Effectiveness of septoplasty compared to medical management in adults with obstruction associated with a deviated nasal septum: the NAIROS RCT.

Background: The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objective: The objective was to determine the clinical effectiveness and cost-effectiveness of septoplasty, with or without turbinate reduction, compared with medical management, in the management of nasal obstruction associated with a deviated nasal septum. Design: This was a multicentre randomised controlled trial comparing septoplasty, with or without turbinate reduction, with defined medical management; it incorporated a mixed-methods process evaluation and an economic evaluation. Setting: The trial was set in 17 NHS secondary care hospitals in the UK. Participants: A total of 378 eligible participants aged > 18 years were recruited. Interventions: Participants were randomised on a 1: 1 basis and stratified by baseline severity and gender to either (1) septoplasty, with or without turbinate surgery (n = 188) or (2) medical management with intranasal steroid spray and saline spray (n = 190). Main outcome measures: The primary outcome was the Sino-nasal Outcome Test-22 items score at 6 months (patient-reported outcome). The secondary outcomes were as follows: patient-reported outcomes - Nasal Obstruction Symptom Evaluation score at 6 and 12 months, Sino-nasal Outcome Test-22 items subscales at 12 months, Double Ordinal Airway Subjective Scale at 6 and 12 months, the Short Form questionnaire-36 items and costs; objective measurements - peak nasal inspiratory flow and rhinospirometry. The number of adverse events experienced was also recorded. A within-trial economic evaluation from an NHS and Personal Social Services perspective estimated the incremental cost per (1) improvement (of ≥ 9 points) in Sino-nasal Outcome Test-22 items score, (2) adverse event avoided and (3) quality-adjusted life-year gained at 12 months. An economic model estimated the incremental cost per quality-adjusted life-year gained at 24 and 36 months. A mixed-methods process evaluation was undertaken to understand/address recruitment issues and examine the acceptability of trial processes and treatment arms. Results: At the 6-month time point, 307 participants provided primary outcome data (septoplasty, n = 152; medical management, n = 155). An intention-to-treat analysis revealed a greater and more sustained improvement in the primary outcome measure in the surgical arm. The 6-month mean Sino-nasal Outcome Test-22 items scores were -20.0 points lower (better) for participants randomised to septoplasty than for those randomised to medical management [the score for the septoplasty arm was 19.9 and the score for the medical management arm was 39.5 (95% confidence interval -23.6 to -16.4; p < 0.0001)]. This was confirmed by sensitivity analyses and through the analysis of secondary outcomes. Outcomes were statistically significantly related to baseline severity, but not to gender or turbinate reduction. In the surgical and medical management arms, 132 and 95 adverse events occurred, respectively; 14 serious adverse events occurred in the surgical arm and nine in the medical management arm. On average, septoplasty was more costly and more effective in improving Sino-nasal Outcome Test-22 items scores and quality-adjusted life-years than medical management, but incurred a larger number of adverse events. Septoplasty had a 15% probability of being considered cost-effective at 12 months at a £20,000 willingness-to-pay threshold for an additional quality-adjusted life-year. This probability increased to 99% and 100% at 24 and 36 months, respectively. Limitations: COVID-19 had an impact on participant-facing data collection from March 2020. Conclusions: Septoplasty, with or without turbinate reduction, is more effective than medical management with a nasal steroid and saline spray. Baseline severity predicts the degree of improvement in symptoms. Septoplasty has a low probability of cost-effectiveness at 12 months, but may be considered cost-effective at 24 months. Future work should focus on developing a septoplasty patient decision aid. Trial registration: This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information.

Septoplasty is an operation to straighten the septum, which is the partition wall between the nostrils inside the nose. Septoplasty can be used as a treatment for people who have a bent septum and symptoms of a blocked nose, such as difficulty sleeping and exercising. Medical management (a saltwater spray to clear the nose followed by a nose steroid spray) is an alternative treatment to septoplasty. The Nasal AIRway Obstruction Study (NAIROS) aimed to find out whether septoplasty or medical management is a better treatment for people with a bent septum and symptoms of a blocked nose. We recruited 378 patients with at least moderately severe nose symptoms from 17 hospitals in England, Scotland and Wales to take part in the NAIROS. Participants were randomly put into one of two groups: septoplasty or medical management. Participants' nose symptoms were measured both when they joined the study and after 6 months, using a questionnaire called the Sino-nasal Outcome Test-22 items. This questionnaire was chosen because patients reported that it included symptoms that were important to them. Other studies have shown that a 9-point change in the Sino-nasal Outcome Test-22 items score is significant. After 6 months, on average, people in the septoplasty group improved by 25 points, whereas people in the medical management group improved by 5 points. We saw improvement after septoplasty among patients with moderate symptoms, and among those with severe symptoms. Most patients who we spoke to after a septoplasty were happy with their treatment, but some would have liked more information about what to expect after their nose surgery. In the short term, septoplasty is more costly than medical management. However, over the longer term, taking into account all the costs and benefits of treatment, suggests that septoplasty would be considered good value for money for the NHS.

Clinical effectiveness of septoplasty versus medical management for nasal airways obstruction: multicentre, open label, randomised controlled trial.

OBJECTIVE: To assess the clinical effectiveness of septoplasty. DESIGN: Multicentre, randomised controlled trial. SETTING: 17 otolaryngology clinics in the UK's National Health Service. PARTICIPANTS: 378 adults (≥18 years, 67% men) newly referred with symptoms of nasal obstruction associated with septal deviation and at least moderate symptoms of nasal obstruction (score >30 on the Nasal Obstruction and Symptom Evaluation (NOSE) scale). INTERVENTIONS: Participants were randomised 1:1 to receive either septoplasty (n=188) or defined medical management (n=190, nasal steroid and saline spray for six months), stratified by baseline symptom severity and sex. MAIN OUTCOME MEASURES: The primary outcome measure was patient reported score on the Sino-Nasal Outcome Test-22 (SNOT-22) at six months, with 9 points defined as the minimal clinically important difference. Secondary outcomes included quality of life and objective nasal airflow measures. RESULTS: Mean SNOT-22 scores at six months were 19.9 (95% confidence interval 17.0 to 22.7) in the septoplasty arm (n=152, intention-to-treat population) and 39.5 (36.1 to 42.9) in the medical management arm (n=155); an estimated 20.0 points lower (better) for participants randomised to receive septoplasty (95% confidence interval 16.4 to 23.6, P<0.001, adjusted for baseline continuous SNOT-22 score and the stratification variables sex and baseline NOSE severity categories). Greater improvement in SNOT-22 scores was predicted by higher baseline symptom severity scores. Quality of life outcomes and nasal airflow measures (including peak nasal inspiratory flow and absolute inhalational nasal partitioning ratio) improved more in participants in the septoplasty group. Readmission to hospital with bleeding after septoplasty occurred in seven participants (4% of 174 who had septoplasty), and a further 20 participants (12%) required antibiotics for infections. CONCLUSIONS: Septoplasty is a more effective intervention than a defined medical management regimen with a nasal steroid and saline spray in adults with nasal obstruction associated with a deviated nasal septum. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16168569.

Screening for silent aspiration in hyperacute stroke: A feasibility study of clinical swallowing examination and cough reflex testing.

BACKGROUND: Silent aspiration (SA) is common post-stroke and associated with increased risk of pneumonia, length of stay and healthcare costs. Clinical swallow examinations (CSEs) are unreliable measures of SA. There is no consensus on the clinical components that best detect SA. Cough reflex testing (CRT) is an alternative/adjunct whose SA detection accuracy also lacks consensus. AIMS: To investigate the feasibility of CSE versus CRT against gold standard flexible endoscopic evaluation of swallowing (FEES) for SA identification and to estimate its prevalence in a hyperacute stroke setting. METHODS & PROCEDURES: A single-arm preliminary, prospective, feasibility study of patients less than 72 h post-stroke, over a 31-day period on a hyperacute stroke unit: the Royal Victoria Infirmary, Newcastle-upon-Tyne, UK. Ethical approval for the study was obtained. The study tested the feasibility and acceptability of introducing CRT and developing a standardized CSE. Consent/assent was obtained for all participants. Patients unfit for study were excluded. OUTCOMES & RESULTS: A total of 62% of patients less than 72 h post-stroke (n = 61) were eligible. A total of 75% of those approached (n = 30) consented. A total of 23 patients completed all tests. The principal barrier was anxiety regarding FEES. Mean test time for CRT = 6 min; CSE = 8 min; FEES = 17 min. Patients rated CRT and FEES on average as moderately uncomfortable. A total of 30% (n = 7) of participants who received FEES presented with SA. CONCLUSIONS & IMPLICATIONS: CRT, CSE and FEES are feasible in 58% of hyperacute stroke patients in this setting. FEES anxiety is the main recruitment barrier and is not always well tolerated. Results support further work to establish optimum methods and differential sensitivity/specificity of CRT and CSE in hyperacute stroke for SA identification. WHAT THIS PAPER ADDS: What is already known on this subject SA significantly increases the risk of pneumonia in the early days post-stroke. CSEs are unreliable for identification of SA risk in this population. CRT is gaining popularity as a potential tool to identify stroke patients at risk of SA, though there are questions regarding the efficacy of the clinical protocol currently being used in the UK. What this study adds to existing knowledge This study demonstrates that it is practical and feasible to carry out a larger scale study in this setting to compare CSE and CRT including a consideration of an approach combining both methods for clinical identification of SA versus FEES. Preliminary findings suggest that CSE may have higher levels of sensitivity than CRT for SA identification. What are the potential or actual clinical implications of this work? The results of this study suggest that further work is needed to establish the optimum methods and differential sensitivity/specificity of clinical tools for SA detection in hyperacute stroke.

Conservative management versus tonsillectomy in adults with recurrent acute tonsillitis in the UK (NATTINA): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Tonsillectomy is regularly performed in adults with acute tonsillitis, but with scarce evidence. A reduction in tonsillectomies has coincided with an increase in acute adult hospitalisation for tonsillitis complications. We aimed to assess the clinical effectiveness and cost-effectiveness of conservative management versus tonsillectomy in patients with recurrent acute tonsillitis. METHODS: This pragmatic multicentre, open-label, randomised controlled trial was conducted in 27 hospitals in the UK. Participants were adults aged 16 years or older who were newly referred to secondary care otolaryngology clinics with recurrent acute tonsillitis. Patients were randomly assigned (1:1) to receive tonsillectomy or conservative management using random permuted blocks of variable length. Stratification by recruiting centre and baseline symptom severity was assessed using the Tonsil Outcome Inventory-14 score (categories defined as mild 0-35, moderate 36-48, or severe 49-70). Participants in the tonsillectomy group received elective surgery to dissect the palatine tonsils within 8 weeks after random assignment and those in the conservative management group received standard non-surgical care during 24 months. The primary outcome was the number of sore throat days collected during 24 months after random assignment, reported once per week with a text message. The primary analysis was done in the intention-to-treat (ITT) population. This study is registered with the ISRCTN registry, 55284102. FINDINGS: Between May 11, 2015, and April 30, 2018, 4165 participants with recurrent acute tonsillitis were assessed for eligibility and 3712 were excluded. 453 eligible participants were randomly assigned (233 in the immediate tonsillectomy group vs 220 in the conservative management group). 429 (95%) patients were included in the primary ITT analysis (224 vs 205). The median age of participants was 23 years (IQR 19-30), with 355 (78%) females and 97 (21%) males. Most participants were White (407 [90%]). Participants in the immediate tonsillectomy group had fewer days of sore throat during 24 months than those in the conservative management group (median 23 days [IQR 11-46] vs 30 days [14-65]). After adjustment for site and baseline severity, the incident rate ratio of total sore throat days in the immediate tonsillectomy group (n=224) compared with the conservative management group (n=205) was 0·53 (95% CI 0·43 to 0·65; <0·0001). 191 adverse events in 90 (39%) of 231 participants were deemed related to tonsillectomy. The most common adverse event was bleeding (54 events in 44 [19%] participants). No deaths occurred during the study. INTERPRETATION: Compared with conservative management, immediate tonsillectomy is clinically effective and cost-effective in adults with recurrent acute tonsillitis. FUNDING: National Institute for Health Research.

The utility of a symptom model to predict the risk of oesophageal cancer.

OBJECTIVE: To assess whether extra-oesophageal symptoms are predictive of oesophageal malignancy. METHODS: A prospective, single-centre cross-sectional questionnaire study at a tertiary referral unit for oesophageal cancer using the Comprehensive Reflux Symptoms Scale (CReSS) questionnaire tool. Respondents with oesophageal malignancy were compared with historical cohorts undergoing airway examination or upper gastrointestinal endoscopy and found to have benign diagnoses. We developed a model for predicting oesophageal cancer using linear discriminant analysis and logistic regression, assessed by Monte Carlo cross validation. RESULTS: Respondents with oesophageal malignancy (n = 146; mean age 70.5; male: female, 71:29) were compared with those undergoing airway examination (n = 177) and upper gastrointestinal endoscopy (n = 351), found to have benign diagnoses. No single questionnaire item, or group of co-varying items (factors), reliably discriminated oesophageal cancer from other diagnoses. Individual items which suggested higher risk of oesophageal malignancy included dysphagia (area under the curve (AUC) 0.68), low appetite (AUC 0.66), and early satiety (AUC 0.58). Conversely, throat pain (AUC 0.38), bloating (AUC 0.38) and heartburn (AUC 0.37) were inversely related to cancer risk. A forward stepwise regression analysis including a subset of 12 CReSS questionnaire items together with age and sex derived a model predictive of oesophageal malignancy in this cohort (AUC 0.89). CONCLUSION: We demonstrate a model comprised of 12 questionnaire items and 2 demographic parameters as a potential predictive tool for oesophageal malignancy diagnosis in this study population. Translating this model for predicting oesophageal malignancy in the general population is a valuable topic for future research.

Tonsillectomy compared with conservative management in patients over 16 years with recurrent sore throat: the NATTINA RCT and economic evaluation.

Background: The place of tonsillectomy in the management of sore throat in adults remains uncertain. Objectives: To establish the clinical effectiveness and cost-effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults, and to evaluate the impact of alternative sore throat patient pathways. Design: This was a multicentre, randomised controlled trial comparing tonsillectomy with conservative management. The trial included a qualitative process evaluation and an economic evaluation. Setting: The study took place at 27 NHS secondary care hospitals in Great Britain. Participants: A total of 453 eligible participants with recurrent sore throats were recruited to the main trial. Interventions: Patients were randomised on a 1 : 1 basis between tonsil dissection and conservative management (i.e. deferred surgery) using a variable block-stratified design, stratified by (1) centre and (2) severity. Main outcome measures: The primary outcome measure was the total number of sore throat days over 24 months following randomisation. The secondary outcome measures were the number of sore throat episodes and five characteristics from Sore Throat Alert Return, describing severity of the sore throat, use of medications, time away from usual activities and the Short Form questionnaire-12 items. Additional secondary outcomes were the Tonsil Outcome Inventory-14 total and subscales and Short Form questionnaire-12 items 6 monthly. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by Tonsil Outcome Inventory-14 score at recruitment. The incremental cost per sore throat day avoided, the incremental cost per quality-adjusted life-year gained based on responses to the Short Form questionnaire-12 items and the incremental net benefit based on costs and responses to a contingent valuation exercise. A qualitative process evaluation examined acceptability of trial processes and ramdomised arms. Results: There was a median of 27 (interquartile range 12-52) sore throats over the 24-month follow-up. A smaller number of sore throats was reported in the tonsillectomy arm [median 23 (interquartile range 11-46)] than in the conservative management arm [median 30 (interquartile range 14-65)]. On an intention-to-treat basis, there were fewer sore throats in the tonsillectomy arm (incident rate ratio 0.53, 95% confidence interval 0.43 to 0.65). Sensitivity analyses confirmed this, as did the secondary outcomes. There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). There were 47 re-admissions following tonsillectomy (20.3%), 35 relating to haemorrhage. On average, tonsillectomy was more costly and more effective in terms of both sore throat days avoided and quality-adjusted life-years gained. Tonsillectomy had a 100% probability of being considered cost-effective if the threshold for an additional quality-adjusted life year was £20,000. Tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Trial processes were deemed to be acceptable. Patients who received surgery were unanimous in reporting to be happy to have received it. Limitations: The decliners who provided data tended to have higher Tonsillectomy Outcome Inventory-14 scores than those willing to be randomised implying that patients with a higher burden of tonsillitis symptoms may have declined entry into the trial. Conclusions: The tonsillectomy arm had fewer sore throat days over 24 months than the conservative management arm, and had a high probability of being considered cost-effective over the ranges considered. Further work should focus on when tonsillectomy should be offered. National Trial of Tonsillectomy IN Adults has assessed the effectiveness of tonsillectomy when offered for the current UK threshold of disease burden. Further research is required to define the minimum disease burden at which tonsillectomy becomes clinically effective and cost-effective. Trial registration: This trial is registered as ISRCTN55284102. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information.

Tonsillectomy is an operation to take out the pair of tonsil glands at the back of the throat. It is an option for adults who suffer from repeated, severe sore throats. Adults who have a tonsillectomy say that they get fewer sore throats afterwards, but it is not clear whether or not they would have got better over time without the operation. There is pressure on doctors to limit the number of tonsillectomies carried out. At the same time, emergency hospital admissions for adults with severe throat infections have been increasing. NAtional Trial of Tonsillectomy IN Adults aimed to find out whether tonsillectomy is an effective and worthwhile treatment for repeated severe sore throats or whether patients would be better off treated without an operation. A total of 453 patients from 27 hospitals in Great Britain took part in the study. Patients were assigned at random to receive either tonsillectomy or conservative management (treatment as needed from their general practitioner). We measured how many sore throats patients had in the next 2 years by sending them text messages every week. We asked about the impact of their sore throats on their quality of life and time off work, and looked at the costs of treatment. We also interviewed 47 patients, general practitioners and hospital staff about their experiences of tonsillectomy and NAtional Trial of Tonsillectomy IN Adults. The typical patient in the tonsillectomy arm had 23 days of sore throat compared with 30 days of sore throat in the conservative management arm. Tonsillectomy resulted in higher quality of life. We looked to see whether or not it was only those with the most severe sore throats who benefited from tonsillectomy, but we found that patients with more or less severe sore throats at the start all did better with tonsillectomy. Patients who had a tonsillectomy were happy to have undertaken this. Our findings suggest a clear benefit of tonsillectomy using modest additional NHS resources for adults with repeated severe sore throats.

Improving patient care pathways in otitis externa.

INTRODUCTION: Referrals for otitis externa (OE) have dramatically increased but the reasons for this remain unclear. We aim to characterize management of patients both pre- and post-referral to identify areas of improvement at the primary-secondary care interface. METHODS: Questionnaire study from consultant-led research clinic specifically set up to prospectively analyse OE referrals at a tertiary referral centre for Otolaryngology. RESULTS: Sixty-two patients were included; 63% female, median age 57 years. One was excluded (clinically not OE). Most patients had multiple primary care visits before referral (average 4 GP; 2 practice nurse). Sixty per cent had received oral antibiotics (16% multiple classes). Eighteen per cent had never had ear drops. Thirty-nine per cent were not advised to keep ears dry. Twenty-one per cent had dermatitis; 13% contact allergy, 30% systemic allergy, 5% diabetes. Less than 10% had narrow canals. Thirty-six per cent had active discharge but <7% needed a wick. Approximately 75% appear suitable for community aural care clinics. CONCLUSIONS: OE occurs most commonly in female patients, often with associated risk factors. Patients often consult primary care several times prior to referral. Lifestyle advice and ototopical drops are frequently overlooked; instead, often inappropriately treated with oral antibiotics. Most ears were anatomically normal, and community aural care clinics may have a role in more timely and accessible treatment.

Psychometric Properties of the MDADI-A Preliminary Study of Whether Less is Truly More?

The MD Anderson Dysphagia Inventory (MDADI) is a 20-item dysphagia-specific QOL questionnaire with four subscales: global, emotional, functional, and physical. It is widely used in clinical practice and in research; however, its psychometric properties have been under-researched. We aim to evaluate the organisation of the MDADI subscales and identify any redundant items. The MDADI is a routinely collected outcome measure at two centres in northeast England. Questionnaires completed at three months following treatment were extracted from these existing databases. Factor analysis was carried out with the aim of reducing redundancy among the set of questionnaire items. Cases with missing values were excluded. A total of 196 complete patient questionnaires were used in factor analysis. A one-factor model accounted for around 50% of the total variance in item responses. The top five endorsed items (abbreviated by the questionnaire item keywords: Excluded, Irritate, Esteem, Social, and Why) in this one factor appeared in three (emotional, functional, and physical) of the four supposed MDADI subscales, i.e. global, emotional, functional, and physical. Our results suggest an overlap of three MDADI subscales across the top five endorsed items. The content of the top five questions all appear related to the psychosocial aspects of swallowing. This implies some redundancy of the items in the original subscales of the questionnaire. Using the most endorsed items, it appears feasible to abbreviate the 20-item MDADI questionnaire to a 5-item "MiniDADI" questionnaire, which is likely to have greater utility in routine clinical practice outside of research settings.

The acid test: Proton pump inhibitors in persistent throat symptoms: A systematic review of systematic reviews.

INTRODUCTION: Proton pump inhibitors (PPIs) have evolved to become a frequent treatment option for patients with persistent throat symptoms. The evidence for their use in this context is, however, conflicting. This review assesses the quality of the published systematic reviews and meta-analyses evaluating PPIs in persistent throat symptoms. METHODS: Following a literature search, systematic review were evaluated using the Reporting of Bias in Systematic Reviews (ROBIS) tool and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Outcome measures were analysed using the "checklist to operationalize measurement characteristics of patient-reported outcome measures." RESULTS: 10 systematic reviews were assessed. All but one were at high risk of bias. No review met the PRISMA checklist criteria. No identified PROM met the checklist requirements for validation. Significant methodological concerns include inappropriate selection of studies for inclusion, poor selection of outcome measures, a lack of appropriate bias assessments and inconsistent reporting of reviews. CONCLUSION: The quality of evidence concerning the role of PPIs in persistent throat symptoms gives serious cause for concern. Collectively, nine studies at high risk of bias have been cited 714 times. Systematic reviews typically attract these high numbers of citations and, if their premises and conclusions do not withstand scrutiny, they are open to widespread misinterpretation, perpetuation of misunderstanding and negative clinical impact.

The immunotherapeutic role of indoleamine 2,3-dioxygenase in head and neck squamous cell carcinoma: A systematic review.

BACKGROUND: Novel cancer immunotherapy seeks to harness the body's own immune system and tip the balance in favour of antitumour activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumour microenvironment (TME) via tryptophan metabolism. The potential immunotherapeutic role of IDO in head and neck squamous cell carcinoma (HNSCC) requires further exploration. We aim to assess the evidence on IDO in HNSCC. METHODS: A systematic review of literature and clinical trials databases. RESULTS: We included 40 studies: seven involved cell lines: eight assessed tumour immunohistochemistry: ten measured IDO gene transcription: 15 reported on clinical trials. Increased cell line IDO expression was postulated to adversely affect tumour metabolism and apoptosis. Immunohistochemical IDO expression correlated with worse survival. Gene transcription studies associated IDO with positive PD-L1 and human papillomavirus (HPV) status. Phase I/II clinical trials showed (a) overall response (34%-55%) and disease control rates (62%-70%) for IDO1 inhibitor in combination with a PD-1 inhibitor, (b) similar safety profiles when both are used in combination therapy compared to each as monotherapies and (c) IDO gene expression as a predictive biomarker for response to PD-L1 therapy. CONCLUSIONS: IDO expression is increased in the TME of HNSCC, which correlates with poor prognosis. However, the exact mechanism of IDO-driven immune modulation in the TME is an enigma. Future translational studies should map IDO activity during HNSCC treatment and elucidate its precise role in the TME, such research will underpin the development of clinical trials establishing the efficacy of IDO inhibitors in HNSCC.

Use of proton pump inhibitors to treat persistent throat symptoms: multicentre, double blind, randomised, placebo controlled trial.

OBJECTIVE: To assess the use of proton pump inhibitors (PPIs) to treat persistent throat symptoms. DESIGN: Pragmatic, double blind, placebo controlled, randomised trial. SETTING: Eight ear, nose, and throat outpatient clinics, United Kingdom. PARTICIPANTS: 346 patients aged 18 years or older with persistent throat symptoms who were randomised according to recruiting centre and baseline severity of symptoms (mild or severe): 172 to lansoprazole and 174 to placebo. INTERVENTION: Random blinded allocation (1:1) to either 30 mg lansoprazole twice daily or matched placebo twice daily for 16 weeks. MAIN OUTCOME MEASURES: Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score. Secondary outcomes included symptom response at 12 months, quality of life, and throat appearances. RESULTS: Of 1427 patients initially screened for eligibility, 346 were recruited. The mean age of the study sample was 52.2 (SD 13.7) years, 196 (57%) were women, and 162 (47%) had severe symptoms at presentation; these characteristics were balanced across treatment arms. The primary analysis was performed on 220 patients who completed the primary outcome measure within a window of 14-20 weeks. Mean RSI scores were similar between treatment arms at baseline: lansoprazole 22.0 (95% confidence interval 20.4 to 23.6) and placebo 21.7 (20.5 to 23.0). Improvements (reduction in RSI score) were observed in both groups-score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms: estimated difference 1.9 points (95% confidence interval -0.3 to 4.2 points; P=0.096) adjusted for site and baseline symptom severity. Lansoprazole showed no benefits over placebo for any secondary outcome measure, including RSI scores at 12 months: lansoprazole 16.0 (13.6 to 18.4) and placebo 13.6 (11.7 to 15.5): estimated difference 2.4 points (-0.6 to 5.4 points). CONCLUSIONS: No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up. TRIAL REGISTRATION: ISRCTN Registry ISRCTN38578686 and EudraCT 2013-004249-17.

Lansoprazole for persistent throat symptoms in secondary care: the TOPPITS RCT.

BACKGROUND: Persistent throat symptoms are commonly attributed to 'laryngopharyngeal reflux'. Despite a limited evidence base, these symptoms are increasingly being treated in primary care with proton pump inhibitors. OBJECTIVE: To assess the value of proton pump inhibitor therapy in patients with persistent throat symptoms. DESIGN: This was a double-blind, placebo-controlled, randomised Phase III trial. SETTING: This was a multicentre UK trial in eight UK ear, nose and throat departments. PARTICIPANTS: A total of 346 participants aged ≥ 18 years with persistent throat symptoms and a Reflux Symptom Index score of ≥ 10, exclusive of the dyspepsia item, were recruited. INTERVENTION: Random allocation (1 : 1 ratio) to either 30 mg of lansoprazole twice daily or matched placebo for 16 weeks. MAIN OUTCOME MEASURE: Symptomatic response (i.e. total Reflux Symptom Index score after 16 weeks of therapy). RESULTS: A total of 1427 patients were screened and 346 were randomised. The mean age was 52 years (standard deviation 13.7 years, range 20-84 years); 150 (43%) participants were male and 196 (57%) were female; 184 (53%) participants had a mild Reflux Symptom Index minus the heartburn/dyspepsia item and 162 (47%) had a severe Reflux Symptom Index minus the heartburn/dyspepsia item. A total of 172 patients were randomised to lansoprazole and 174 were randomised to placebo. MAIN OUTCOMES: A total of 267 participants completed the primary end-point visit (lansoprazole, n = 127; placebo, n = 140), of whom 220 did so between 14 and 20 weeks post randomisation ('compliant' group); 102 received lansoprazole and 118 received placebo. The mean Reflux Symptom Index scores at baseline were similar [lansoprazole 22.0 (standard deviation 8.0), placebo 21.7 (standard deviation 7.1), overall 21.9 (standard deviation 7.5)]. The mean Reflux Symptom Index scores at 16 weeks reduced from baseline in both groups [overall 17.4 (standard deviation 9.9), lansoprazole 17.4 (standard deviation 9.9), placebo 15.6 (standard deviation 9.8)]. Lansoprazole participants had estimated Reflux Symptom Index scores at 16 weeks that were 1.9 points higher (worse) than those of placebo participants (95% confidence interval -0.3 to 4.2; padj = 0.096), adjusted for site and baseline severity. SECONDARY OUTCOMES: Ninety-five (43%) participants achieved a Reflux Symptom Index score in the normal range (< 12) at 16 weeks: 42 (41%) in the lansoprazole group and 53 (45%) in the placebo group. A total of 226 participants completed the end-of-trial follow-up visit (lansoprazole, n = 109; placebo, n = 117), of whom 181 were 'compliant'. The mean Reflux Symptom Index scores at 12 months reduced from baseline in both groups [lansoprazole 16.0 (standard deviation 10.8), placebo 13.6 (standard deviation 9.6), overall 14.7 (standard deviation 10.2)]. A total of 87 (48%) participants achieved a Reflux Symptom Index score in the normal range at 12 months: 33 (40%) in the lansoprazole group and 54 (55%) in the placebo group. Likewise, the Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life total scores and subscales all showed very similar changes in the lansoprazole and placebo cohorts at both 16 weeks and 12 months. LIMITATIONS: Drop-out rate and compliance are issues in pragmatic clinical trials. The Trial Of Proton Pump Inhibitors in Throat Symptoms (TOPPITS) aimed to detect clinically relevant difference with 90% power. The 346 randomised participants reduced to 283 at the primary end point; 267 completed the primary outcome measure, 220 within the protocol time scale. Despite this, the powers to detect the clinically relevant difference in Reflux Symptom Index score at 16 weeks were 82% (compliant comparison) and 89% (pragmatic comparison). The lack of difference between lansoprazole and placebo is generalisable across NHS clinics. CONCLUSIONS: Participants on lansoprazole did not report significantly better outcomes than participants on placebo on any of the three patient-reported outcome tools (Reflux Symptom Index, Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life). This multicentre, pragmatic, powered, definitive Phase III trial found no evidence of benefit for patients by treating persistent throat symptoms with lansoprazole. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38578686 and EudraCT number 2013-004249-17. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 3. See the NIHR Journals Library website for further project information.

BACKGROUND: One of the commonest reasons for patients attending hospital throat or voice clinics is persistent throat symptoms, which include a feeling of a lump in the throat, a cough or a hoarse voice. Over time, more of these patients are being treated with proton pump inhibitors to suppress stomach acid in the belief that stomach acid entering the throat causes the symptoms, but there is little evidence that these medications work. STUDY AIM: The aim of this study is to explore whether or not having a 16-week course of proton pump inhibitors has any impact on throat symptoms. We also tested the usefulness of three different questionnaires in measuring throat symptoms, explored side effects and whether or not patients adhere to treatment, and measured patients' quality of life. METHODS: Patients with persistent (lasting for more than 6 weeks) throat symptoms who agreed to participate were randomised to receive either the proton pump inhibitor lansoprazole or a placebo. Participants took lansoprazole or placebo for 16 weeks. Symptoms and quality of life were measured before patients were randomised and at 4 and 12 months after randomisation. RESULTS: The total number of participants was 346. The mean Reflux Symptom Index outcome score (higher scores meaning worse symptoms) was 22 before the 4-month course of capsules, 16 after 4 months and 15 after 12 months. Participant-reported throat symptoms and quality of life in all participants improved over the 12 months of the study. There was no difference in the symptom improvement experienced by proton pump inhibitor and placebo participants. CONCLUSIONS: This study shows that proton pump inhibitors do not benefit patients with persistent throat symptoms. Future research should focus on other available therapies.

Nasal Airway Obstruction Study (NAIROS): a phase III, open-label, mixed-methods, multicentre randomised controlled trial of septoplasty versus medical management of a septal deviation with nasal obstruction.

BACKGROUND: Septoplasty (surgery to straighten a deviation in the nasal septum) is a frequently performed operation worldwide, with approximately 250,000 performed annually in the US and 22,000 in the UK. Most septoplasties aim to improve diurnal and nocturnal nasal obstruction. The evidence base for septoplasty clinical effectiveness is hitherto very limited. AIMS: To establish, and inform guidance for, the best management strategy for individuals with nasal obstruction associated with a deviated septum. METHODS/DESIGN: A multicentre, mixed-methods, open label, randomised controlled trial of septoplasty versus medical management for adults with a deviated septum and a reduced nasal airway. Eligible patients will have septal deflection visible at nasendoscopy and a nasal symptom score ≥ 30 on the NOSE questionnaire. Surgical treatment comprises septoplasty with or without reduction of the inferior nasal turbinate on the anatomically wider side of the nose. Medical management comprises a nasal saline spray followed by a fluorinated steroid spray daily for six months. The recruitment target is 378 patients, recruited from up to 17 sites across Scotland, England and Wales. Randomisation will be on a 1:1 basis, stratified by gender and severity (NOSE score). Participants will be followed up for 12 months post randomisation. The primary outcome measure is the total SNOT-22 score at 6 months. Clinical and economic outcomes will be modelled against baseline severity (NOSE scale) to inform clinical decision-making. The study includes a recruitment enhancement process, and an economic evaluation. DISCUSSION: The NAIROS trial will evaluate the clinical effectiveness and cost-effectiveness of septoplasty versus medical management for adults with a deviated septum and symptoms of nasal blockage. Identifying those individuals most likely to benefit from surgery should enable more efficient and effective clinical decision-making, and avoid unnecessary operations where there is low likelihood of patient benefit. TRIAL REGISTRATION: EudraCT: 2017-000893-12, ISRCTN: 16168569. Registered on 24 March 2017.

A systematic review and meta-analysis of antimicrobial resistance in paediatric acute otitis media.

OBJECTIVE OF REVIEW: Acute otitis media (AOM) is the largest cause of antimicrobial prescriptions amongst children in developed countries. Excessive and inappropriate prescribing is known to drive antimicrobial resistance, but less is known of antimicrobial resistance in AOM-associated bacteria. TYPE OF REVIEW & SEARCH STRATEGY: We conducted a systematic review and meta-analysis of bacterial prevalence and antimicrobial resistance in studies of paediatric AOM identified from Ovid Medline, Embase and the Cochrane library. RESULTS: From 48 unique studies, 15,871 samples were included. Only 0.67 (CI 0.63-0.71) of all ear samples grew a bacterial pathogen. The most common bacterial causes of AOM in children were Streptococcus pneumoniae 0.30 (CI 0.27-0.32), Haemophilus influenza 0.23 (CI 0.20-0.26), and Moraxella catarrhalis 0.05 (CI 0.04-0.06). Resistance patterns varied amongst organisms and antimicrobial agents. The pooled proportion of bacterial culture-positive episodes of AOM that could be effectively treated with amoxicillin was 0.85 (CI 0.76-0.94), erythromycin was 0.64 (0.48-0.78) and amoxicillin-clavulanate was 0.95 (CI 0.85-0.98). CONCLUSION: We have demonstrated the bacteriology and antimicrobial resistance patterns of AOM. Of samples which grew bacteria, on average approximately 15% of isolates demonstrated resistance to amoxicillin; a typical first-line agent. Greater understanding of local bacteriology and resistance patterns is needed to enable improved antimicrobial stewardship.

Establishment of an immortalized human subglottic epithelial cell line.

OBJECTIVE: Translational research into subglottic disease is restricted by the availability of primary human tissue originating from this subsite. Primary epithelial cells are also limited by their inability to survive beyond several divisions in culture outside of the body. Specific subglottic cell lines, useful for in vitro studies, have not yet been described. We therefore demonstrate what we believe to be the first immortalized subglottic epithelial cell line. METHODS: Subglottic tissue was derived from a single adult patient's neoplasia-free human subglottic brushing specimen. Cells were immortalized using a lentiviral vector expressing simian virus 40 T antigen. Karyotyping was performed on the transformed cells using single nucleotide polymorphism array comparative genomic hybridization. Transformed cells were phenotypically characterized by light microscopy, immunohistochemistry, and electrophysiology studies. RESULTS: The immortalized subglottic cell line (SG01) was able to divide successfully beyond 20 passages. Karyotyping demonstrated no significant genomic imbalance after immortalization. The cells demonstrated normal epithelial morphology and cytokeratin expression throughout. SG01 cells were also successfully cultured at air-liquid interface (ALI). At ALI cells demonstrated cilia, mucus production, and relevant ion channel expression. CONCLUSION: The novel SG01 subglottic epithelial cell line has been established. This cell line provides a unique resource for researchers to investigate subglottic diseases, such as subglottic stenosis. LEVEL OF EVIDENCE: NA. Laryngoscope, 129:2640-2645, 2019.

Autonomic nervous system dysfunction and sinonasal symptoms.

BACKGROUND: The autonomic nervous system (ANS) richly innervates the nose and paranasal sinuses, and has a significant role in lower airway diseases, e.g., asthma. Nonetheless, its contribution to sinonasal symptoms is poorly understood. This review aimed to explore the complex relationship between the ANS and sinonasal symptoms, with reference to systemic diseases and triggers of ANS dysfunction. METHODS: A review of articles published in English was conducted by searching medical literature databases with the key words "autonomic nervous system" and ("sinusitis" or "nose" or "otolaryngology"). All identified abstracts were reviewed, and, from these, relevant published whole articles were selected. RESULTS: The ANS has a significant role in the pathophysiologic mechanisms that produce sinonasal symptoms. There was limited evidence that describes the relationship of the ANS in sinonasal disease with systemic conditions, e.g. hypertension. There was some evidence to support mechanisms related to physical and psychological stressors in this relationship. CONCLUSION: The role of ANS dysfunction in sinonasal disease is highly complex. The ANS sits within a web of multiple factors, including personality and psychological distress, that contribute to sinonasal symptoms. Further research will help to clarify the etiology of ANS dysfunction and its contribution to common systemic conditions.

Is Scottish Intercollegiate Guidelines Network guidance for GP management of tonsillitis suitable? A qualitative study.

Background: The Scottish Intercollegiate Guidelines Network (SIGN) developed guidelines for the management of sore throat and indications for tonsillectomy in 1999 to address concerns of unnecessary surgery. Emergency admissions to hospital for tonsillitis have since increased. Adults experience an average of 27 episodes of tonsillitis before undergoing tonsillectomy. We wished to explore the appropriateness of the guidance and/or its implementation in primary care. Aim: To explore the attitudes of GPs to the referral criteria they use when managing adults presenting with acute tonsillitis. Design: Secondary analysis of qualitative data from the NAtional Trial of Tonsillectomy IN Adults (NATTINA) feasibility and process evaluation. Participants and Setting: Twenty-one GPs from practices throughout the UK. Method: In-depth interviews with GPs concerning both the feasibility and process evaluation phases of NATTINA. Analysis was conducted using the framework method. Results: GPs felt it was rarely necessary to refer patients. They were aware of guidelines and would refer if requested by a patient who fulfilled the guidelines criteria and/or who were missing considerable amounts of work. Conclusion: The introduction of the guidelines appears to coincide with what some may have hoped to be a desired effect of reducing adult sore throat referrals and subsequent tonsillectomies by increasing the number of episodes a patient must suffer before the referral threshold is met. GPs may find equipoise for tonsillectomy referral challenging as many patients express a strong preference for surgery. We believe this paper reinforces GP professionalism and patient-centred consultations, and challenges the role of clinical guidelines.

Excess Mucin Impairs Subglottic Epithelial Host Defense in Mechanically Ventilated Patients.

RATIONALE: Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP. OBJECTIVES: To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth. METHODS: Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium. CONCLUSIONS: Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.