Background: The asthma-COPD overlap is widely recognized, but its characteristics are not fully understood. This is largely true for the clinical presentation characterized by various ACO definitions. The purpose of this study was to investigate the pattern of comorbidities among patients with ACO, defined by various criteria. Methods: The data came from the multicenter cross-sectional study conducted in a mixed population of patients with asthma and COPD. Patients were classified into five groups according to five different definitions of ACO (GINA/GOLD/30%, Spanish criteria, COPD + asthma < 40, Gibson's criteria, clinician's diagnosis), reference ACO groups, and a group of patients with obstructive pulmonary diseases who were not diagnosed with ACO. To demonstrate the differences between groups, we compared the prevalence of comorbidities between all ACO and non-ACO groups. Data on age, severity of airflow obstruction, and smoking history were recorded for all patients. Results: For the final analysis, 1609 patients were included. Patients belonging to the ACO groups had a higher burden of comorbidities, poorer lung function, and a higher number of pack-years of smoking history compared to patients without an ACO diagnosis. Comorbidities were significantly more prevalent in ACO groups. Compared to the non-ACO group, nine diseases were more common in the GINA/GOLD/30% group, seven in both the COPD + asthma < 40 group and the clinician's diagnosis group, five in the Gibson's criteria group, and two in the Spanish criteria group. The most common comorbidities in the ACO groups were hypertension, coronary artery disease, GERD, musculoskeletal disorders, diabetes, and chronic sinusitis. Chronic sinusitis was more frequent in ACO groups defined by more precise asthma criteria. Conclusions: The definitions of ACO used in clinical practice vary widely and describe different populations. ACO populations vary in terms of comorbidities, lung function, smoking history, and age. Chronic sinusitis is a comorbidity that occurs more frequently in ACO groups defined by more precise asthma criteria. Patients with ACO differ in their clinical outcomes from those with other obstructive airway diseases.

A man in his 60s presented with diplopia, headache and facial numbness. Examination demonstrated a unilateral right abducens nerve palsy which rapidly progressed to a bilateral abducens palsy, partial right third nerve palsy and bilateral facial numbness. Nasendoscopy and imaging findings suggested an erosive fungal lesion centred on the sphenoid sinus. He underwent aggressive clearance with functional endoscopic sinus surgery, which revealed pan-sinus allergic fungal disease with marked bony erosion of the sphenoid, exposing the dura and optic chiasm. Corticosteroids and systemic antifungals were commenced postoperatively. Histopathology demonstrated eosinophilic mucin and no invasive features. However, no fungal organism was identified. His diplopia persisted for 8 weeks, resolving fully by twelve weeks. This case highlights chronic allergic fungal sinusitis as an important differential in patients with ocular complications, the diagnostic challenges which require multimodal assessment and MDT involvement, and the role of aggressive surgical management and postoperative corticosteroid and antifungal therapies.

Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the nose and paranasal sinuses associated with poor quality of life and high health care burden. CRS is broadly classified into two subtypes based on whether nasal polyps are present (CRSwNP) or absent (CRSsNP). While CRSsNP is more prevalent, the underlying mechanisms contributing to CRSwNP pathogenesis have been more extensively defined over the years. CRSwNP is characterized by type 2 (T2) inflammation as well as epithelial barrier dysfunction and in the past 3 years, a new endotype has been defined, inflammatory cell heterogeneity has been identified, novel cell populations have been discovered, and mechanisms contributing to epithelial barrier dysfunction have been advanced. Clinically, 4 biologics targeting T2 inflammation are now approved for CRSwNP. As these therapies become increasingly common in clinical practice, ongoing investigations have focused on comparing their efficacy and defining their role alongside more established interventions such as corticosteroids and sinus surgery. In this review, novel mechanistic findings and recent clinical developments in CRS between 2023 and 2025 will be highlighted.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nasal cavity and paranasal sinuses. Eosinophilic CRS (ECRS) is a refractory subtype characterized by persistent type 2 inflammation. Epidemiological and animal studies suggest that CRS may affect brain function and that microbiota dysbiosis may contribute to the pathophysiology of CRS. However, the relationship between microbiota alterations and neuroimmune changes remains poorly understood in CRS. In this study, we investigated nasal and gut microbiota together with glial and inflammatory gene expression in the olfactory bulb (OB) and hippocampus in a mouse model of ECRS, and examined their associations. The nasal and cecal microbiota were analyzed by 16S rRNA gene amplicon sequencing, and glial and inflammatory gene expression in the OB and hippocampus was assessed by real-time RT-PCR. Associations between microbial taxa and brain gene expression were analyzed using MaAsLin2. While alpha diversity was unchanged, beta diversity of both nasal and gut microbiota differed significantly in ECRS mice. Differential abundance analyses identified several nasal and gut bacterial taxa altered in ECRS. In parallel, expression of glial markers was increased in the OB and hippocampus, and expression of the pro-inflammatory cytokine gene Il-6 was elevated in the hippocampus. Notably, multiple nasal microbial taxa, but not gut bacteria, were significantly associated with hippocampal glial and inflammatory gene expression. These findings indicate that ECRS is accompanied by dysbiosis of the nasal and gut microbiota together with hippocampal neuroimmune alterations and suggest a potential link between nasal microbiota composition and hippocampal neuroimmune alterations.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is uncommon in pediatric populations but may significantly impair quality of life. Adult data support biologics targeting type 2 inflammatory pathways, whereas pediatric evidence remains sparse and largely indirect. This systematic review aimed to summarize the available evidence on both efficacy and safety, rather than to estimate a precise treatment effect. A systematic review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Scopus, and Cochrane Library databases were searched from inception to March 2026 for studies investigating biologics in pediatric CRSwNP or pediatric type 2 airway disease with CRSwNP-related sinonasal outcomes. Studies focused on cystic fibrosis-associated nasal polyposis or allergic fungal rhinosinusitis (AFRS) were excluded from the primary synthesis and retained only for sensitivity/contextual analyses. Risk of bias was assessed using design-appropriate tools. Of 404 identified records, six studies were eligible for qualitative review. Four studies (three case series and one retrospective observational study) were retained in the primary synthesis after exclusion of cystic fibrosis-associated nasal polyposis and AFRS; two studies were considered in sensitivity analyses. The available evidence was predominantly low-level, heterogeneous, and based on small samples. Dupilumab, omalizumab, and mepolizumab showed signals of potential benefit in selected type 2 inflammatory phenotypes, but sinonasal outcomes were inconsistently reported. No major treatment-related safety issues were reported, although adverse-event reporting was inconsistent, and follow-up duration was limited and variable. For dupilumab, pediatric CRSwNP-specific safety data remain sparse, and known adverse events described in broader prescribing information, including injection-site reactions, eosinophilia, conjunctivitis, skin reactions, and arthralgia, require active monitoring. Biologics may represent a promising steroid-sparing option for selected pediatric patients with refractory type 2 inflammatory CRSwNP. However, current evidence is predominantly based on case series and indirect cohorts; therefore, conclusions should be considered cautious and hypothesis-generating. Prospective pediatric studies with standardized sinonasal outcomes and longer follow-up are required.

Chronic rhinosinusitis with nasal polyps (CRSwNP) presents three persistent clinical enigmas that conventional immunological frameworks have failed to resolve. These include the paradox of locally elevated specific IgE in the absence of systemic sensitization, a high polyp recurrence rate exceeding 60% following technically complete functional endoscopic sinus surgery (FESS), and disease rebound observed in the majority of patients within 6 to 12 months after discontinuation of dupilumab. Converging lines of evidence suggest that tertiary lymphoid structures (TLS), organized ectopic lymphoid aggregates capable of sustaining autonomous adaptive immune responses, may represent a unifying structural framework that could contribute to all three phenomena. Within CRSwNP tissue, mature TLS are proposed to harbor functional germinal centers that drive local IgE class-switch recombination independent of systemic sensitization. These structures may also serve as protected niches for tissue-resident memory T (TRM) cells refractory to systemic biologic blockade, and they may maintain self-sustaining immune circuits that persist after surgical removal of gross polyp tissue. This review synthesizes current knowledge of TLS formation biology, proposes a Trifunctional TLS Model as a conceptual framework. It further integrates recent spatial transcriptomic data from large cohorts to hypothesize that TLS anatomical depth may determine functional phenotype and therapeutic vulnerability. We further propose a TLS grading framework as a research instrument to structure future validation studies, and outline hypothesis-driven, testable implications for surgical extent, biologic targeting strategies, and future research directions. If validated, reframing CRSwNP as a TLS-driven, structurally semi-autonomous inflammatory disease could shift the therapeutic paradigm from symptom suppression toward immunological restructuring.

Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is characterized by type 2 inflammation, including M2 macrophage infiltration. Baicalein is a flavonoid with anti-inflammatory properties. This study aimed to investigate the therapeutic effect of baicalein in a papain-induced eosinophilic rhinosinusitis model and to determine whether it acts through arachidonate 15-lipoxygenase (ALOX15)-dependent M2 macrophage function. Clinical nasal samples from controls, non-eosinophilic CRSwNP (neCRSwNP), and eCRSwNP were analyzed for ALOX15 expression and localization. THP-1 cells were differentiated and polarized toward M2 macrophages, and the effects of baicalein on ALOX15 expression, lipid peroxidation, cytokine secretion, and transcriptomic profile were examined. The ALOX15 inhibitor PD146176 was used for target validation. A murine eosinophilic rhinosinusitis model was established by intranasal papain instillation, followed by baicalein treatment. Mucosal inflammation, IgE levels, proteoglycan 2 (PRG2)/ALOX15 expression, and immune cell infiltration were evaluated. ALOX15 was upregulated in eCRSwNP tissues and localized to CD68[+]CD206[+] M2 macrophages. In vitro, M2 polarization increased ALOX15 expression and lipid peroxidation. Baicalein suppressed ALOX15 expression, lipid peroxidation, and the secretion of CCL22, CCL2, CXCL12, FGF-2, and IL-15. PD146176 produced similar effects, and baicalein showed no additional effect after ALOX15 blockade. RNA sequencing revealed transcriptional remodeling in M2 macrophages after baicalein treatment. In vivo, papain increased ethmoid sinus mucosal thickening, serum IgE, PRG2/ALOX15 positive cells, and infiltration of CD45[+] immune cells, CD170[+] eosinophils, F4/80[+] macrophages, and B220[+] B cells. Baicalein significantly alleviated all these pathological changes. In conclusion, baicalein attenuates papain-induced eCRSwNP-like inflammation by inhibiting lipid peroxidation and ALOX15-associated M2 macrophage secretory function. The ALOX15/M2 macrophage axis may represent a potential therapeutic target for eCRSwNP.