Breathing pattern disorder in chronic rhinosinusitis with severe asthma: nasal obstruction and polyps do not increase prevalence.

OBJECTIVES: Chronic rhinosinusitis (CRS) with severe asthma are associated with breathing pattern disorder (BPD). Mouth breathing is a sign of breathing pattern disorder, and nose breathing a fundamental part of breathing pattern retraining for BPD. The prevalence of BPD in relation to CRS subtypes and the relationship of nasal obstruction to BPD in CRS and associated severe asthma is unknown. The breathing pattern assessment tool (BPAT) can identify BPD. Our objective was to thus investigate the prevalence of BPD, nasal airflow obstruction and measures of airway disease severity in CRS with (CRSwNP) and without nasal polyps (CRSsNP) in severe asthma. METHODS: We determined whether CRS status, peak nasal inspiratory flow (PNIF) or polyp disease increased BPD prevalence. Demographic factors, measures of airway function and breathlessness in relation to BPD status and CRS subtypes were also evaluated. RESULTS: 130 Patients were evaluated (n = 69 had BPD). The prevalence of BPD in CRS with severe asthma was 53.1%. There was no difference between BPD occurrence between CRSwNP and CRSsNP. The mean polyp grade and PNIF were not statistically different between the BPD and non-BPD group. The presence of nasal polyps did not increase breathlessness. CONCLUSIONS: BPD and CRS are commonly co-associated. CRS status and nasal obstruction per se does not increase BPD prevalence.

Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective.

Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.

Novel Biomarkers in Sinonasal Cancers: from Bench to Bedside.

PURPOSE OF REVIEW: Sinonasal cancers are a heterogenous group of rare cancers for which histopathological diagnosis can be very challenging and treatment options are limited for advanced disease in particular. Here, we review the candidacy of novel diagnostic and prognostic biomarkers, and therapeutic targets for sinonasal cancers. RECENT FINDINGS: Molecular multidimensional analyses of sinonasal cancers have been lagging behind other major cancers, but there are numerous publications describing the discovery of novel candidate biomarkers, e.g. the methylation classifier, originally developed for brain cancers, and gene expression panels for the prediction of response to induction chemotherapy in sinonasal undifferentiated carcinoma. The most promising biomarkers are summarized and discussed further with regard to their clinical applicability and future potential. Many of the described novel biomarkers for sinonasal cancers will eventually overcome the pitfalls associated with the frequently non-specific immunohistological tests. With comprehensive, multidimensional molecular testing of these tumours in collaborative consortia projects, our better understanding of the molecular mechanisms of sinonasal cancers and their carcinogenesis will determine the most useful diagnostic and prognostic biomarkers, allow stringent multi-institutional validation and guide trials on targeted therapies.

Peak nasal inspiratory flow measurement and visual analogue scale in a large adult population.

OBJECTIVES: Nasal obstruction is the most common symptom in nasal diseases. It can be evaluated objectively, that is by means of peak nasal inspiratory flow (PNIF) measures and/or subjectively by means of validated questionnaires. However, it has been reported that there is a lack of reliable correlation between subjective and objective measurements of nasal obstruction. The aim of the present study was to evaluate the correlation between PNIF measurements and the subjective sensation of nasal obstruction measured by means of a visual analogue scale (VAS) in a large population of consecutive rhinologic patients. DESIGN: Prospective clinical study. SETTING: Tertiary rhinological referral centre. PARTICIPANT MAIN OUTCOME MEASURES: A total of 641 consecutive subjects were enrolled. Visual analogue scale and PNIF were performed to assess nasal obstruction. Nasal septal deviation was classified according to Mladina classification, and its severity was assessed using three levels of severity. RESULTS: Although weak, there was a significant negative correlation (r = -0.13, P = 0.001) between PNIF and VAS. Dividing the population in those affected by nasal septal deviation (NSD) and those affected by chronic rhinosinusitis (CRS), a week negative correlation between PNIF and VAS was again confirmed in both groups (r = -0.208, P = 0.006 for NSD and r = -0.13, P = 0.04 for CRS). Peak nasal inspiratory flow and VAS were also evaluated according to the grade of polyps and the type and level of septal deviation. CONCLUSIONS: Visual analogue scale and PNIF significantly correlated, although with a low degree, in a large population of rhinologic patients. Peak nasal inspiratory flow, being cheap and simple to use, could be a good candidate to assist clinicians dealing with "airway" diseases in their daily clinical practice in order to provide comprehensive information on nasal function. Peak nasal inspiratory flow can in fact give some important rough insights on VAS, but these measurements cannot be alternative to each other.

DNA methylation-based reclassification of olfactory neuroblastoma.

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

Correction to: DNA methylation-based reclassification of olfactory neuroblastoma.

In the original publication, the second name of the twentieth author was incorrect. It should read as 'Miguel Sáinz-Jaspeado'. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.

Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial.

BACKGROUND: Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. OBJECTIVE: We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. METHODS: This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. RESULTS: One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. CONCLUSION: In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.

Antibodies and superantibodies in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps is associated with local immunoglobulin hyperproduction and the presence of IgE antibodies against Staphylococcus aureus enterotoxins (SAEs). Aspirin-exacerbated respiratory disease is a severe form of chronic rhinosinusitis with nasal polyps in which nearly all patients express anti-SAEs. OBJECTIVES: We aimed to understand antibodies reactive to SAEs and determine whether they recognize SAEs through their complementarity-determining regions (CDRs) or framework regions. METHODS: Labeled staphylococcal enterotoxin (SE) A, SED, and SEE were used to isolate single SAE-specific B cells from the nasal polyps of 3 patients with aspirin-exacerbated respiratory disease by using fluorescence-activated cell sorting. Recombinant antibodies with "matched" heavy and light chains were cloned as IgG1, and those of high affinity for specific SAEs, assayed by means of ELISA and surface plasmon resonance, were recloned as IgE and antigen-binding fragments. IgE activities were tested in basophil degranulation assays. RESULTS: Thirty-seven SAE-specific, IgG- or IgA-expressing B cells were isolated and yielded 6 anti-SAE clones, 2 each for SEA, SED, and SEE. Competition binding assays revealed that the anti-SEE antibodies recognize nonoverlapping epitopes in SEE. Unexpectedly, each anti-SEE mediated SEE-induced basophil degranulation, and IgG1 or antigen-binding fragments of each anti-SEE enhanced degranulation by the other anti-SEE. CONCLUSIONS: SEEs can activate basophils by simultaneously binding as antigens in the conventional manner to CDRs and as superantigens to framework regions of anti-SEE IgE in anti-SEE IgE-FcεRI complexes. Anti-SEE IgG1s can enhance the activity of anti-SEE IgEs as conventional antibodies through CDRs or simultaneously as conventional antibodies and as "superantibodies" through CDRs and framework regions to SEEs in SEE-anti-SEE IgE-FcεRI complexes.

The Role of Macrolides in Chronic Rhinosinusitis (CRSsNP and CRSwNP).

PURPOSE OF REVIEW: We assess the literature on the pharmacokinetics, indications, important considerations, and effectiveness of long-term, low-dose macrolide antibiotics in chronic rhinosinusitis (CRS). RECENT FINDINGS: The key to effective implementation of macrolide therapy in CRS is appropriate patient selection. Macrolides have demonstrated the most benefit in Th1-mediated non-eosinophilic CRS when used for durations of at least 3 months. Macrolide antibiotics have demonstrated great benefit when used for their anti-inflammatory or immunomodulatory properties, which include the blockage of pro-inflammatory cytokines, such as interleukin (IL)-8 and tumor necrosis factor-α (TNF-α). They have been used in CRS patients not responding to traditional corticosteroid-based treatment regimens, but appear to be most effective specifically in Th1-mediated non-eosinophilic CRS in long durations and low doses. Further research is needed to better identify characteristics known to correlate with macrolide response so early directed therapy can be implemented.

IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown. OBJECTIVE: We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. METHODS: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable ß-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. RESULTS: IL-25 receptor (IL-17RB)-expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB(+)CD4(+) polyp-derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB(+)CD4(+) T cells, several identical T-cell receptor variable ß-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17-producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells. CONCLUSION: IL-25 and IL-33 can interact locally with IL-17RB(+)ST2(+) polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.

Endoscopic sinus surgery and musculoskeletal symptoms.

BACKGROUND: Endoscopic sinus surgery is a common surgical procedure, with low morbidity for patients. Studies have shown that endoscopic and laparoscopic surgeons have a significant risk of developing musculoskeletal symptoms, with potential adverse effects on their careers as well as patient care. We aimed to identify the prevalence of such symptoms, and any associated risk factors relating to surgical technique, in European rhinologists. METHODOLOGY: An online survey was distributed to all members of the European Rhinologic Society and data collected for statistical analysis. The relevant literature was reviewed, and ergonomic recommendations made. RESULTS: There were 250 responses, with nearly 80% of surgeons experiencing musculoskeletal symptoms. The neck and back were the most common site of symptoms, in approximately 60% of cases. There were significant correlations between musculoskeletal symptoms and the number of procedures performed each year, operating in a standing position, and operating without a monitor. CONCLUSIONS: There is a high prevalence of musculoskeletal symptoms in endoscopic sinus surgeons, which appears to be particularly related to posture during surgery. Surgeons need to be more aware of the risk factors, and good ergonomic habits should be encouraged to try and reduce the development of such symptoms.

Safety of human olfactory mucosal biopsy for the purpose of olfactory ensheathing cell harvest and nerve repair: a prospective controlled study in patients undergoing endoscopic sinus surgery.

BACKGROUND: Nasal olfactory mucosa is an accessible source of olfactory ensheathing cells for spinal cord regeneration. However, safety of the biopsy technique and the effects on sense of smell and nasal function have not been robustly assessed in the form of a prospective controlled study. METHODOLOGY: National Health Service ethical approval was granted for this study of 131 patients. The primary outcome measure was olfactory function and the secondary outcomes included postoperative complication rates as well as the SNOT 22, NOSE scale scores and surgeon reported (Lund-Kennedy score) nasal function outcomes. RESULTS: 65 patients underwent functional endoscopic sinus surgery (FESS) and superior turbinate biopsy, and 66 patients underwent FESS only as the control group. There was no significant difference in complication rates between the two groups. All Olfactory function outcomes were unaffected following olfactory biopsy. We demonstrated that the patients quality of life and nasal patency as well as surgeon reported outcome measurements remain unaffected following olfactory harvesting. CONCLUSIONS: We have uniquely provided level 2a evidence for the safety of endoscopic biopsy of olfactory mucosa, which does not affect nasal function or the sense of smell compared to standard FESS without biopsy.

Peak nasal inspiratory flow and peak expiratory flow. Upright and sitting values in an adult population.

BACKGROUND: Nasal obstruction is correlated with a decreased quality of life . An easy way to evaluate nasal patency is the peak nasal inspiratory flow (PNIF) measurement. Normal PNIF values have been published by many authors. However, some authors evaluated volunteers in a sitting position, while others have measured PNIF values in standing volunteers. Body position has been shown to influence pulmonary function, with differences between sitting and upright positions. As nasal and pulmonary flows are strictly related, the present pilot study tried to establish whether PNIF/PEF changed with body position in adults. METHODOLOGY: PNIF and PEF were measured in sitting and standing positions with the order of testing randomized in 76 healthy volunteers, 30 male (40 ± 16 years). RESULTS: In the group as a whole between sitting and upright position, PEF was significantly different (p=0.009), while PNIF showed a trend towards a significant difference (p=0.10). CONCLUSIONS: The present study, although showing a generally positive effect of the standing position on PEF values, does not show a clear effect on PNIF.

Management of rhinosinusitis during pregnancy: systematic review and expert panel recommendations.

BACKGROUND: Management of rhinosinusitis during pregnancy requires special considerations. OBJECTIVES: 1. Conduct a systematic literature review for acute and chronic rhinosinusitis (CRS) management during pregnancy. 2. Make evidence-based recommendations. METHODS: The systematic review was conducted using MEDLINE and EMBASE databases and relevant search terms. Title, abstract and full manuscript review were conducted by two authors independently. A multispecialty panel with expertise in management of Rhinological disorders, Allergy-Immunology, and Obstetrics-Gynecology was invited to review the systematic review. Recommendations were sought on use of following for CRS management during pregnancy: oral corticosteroids; antibiotics; leukotrienes; topical corticosteroid spray/irrigations/drops; aspirin desensitization; elective surgery for CRS with polyps prior to planned pregnancy; vaginal birth versus planned Caesarian for skull base erosions/ prior CSF rhinorrhea. RESULTS: Eighty-eight manuscripts underwent full review after screening 3052 abstracts. No relevant level 1, 2, or 3 studies were found. Expert panel recommendations for rhinosinusitis management during pregnancy included continuing nasal corticosteroid sprays for CRS maintenance, using pregnancy-safe antibiotics for acute rhinosinusitis and CRS exacerbations, and discontinuing aspirin desensitization for aspirin exacerbated respiratory disease. The manuscript presents detailed recommendations. CONCLUSIONS: The lack of evidence pertinent to managing rhinosinusitis during pregnancy warrants future trials. Expert recommendations constitute the current best available evidence.

Endoscopic surgery for malignant sinonasal tumours: an eighteen year experience.

INTRODUCTION: Curative resection of malignant tumours of the skull base is increasingly undertaken endoscopically. Hitherto the diverse histology, rarity and long natural history have made it difficult to accrue statistically robust cohorts for comparison with conventional craniofacial resection. It is now possible to make such a comparison in a large personal cohort. METHOD: Data on all cases of sinonasal malignancy undergoing endoscopic resection with curative intent over an eighteen year period were collected prospectively and analysed for survival and prognostic factors. RESULTS: There were 140 cases, 68 men and 72 women, aged 20-92 years (mean 63 yrs). Follow-up ranged from 6-184 months (mean 60 months). Eighteen different histopathologies were represented with olfactory neuroblastoma (36), malignant melanoma (33) and adenocarcinoma (19) being the commonest. Additional radiotherapy was given in 95 cases and chemotherapy in 49. Overall survival is 84% at 5 years and 69% at 10 years. Overall disease-free survival was 77% at 5 years and 56% at ten. Overall and disease-free survival at 5 (and 10) years is, respectively, 97% and 90% for olfactory neuroblastoma, 79% and 68% for adenocarcinoma and 56% and 39% for malignant melanoma. CONCLUSION: These results show that endoscopic resection is an alternative to conventional craniofacial resection in selected cases.

Hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia is an autosomal dominant vascular disease characterized by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. METHODOLOGY: The genetic basis and pathophysiology of the disease are discussed. Diagnostic criteria and the clinical course of the condition are considered. The current management options, both medical and surgical, are reviewed. CONCLUSIONS: Hereditary haemorrhagic telangiectasia requires specialist treatment for the problems it causes, and is best managed in specialist centres. Epistaxis is often the major symptom, significantly affecting patients' quality of life. An understanding of the available treatment options is therefore important for the otorhinolaryngologist.

Peak nasal inspiratory flow: a useful and handy tool for the diagnosis of nasal obstruction in the elderly.

The global population is aging, with the over-65 age group expected to double in the USA by 2030. Three subcategories of elderly people have been identified: "young old" (from 65 to 74 years), "older old" (from 75 to 84) and "oldest old" (85 or more). Rhinosinusitis is a common disease that affects more than 31 million people in the USA every year. Nasal obstruction is one of the most common symptoms in patients affected by rhinosinusitis. An accurate nasal obstruction evaluation in the elderly is becoming of increasing interest for medical doctors, especially for geriatricians. Peak nasal inspiratory flow (PNIF) is a cheap and easy method for assessing nasal patency. The purpose of the study was to compare young old normal PNIF values with older old normal PNIF values. Charts relating PNIF normal values in the elderly with various explanatory variables have been provided. PNIF measurements were performed in 113 volunteers aged 65-84 years. One hundred and five of them fulfilled the study criteria and were self-reported healthy elderly. None of them complained of nasal symptoms. Data were statistically analyzed and figures and tables were produced relating PNIF to height, sex and age. PNIF values decreased with age (p = 0.0053) and were significantly lower in the "older old" sub-cohort than in the "young old" group (p = 0.007). Nasal obstruction in the elderly is a common problem and appropriate diagnosis and treatment are important for improving their quality of life. The measurement of PNIF could be useful in evaluating elderly patients who complain of nasal obstruction.

Measuring the breath of life.

The inability to breathe freely and clearly is a major source of concern to patients and a common symptom in many sinonasal conditions (1). There are of course some semantic differences between terms such as 'obstruction', congestion' and 'blockage', which have to be clarified when taking a clinical history as the presence of inflammation may produce the sensation of congestion without actually being associated with mechanical obstruction to airflow (2). Notwthstanding this, nasal obstruction is the commonest complaint in chronic rhinosinusitis with and without nasal polyps (3) and is a major feature of conditions from the common cold and acute bacterial rhinosinusitis to allergic and non-allergic rhinitis, septal deformity or a tumour. Paradoxically, many people, myself included, go through life largely oblivious to a significant septal deflection. It therefore begs the question as to why an individual with a long-standing anatomical variant such as this, suddenly presents with the symptom of nasal blockage and it is important that we do not simply focus on the septum (or turbinate) but rather ask ourselves 'Why now?' instead of simply listing the patient for septal surgery.