Sensitisation to <scp> <i>Staphylococcus Aureus</i> </scp> Enterotoxin; a Driver of Airway Inflammation in Severe Asthma?

Allergic sensitisation to Staphylococcus aureus enterotoxins (SE-IgE) is associated not only with asthma severity but also constitutes an independent risk factor for disease development [1]. Patients with SE-IgE-positive (+SE-IgE) asthma show increased prevalence of chronic rhinosinusitis with nasal polyps (CRSwNP), particularly with higher SE-IgE levels [2]. In addition, severe asthma patients with nasal polyps exhibit elevated sputum autoantibodies against eosinophil peroxidase (anti-EPX) and macrophage receptor with collagenous structure (anti-MARCO), suggesting a potential autoimmune component in this phenotype [3]. In vitro, autoantibodies such as anti-EPX, can trigger eosinophilic degranulation with the release of free eosinophilic granules (FEG) [4] and their presence in severe asthma has been linked to a suboptimal response to biologic therapy [5]. The implications of SE sensitisation in severe asthma patients remain poorly understood, and a possible link between SE sensitisation and airway autoimmunity has not previously been investigated. We aimed to investigate the prevalence of SE sensitisation in severe asthma and examine its association with eosinophilic inflammation and airway autoimmunity. This was a cross-sectional study utilizing baseline data from the prospective intervention study SIGNATURE and the cross-sectional SATS study. Informed consent was signed by all participants. We included 120 patients with severe asthma. Serum IgE against S. aureus enterotoxins A and B was measured, and SE sensitisation was defined as SE-IgE ≥ 0.1 kU/L. Clinical characteristics, T2 biomarkers, and airway autoimmunity (defined by positive sputum anti-eosinophil-peroxidase (anti-EPX) and/or anti-macrophage receptor with collagenous structure (anti-MARCO)) were evaluated. Full methods are provided in the open-access repository (DOI: 10.5281/zenodo.15478667). Full demographic data is available in the repository (DOI: 10.5281/zenodo.15478667). Our findings show that SE allergic sensitisation is common in severe asthma, and defines a phenotype characterised by pronounced airway eosinophilia, eosinophilic degranulation and airway autoimmunity (Figure 1). Of note, FeNO levels were not significantly elevated in +SE-IgE patients, suggesting a possible deviation from classical IL-13-driven T2 inflammation. As a sign of significant eosinophilic degranulation, FEGs were frequent in +SE-IgE sputum, and anti-EPX—present in 23% of +SE-IgE vs. 7% of −SE-IgE (p = 0.03)—may serve as both a biomarker of activation and a perpetuator of eosinophilic inflammation. This supports a model of self-amplifying airway eosinophilia in this phenotype. 65% of +SE-IgE patients were men, a sex difference previously observed in other studies both in terms of SE-sensitisation and S. aureus carrier status [6, 7]. The cross-sectional design limits causal inference, but a causal pathway between SE sensitisation and asthma severity is biologically plausible: S. aureus can trigger Th2 immune responses via enterotoxins, and in the EGEA cohort, a 20-year prospective cohort investigating genetic and environmental factors in asthma, a SE-IgE ≥ 0.1 kU/L was associated with an increased risk of severe asthma 20 years later [1]. Still, confounding factors—such as healthcare exposure—may muddle this picture, although NHANES data showed a persistent relationship between S. aureus carriage and asthma risk in children even after adjusting for such exposures [8]. In regard to atopy, Schleich et al. recently reported that SE-IgE monosensitised patients had even higher T2 biomarker levels and more exacerbations than their atopic counterparts, underscoring SE-IgE as a distinct inflammatory driver [9]. In our study, only seven patients were monosensitised, limiting analyses of this subgroup. Additionally, it is yet unclear whether S. aureus plays a direct role in the autoimmune pathway of severe asthma or whether the effect on observed autoantibodies could be an indirect consequence of S. aureus-mediated severe disease. In vitro studies on anti-EPX formation upon S. aureus stimulation may shed light on any causality. Our study was also limited by a lack of microbiological data. Park et al. 2022, found no significant association between S. aureus nasal carriage and SE-sensitisation, and only SE-sensitised carriers showed increased Th2 inflammation [10]. Treatment with antibiotics may have only temporary effects on the condition as the risk of S. aureus reinfection is high. Whether this phenotype responds differently to biologics warrants further study. Prior findings suggest that airway autoimmunity, particularly anti-EPX positivity, may predict suboptimal response to anti-IL-5 therapies [5]. In conclusion, this study identifies SE sensitisation as a clinically relevant marker of airway autoimmunity and enhanced eosinophilic activity in severe asthma. Future longitudinal studies are needed to clarify causal pathways and determine whether SE sensitisation marks a distinct endotype with therapeutic implications. Freja Friis Lajer: formal analysis, writing of original draft. Laurits Frøssing: investigation, resources, review and editing. Morten Hvidtfeldt: investigation, resources, review and editing. Anna von Bülow: investigation, resources, review and editing. Lise Lotte Eriksen: sample analysis, review and editing. Nanna Dyhre-Petersen: sample analysis, review and editing. Celeste Porsbjerg: conceptualization, supervision, review and editing. We thank the Novo Nordisk Foundation Pre-graduate Fellowship for funding. This work was supported by Novo Nordisk Foundation. The authors declare no conflicts of interest. The data that support the findings of this study are openly available in Zenodo at https://doi.org/10.5281/zenodo.15478667.