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In patients with chronic severe rhinosinusitis and nasal polyps, tezepelumab therapy led to greater reductions in polyp size and nasal congestion and less use of surgery and glucocorticoids than placebo.

A paucity of evidence regarding use of endoscopic sinus surgery and antibiotics in managing chronic rhinosinusitis has contributed to a five-times variation in endoscopic sinus surgery rates, as well as variation in the use of antibiotics. The main aim of the present trial was to compare the clinical effectiveness of endoscopic sinus surgery or 3 months of clarithromycin treatment alongside intranasal medication in adults with chronic rhinosinusitis with or without nasal polyps. In this pragmatic, three-arm, randomised, placebo-controlled phase 4 trial, participants were recruited from 20 secondary and tertiary care sites in the UK. Adults (aged ≥18 years) with chronic rhinosinusitis remaining symptomatic following appropriate medical therapy (intranasal corticosteroids, saline nasal irrigations, and a short course of antibiotics) were randomly assigned (1:1:1) to receive endoscopic sinus surgery (within 6 weeks of randomisation if waiting lists allowed) plus intranasal medication, clarithromycin (250 mg twice a day for 2 weeks then 250 mg once a day for 10 weeks) plus intranasal medication, or placebo plus intranasal medication. Intranasal medication comprised intranasal corticosteroids and saline irrigations. Participants were allocated with an automated, web-based secure randomisation system in permuted blocks of varying size (block sizes of three and six), stratified by the presence of polyps and trial site. Participants and site teams were masked to the clarithromycin and placebo allocations, including for outcome assessment. The primary outcome measure was the total score on the 22-item Sino-Nasal Outcome Test (SNOT-22) quality-of-life questionnaire at 6 months after randomisation, with analysis by intention to treat (ITT; available-case basis). Adverse reactions were assessed in the safety population (clarithromycin and placebo), and serious adverse events in the ITT population (all groups). The trial was registered on the ISRCTN registry, ISRCTN36962030, and EudraCT, 2018-001100-11, and is complete, with optional long-term follow-up ongoing. Between Nov 1, 2018, and Oct 13, 2023, 514 participants (181 [35%] female and 333 [65%] male), with chronic rhinosinusitis with nasal polyps (n=410) or chronic rhinosinusitis without nasal polyps (n=104), were recruited and randomly assigned to receive endoscopic sinus surgery (n=171), clarithromycin (n=172), or placebo (n=171), all with intranasal medication. SNOT-22 scores at 6 months after randomisation were significantly lower (at the 98·33% confidence level after Bonferroni adjustment) in the endoscopic sinus surgery group than in the clarithromycin group (adjusted mean difference –18·13 [98·33% CI –24·26 to –11·99], p<0·0001) and placebo group (–20·44 [–26·42 to –14·46], p<0·0001). 6-month SNOT-22 scores did not differ significantly between participants randomly assigned to clarithromycin versus placebo (–3·11 [–8·56 to 2·33], p=0·17). Ten serious adverse events occurred in nine participants (two events in two [1%] of 172 participants allocated to clarithromycin, three events in three [2%] of 171 allocated to placebo, and five events in four [2%] of 171 allocated to endoscopic sinus surgery), none of which were fatal. The MACRO trial shows that endoscopic sinus surgery has clinical effectiveness in patients with chronic rhinosinusitis, providing significantly improved disease-specific quality of life at 6 months. Conversely, the trial findings do not support routine long-term use of low-dose clarithromycin. Endoscopic sinus surgery should be recommended if intranasal medication alone is unable to achieve symptom control. National Institute for Health and Care Research Programme Grants for Applied Research.

Chronic rhinosinusitis with nasal polyps (CRSwNP) symptoms are frequently driven by type 2 inflammation. Depemokimab is the first ultra-long-acting biological drug engineered with enhanced interleukin-5 binding affinity, high potency, and an extended half-life, enabling twice per year dosing and sustained type 2 inflammation inhibition. The ANCHOR-1 and ANCHOR-2 trials investigated the efficacy and safety of depemokimab in people with CRSwNP. ANCHOR-1 and ANCHOR-2 were randomised, double-blind, placebo-controlled, parallel-group, replicate phase 3 trials conducted concurrently at 190 centres (hospitals, specialised clinics, and clinical trial sites) in 16 countries (Argentina, Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Romania, Spain, Sweden, Türkiye, the UK, and the USA). Individuals aged 18 years or older at the time of consent, with inadequately controlled CRSwNP, an endoscopic bilateral nasal polyps score of 5 or more, previous surgery for CRSwNP or previous treatment with or intolerance to systemic corticosteroids, and severe symptoms were stratified by previous CRSwNP surgery and randomly assigned 1:1 to receive either depemokimab (100 mg subcutaneously) or placebo every 26 weeks (with standard of care). Allocation was computer generated. The trial sponsor, site staff, and participants were masked. The coprimary endpoints were change from baseline in total endoscopic nasal polyps score (0–8) at week 52 and mean nasal obstruction score (verbal response scale [0–3]) over weeks 49–52, assessed in the full analysis set. Integrated analyses were conducted. Adverse events on treatment and after treatment were monitored. The trials are complete and are registered with ClinicalTrials.gov (NCT05274750 and NCT05281523). Between April 18, 2022, and Aug 7, 2023, 540 individuals were randomly assigned across ANCHOR-1 and ANCHOR-2; 528 participants comprised the full analysis set (depemokimab, n=272; placebo, n=256). Depemokimab had statistically significant improvements from baseline versus placebo in the coprimary endpoints of total nasal polyps score (treatment difference: ANCHOR-1, –0·7, 95% CI –1·1 to –0·3; p<0·001; ANCHOR-2, –0·6, –1·0 to –0·2; p=0·004; integrated, –0·7, –0·9 to –0·4) and mean nasal obstruction verbal response scale score (ANCHOR-1, –0·23, –0·46 to 0·00; p=0·047; ANCHOR-2, –0·25, –0·46 to –0·03; p=0·025; integrated, –0·24, –0·39 to –0·08). Adverse events were similar between depemokimab and placebo in ANCHOR-1 (74% [n=106] vs 79% [n=101]) and ANCHOR-2 (76% [n=98] vs 80% [n=102]). Depemokimab significantly improved clinically relevant coprimary endpoints versus placebo and was well tolerated, supporting its use as a twice per year treatment option, with the potential to reduce treatment burden for people with CRSwNP. GSK.

Chronic rhinosinusitis is the leading cause of olfactory dysfunction in adults. Although mechanical obstruction and type 2 inflammation remain important explanations for smell loss in chronic rhinosinusitis, emerging multi-omics studies suggest that disruption of the olfactory cleft microenvironment may also contribute to olfactory dysfunction. In this review, we propose the microbiota-metabolite-immune (MMI) axis as an integrative framework linking microbial dysbiosis, metabolite perturbation, and local immune remodeling in CRS-associated olfactory dysfunction. We systematically examine four interconnected domains. First, several studies have reported dysbiosis within the olfactory niche, including enrichment of Acinetobacter johnsonii in one CRS-OD cohort together with depletion of putative commensals. Second, altered metabolite profiles in CRS-OD have been associated with disturbed purine metabolism, uric acid accumulation, and reduced levels of the potentially protective metabolite indole-3-acetic acid. These changes may contribute to innate inflammatory signaling, including Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR4/NF-κB)-related pathways. Third, Staphylococcus aureus superantigens may promote T helper 2 (Th2) polarization, alter regulatory T-cell function, disrupt tight junction integrity, and impair olfactory neurogenesis, thereby sustaining bidirectional immune-microbial crosstalk. Fourth, emerging microbiota-targeted therapeutics, including xylitol irrigation, probiotics, and Interleukin-4 receptor alpha (IL-4Rα) blockade, offer novel intervention strategies. Throughout this review, we distinguish olfactory cleft-specific evidence from broader sinonasal data and acknowledge the current predominance of association studies over causal validation. Taken together, the MMI axis provides a useful framework for understanding CRS-associated OD and for identifying testable therapeutic hypotheses.

Circular RNAs (circRNAs) constitute a recently identified class of non-coding RNAs that are widely distributed in eukaryotes. Characterized by the absence of 5' caps and 3' polyadenylated tails, circRNAs may regulate gene expression through multiple mechanisms. Recent studies have shown that certain circRNAs contain binding sites complementary to microRNAs (miRNAs), enabling them to function as molecular sponges that sequester miRNAs and inhibit their suppressive effects on mRNA expression. Emerging evidence indicates that specific circRNAs are involved in the regulation of immune cells and cytokines associated with type 2 chronic rhinosinusitis; however, direct clinical evidence supporting associations between circRNAs and the diagnosis or severity of type 2 chronic rhinosinusitis remains unavailable. In this study, the molecular mechanisms of circRNAs in type 2 inflammation are systematically summarized, established experimental evidence is distinguished from clinical applications that remain to be validated, and a theoretical basis is provided for future research on type 2 chronic rhinosinusitis.

Chronic Rhinosinusitis with Nasal polyps (CRSwNP) are characterized by chronic inflammation and occur in 1-4% of the population worldwide. Patients often have comorbid asthma, and standard treatments among them are hindered by significant recurrence and lack of durability. Currently, knowledge of the molecular circuitry and immune microenvironmental interplay that utilizes metabolic reprogramming within CRSwNP is incomplete. Utilizing CRSwNP datasets from the GEO database, we performed bioinformatics analysis to identify differentially expressed genes (DEGs) implicated in metabolic reprogramming. Key regulatory genes were subsequently selected by weighted gene co-expression network analysis (WGCNA) and machine learning algorithms; their relationship with the immune microenvironment was then evaluated. To further investigate the underlying pathogenic mechanisms, we performed single-cell RNA sequencing (scRNA-seq) to map cellular expression patterns and applied Mendelian randomization (MR) analysis to assess potential causal relationships. Key molecules were subsequently experimentally validated by quantitative real-time PCR (qRT-PCR). We identified 21 DEGs associated with metabolic reprogramming that are relevant to CRSwNP. This subset was then analyzed using machine learning to identify 8 hub genes - ERBB4, FBP1, HMGCS2, LYZ, NDRG2, PIP, PYCR1, and SLC43A1. A prediction model built using these biomarkers yielded high diagnostic performance (AUC = 0.979). Single-cell resolution analysis revealed that distinct expression patterns were exhibited by these genes across subsets of immune cells. MR analysis determined that lower expression of FBP1, LYZ and NDRG2 could be risk factors for CRSwNP. Subsequent qRT-PCR in independent samples validated the downregulation of these genes in CRSwNP tissues. We systematically identify and validate a set of metabolic reprogramming-related genes with diagnostic value in CRSwNP. Collectively, these findings not only heighten the current mechanistic understanding of CRSwNP pathogenesis but also offer a novel platform to devise diagnostic and therapeutic avenues focusing on metabolism.

Purpose of ReviewThe purposes of the review are as follows: (1) to define acute rhinosinusitis (ARS) and their phenotypes, (2) to highlight the ARS management according to international guidelines, (3) to compare the physicians’ management with the ARS guideline recommendations, and (4) to report ARS socioeconomic burden.Recent FindingsBacterial and non-bacterial ARS have similar symptoms, although they can be discriminated by using a combination of specific signs and symptoms. The prescription of antibiotics should be limited to clearly suspected bacterial ARS. There is an overuse of diagnosis tools and treatment prescriptions. The total cost per ARS episode in Europe is over €1000.SummaryARS is mainly an inflammatory disease triggered by viral infection, and few cases end up developing bacterial infection. In most of the cases, it is a self-resolving disease which diagnosis is mainly clinical and the treatment symptomatic. The incidence of complications is low and independent of antibiotic use. There is a high socioeconomic burden associated to ARS.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.

Chronic rhinosinusitis (CRS) with and without nasal polyps has a prevalence of around 10%, being one of the most common chronic diseases in Europe. It is characterized by a wide range of symptoms leading to a high individual, clinical and socioeconomic burden due to loss of productivity of individual patients and challenging therapeutic processes. This study aimed to investigate the effects of functional endoscopic sinus surgery (FESS) on olfactory function and associated quality of life of CRS patients, particularly regarding postoperative differences in neuronal processes. Using psychophysical and electrophysiological tools, the goal was to quantify postoperative changes to predict the neuronal functions related to olfactory improvements after FESS and ultimately provide better therapeutic recommendations in the future. Twenty-five CRS patients with nasal polyps aged from 30 to 64 years (CRS group) and 20 healthy controls aged from 23 to 54 years (control group) participated in this study. Both groups were tested twice (interval 3 to 6 months), with the first examination of the patients taking place a few days before surgery. Testing included questionnaires (medical history including self-ratings of olfactory function and nasal breathing, SNOT-20 questionnaire), psychophysical methods (Sniffin Sticks for olfactory function [TDI score], Peak Nasal Inspiratory Flow) and electrophysiological methods (olfactory and trigeminal event-related potentials). CRS group patients were also subjected to preoperative clinical examination and preoperative CT-scans. While the CRS group improved in terms of self-ratings of the sense of smell and TDI scores, as well as nasal breathing and quality of life, the control group did not show major longitudinal differences. In addition, electrophysiological measures suggested that trigeminal sensitivity decreased after surgery. CRS patients showed benefits from surgery in terms of olfaction, nasal breathing and quality of life, at least 3–6 months after the intervention. Interestingly, electrophysiological measurements suggested a postoperative decrease of trigeminal sensitivity.

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is a persistent inflammatory disease that may be resistant to medical management and recurs with traditional surgery. We report a 28‐year‐old male with a history of CRSwNP with comorbid asthma, who was resistant to all medical management, including saline irrigation, intranasal corticosteroids (INCS), and multiple courses of antibiotics, and elected against surgical intervention. Nasal endoscopy and imaging studies demonstrated bilateral polyposis and opacification of the ostia of all sinuses (Meltzer score 5 and Lund‐Mackay score of 18). Serum IgE level remained significantly high. The patient declined surgical intervention but consented to treatment with human umbilical cord MSC‐Exo (hUCMSC‐Exo) intramucosal and intrapolyp injections while continuing his standard regimen of saline irrigation and INCS. The treatment was well tolerated, with only reported mild and transient epistaxis. At follow‐up after two months, the patient experienced a rapid decrease in SNOT‐22 score (56–6). However, the symptomatic relief had abated, and the symptoms returned gradually but did not reach baseline (SNOT‐22 increased to 41). Conversely, asthma control remained stable during this time, and the serum IgE level showed an overall negative trend. Given the single‐patient, uncontrolled design with concurrent INCS and short follow‐up, causality cannot be inferred. This case supports feasibility/tolerability and generates hypotheses for larger controlled studies of this cell‐free approach.