Multiple instance learning for eosinophil quantification of sinonasal histopathology images: A hierarchical determination on whole slide images.

KEY POINTS: We proposed a hierarchical framework including an unsupervised candidate image selection and a weakly supervised patch image detection based on multiple instance learning (MIL) to effectively estimate eosinophil quantities in tissue samples from whole slide images. MIL is an innovative approach that can help deal with the variability in cell distribution detection and enable automated eosinophil quantification from sinonasal histopathological images with a high degree of accuracy. The study lays the foundation for further research and development in the field of automated histopathological image analysis, and validation on more extensive and diverse datasets will contribute to real-world application.

Modified screening and management strategies for chronic rhinosinusitis in hematologic patients receiving hematopoietic stem cell transplantation.

OBJECTIVES: Given the lack of consensus on the screening and treatment for chronic rhinosinusitis (CRS) in the patients undergoing hematopoietic stem cell transplantation (HSCT), we reviewed the risk factors for CRS to improve the efficiency of sinonasal screening and analyzed the effect of treating CRS in search of guidance for modifying current management strategies for rhinosinusitis in HSCT patients. METHODS: We conducted a nested case-control study in a retrospective cohort of hematologic patients receiving HSCT from April 2011 to April 2021 and collected data on demographics, smoking/atopic status, hematological diseases, and features of rhinosinusitis for analysis. The associated factors for control of rhinosinusitis and survival were analyzed. RESULTS: Fifty-eight CRS patients were identified, and another 116 age- and sex-matched controls were selected from HSCT patients without CRS. Allergy and smoking were risk factors for CRS in HSCT patients. The multivariable logistic analysis indicated that endoscopic sinus surgery (ESS) was an independent factor for better control of CRS. However, survival was not associated with rhinosinusitis-related factors, but only with hematologic-related factors, including allogenic HSCT, reduced-intensity conditioning, and remission. CONCLUSIONS: Sinonasal evaluation should be targeted to the high-risk group. ESS is effective in managing CRS, while control of CRS is not determinant of overall survival in patients receiving HSCT.

Comprehensive evaluation of type 2 endotype and clinical features in patients with chronic rhinosinusitis with nasal polyps in Taiwan: a cross-sectional study.

PURPOSE: Endotype-driven treatment has been introduced in the management of chronic rhinosinusitis with nasal polyps (CRSwNP), and an understanding of the associations between phenotypes and endotypes of CRSwNP will be beneficial in identifying responders. We aimed to determine the correlations between clinical manifestations and type 2 inflammatory mediators of sinonasal tissues. METHODS: Adult patients undergoing endoscopic sinus surgery for bilateral CRSwNP were prospectively enrolled. Tissue eosinophilia and type 2 mediator expression in tissue homogenates were assessed and correlated with clinical features, including symptoms, comorbidities, blood eosinophil counts, specific allergen immunoglobulin (IgE) testing, computed tomography (CT) scan findings, and Sino-Nasal Outcome Test-22 scores. RESULTS: A total of 93 subjects were recruited in our study. Fifty-nine (63.4%) cases were identified as the eosinophilic endotype, demonstrating with higher rates of comorbidity of asthma, blood eosinophilia and a high ethmoid-maxillary ratio on CT images. To correlate of phenotypes with the inflammatory mediator profile, multivariate analyses revealed the associations of IgE expression in nasal polyp tissues with allergen sensitization (p = 0.042), CT ethmoid-maxillary ratio (p = 0.001) and tissue eosinophil counts (p = 0.022); the association of interleukin (IL-5) expression with the blood eosinophil percentage (p = 0.020); and the association of IL-13 expression with white blood cell count (p = 0.002) and central compartment-type inflammation (p < 0.001). CONCLUSION: We demonstrated associations of IgE and IL-5 expression with clinical features of eosinophilic-type inflammation and a significantly elevated level of IL-13 in patients with central-compartment-type CRSwNP. These observations may be useful when considering the use of type 2 biologic treatment and require further validation studies.

The link between allergic rhinitis and chronic rhinosinusitis.

PURPOSE OF REVIEW: Allergic rhinitis and chronic rhinosinusitis (CRS) are common disorders affecting millions of people worldwide. Although allergic rhinitis and CRS are distinct clinical entities, certain CRS endotypes share similar pathological mechanisms as those seen in patients with allergic rhinitis. This review assesses the literature behind the similarities and differences seen in patients with CRS and allergic rhinitis, and the role atopy might play in the pathophysiology of CRS. RECENT FINDINGS: In examining the associations between allergic rhinitis and CRS, most studies have focused primarily on CRS with nasal polyps and type 2 inflammation in CRS. Recent studies have demonstrated the similarities and differences in pathologic mechanisms behind allergic rhinitis and CRS, with an emphasis on patient endotypes, genetics, and the nasoepithelial immunologic barrier. Related immunopathology shared by allergic rhinitis and type 2 inflammation in CRS has allowed for therapeutic overlap with biologic treatments. SUMMARY: Allergic rhinitis and CRS often present as comorbid conditions, and understanding the relationship between allergic rhinitis and CRS is important when considering treatment options. Advances in understanding the genetics and immunology, as well as biologic and immunotherapeutic treatments have improved outcomes in patients with CRS, especially in the setting of atopy.

Recent Updates of Immunotherapy for Allergic Rhinitis in Children.

Purpose of Review: Allergen immunotherapy (AIT) is a novel treatment approach with disease-modifying and preventative benefits that are not shared with other strategies for treating allergic illnesses. It has been demonstrated to be safe and effective in children. This review provides the most recent information on AIT in children as well as any pertinent updates. Recent Findings: Although there is not a standard way to begin AIT, there are clear indications for AIT. Each case needs to be evaluated on its own by weighing the pros and downsides. AIT has been proven to significantly improve symptoms and quality of life in children with allergic illness, reduce medication use, stop the development of new allergen sensitizations, and stop the progression of allergic rhinitis to asthma. Novel approaches are under investigation to overcome some known AIT disadvantages. Summary: This review provides a thorough summary of the most recent research and updates on AIT in children.

Improved nasal recovery and intact olfactory function after a transseptal approach for endoscopic endonasal transsphenoidal adenomectomy: A retrospective analysis.

Objectives: Endoscopic endonasal transsphenoidal adenomectomy (TSA) is the most frequently performed skull base surgery, and researchers have recently focused on preserving nasal function. The endoscopic transseptal approach is a promising procedure due to its reduced injury to the nasal mucosa; however, there are no studies comparing rhinological and neurosurgical outcomes concurrently with the standard endoscopic transnasal approach. Therefore, we conducted this study to investigate whether the transseptal approach could reduce nasal morbidities with comparable neurosurgical outcomes. Methods: We retrospectively reviewed 25 patients who underwent endoscopic endonasal transseptal TSA for pituitary adenoma without encasement of internal carotid artery from January 2019 to December 2020. Another 25 patients who received transnasal approach from January 2017 to December 2018 were selected as controls. Patients with diseases affecting the nasal cavity/olfaction or usage of a nasoseptal flap were excluded for a better comparison of the two procedures. We collected data from radiological studies, endocrine studies, endoscopic evaluations, 22-item sinonasal outcome tests (SNOT-22) and Top International Biotech Smell Identification Test (TIBSIT) for comparison. Results: Lower postoperative SNOT-22 and Lund-Kennedy endoscopic scores were observed in the transseptal group. The effect size of differences were classified as large effect (The absolute value of Cohen's d > 0.8). Nevertheless, the TIBSIT scores were not significantly different. The rates of gross total resection, recovery of hormonal abnormalities, and complications were not significantly different. After controlling possible confounding factors using multivariate analysis, the endoscopic transseptal approach remained an independent factor for lower SNOT-22 scores and Lund-Kennedy endoscopic scores. Conclusions: The endoscopic transseptal approach provides improved recovery of nasal mucosa and intact olfaction without compromising neurosurgical outcomes. Level of Evidence: 2b.

Studies on Clinical Features, Mechanisms, and Management of Olfactory Dysfunction Secondary to Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is one of the most common causes of inflammation of the olfactory system, warranting investigation of the link between chronic inflammation and the loss of olfactory function. Type 2 inflammation is closely related to the clinical features and disease mechanisms of olfactory dysfunction secondary to CRS. Patients with eosinophilic CRS, aspirin-exacerbated respiratory disease, and central compartment atopic disease report increased olfactory dysfunction. Increased levels of interleukin-(IL-)2, IL-5, IL-6, IL-10, and IL-13 in the mucus from the olfactory slit have been reported to be associated with reduced olfactory test scores. The influence of several cytokines and signaling transduction pathways, including tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinases, on olfactory signal processing and neurogenesis has been demonstrated. Corticosteroids are the mainstay treatment for olfactory dysfunction secondary to CRS. Successful olfaction recovery was recently demonstrated in clinical trials of biotherapeutics, including omalizumab and dupilumab, although the treatment effect may diminish gradually after stopping the use of the medications. Future studies are required to relate the complex mechanisms underlying chronic inflammation in CRS to dysfunction of the olfactory system.

U-Shape Relationship between Plasma Leucine Level and Mortality in the Intensive Care Unit.

Patients in the intensive care unit (ICU) are at high risk of mortality which is not well predicted. Previous studies noted that leucine has prognostic value in a variety of diseases. This study investigated whether leucine concentration was a useful biomarker of metabolic and nutritional status and 6-month mortality in ICU. We recruited 454 subjects admitted to ICU (348 and 106 in the initiation and validation cohorts, respectively) with an acute physiology and chronic health evaluation (APACHE II) score ≥ 15. We measured plasma leucine concentrations, traditional biomarkers, and calculated APACHE II and sequential organ failure assessment (SOFA) scores. Leucine levels were weakly correlated with albumin, prealbumin, and transferrin levels (r = 0.30, 0.12, and 0.15, p = 0.001, 0.029, and 0.007, respectively). During follow-up, 116 (33.3%) patients died. Compared to patients with leucine levels between 109 and 174 µM, patients with leucine > 174 µM or <109 µM had a lower cumulative survival rate. Death was also associated with age, higher APACHE II and SOFA scores, C-reactive protein, and longer stays in the ICU, but with lower albumin, prealbumin, and transferrin. Patients with leucine levels > 174 µM had higher alanine aminotransferase levels, but no significant differences in other variables; patients with leucine levels < 109 µM had higher APACHE II and SOFA scores, higher incidence of using inotropic agents, longer ICU and hospital stays, but lower albumin and transferrin levels. Multivariable analysis demonstrated that leucine > 174 µM was an independent predictor of mortality, especially early mortality. However, among patients who stayed in ICU longer than two weeks, leucine < 109 µM was an independent predictor of mortality. In addition, leucine < 109 µM was associated with worse ventilator weaning profiles. These findings were similar in the validation cohort. Our study demonstrated a U-shape relationship between leucine levels and mortality rate in ICU.

Endonasal and Endoscopic Repair of Nasal Septal Perforation with an Autologous Fascia Lata Graft.

Importance: We propose a novel technique utilizing both a headlight and an endoscope to repair large iatrogenic septal perforations using autologous fascia lata grafts and extended pedicled mucosal flaps. Objective: The use of an autologous fascia graft, a fat graft, and an extended pedicled mucosal flap enables the closure of a large and anterior perforation of the nasal septum. This approach is an effective and applicable method for nasal septal perforation repair.

The association between low protein diet and body composition, muscle function, inflammation, and amino acid-based metabolic profile in chronic kidney disease stage 3-5 patients.

BACKGROUND: Chronic kidney disease (CKD) is a global burden in the world. Low protein diet (LPD) recommendation is suggested in CKD patients to avoid or defer dialysis initiation and slow down CKD progression. However, nutritional imbalance and protein energy wasting represent key worries. The amino acid-based metabolic profile may provide a sensitive biomarker to evaluate CKD patients' nutrition status with LPD recommendations. METHODS: We conducted a cross-sectional study in CKD stage 3-5 patients who had received LPD recommendation to evaluate the association between LPD and traditional markers (including plasma levels of albumin, pre-albumin, transferrin, total iron-binding capacity), inflammation markers (including peripheral leukocyte count and plasma levels of high-sensitivity C-reactive protein), body composition, muscle strength, and physical function, and novel nutrition markers (including amino acid-based metabolic profile) in CKD stage 3-5 patients. RESULTS: In our study CKD stage 3-5 patients with the total number of 73, the mean age was around 71 ± 10 years old. The mean daily protein intake (DPI) was around 0.9 ± 0.3 g/kg/day and 25 (34%) patients met the recommended goal of DPI <0.8 g/kg/day. The mean daily calorie intake (DCI) was around 23 ± 6 kcal/kg/day, with only 11 (15%) patients met the recommend DCI with 30-35 kcal/kg/day. Compared to CKD patients with non-LPD, patients with LPD had significantly lower hemoglobin and albumin levels, shorter 6-min walking distance (6MWD), and lower leucine levels. Multivariable analysis found that lower hemoglobin and leucine levels, and shorter 6MWD were negatively and independently associated with LPD (all p < 0.05). Then ROC curve analysis found that the optimal cut-off value of leucine plasma levels was 95.5 µM with 60% sensitivity and 71% specificity to predict those CKD patients with LPD with the area under the curve of 0.646 (95% CI: 0.512-0.780). CONCLUSION: LPD attainment was noted in 34% patients and most of CKD stage 3-5 patients (around 85%) had inadequate daily calorie intake although receiving standard dietary counseling routinely. A low protein diet and inadequate daily calorie intake in CKD patients were associated with shorter 6MWD, and lower hemoglobin and leucine levels. Plasma leucine levels lower than 95.5 µM may be a herald for muscle wasting and malnutrition in these CKD stage 3-5 patients with inadequate calorie intake.

Clinical characteristics and cytokine profiles of central-compartment-type chronic rhinosinusitis.

BACKGROUND: The clinical characteristics of central-compartment-type chronic rhinosinusitis (CRS) in East Asian individuals are not clear. We sought to investigate the clinical features and the cytokine profiles of central-compartment-type CRS in our patient group. METHODS: Adult patients diagnosed with bilateral CRS were recruited, and patients who had previously undergone sinus surgery and pansinusitis (Lund-Mackay scores >23) were excluded. Central-compartment-type CRS was defined by both endoscopic and radiological features. The symptoms, inhalant allergen sensitization status, endoscopic findings, and radiological assessments were recorded and compared between patients with central-compartment-type CRS and other types of CRS. We also examined the extent of tissue eosinophilia and specific cytokine protein levels (eosinophil cationic protein [ECP], myeloperoxidase [MPO], immunoglobulin E [IgE], interleukin [IL]-4, IL-5, and IL-13) in the sinonasal tissues. RESULTS: Central-compartment-type CRS was found in 16 (23.9%) patients, and non-central-compartment-type CRS was found in 51 (76.1%) patients. Hyposmia or anosmia as the major symptom was more common in the central-compartment-type CRS group. The numbers of eosinophils in tissue and serum were significantly higher in the central-compartment-type CRS patients. The presence of allergen sensitization was not significantly different between groups. The levels of IL-5 and IL-13 were increased in middle turbinate tissues of patients with central-compartment-type CRS. CONCLUSION: Central-compartment-type CRS was associated with hyposmia or anosmia, eosinophilic subtypes, and elevated levels of IL-5 and IL-13 in middle turbinate tissues but not necessarily correlated with allergic disease in our patients.

The clinical features of endoscopic treated isolated sphenoid sinus diseases.

BACKGROUND: Isolated sphenoid sinus disease (ISSD) is a rare clinical entity with potentially serious complications. The etiological distribution of ISSD varies among different areas and ethnicities. We aimed to investigate the clinical features of patients with endoscopic treated ISSD. METHODS: We retrospectively reviewed all patients with ISSD who had undergone endoscopic surgery between April 2013 and May 2019. The patient records were reviewed for demographic data, clinical presentations, endoscopic and imaging study findings, surgical outcomes and complications. RESULTS: A total of 37 patients with ISSD who underwent surgery were recruited. We divided patients into three groups according to etiology, including inflammatory diseases (78.4%), neoplasms (13.5%) and spontaneous cerebrospinal fluid (CSF) leaks (8.1%); fungal ball (62.2%) constituted the major cause of ISSD. Overall, the most common presenting symptom was headache or facial pain (65.5%). The endoscopic findings of bloody discharge and tumor lesions were mainly from the neoplasm group. Bony defects were more obvious on computed tomography in the neoplasm and CSF leak groups. Magnetic resonance imaging revealed a higher rate of involvement of the cavernous sinus (40.0%) and intracranial extensions (40.0%) in the neoplasm group. To summarize the surgical outcomes, the success rate was 97.1%, and the major complication rate was 5.4%. CONCLUSION: ISSD represents a variety of etiologies, mostly comprising fungal ball in our area, while there is still a considerable proportion of ISSDs attributed to neoplasm and CSF leak. Untreated ISSD can result in serious complications. We recommend early surgical intervention for all patients with ISSD.

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Elevated plasma phenylalanine predicts mortality in critical patients with heart failure.

AIMS: Previous studies found a relationship between elevated phenylalanine levels and poor cardiovascular outcomes. Potential strategies are available to manipulate phenylalanine metabolism. This study investigated whether increased phenylalanine predicted mortality in critical patients with either acute heart failure (HF) or acute on chronic HF, and its correlation with inflammation and immune cytokines. METHODS AND RESULTS: This study recruited 152 subjects, including 115 patients with HF admitted for critical conditions and 37 normal controls. We measured left ventricular ejection fraction (LVEF), plasma concentrations of phenylalanine, C-reactive protein, albumin, pre-albumin, transferrin, and pro-inflammatory and immune cytokines. Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and maximal vasoactive-inotropic scores (VISmax ) were calculated. Patients were followed up until death or a maximum of 1 year. The primary endpoint was all-cause death. Of the 115 patients, 37 (32.2%) were admitted owing to acute HF, and 78 (67.8%) were admitted owing to acute on chronic HF; 64 (55.7%) had ST elevation/non-ST elevation myocardial infarction. An LVEF measured during the hospitalization of <40%, 40-50%, and ≥50% was noted in 51 (44.3%), 15 (13.1%), and 49 (42.6%) patients, respectively. During 1 year follow-up, 51 (44.3%) patients died. Death was associated with higher APACHE II, SOFA, and VISmax scores; higher levels of C-reactive protein and phenylalanine; higher incidence of atrial fibrillation and use of inotropic agents; lower cholesterol, albumin, pre-albumin, and transferrin levels; and significant changes in pro-inflammatory and immune cytokines. Phenylalanine levels demonstrated an area under the receiver operating characteristic curve of 0.80 for mortality, with an optimal cut-off value set at 112 µM. Phenylalanine ≥ 112 µM was associated with a higher mortality rate than was phenylalanine < 112 µM (80.5% vs. 24.3%, P < 0.001) [hazard ratio = 5.07 (2.83-9.05), P < 0.001]. The Kaplan-Meier curves revealed that phenylalanine ≥ 112 µM was associated with a lower accumulative survival rate (log rank = 36.9, P < 0.001). Higher phenylalanine levels were correlated with higher APACHE II and SOFA scores, higher C-reactive protein levels and incidence of using inotropic agents, and changes in cytokines suggestive of immunosuppression, but lower levels of pre-albumin and transferrin. Further multivariable analysis showed that phenylalanine ≥ 112 µM predicted death over 1 year independently of age, APACHE II and SOFA scores, atrial fibrillation, C-reactive protein, cholesterol, pre-albumin, transferrin, and interleukin-8 and interleukin-10. CONCLUSIONS: Elevated phenylalanine levels predicted mortality in critical patients, phenotypically predominantly presenting with HF, independently of traditional prognostic factors and cytokines associated with inflammation and immunity.

Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

Influenza A virus infection induces indoleamine 2,3-dioxygenase (IDO) expression and modulates subsequent inflammatory mediators in nasal epithelial cells.

Background: Nasal epithelial cells are the first site of encounter of the influenza virus, and their innate immune response might define subsequent inflammatory direction.Aims/objectives: We used metabolomics analysis to identify metabolic changes and the regulation of inflammatory cytokines in nasal epithelial cells upon influenza virus infection.Material and methods: We cultured nasal epithelial cells using air-liquid interface (ALI) model. Influenza virus (PR8) infection followed by metabolomic analysis was performed. Furthermore, cytokine expression was analyzed by cytokine array and RT-qPCR.Results: Metabolomic analysis revealed depletion of the tryptophan and accumulation of its metabolite, kynurenine, within 48 h. The major enzyme involved in the tryptophan metabolic pathway, indoleamine 2,3-dioxygenase (IDO), was overexpressed after infection. Cytokine expression array after infection showed increased levels of IL-1α, CCL2, IL-6, CXCL10, CCL5, and CXCL11, and after using 1-methyltryptophan (1-MT) as inhibitor, the expression levels of IL-6 and G-CSF were reduced.Conclusions and significance: Viral infection results in depletion of tryptophan and accumulation of kynurenine via increased cellular IDO activity. Inhibition of IDO activity or replenishment of tryptophan by local application may be a good therapeutic strategy for limiting the initial damage caused by influenza virus in nasal epithelial cells.

Allergy accelerates the disease progression of chronic rhinosinusitis.

BACKGROUND: The role of allergy in the development of chronic rhinosinusitis (CRS) in East Asians is not clear. AIMS/OBJECTIVES: The aim was to investigate the impact of allergies in the clinical characteristics of chronic rhinosinusitis. MATERIAL AND METHODS: A total of 138 CRS patients who underwent endoscopic sinus surgery were included. A brief history of rhinosinusitis symptoms, blood eosinophil count, blood-specific allergen tests, computed tomography (CT) scan findings, Lund-Mackay (LM) CT scores, and Sino-Nasal Outcome Test (SNOT-22) Questionnaire scores, and sinoscopy findings at 3 and 6 months postoperatively. RESULTS: The ImmunoCAP test was positive in 71(51%) patients and negative in 67(49%) patients. The mean age of those who received endoscopic sinus surgery was 7-years younger in the allergic group compared with the non-allergic group (p = .008). The peripheral eosinophil count in the allergic group was higher than that of the non-allergic group (p = .008). The LM scores and SNOT-22 scores were not significantly different between the two groups. The recurrence rate of nasal polyps in the allergic group was higher but without statistical significance. CONCLUSIONS AND SIGNIFICANCE: Allergy may accelerate the disease progression of CRS. The presence of the serum-specific IgE was correlated with peripheral eosinophil percentage, especially in the CRSwNP patients.