Management of Aspirin-Exacerbated Respiratory Disease: What Does the Future Hold?

Aspirin-exacerbated respiratory disease (AERD) is a subtype of chronic rhinosinusitis with polyps (CRSwNP) and asthma with higher recurrence of nasal polyps after surgery and severe asthma. Patients with CRSwNP and asthma should be screened for AERD by detailed history of aspirin/nonsteroidal anti-inflammatory drug reactions and review of medications that may mask aspirin reaction or directly by aspirin challenge. Treatment of AERD may require more intensive therapy, including endoscopic sinus surgery, daily aspirin therapy, leukotriene modifiers, or biologics.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Perioperative management of mastocytosis.

PURPOSE: Patients with mastocytosis have an increased risk of anaphylaxis during surgical procedures with general anesthesia. Therefore, we reviewed the anesthesia course of a large cohort of patients with mastocytosis. METHODS: We retrospectively reviewed adult and pediatric patients with mastocytosis who underwent surgical procedures with general anesthesia at Mayo Clinic from January 1, 2000, through June 30, 2021. We also included any procedures with general anesthesia that occurred during the 3-year period preceding mastocytosis diagnosis and designated the patients who underwent these procedures as having an unknown diagnosis at the time of their surgical procedure. We analyzed whether patients received chronic antimediator treatment for mastocytosis and/or prophylactic medications before the procedures. We also determined whether medications indicative of mastocytosis-related adverse events were intraoperatively administered. RESULTS: We identified 113 patients who underwent 219 procedures during the study period; 25 procedures were performed before mastocytosis diagnosis. Of 194 procedures in patients with known mastocytosis, patients received chronic antimediator therapy and/or perioperative prophylactic medications for 178 (91.8%) procedures. Among these procedures, 10 were potentially complicated by mast cell activation, which was inferred from administration of inhaled albuterol (n = 3) or intravenous diphenhydramine (n = 8). In addition, there was only one case of intraoperative anaphylaxis which occurred in a patient who underwent anesthesia before mastocytosis diagnosis and therefore did not receive prophylaxis. CONCLUSION: Intraoperative anaphylaxis can be the first presenting sign of mastocytosis. Patients with mastocytosis who received chronic antimediator therapy and/or preoperative prophylactic medications had an uneventful surgical course.

Unified Airway Disease: Diagnosis and Subtyping.

The concept of a unified airway posits that pathology affects the respiratory tract in a continuum and that disease in one part of the respiratory tract may be associated with or directly or indirectly affect the function of a different part. Transcriptomic analysis has shown 91% homology between the genes expressed in the upper and the lower airway. Approaching inflammatory airway disorders using the unified airway hypothesis allows for a better clarification of disease process and provides a detailed and a high-level overview of dysfunction. There are several tools available to the clinician to use to subtype and diagnose accurately the abnormal pathways operating in inflammatory airway disorders. These tools include clinical history, physical examination findings, imaging (computed tomography and MRI), allergy and laboratory testing, pulmonary function testing (PFT), and tissue histopathology. Tests can be categorized based on platform, by specimen, or the marker being studied.

Aspirin-Exacerbated Respiratory Disease and the Unified Airway: A Contemporary Review.

Aspirin-exacerbated respiratory disease (AERD) is characterized by abnormal arachidonic acid metabolism leading to chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and upper and/or lower respiratory symptoms after ingestion of cyclooxygenase-1 inhibiting nonsteroidal antiinflammatory drugs. Diagnosis is clinical and may involve an aspirin challenge. Inflammatory biomarkers may be useful for diagnosis and treatment monitoring. Conventional medical management for asthma and CRSwNP is often inadequate. Endoscopic sinus surgery followed by continued medical management with or without aspirin desensitization frequently improves symptoms and objective disease measures. Biological agents targeting eosinophilic inflammation are promising alternatives to conventional management.

Automated Identification of Aspirin-Exacerbated Respiratory Disease Using Natural Language Processing and Machine Learning: Algorithm Development and Evaluation Study.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is an acquired inflammatory condition characterized by the presence of asthma, chronic rhinosinusitis with nasal polyposis, and respiratory hypersensitivity reactions on ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Despite AERD having a classic constellation of symptoms, the diagnosis is often overlooked, with an average of greater than 10 years between the onset of symptoms and diagnosis of AERD. Without a diagnosis, individuals will lack opportunities to receive effective treatments, such as aspirin desensitization or biologic medications. OBJECTIVE: Our aim was to develop a combined algorithm that integrates both natural language processing (NLP) and machine learning (ML) techniques to identify patients with AERD from an electronic health record (EHR). METHODS: A rule-based decision tree algorithm incorporating NLP-based features was developed using clinical documents from the EHR at Mayo Clinic. From clinical notes, using NLP techniques, 7 features were extracted that included the following: AERD, asthma, NSAID allergy, nasal polyps, chronic sinusitis, elevated urine leukotriene E4 level, and documented no-NSAID allergy. MedTagger was used to extract these 7 features from the unstructured clinical text given a set of keywords and patterns based on the chart review of 2 allergy and immunology experts for AERD. The status of each extracted feature was quantified by assigning the frequency of its occurrence in clinical documents per subject. We optimized the decision tree classifier's hyperparameters cutoff threshold on the training set to determine the representative feature combination to discriminate AERD. We then evaluated the resulting model on the test set. RESULTS: The AERD algorithm, which combines NLP and ML techniques, achieved an area under the receiver operating characteristic curve score, sensitivity, and specificity of 0.86 (95% CI 0.78-0.94), 80.00 (95% CI 70.82-87.33), and 88.00 (95% CI 79.98-93.64) for the test set, respectively. CONCLUSIONS: We developed a promising AERD algorithm that needs further refinement to improve AERD diagnosis. Continued development of NLP and ML technologies has the potential to reduce diagnostic delays for AERD and improve the health of our patients.

Urine Leukotriene E4: Implications as a Biomarker in Chronic Rhinosinusitis.

OBJECTIVE: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. DATA SOURCES: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. REVIEW METHODS: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. CONCLUSIONS: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. IMPLICATIONS FOR PRACTICE: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.

Elevated Urine Leukotriene E4 Is Associated With Worse Objective Markers in Nasal Polyposis Patients.

OBJECTIVES: Urine leukotriene E4 (uLTE4) is a biomarker of leukotriene synthesis and is elevated in patients with aspirin-exacerbated respiratory disease (AERD). It can also be useful to help delineate aspirin-tolerant chronic rhinosinusitis with nasal polyposis (CRSwNP) patients from AERD patients. The purpose of this study is to determine if uLTE4 biomarker levels are associated with objective and subjective markers of disease severity in patients with CRSwNP. METHODS: A retrospective analysis of CRSwNP patients who underwent uLTE4 testing was completed to determine the association of uLTE4 levels to markers of disease severity. uLTE4 levels, as well as presenting subjective (Sinonasal Outcome Test 22 [SNOT22] scores, asthma control test [ACT] scores) and objective data (Lund-Mackay CT score, spirometry and lab values) were collected. RESULTS: Among the 157 CRSwNP patients who met inclusion criteria, uLTE4 levels were associated with history of asthma (P < .001), aspirin sensitivity (P < .001), worse Lund-Mackay CT scores (P = .002) and other objective markers of disease severity including serum IgE (P = .05), presenting blood eosinophil level (P < .001), and the highest recorded eosinophil level (P < .001). In subgroup analysis, associations of uLTE4 to disease markers had stronger correlations in the aspirin sensitive CRSwNP group (R range 0.31-0.52) than the aspirin tolerant CRSwNP group (R range -0.30-0.24). uLTE4 levels were not associated with subjective symptom scores (SNOT22 and ACT scores). CONCLUSION: Elevated uLTE4 biomarker levels are associated with worsened objective markers of disease severity in CRSwNP patients but not patient-reported symptom measures. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:961-966, 2021.

How High-Risk Comorbidities Co-Occur in Readmitted Patients With Hip Fracture: Big Data Visual Analytical Approach.

BACKGROUND: When older adult patients with hip fracture (HFx) have unplanned hospital readmissions within 30 days of discharge, it doubles their 1-year mortality, resulting in substantial personal and financial burdens. Although such unplanned readmissions are predominantly caused by reasons not related to HFx surgery, few studies have focused on how pre-existing high-risk comorbidities co-occur within and across subgroups of patients with HFx. OBJECTIVE: This study aims to use a combination of supervised and unsupervised visual analytical methods to (1) obtain an integrated understanding of comorbidity risk, comorbidity co-occurrence, and patient subgroups, and (2) enable a team of clinical and methodological stakeholders to infer the processes that precipitate unplanned hospital readmission, with the goal of designing targeted interventions. METHODS: We extracted a training data set consisting of 16,886 patients (8443 readmitted patients with HFx and 8443 matched controls) and a replication data set consisting of 16,222 patients (8111 readmitted patients with HFx and 8111 matched controls) from the 2010 and 2009 Medicare database, respectively. The analyses consisted of a supervised combinatorial analysis to identify and replicate combinations of comorbidities that conferred significant risk for readmission, an unsupervised bipartite network analysis to identify and replicate how high-risk comorbidity combinations co-occur across readmitted patients with HFx, and an integrated visualization and analysis of comorbidity risk, comorbidity co-occurrence, and patient subgroups to enable clinician stakeholders to infer the processes that precipitate readmission in patient subgroups and to propose targeted interventions. RESULTS: The analyses helped to identify (1) 11 comorbidity combinations that conferred significantly higher risk (ranging from P<.001 to P=.01) for a 30-day readmission, (2) 7 biclusters of patients and comorbidities with a significant bicluster modularity (P<.001; Medicare=0.440; random mean 0.383 [0.002]), indicating strong heterogeneity in the comorbidity profiles of readmitted patients, and (3) inter- and intracluster risk associations, which enabled clinician stakeholders to infer the processes involved in the exacerbation of specific combinations of comorbidities leading to readmission in patient subgroups. CONCLUSIONS: The integrated analysis of risk, co-occurrence, and patient subgroups enabled the inference of processes that precipitate readmission, leading to a comorbidity exacerbation risk model for readmission after HFx. These results have direct implications for (1) the management of comorbidities targeted at high-risk subgroups of patients with the goal of pre-emptively reducing their risk of readmission and (2) the development of more accurate risk prediction models that incorporate information about patient subgroups.

Temozolomide desensitization followed by metronomic dosing in patients with hypersensitivity.

PURPOSE: Temozolomide is the most effective chemotherapy for malignant glioma. Hypersensitivity requiring interruption of therapy may significantly impact patient survival. We have successfully employed temozolomide desensitization followed by metronomic dosing of temozolomide. Our purpose was to report patient characteristics and outcomes in patients with glioma (Grade 2-4) and temozolomide hypersensitivity managed by desensitization and metronomic dosing. METHODS: We performed an observational study of 15 patients at Mayo Clinic (Rochester) with a diagnosis of glioma who underwent temozolomide desensitization with subsequent metronomic dosing from May 2012 to January 2017. We calculated overall and progression-free survival using the Kaplan-Meier method, and log-rank analyses to assess for differences in survival by WHO Grade or treatment initiation. RESULTS: Median age at time of desensitization was 49.3 years (26.8-64.7 years). Median follow-up after desensitization was 35.5 months. One patient (6.7%) was unable to resume temozolomide due to recurrent allergy. The median time from first desensitization to discontinuation of metronomic temozolomide was 4.2 months (0-15.2 months). Median OS and PFS for the whole sample were 181.7 months and 44.9 months. For Grade 4, OS was 100% at 1 year, 40% at 3 years, 20% at 5 years; and PFS was 60% at 1 year, 40% at 3 years, and 20% at 5 years. CONCLUSION: Our results suggest that rapid-desensitization followed by metronomic temozolomide should be considered in patients with glioma who experience hypersensitivity. This strategy provides comparable outcomes to therapy with standard protocols, with the majority of patients able to tolerate temozolomide after desensitization with favorable disease control.

Asthma in the older adult.

Objective: The older adult population is increasing worldwide, and a significant percentage has asthma. This review will discuss the challenges to diagnosis and management of asthma in older adults. Data Sources: PubMed was searched for multiple terms in various combinations, including asthma, older adult, elderly, comorbid conditions, asthma diagnosis, asthma treatment, biologics and medication side effects, and adverse events. From the search, the data sources that were utilized included peer reviewed scholarly review articles, peer reviewed scientific research articles, and peer reviewed book chapters. Study Selections: Study selections that were utilized included peer reviewed scholarly review articles, peer reviewed scientific research articles, and peer reviewed book chapters. Results: Asthma in older adults is frequently underdiagnosed and has higher morbidity and mortality rates compared to their younger counterparts. A detailed history and physical examination as well as judicious testing are essential to establish the asthma diagnosis and exclude alternative ones. Medical comorbidities, such as cardiovascular disease, cognitive impairment, depression, arthritis, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis are common in this population and should also be assessed and treated. Non-pharmacologic management, including asthma education on inhaler technique and self-monitoring, is vital. Pharmacologic management includes standard asthma therapies such as inhaled corticosteroids (ICS), inhaled corticosteroid-long acting ß-agonist combinations (ICS-LABA), leukotriene antagonists, long acting muscarinic antagonists (LAMA), and short acting bronchodilators (SABA). Newly approved biologic agents may also be utilized. Older adults are more vulnerable to polypharmacy and medication adverse events, and this should be taken into account when selecting the appropriate asthma treatment. Conclusions: The diagnosis and management of asthma in older adults has certain challenges, but if the clinician is aware of them, the morbidity and mortality of this condition can be improved in this growing population.

Revision endoscopic sinus surgery rates by chronic rhinosinusitis subtype.

BACKGROUND: Revision surgery rates following endoscopic sinus surgery (ESS) range between 7% and 50% and are influenced by many factors. This study investigates ESS outcomes for chronic rhinosinusitis (CRS) subtypes. METHODS: Retrospective review of adult CRS patients undergoing ESS with a single surgeon (2010-2015) was conducted. Outcomes were analyzed by CRS subtypes. RESULTS: ESS was performed in 424 CRS patients (CRS with nasal polyps [CRSwNP], n = 170; CRS without polyps [CRSsNP], n = 254). Most patients (309; 72.9%) could not be specifically subtyped; 115 (27.1%) were subtyped as follows: aspirin-exacerbated respiratory disease (AERD), n = 47 (11.1%); allergic fungal sinusitis (AFS), n = 39 (9.2%); immunodeficiency, n = 21 (5.0%); granulomatosis with polyangiitis (GPA), n = 5 (1.2%); and eosinophilic granulomatosis with polyangiitis (EGPA), n = 3 (0.7%). All subgroups experienced clinically meaningful reduction in postoperative 22-item Sino-Nasal Outcome Test (SNOT-22) scores. At median follow-up of 28 months (interquartile range [IQR], 10-47 months), 19 patients (4%) underwent revision ESS (CRSwNP, n = 6; CRSsNP, n = 13). Revision ESS rates were 3.5% and 5.1% for CRSwNP and CRSsNP, respectively. Revision ESS rate for subtypes were: AERD 2%; AFS 2%; immunodeficiency 14%; GPA 40%; EGPA 0%; and "all other CRS" 4% at median follow-up duration of 36, 28, 41, 37, 44, and 26 months, respectively. CONCLUSION: All CRS subtypes demonstrated clinically meaningful improvement in postoperative SNOT-22 scores following ESS. Our overall revision ESS rate was 4% (3.5% in CRSwNP). AFS, AERD, and EGPA groups demonstrated low revision rates, while immunodeficiency and GPA patients required more revision surgery. A contemporary understanding of CRSwNP subtypes facilitated surgical and medical strategies in improving outcomes for AERD, AFS, and EGPA patients. CRSsNP subtypes with immunodeficiency and GPA merit further investigation to optimize outcomes.

Recent advances in biologic therapy of asthma and the role in therapy of chronic rhinosinusitis.

Great strides have been made in the last five years in understanding the pathology of chronic rhinosinusitis (CRS). CRS is now accepted to be the end-stage manifestation of inflammation resultant from various pathogenetic mechanisms. This has resulted in increasing recognition of distinct CRS endotypes. Such endotypes encompass a cluster of patients with similar pathogenic mechanisms that may have common therapeutic targets and responsiveness to interventions. The elucidation of mechanisms leading to the development of chronic upper (sino-nasal) airway inflammation has to some extent paralleled investigations of aberrant pathways operant in asthma. In this review, we focus on recent developments in understanding the innate immune pathways as well as adaptive (late) immune responses in CRS and asthma and their implication as potentially modifiable targets in CRS. Specific biologic therapy (that is, monoclonal antibodies targeting cytokines, cytokine receptors, or specific key molecules targeting inflammation) is an exciting proposition for the future of medical management of CRS. As of the writing of this article, the agents described are not approved for use in CRS; many have partial approval for use in asthma or are considered experimental.

SNOT-22-based clusters in chronic rhinosinusitis without nasal polyposis exhibit distinct endotypic and prognostic differences.

BACKGROUND: Endotypic and prognosticating features of chronic rhinosinusitis without nasal polyposis (CRSsNP) are poorly understood. Our objectives were to use an unbiased symptom-based approach to: (1) study symptoms, clinical and endotypic features; and (2) identify features predicating outcomes from endoscopic sinus surgery (ESS). METHODS: Clinical, computed tomography (CT), histopathology, and 22-item Sino-Nasal Outcome Test (SNOT-22) data was collected on 146 adult CRSsNP patients who underwent ESS. Unsupervised network modeling of presurgical SNOT-22 scores was performed to classify symptom-based clusters. Subject characteristics and post-ESS SNOT-22 scores were compared between clusters. RESULTS: Baseline characteristics of the subject population were as follows: females, 56.2%; revision ESS status in 35%; asthma prevalence, 32.6%; median Lund-Mackay CT score, 8; and median SNOT-22 total score, 43. Network mapping and unsupervised clustering of preoperative SNOT-22 scores revealed 4 clusters: (A) severely burdened with high scores in all 4 subdomains; (B) moderately burdened with high scores in the rhinologic subdomain; (C) moderately burdened with high scores in psychological-sleep subdomains; and (D) mildly burdened. The number of previous ESS and asthma prevalence differed significantly between clusters; CT scores were similar. Asthma burden and tissue eosinophilia were greatest in cluster A (p = 0.03). All groups showed significant improvement at 3 months post-ESS (p < 0.0001). At 6 months, patients in cluster C tended to worsen. CONCLUSION: SNOT-22-based network modeling of CRSsNP patients yielded 4 clusters with distinct features. Asthma prevalence and tissue eosinophilia were highest in the cluster with highest SNOT-22 scores. All patients showed significant improvement from ESS at 3 months; those with high sleep-psychosocial symptoms tended to show worsening at 6 months.

Predictors of granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency.

BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) develop granulomatous lymphocytic interstitial lung disease (GLILD), which is associated with early mortality. OBJECTIVE: To determine a set of clinical and/or laboratory parameters that correlate with GLILD. METHODS: A retrospective, nested case-control (patients with CVID diagnosed with GLILD compared with patients with CVID without a diagnosis of GLILD) medical record review was undertaken at Mayo Clinic, Rochester, MN. Network and univariate analysis was used to identify clinical and laboratory parameters at the time of diagnosis that are associated with GLILD. RESULTS: Twenty-six cases with radiologic evidence of GLILD were included in this study. Eighteen cases (69%) cases had coexistent splenomegaly with lower IgA levels (P = .04) compared with the controls. Patients with low IgA levels (<13 mg/dL) also had percentage expansion of low CD21 B cells (CD21low >5%) (P = .007). Univariate analysis revealed that splenomegaly (odds ratio [OR], 17.3; 95% confidence interval [CI], 3.9-74.5), history of immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) (OR, 4.8; 95% CI, 1.1-20.2), low IgA level (OR, 3.6; 95% CI, 1.2-11.9), and percentage expansion of CD21low (OR, 5.8; 95% CI, 1.6-24.7) were independently associated with GLILD. Logistic regression analysis revealed that splenomegaly, history of ITP or AIHA, low IgA level, and percentage expansion of CD21low B cells are highly sensitive in predicting presence of GLILD (area under the receiver operating curve of 0.86). CONCLUSION: Presence of splenomegaly, history of ITP or AIHA, low serum IgA level, and percentage expansion of CD21low B cells may be useful to identify a group of patients at high risk for development of GLILD.

Urinary Leukotriene E4 to Determine Aspirin Intolerance in Asthma: A Systematic Review and Meta-Analysis.

BACKGROUND: Urinary leukotriene E4 (ULTE4) may be a biomarker that distinguishes aspirin-intolerant asthma from other asthma subtypes. OBJECTIVE: To estimate the diagnostic testing accuracy of ULTE4 as a marker of aspirin intolerance in patients with asthma using previously published studies. METHODS: We identified relevant clinical studies from a systematic review of English and non-English articles using MEDLINE, EMBASE, and CENTRAL (inception to February 10, 2015). Articles were screened at the abstract and full-text level by 2 independent reviewers. We included previously published studies that analyzed ULTE4 in human subjects with asthma characterized as having or not having aspirin intolerance on the basis of a specified definition: convincing history of aspirin intolerance, positive aspirin challenge, or both as the criterion standard. Individual-level data points from all included studies were obtained and analyzed. RESULTS: The search strategy identified 867 potential articles, of which 86 were reviewed at the full-text level and 10 met criteria for inclusion. The sensitivity, specificity, positive predictive value, and negative predictive values of ULTE4 to determine aspirin intolerance in subjects with asthma were 0.55, 0.82, 0.75, and 0.66 (Amersham-enzyme immunoassay); 0.76, 0.77, 0.70, and 0.78 (Cayman-enzyme immunoassay); 0.70, 0.81, 0.86, and 0.79 (mass spectrometry); and 0.81,0.79, 0.65, and 0.88 (radioimmunoassay) at optimal thresholds of 192, 510, 167 to 173, and 66 to 69 pg/mg Cr, respectively. The diagnostic odds ratio for each methodology was 6.0, 11.9, 10.5, and 19.1, respectively. CONCLUSIONS: ULTE4 is a marker for aspirin-intolerant asthma and could potentially be used as a clinical test to identify the risk of aspirin intolerance in subjects with asthma.

Unsupervised network mapping of commercially available immunoassay yields three distinct chronic rhinosinusitis endotypes.

BACKGROUND: Endotyping chronic rhinosinusitis (CRS) through simplified cytokine assays may help direct individualized therapy such as corticosteroids, antibiotics, or biologics. We performed an unsupervised network analysis to endotype CRS and control subjects using a commercially available cytokine-chemokine immunoassay. METHODS: A 41-plex cytokine-chemokine array along with major basic protein (MBP) assay was performed on sinonasal surgical tissue of 32 adults. Subjects were defined as non-CRS controls (n = 6), CRS with nasal polyps (CRSwNP; n = 13), and CRS without nasal polyps (CRSsNP; n = 13). Unsupervised network modeling was performed to reveal association cytokine-chemokine ("analyte") clusters and "subject" groups. RESULTS: Network mapping and unsupervised clustering revealed 3 analyte clusters and 3 subject groups. Analyte cluster-1 was composed of T helper 1 (Th1)/Th17 type markers, analyte cluster-2 Th2 markers, and analyte cluster-3 chemokines (CC) and growth factors (GF). Subject group-1 was devoid of CRSwNP, had fewer asthmatics, and was associated most strongly with analyte cluster-3 (CC/GF) (p < 0.001). Subject group-2 was characterized with the most asthmatics (86%) and CRSwNP (100%) patients, and was associated with analyte cluster-2 (Th2; p < 0.001). Subject group-3 was associated with both analyte cluster-1 (Th1/Th17) and analyte cluster-3 (CC/GF) (p < 0.001), and had the highest proportion of CRSsNP patients (62.5%). Tissue levels of MBP, eosinophilia, and computed tomography (CT) scores were significantly higher in subject group-2 vs other groups (p ≤ 0.05). CONCLUSION: An unbiased network-mapping approach using a commercially available immunoassay kit reveals 3 distinct tissue cytokine-chemokine signatures that endotype CRS patients and controls. These signatures are prominent even in a limited number of patients, and may help formulate individualized therapy and optimize outcomes.

Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity.

BACKGROUND: Urinary leukotriene E4 (LTE4) is a well-validated marker of the cysteinyl leukotriene pathway, and LTE4 elevation has been described in conditions such as asthma, aspirin sensitivity, and chronic rhinosinusitis (CRS). There have been a number of reports investigating the role of spot urine LTE4 to predict aspirin sensitivity; however, variability in urinary LTE4 may affect the accuracy of this approach. OBJECTIVE: Here, we explored the utility of 24-hour urinary LTE4 in 5 clinical diagnoses of allergic rhinitis, asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), CRS without nasal polyps, and aspirin sensitivity. METHODS: This was a retrospective review of patients who had 24-hour quantification of urinary LTE4 by a clinically validated liquid chromatography tandem mass spectrometry method and their assigned diagnoses after assessment and clinical care. RESULTS: Twenty-four-hour urinary LTE4 elevations were seen in those with asthma and those with CRSwNP but influenced by underlying aspirin sensitivity. Elevation in LTE4 was significant in those with CRSwNP after adjusting for aspirin sensitivity. Allergic rhinitis was not associated with elevated LTE4 excretion. Receiver operator characteristic analysis of 24-hour urinary LTE4 showed that a cutoff value of 166 pg/mg Cr suggested the presence of history of aspirin sensitivity with 89% specificity, whereas a cutoff value of 241 pg/mg Cr discriminated "challenge-confirmed" aspirin-sensitive subjects with 92% specificity. CONCLUSIONS: Elevated 24-hour excretion of urinary LTE4 is a reliable and simple test to identify aspirin sensitivity in patients with respiratory diagnoses.

Gender-specific analysis of outcomes from endoscopic sinus surgery for chronic rhinosinusitis.

BACKGROUND: Women electing endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) report higher symptom burden but have lower computed tomography (CT) scores. Gender-specific analysis of outcomes from ESS therefore merits further study. The objective of this work was to study gender-specific differences in outcomes from ESS for CRS by analyzing preoperative and postoperative 22-item Sino-Nasal Outcome Test (SNOT-22) scores. METHODS: Data from adult CRS patients electing ESS (2011-2013) were retrospectively collected. SNOT-22 total, rhinologic/nonrhinologic subdomain, and individual item scores were analyzed for gender-specific differences. RESULTS: Two hundred and forty-eight patients met study criteria (mean age 55.4 years; 49.6% female). Preoperatively, mean Lund-Mackay CT score was 11.1; average total SNOT-22 score was 41.9. Compared to men, women had lower CT score (10.2 vs 12.0; p = 0.004) but higher total SNOT-22 score (44.7 vs 39.1; p = 0.02). Both genders showed significant improvement in total SNOT-22 scores at 3, 6, 12, and 24 months following ESS (p < 0.001), with largely similar slopes of improvement. The greatest improvement occurred at 3 months (SNOT-22 decreased by 25.4 points), with stable improvement after 12 months (SNOT-22 decreased by 21.3 points). Higher total SNOT-22 scores in females were noted preoperatively and until 6 months post-ESS; these were driven by rhinologic and nonrhinologic-otolaryngic subdomain items. No gender differences in anxiety/depression prevalence or psychological subdomain scores were noted preoperatively or postoperatively. CONCLUSION: Both male and female CRS patients showed significant and durable symptom relief following ESS. Women reported higher symptom burden prior to surgery, and in the early postoperative period. However, after 1-year post-ESS, both genders showed similar symptom scores. The trend and magnitude of improvement were similar in both genders.