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If the LANTERN results are confirmed in the ongoing pivotal studies (NCT05219968, NCT05295459), LYR-210 (7500 g) may be a promising treatment that could improve the QoL of CRS patients. Keywords: chronic rhinosinusitis; quality of life; SNOT-22; topical therapy for chronic rhinosinusitis EN chronic rhinosinusitis quality of life SNOT-22 topical therapy for chronic rhinosinusitis 1821 1824 4 08/25/23 20230901 NES 230901 INTRODUCTION Chronic rhinosinusitis (CRS) is a highly prevalent disorder with a decreased quality of life (QoL).[1] Persistent sinonasal symptoms, fatigue, sleep disruption, and depression negatively affect the well-being and productivity of CRS patients.[1] Intranasal corticosteroid sprays fail to adequately control symptoms in all CRS patients due to inconsistent delivery of effective corticosteroid doses deep into the sinuses, rapid mucosal clearance, and poor compliance.[[1], [3]] Limitations of current CRS therapies demonstrate the need for long-acting, local anti-inflammatory treatments that provide targeted therapy to the sinonasal mucosa and improve symptoms and QoL. The SNOT-22 subdomain results are consistent with the ~40-point improvement from baseline in the SNOT-22 total score for LYR-210 (7500 g).[4] LYR-210 (7500 g)-treated subjects on average reported >2× the MCIDs for the SNOT-22 subdomains[9] at week 24. [Extracted from the article]

Background: Topical steroids are first‐line treatment for chronic rhinosinusitis (CRS), but fail to provide adequate symptom control for all patients. Designed for medical treatment failures, LYR‐210 is an implantable matrix that locally elutes mometasone furoate to inflamed sinonasal tissue for up to 24 weeks in CRS patients. In an open‐label phase 1 study, LYR‐210 demonstrated clinically relevant improvement in the 22‐item Sino‐Nasal Outcome Test (SNOT‐22). Safety and efficacy of LYR‐210 in CRS were evaluated in the LANTERN Phase 2 study. Methods: Sixty‐seven surgically naive adult CRS patients who were inadequately controlled by previous medical management and seeking an alternative treatment enrolled in a multicenter, blinded, controlled, dose‐ranging study. Patients had moderate‐to‐severe disease based on SNOT‐22 and composite 7‐day average scores of the 4 cardinal CRS symptoms (4CS), with diagnosis confirmed by nasal endoscopy and magnetic resonance imaging. Patients were randomized (1:1:1) to saline irrigation–only control or bilateral in‐office administration of LYR‐210 (2500 μg) or LYR‐210 (7500 μg). Safety and efficacy were evaluated over 24 weeks. Results: Both LYR‐210 doses were safe and well‐tolerated over the 24‐week treatment period. LYR‐210 demonstrated rapid and durable dose‐dependent symptom improvement based on 4CS and SNOT‐22, with LYR‐210 (7500 μg) achieving statistical significance as early as 8 weeks and out to 24 weeks compared with control. LYR‐210 (7500 μg) reduced rescue treatment use and radiographic ethmoid opacification at week 24. Conclusions: LYR‐210 is the first implantable sinonasal treatment to achieve up to 24 weeks of benefit from a single administration in surgically naive CRS patients with and without nasal polyps. [ABSTRACT FROM AUTHOR]

Abstract Otitis media (OM) is one of the most common infectious diseases in children and the leading cause for medical consultations and antibiotic prescription in this population. The burden of disease associated with OM is greater in developing nations and indigenous populations where the associated hearing loss contributes to poor education and employment outcomes. Current treatment and prevention is largely focused on vaccination and antibiotics. However, rates of OM, particularly in indigenous populations, remain high. With growing concerns regarding antibiotic resistance and antibiotic-associated complications, an alternative, more effective treatment is required. Administration of probiotics, both locally and systemically have been investigated for their ability to treat and prevent OM in children. This review explores the theoretical bases of probiotics, successful application of probiotics in medicine, and their use in the treatment and prevention of OM. We conclude that local administration of niche-specific probiotic bacteria that demonstrates the ability to inhibit the growth of otopathogens in vitro shows promise in the prevention and treatment of OM and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective: To evaluate the efficacy and safety of intranasal AZD8848. Methods: In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/ treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30- 100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/ treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. Conclusions: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. [ABSTRACT FROM AUTHOR]

Macrolides can be clinically effective in chronic rhinosinusitis (CRS). However, little is known about how these drugs affect pathophysiological features of CRS in vivo. In the present study, patients with CRS were subjected to long-term treatment with clarithromycin. Nasal lavages with and without histamine (40 and 400 μg ml−1) were carried out prior to and late into the treatment period. Histamine was included as a tool to produce plasma exudation, a process known to move free cellular products from the mucosal tissue into the airway lumen thereby enriching nasal surface liquids with such products. Interleukin-8 (IL-8), myeloperoxidase (MPO), eosinophil cationic protein (ECP), α2-macroglobulin and fucose were monitored as indices of pro-inflammatory cytokine production, neutrophil and eosinophil granulocyte activities, plasma exudation and mucinous secretion, respectively. Clarithromycin reduced the lavage fluid levels of IL-8 at the low-dose histamine observation ( P<0·001). There was a trend towards reduced MPO by the treatment, whereas ECP was significantly reduced at the low-dose histamine observation ( P<0·05). α2-Macroglobulin was reduced by clarithromycin (saline lavages) ( P = 0·05), whereas fucose was unaffected. The exudative responsiveness to high-dose histamine was significantly reduced by the treatment ( P<0·05). Furthermore, significantly lower levels of fucose were observed at the low-dose histamine observation ( P<0·01). We conclude that long-term clarithromycin treatment likely exerts an anti-inflammatory effect in CRS. [ABSTRACT FROM AUTHOR]

Objective—Nitric oxide (NO) is an important mediator and inflammatory marker in human upper airways. Enzymes responsible for NO production have been demonstrated both in the nose and in the paranasal sinuses, but NO levels in the sinuses are reported to be several times higher than those in the nose. It has been postulated that the paranasal sinuses may be the primary sites for NO production in the upper respiratory tract. The present study was designed to compare the NO levels sampled from the nose with those found in the paranasal sinuses. Material and methods—NO levels in the maxillary sinus and nose were determined using a continuous chemiluminescence measuring technique in seven healthy volunteers. Results—When NO was sampled, via a drainage tube inserted into the maxillary sinus, a transient peak in NO level was recorded. The maximal NO level (5,761 ± 1,513 ppb; n = 7) was reached within 10 s and was followed by the establishment of a lower steady-state level (304 ± 51 ppb). When NO was continuously sampled from the nose a steady-state level, similar to that found in the sinus, was immediately established (313 ± 52 ppb). Conclusion—The data presented confirm previous findings of extremely high NO levels in the paranasal sinuses and suggest that these cavities may also function as reservoirs for NO. [ABSTRACT FROM AUTHOR]

The paranasal sinuses are connected to the nasal cavity via small osties. Ostial occlusion, caused by mucosal swelling, will result in a slowly increasing negative pressure inside the sinus cavity. In parallel, the oxygen content in the sinus will decrease, resulting in the development of relative hypoxia. Hypoxia is a powerful inducer of nitric oxide (NO) synthase, and inducible NO synthase has been shown to be present in considerable amounts in the upper airways, including the sinuses. The present study was designed to investigate whether a reduction in sinus pressure would affect upper airway NO production. Thirteen healthy volunteers were investigated. A pressure chamber was used to lower the ambient pressure to-4.9 kPa. NO was sampled from one nostril or via a drainage tube inserted into the maxillary sinus before, during and after the hypobaric exposure. When the pressure was decreased, NO levels increased from 256±15 to 316±19 ppb (n =13, p <0.001). The NO levels remained elevated (282±21 ppb; p <0.05) when measurements were repeated 20 min after leaving the chamber. The nasal airway resistance (V2[sub tot] ) also increased as a result of the chamber session (from 16±2° before to 21±3° after; p <0.05). An increase in NO levels was also found when the experiments were repeated with NO sampled directly from the maxillary sinus (225±6 before and 265±9 ppb after; n =6, p <0.001). For control purposes the nasal analyses were repeated again, this time under hyperbaric conditions (+4.9 kPa). This resulted in a slight decrease in the NO levels (from 273±22 to 241±17 ppb; n =10, p <0.001), but there was no change in the nasal airway resistance. We conclude that a reduction in sinus pressure, as seen in upper airway allergy or infection, may result in an increase in upper airway NO production. [ABSTRACT FROM AUTHOR]

Macrolides have been used for decades as an important chemotherapeutic agent in the treatment of infectious diseases. In the last 10 years there has also been increasing interest in the interaction between macrolide antibiotics and the immune system. The aim of this review is to focus on the anti-inflammatory action of erythromycin and its derivatives in the treatment of chronic sinusitis and nasal polyps. Systematic clinical investigations have been few and to the author's knowledge there have been no placebo-controlled studies. However there have been, especially from Japan, a number of clinical reports stating that long-term, low-dose macrolide antibiotics are effective in treating chronic sinusitis incurable by surgery or glucocorticosteroid treatment, with an improvement in symptoms varying between 60% and 80% in different studies. In animal studies macrolides have increased mucociliary transport, reduced goblet cell secretion and accelerated apoptosis of neutrophils, all factors that may reduce the symptoms of chronic inflammation. There is also increasing evidence in vitro of the anti-inflammatory effects of macrolides. Several studies have shown macrolides to inhibit interleukin gene expression for IL-6 and IL-8 and also to inhibit the expression of intercellular adhesion molecule essential for the recruitment of inflammatory cells. There is also evidence in vitro, as well as clinical experience, showing that macrolides reduce the virulence and tissue damage caused by chronic bacterial colonization without eradicating the bacteria. The benefit of long-term, low-dose macrolide treatment seems to be that it is, in selected cases, effective when steroids fail. The exact mechanism of action is not known, but it probably involves downregulation of the local host immune response as well as a downgrading of the virulence of the colonizing bacteria. In the future, placebo-controlled studies should be performed to establish the efficacy of macrolides if this treatment is to be accepted as evidence-based medicine. [ABSTRACT FROM AUTHOR]

Aims To investigate the effect of Lactobacillus rhamnosus on viral replication and cellular response to human rhinovirus (HRV) infection, including the secretion of antiviral and inflammatory mediators from well-differentiated nasal epithelial cells (WD-NECs). Methods and results The WD-NECs from healthy adult donors (N  = 6) were cultured in vitro , exposed to different strains of L. rhamnosus (D3189, D3160, or LB21), and infected with HRV (RV-A16) after 24 h. Survival and adherence capacity of L. rhamnosus in a NEC environment were confirmed using CFSE-labelled isolates, immunofluorescent staining, and confocal microscopy. Shed virus and viral replication were quantified using TCID50 assays and RT-qPCR, respectively. Cytotoxicity was measured by lactate dehydrogenase (LDH) activity. Pro-inflammatory mediators were measured by multiplex immunoassay, and interferon (IFN)-λ1/3 was measured using a standard ELISA kit. Lactobacillus rhamnosus was able to adhere to and colonize WD-NECs prior to the RV-A16 infection. Lactobacillus rhamnosus did not affect shed RV-A16, viral replication, RV-A16-induced IFN-λ1/3 production, or LDH release. Pre-exposure to L. rhamnosus , particularly D3189, reduced the secretion of RV-A16-induced pro-inflammatory mediators by WD-NECs. Conclusions These findings demonstrate that L. rhamnosus differentially modulates RV-A16-induced innate inflammatory immune responses in primary NECs from healthy adults. [ABSTRACT FROM AUTHOR]

Background: Chronic or recurrent rhinosinusitis without polyps (CRSsNP) is characterized by a persistent inflammation of the sinonasal mucosa. The underlying cause is unclear but increasing interest has been directed toward changes in the sinonasal microbiome as a potential driver. Methods: Twenty‐two patients diagnosed with CRSsNP were treated with antibiotics for 13 days, followed by 5 consecutive days of nasal microbiome transplants from healthy donors. Outcome measures were 22‐item Sino‐Nasal Outcome Test (SNOT‐22) questionnaire, total nasal symptom score (TNSS), endoscopic grading, 16S ribosomal RNA (rRNA) next generation sequencing (microbiome analysis), and nasal lavage fluid analysis of inflammatory cytokines. Patients were examined at the start of the study and after antibiotic treatment as well as 10 days and 3 months after the transplant series. Results: At the end of the study, patients reported significantly reduced SNOT‐22 scores and microbiome analysis showed significantly increased abundance and diversity. No significant change was observed for TNSS or endoscopic scoring. Conclusion: Nasal microbiome transplants obtained from healthy individuals and administered as nasal lavages to patients with CRSsNP are feasible. The patients reported significant and lasting reduction of symptoms and these findings were associated with a lasting increase in abundance and diversity of the local bacterial flora. The observations, which need to be confirmed by randomized controlled trials, may constitute a new treatment avenue for these difficult to treat patients where antibiotics only provide short lasting symptom control. [ABSTRACT FROM AUTHOR]

Background: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.Objective: To evaluate the efficacy and safety of intranasal AZD8848.Methods: In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30-100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848.Conclusions: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.Trial Registration: NCT00688779 and NCT00770003 as indicated above. [ABSTRACT FROM AUTHOR]

Background: Topical probiotics have been suggested as a treatment option for allergic rhinitis, as they may skew the immune response towards a beneficial type‐1 non‐allergic profile. So far observations in man have exclusively involved oral intake. The aim of this study was to examine whether a topical/nasal administration of a probiotic assemblage (PA) affects quality of life, symptoms and signs of allergic rhinitis in a nasal allergen challenge (NAC) model. Methods: In a placebo‐controlled and crossover design, 24 patients with seasonal allergic rhinitis were randomised to topical/nasal administration with a PA of Lactobacillus rhamnosus SP1, Lactobacillus paracasei 101/37 and Lactococcus lactis L1A or placebo for 3 weeks. Participants and investigators were blind to treatment allocation. The last week of each treatment period was combined with a NAC series. Efficacy variables were "Mini‐Rhinoconjunctivitis Quality of Life Questionnaire" (Mini‐RQLQ), "Total Nasal Symptom Score" (TNSS), "Peak Nasal Inspiratory Flow" (PNIF) and "Fractional Exhaled Nitric Oxide" (FeNO). In addition, to assess whether or not the PA produced any pro‐inflammatory effect per se, soluble analytes were monitored in nasal lavage fluids. Finally, bacterial cultures, sampled using swabs from the middle nasal meatus, were assessed for the presence of the PA by MALDI‐TOF analysis. Results: Administration of the PA did not produce any nasal symptoms (cf. placebo). An innate immune response was discerned within the PA run (cf. baseline), but no change in nasal lavage fluid levels of cytokines/mediators was observed cf. placebo except for IL‐17/IL‐17A (a minor increase in the PA run). Administration of the PA did neither affect Mini‐RQLQ, TNSS, PNIF nor FeNO. No evidence of persistent colonization was observed. Conclusions: Topical/nasal administration of a PA comprising Lactobacillus rhamnosus SP1, Lactobacillus paracasei 101/37 and Lactococcus lactis L1A, while likely evoking a minor innate immune response yet being safe, does not affect quality of life, symptoms or signs of allergic rhinitis. Trial registration: not registered. [ABSTRACT FROM AUTHOR]

Aims: To explore the in vitro ability of alpha haemolytic streptococcus (AHS) and lactobacilli (LBs), from Indigenous Australian children, to inhibit the growth of respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis), also from Indigenous Australian children. Methods and Results: The bacterial interference of 91 isolates, from Indigenous Australian children both with and without otitis media (OM) or rhinorrhoea, was investigated using agar overlay and cell‐free supernatant. Promising isolates underwent whole genome sequencing to investigate upper respiratory tract tropism, antibiotic resistance and virulence. Antibiotic susceptibility was examined for ampicillin, amoxicillin +clavulanic acid and azithromycin. Differences in the strength of bacterial inferences in relation to OM was examined using a case series of three healthy and three children with OM. LBs readily inhibited the growth of pathogens. AHS were less effective, although several isolates inhibited S. pneumoniae. One L. rhamnosus had genes coding for pili to adhere to epithelial cells. We detected antibiotic resistance genes coding for antibiotic efflux pump and ribosomal protection protein. LBs were susceptible to antimicrobials in vitro. Screening for virulence detected genes encoding for two putative capsule proteins. Healthy children had AHS and LB that were more potent inhibitors of respiratory pathogens in vitro than children with OM. Conclusions: L. rhamnosus from remote Indigenous Australian children are potent inhibitors of respiratory pathogens in vitro. Significance and Impact of Study: Respiratory/ear disease are endemic in Indigenous Australians. There is an urgent call for more effective treatment/prevention; beneficial microbes have not been explored. L. rhamnosus investigated in this study are potent inhibitors of respiratory pathogens in vitro and require further investigation. [ABSTRACT FROM AUTHOR]

Background We explored the nasal microbiota in Indigenous Australian children in relation to ear and nasal health. Methods In total, 103 Indigenous Australian children aged 2–7 years (mean 4.7 years) were recruited from 2 Queensland communities. Children's ears, nose, and throats were examined and upper respiratory tract (URT) swabs collected. Clinical histories were obtained from parents/medical records. URT microbiota were characterized using culturomics with Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification. Real-time PCR was used to quantify otopathogen (Haemophilus influenzae , Streptococcus pneumoniae , and Moraxella catarrhalis) loads and detect respiratory viruses. Data were analyzed using beta diversity measures, regression modeling, and a correlation network analysis. Results Children with historical/current otitis media (OM) or URT infection (URTI) had higher nasal otopathogen detection and loads and rhinovirus detection compared with healthy children (all P <.04). Children with purulent rhinorrhea had higher nasal otopathogen detection and loads and rhinovirus detection (P <.04) compared with healthy children. High otopathogen loads were correlated in children with historical/current OM or URTI, whereas Corynebacterium pseudodiphtheriticum and Dolosigranulum pigrum were correlated in healthy children. Conclusions Corynebacterium pseudodiphtheriticum and D. pigrum are associated with URT and ear health. The importance of the main otopathogens in URT disease/OM was confirmed, and their role relates to co-colonization and high otopathogens loads. [ABSTRACT FROM AUTHOR]

Compares a protein D-producing and a nonproducing nontypeable Haemophilus influenzae strains in their ability to cause damage in a human nasopharyngeal tissue cultures. Measurement of the ciliary beat frequency (CBF) of tissue specimens; Manifestation of decreased CBF by inoculated cultures.

Background: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.Methods: LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454.Findings: Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo.Interpretation: In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options.Funding: Sanofi and Regeneron Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) patients who fail medical management have few treatment options other than endoscopic sinus surgery (ESS). A novel biodegradable mometasone furoate drug delivery system (LYR‐210) providing continuous topical steroid therapy to sinonasal mucosa over 24 weeks was developed to treat unoperated CRS patients who have failed medical management prior to ESS. LYR‐210 was designed to slowly expand in the middle meatus, ensuring efficient drug delivery as mucosal swelling reduces. Methods: A prospective, multicenter, open‐label study was conducted in 20 CRS subjects who were determined to be candidates for ESS. Under endoscopic guidance and topical anesthesia, LYR‐210 was placed in both middle meatuses. The primary endpoint was product‐related serious adverse events (SAEs) at 4 weeks. Additional assessments included plasma drug concentration, morning serum cortisol levels, intraocular pressures (IOPs), and Sino‐Nasal Outcome Test (SNOT‐22) scores. Results: LYR‐210 was successfully placed bilaterally in 20 subjects (12 without nasal polyps and 8 with polyps) in an office setting. There were no product‐related SAEs through 24 weeks, at which point 86% of LYR‐210 depots were still retained in the middle meatus. Serum cortisol, IOP, and plasma drug concentrations supported systemic safety at all time points tested. Subjects experienced significant reductions in their SNOT‐22 scores as early as week 1, and this reduction persisted through week 24 (p < 0.01). Significant symptom improvement was achieved in the SNOT‐22 rhinologic, extranasal rhinologic, ear‐facial, psychological, and sleep dysfunction subdomains at 24 weeks (p < 0.05). Conclusion: LYR‐210 is safe and well‐tolerated in ESS‐naive CRS patients and leads to sustained symptom improvement in patients. [ABSTRACT FROM AUTHOR]

Purpose: Septoplasty is a common rhinological procedure intended to relieve symptoms of chronic nasal obstruction. However, there remains a question as to whether patients obtain symptom improvement and are satisfied with surgical outcomes in the months and years after septoplasty. This review aims to evaluate the long-term efficacy of functional septoplasty for nasal septal deviation.Methods: A systematic review of the literature was conducted from November 2014 to March 2016 using the Cochrane, EMBASE, and PubMed databases. Prospective trials concerning functional septoplasty, which assessed subjective outcomes and included long-term follow-up data (≥ 9 month post-septoplasty) were included.Results: 2189 articles were screened with seven meeting the criteria for inclusion. Patient satisfaction was assessed in six studies, with rates of satisfaction provided in three of these, ranging from 69 to 100%. Two studies assessed the degree of patient satisfaction, with one study indicating that 88% of patients were moderately satisfied or better at 1 year post-op, and the other reporting that 50% of patients were satisfied. In assessing symptom relief, several methods were used, including validated questionnaires, with varying degrees of improvement in nasal obstruction reported.Conclusions: Septoplasty appears to be a far from perfect treatment for nasal obstruction due to septal deviation. However, given the heterogeneity of data and lack of randomized controlled trials (RCTs), future RCTs and use of validated questionnaires would enable generation of superior levels of evidence. We suggest future prospective trials evaluating prognostic factors in septoplasty, to better inform patients and facilitate the development of guidelines for surgical intervention. [ABSTRACT FROM AUTHOR]

Background Recent evidence has challenged the practice of tonsillectomy in children with sleep-disordered breathing. Tonsillotomy (subtotal/partial/intracapsular tonsillectomy) has been proposed as an alternative with equivalent effectiveness and decreased post-operative morbidity, thus improving cost-effectiveness. Objective To systematically review the literature comparing clinical efficacy, post-operative morbidity, and cost-effectiveness of tonsillotomy and tonsillectomy in paediatric (<16yo) patients with sleep-disordered breathing. Data sources A systematic search of MEDLINE, EMBASE, and CENTRAL (1984–July 2014) was conducted. Papers in English directly comparing post-operative outcomes in tonsillectomy and tonsillotomy in children undergoing surgery for sleep-disordered breathing were included. Review methods Two authors independently assessed abstracts for relevance, with disagreements resolved by a third author. Selected studies were independently assessed regarding inclusion and exclusion criteria. Results Thirty-two studies satisfied inclusion and exclusion criteria (19 randomised, 13 non-randomised). Patient satisfaction, quality-of-life, and polysomnographic improvement post-surgery did not vary between tonsillotomy and tonsillectomy. Tonsillotomy reduced the odds of a secondary haemorrhage by 79% (OR 0.21, 95% CI 0.17–0.27, p < 0.01), decreased post-operative pain and reduced return to normal oral intake by 2.8 days (95% CI 1.08–4.52, p < 0.01). The odds of readmission were decreased by 62% (OR 0.38, 95% CI 0.23–0.60, p < 0.01). Tonsillotomy had a slightly higher rate of symptom recurrence (4.51%) than tonsillectomy (2.55%), the long-term impact of which was unclear. Conclusion Current evidence supports tonsillotomy in children with obstructive surgical indications. It is likely to reduce post-operative haemorrhage, pain, and facilitate a faster return to normal diet and activity. Healthcare burden is decreased due to fewer post-operative complications and reduced need for medical re-contact. More research is necessary to assess the risk of recurrence, and further classification of secondary haemorrhage severity is required to fully clarify the clinical benefit of tonsillotomy. [ABSTRACT FROM AUTHOR]

Objective A locally disturbed commensal microbiome might be an etiological factor in chronic rhinosinusitis (CRS) in general and in CRS without nasal polyps (CRSsNP) in particular. Lactic acid bacteria (LAB) have been suggested to restore commensal microbiomes. A honeybee LAB microbiome consisting of various lactobacilli and bifidobacteria have been found potent against CRS pathogens in vitro. Recently, we examined effects of single nasal administrations of this microbiome in healthy subjects and found it inert. In this study, we examined effects of repeated such administrations in patients with CRSsNP. Study Design The study was of a randomized, double-blinded, crossover, and sham-controlled design. Methods Twenty patients received 2 weeks' treatment administered using a nasal spray-device. The subjects were monitored with regard to symptoms (SNOT-22 questionnaire, i.e., the primary efficacy variable), changes to their microbiome, and inflammatory products (IL-6, IL-8, TNF-, IL-8,a, and MPO) in nasal lavage fluids. Results Neither symptom scores, microbiological explorations, nor levels of inflammatory products in nasal lavage fluids were affected by LAB (c.f. sham). Conclusion Two weeks' nasal administration of a honeybee LAB microbiome to patients with CRSsNP is well tolerated but affects neither symptom severity nor the microbiological flora/local inflammatory activity. Level of Evidence 1b [ABSTRACT FROM AUTHOR]

Objective Endoscopic pituitary surgery has shown favorable clinical outcomes. Less is known about the impact of surgical approaches on health-related quality of life (HRQoL) and work capacity. The present study was undertaken to compare transsphenoidal microscope-assisted surgery with endoscopic transsphenoidal surgery regarding preoperative and surgical factors for the final outcome of HRQoL and work capacity. Methods In a retrospective study of patients operated on for pituitary adenoma, outcome was compared between those operated on before and after transition with endoscopic surgery at our department. Data were gathered via patient questionnaires and patients' files. Results After exclusions, 235 patients were included (99 microsurgical and 136 endoscopic). Frequency of complications was similar but tumor size was significantly larger in the endoscopic group. Complications did not affect HRQoL or work capacity. HRQoL was not affected by surgical technique but showed an overall trend toward lower values compared with the general population. Sick leave, return to work frequency, and permanent sick leave were not affected by surgical technique. Female gender was a factor for lower ratings in all outcome variables. Conclusions Surgical technique does not influence HRQoL or work capacity in this long-term follow-up although both are decreased compared with the general population. We conclude that fully endoscopic pituitary surgery, despite including larger tumors, bears the same risk for complications as microsurgery. In addition, females have a greater risk for decrease in HRQoL and work ability. This factor should be taken into account when informing patients and appreciating expectations of treatment. [ABSTRACT FROM AUTHOR]

Background Lactic acid bacteria (LAB) can restore commensal microbiomes and prevent infections. Arguably, nasal administrations of LAB may therefore be beneficial in chronic rhinosinusitis (CRS). Previous studies have examined effects of topical/nasal LAB in children with secretory otitis media, but little is as yet known about their effects on the human nasal airway. The aim of this pilot study was to examine effects on nasal symptoms and commensal bacteria in healthy subjects of nasal administration of a honeybee LAB microbiome; ie, a mixture of 9 Lactobacillus spp. and 4 Bifidobacterium spp. obtained from the honeybee Apis mellifera. Furthermore, we aimed to assess whether or not the honeybee LAB produced a local inflammatory response. Methods Twenty-two healthy subjects received a single administration of honeybee LAB in a sham-controlled, double-blinded, and crossover design. Using questionnaires, microbiological methods, and nasal lavages, they were assessed regarding symptoms, changes to commensal bacteria, and inflammatory products in nasal lavage fluids. Results The honeybee LAB did not produce any symptoms or other untoward effects. No changes were observed of commensal bacteria by the honeybee LAB, and no inflammatory response was detected (compared to sham); ie, unaffected nasal lavage fluid levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), monokine induced by interferon-γ (MIG), interleukin-15 (IL-15), epidermal growth factor (EGF), eotaxin, interferon gamma-induced protein-10 (IP-10), and interleukin-1 receptor antagonist (IL-1RA). Conclusion A single human nasal administration of a honeybee LAB microbiome is well tolerated. Specifically, it does not affect commensal bacteria and does not produce an inflammatory response. [ABSTRACT FROM AUTHOR]

Objective and design: The purpose of the study was to examine effects of pre-treatment with a Toll-like receptor 7 (TLR7) agonist (AZD8848) in allergic rhinitis and to evaluate clinical effects of two dosing regimens. Subjects: The study involved 83 patients with allergic rhinitis. Data on effects of AZD8848 on symptoms were analysed with data from a previous study ( n = 68) of identical double blind, parallel group design (NCT00770003). Treatment: The treatment involved intranasal AZD8848 20 µg three times weekly, 60 µg once weekly, or placebo for 5 weeks. Methods: Nasal lavage and plasma were analysed for proof-of-mechanism markers. Daily nasal allergen challenges were given for 7 days, starting 24 h after the final AZD8848 dose. Symptoms were monitored after each challenge and every morning and evening. Results: Markers of TLR-activation increased following AZD8848 administration (CXCL10, TNFα, IL-6, IFNγ). Symptoms recorded soon after allergen challenge were reduced up to eight days after the final dose of AZD8848. Morning and evening symptoms were also reduced, and these changes reached statistical significance for morning observations. Adverse effects were more frequent in the 20 µg three times weekly group. Conclusions: Repeated administration of AZD8848 activated TLR7 and produced IFN-induced effects. This was associated with a sustained reduction in allergen responsiveness. [ABSTRACT FROM AUTHOR]

To perform a comprehensive review of otitis media microbiome literature published between 1st July 2015 and 30th June 2019. PubMed database, National Library of Medicine. Key topics were assigned to each panel member for detailed review. Draft reviews were collated and circulated for discussion when the panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019. The final draft was prepared with input from all panel members. Much has been learned about the different types of bacteria (including commensals) present in the upper respiratory microbiome, but little is known about the virome and mycobiome. A small number of studies have investigated the middle ear microbiome; however, current data are often limited by small sample sizes and methodological heterogeneity between studies. Furthermore, limited reporting of sample collection methods mean that it is often difficult to determine whether bacteria detected in middle ear fluid specimens originated from the middle ear or the external auditory canal. Recent in vitro studies suggest that bacterial interactions in the nasal/nasopharyngeal microbiome may affect otitis media pathogenesis by modifying otopathogen behaviours. Impacts of environmental pressures (e.g. smoke, nutrition) and clinical interventions (e.g. vaccination, antibiotics) on the upper respiratory and middle ear microbiomes remain poorly understood as there are few data. Advances in understanding bacterial dynamics in the upper airway microbiome are driving development of microbiota-modifying therapies to prevent or treat disease (e.g. probiotics). Further advances in otitis media microbiomics will likely require technological improvements that overcome the current limitations of OMICs technologies when applied to low volume and low biomass specimens that potentially contain high numbers of host cells. Improved laboratory models are needed to elucidate mechanistic interactions among the upper respiratory and middle ear microbiomes. Minimum reporting standards are critically needed to improve inter-study comparisons and enable future meta-analyses. [ABSTRACT FROM AUTHOR]