Divekar, Rohit

BackgroundEndotypic 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).MethodsClinical, 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.ResultsBaseline 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.ConclusionSNOT‐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.

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.

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.

BackgroundThe objective of this study was to investigate gender‐specific differences in chronic rhinosinusitis (CRS) patients electing endoscopic sinus surgery (ESS).MethodsThis study was a retrospective review of CRS patients electing ESS (2011–2013) at a tertiary‐care center.ResultsESS was elected by 272 patients (mean age 54.6 years; 48.5% female). Mean Lund‐Mackay computed tomography (CT) score was 10.9; total 22‐item Sino‐Nasal Outcome Test (SNOT‐22) score was 41.8. Compared to men, women electing ESS had lower CT score (10.1 vs 11.7; p = 0.01) but higher total SNOT‐22 score (44.9 vs 39; p = 0.02). Women reported significantly worse postnasal drainage (p < 0.0001) and embarrassment (p = 0.0021). SNOT‐22 scores declined with advancing age (women, p = 0.003; men, p = 0.0005). Reduction in CT scores with age was seen only in males (p = 0.03). Stratifying by age, females aged 61 to 80 years had higher SNOT‐22 scores compared to male counterparts (p = 0.04), whereas CT scores were similar. More women underwent surgery for CRS without nasal polyps (CRSsNP) (54.9%) whereas more men underwent surgery for CRS with nasal polyps (CRSwNP) (57.4%), but this difference missed statistical significance (p = 0.052). Women with CRSwNP had higher SNOT‐22 scores than men (p = 0.02) for similar CT scores. Men electing ESS for CRSsNP had higher CT scores than women (p = 0.02). Women with CRSsNP aged 18 to 40 years reported higher SNOT‐22 scores than men (p = 0.003), even though CT scores were lower (p = 0.005).ConclusionEquivalent numbers of men and women underwent ESS for CRS. Overall, women electing ESS had higher total SNOT‐22 scores and lower Lund‐Mackay CT scores than men. Women reported more problems with postnasal drainage (CRS overall, CRSsNP, and CRSwNP), embarrassment (CRS overall and CRSwNP), and facial pain (CRSwNP). Gender differences in CRS are poorly understood and merit further study.

AbstractBackgroundThe utility of measuring histamine and prostaglandin metabolites in the urine of patients with mastocytosis has not been critically examined in a large series of patients. This study examined the relationship between the extent of increase in urinary excretion of 11β‐prostaglandinF2α and N‐methyl histamine, with serum tryptase, whole blood serotonin, and bone marrow findings including morphology, percentage involvement, and abnormal mast cell phenotype.MethodsThis was a retrospective analysis of 90 patients who were continuously enrolled in the study for a period of 6 years (2008–2014). We recorded serum tryptase, whole blood serotonin, levels of urinary mast cell metabolites 11β‐prostaglandinF2α and N‐methyl histamine (NMH), and bone marrow findings.ResultsUrinary mast cell metabolites 11β‐prostaglandinF2α and N‐methyl histamine correlated with levels of serum tryptase, mast cell burden in the bone marrow, the presence of mast cell aggregates, and atypical mast cells on bone marrow biopsy. Whole blood serotonin did not have a significant correlation with the serum tryptase or mast cell burden in the bone marrow. Urinary NMH was significantly different between c‐kit D816V‐positive and c‐kit D816V‐negative patients, while 11β‐prostaglandinF2α was not. Urinary 11β‐prostaglandinF2α 24‐h excretion >3500 ng and NMH levels >400 μg/gm Cr corresponded with the high degree of bone marrow biopsies positive for atypical mast cells, the presence of aggregates, and c‐kit mutation.ConclusionsEasily obtained and quantified urinary metabolites of histamine (greater than twice the upper limit of normal) and prostaglandin D2 (>3.4 times the upper limit of normal) correlate well with bone marrow findings of mastocytosis.

BackgroundThe objective of this work was to study patient and 22‐item Sino‐Nasal Outcome Test (SNOT‐22) characteristics in primary headache disorders (PHDs).MethodsRetrospective chart review of “sinus” headache/pressure/pain patients was conducted. Patients that had rhinosinusitis excluded (negative endoscopy/computed tomography [CT]), and neurologist‐confirmed PHD were studied. Patterns in symptom and SNOT‐22 items were analyzed by network visualization and cluster analysis.ResultsForty‐six patients met study criteria. Forty‐three (93.5%) reported “need to blow nose” and 40 (86.9%) reported postnasal drainage. Sneezing was reported by 37 (80.4%) patients, “blockage/congestion of nose” by 33 (71.8%), and “runny nose by 32 (69.6%) patients. The median SNOT‐22 score was 54 (interquartile range [IQR], 40 to 63). Past history included neurological diagnoses (60%), rhinologic disease (39%; chronic rhinosinusitis [CRS], rhinitis, recurrent acute sinusitis), asthma (28%), and allergen‐sensitivity (26%). Previous sinonasal surgery had been performed in 41%. Network layout and cluster analysis identified 2 patient clusters and 2 symptom clusters. Two‐thirds (31) of patients formed a tight cluster (cluster 1) linking to a symptom cluster of psychosocial items wrapped tightly with “facial pain/pressure.” The remaining one‐third of patients (cluster 2) linked to rhinologic symptoms loosely grouped away from “facial pressure/pain.” In contrast to patients in cluster 2, patients in cluster 1 were predominantly female (p < 0.04), had significantly higher (p < 0.0001) median SNOT‐22 scores (60 vs 34; IQR, 53 to 67 vs 17 to 42), were more likely to have migraine history (p = 0.058), and reported being “sad” (p < 0.0001) or “embarrassed” (p < 0.006).ConclusionProminent rhinologic symptoms can be present in PHD patients in the absence of rhinosinusitis. In particular, high symptom‐burden/SNOT‐22 scores and high psychosocial symptoms should raise suspicion of PHD when endoscopy and/or CT results do not correlate with symptoms.

Despite years of preclinical development, biological interventions designed to treat complex diseases such as asthma often fail in phase III clinical trials. These failures suggest that current methods to analyze biomedical data might be missing critical aspects of biological complexity such as the assumption that cases and controls come from homogeneous distributions. Here we discuss why and how methods from the rapidly evolving field of visual analytics can help translational teams (consisting of biologists, clinicians, and bioinformaticians) to address the challenge of modeling and inferring heterogeneity in the proteomic and phenotypic profiles of patients with complex diseases. Because a primary goal of visual analytics is to amplify the cognitive capacities of humans for detecting patterns in complex data, we begin with an overview of the cognitive foundations for the field of visual analytics. Next, we organize the primary ways in which a specific form of visual analytics called networks has been used to model and infer biological mechanisms, which help to identify the properties of networks that are particularly useful for the discovery and analysis of proteomic heterogeneity in complex diseases. We describe one such approach called subject‐protein networks, and demonstrate its application on two proteomic datasets. This demonstration provides insights to help translational teams overcome theoretical, practical, and pedagogical hurdles for the widespread use of subject‐protein networks for analyzing molecular heterogeneities, with the translational goal of designing biomarker‐based clinical trials, and accelerating the development of personalized approaches to medicine.

SummaryBackgroundThe mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease.ObjectiveTo characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls.MethodsThis was a non‐interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post‐visit 2 weeks later. The sinonasal outcome test‐22 (SNOT‐22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis.ResultsBoth CRSwNP patients and control subjects showed a significant increase in SNOT‐22 scores during acute exacerbation. Increased nasal levels of IL‐6, IL‐5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM‐CSF levels were notable and were validated by a conventional analysis.ConclusionsCRSwNP patients demonstrate distinct immunological changes locally and systemically during acute exacerbation. Growth factors VEGF and GM‐CSF may be involved in the immunopathogenesis of subjects with CRS and nasal polyps experiencing exacerbation.