Background: In patients with a beta-lactam antibiotic (BA) allergy label, avoidance of the whole group of BAs leads to displacement of first-line therapies potentially influencing patient outcomes and antimicrobial resistance. Studies previously published on BA cross-reactivity use different sets of BA and seem to contain conflicting recommendations on safe BA alternatives in case of (suspected) BA allergy.
Methods: The objectives were (i) to identify discrepancies between studies regarding cross-allergy in BA and (ii) to identify research gaps. The tables and errata of 4 studies (Romano et al., Trubiano et al., Zagursky et al., SWAB-guideline by Wijnakker et al.) were evaluated and compared head-to-head.
Results: A total of 51 antibiotics were covered by the four authors, theoretically leading to 2550 potential recommendations regarding alternatives in case of specific allergies. Internal discrepancies existed in 2 tables. Since none of the tables included all 51 BAs, in 356 situations data were lacking regarding specific alternatives. In 1104 situations, only one author gave advice about a specific alternative. Harmony and disharmony between authors could be evaluated in 1090 cases. The advice regarding alternative BAs was 696 times in harmony (482 safe, 214 unsafe), while discrepancies were found in 394 cases. This led to a different advice (safe vs. unsafe) in 272 cases or 69%.
Conclusion: Disharmony between authors was identified in 36% of the cases. In 69%, this led to a clinically relevant, different advice. This indicates the need for synchronisation of cross-reactivity tables and answering remaining research gaps.
Post hoc analysis of clinical trials shows blood eosinophil counts (BEC) predict future preschool wheeze attacks; however, prospective usefulness in a clinical setting is unreported. We assessed the feasibility of point-of-care (POC) eosinophil measurements in preschool wheezers and related BEC to symptoms, lung function, and utility in predicting attacks.
Children aged 1–5 years with recurrent wheeze underwent finger-prick sampling during the outpatient clinic for POC eosinophils, forced oscillation technique (FOT) and/or spirometry, and symptom score (TRACK questionnaire). The utility of BEC and/or the other tests in predicting wheeze attacks in the subsequent 3 months was analysed by comparing those with and without an attack and using a predictive decision tree (DT) model.
Seventy-three children (median age 4.27 years) were recruited; BEC were higher in atopic children (median 0.5 × 109/L vs. 0.3 × 109/L non-atopic, p < 0.01). BEC moderately correlated with FOT reactance bronchodilator reversibility z-score changes (r = 0.495, p = 0.005), but no other lung function measures or TRACK score.
68/73 (93%) children were followed up at 3 months. 29/68 (43%) children had > 1 wheeze attack requiring unscheduled healthcare attendance. Absolute and %eosinophils at the baseline visit were higher in those who had an attack (median 0.5 × 109/L vs. 0.3 × 109/L, p = 0.03 and median 6% vs. 4%, p < 0.01). The DT model showed children with BEC ≥ 4% and TRACK score < 75 were more likely to have a future attack (probability 0.63).
POC blood eosinophils were feasible in a clinical setting. Our preliminary data suggest elevated BEC with a low symptom score predicts a wheeze attack within 3 months.
Background: Mast cells (MCs) respond to an array of allergens that drive allergic and inflammatory diseases. Stem cell factor (SCF), the ligand for the receptor KIT, is required for MC survival and function. Thymic stromal lymphopoietin (TSLP) is an alarmin that promotes Type 2 inflammation in asthma and other inflammatory diseases. We describe CDX-622, a bispecific antibody (bsAb), that targets both SCF and TSLP to neutralize these distinct cytokines.
Methods: The bsAb CDX-622 was developed from novel antagonist monoclonal antibodies (mAbs) to SCF (SCF-12) and TSLP (1D10). CDX-622 encodes the full-length 1D10 mAb and the single-chain variable fragment of SCF-12, linked to the C-terminus of the 1D10 heavy chain. CDX-622 was modified to prevent Fcγ receptor interactions and enhance FcRn binding. CDX-622 was tested using in vitro assays of MC and dendritic cell (DC) activation, an ex vivo human skin model, and in vivo studies in nonhuman primates.
Results: Novel SCF and TSLP mAbs with neutralizing activity were generated. The bsAb CDX-622 potently inhibited SCF-driven MC degranulation and TSLP-mediated CCL17 release by DCs. In human skin samples treated with SCF and TSLP, CDX-622 markedly reduced proinflammatory, MC, and DC-related RNA signatures. Additionally, CDX-622 and SCF-12 mAb administered to cynomolgus macaques (Macaca fascicularis) had a profound effect on MCs without any observed toxicity.
Conclusions: CDX-622 is a potent inhibitor of MCs through the neutralization of SCF and effectively blocks Type 2 inflammatory responses driven by TSLP. Dual inhibition of these cytokines may lead to improved clinical outcomes in certain inflammatory disorders.
Asthma is a chronic airway inflammatory disorder, affecting over 350 million people worldwide, with allergic asthma being the most common form of the disease. Allergic asthma is characterized by a type 2 (T2) inflammatory response triggered by numerous allergens beginning in the airway epithelium, which acts as a physical barrier to allergens as well as other external irritants including infectious agents, and atmospheric pollutants. T2 inflammation is propagated by several key cell types including T helper 2 (Th2) cells, eosinophils, mast cells, and B cells. Immunoglobulin E (IgE), produced by B cells, is a key molecule in allergic airway disease and plays an important role in T2 inflammation, as well as being central to remodeling processes within the airway epithelium. Blocking IgE with omalizumab has been shown to be efficacious in treating allergic asthma however, the role of IgE on airway epithelial cells is less communicated. Developing a deeper explanation of the complex network of interactions between IgE and the airway epithelium will facilitate an improved understanding of asthma pathophysiology. This review discusses the indirect and direct roles of IgE on airway epithelial cells, with a focus on allergic asthma disease.
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