the case of a 60-year-old man who underwent endoscopic, endonasal transsphenoidal surgery with septal flap reconstruction who developed a sphenoid sinus mucocele postoperatively. We also have reviewed the literature for similar findings and discuss this complication in the setting of pituitary surgery and endoscopic skull base repair. Although likely a rare occurrence, mucocele formation after septal flap reconstruction should be recognized and monitored with postoperative nasal endoscopy and radiologic imaging. Reoperation or mucocele drainage may be necessary if symptomatic or in cases of rapid enlargement.