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Medical Journal Review

September 2023

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Asthma hospitalisations and heat exposure in England: A case-crossover study during 2002-2019
Konstantinoudis G, Minelli C, Lam HCY et al
Thorax 2023;78(9):875-881

Previous studies have reported an association between warm temperature and asthma hospitalization, but little is known about cofactors. This study aims to evaluate the association between asthma hospitalization and warm temperature and investigate vulnerabilities by age, sex, time, and space. In this study, the authors explored individual-level data on summer asthma hospitalization at high temporal (daily) and spatial (postcodes) resolutions during 2002–2019 in England from the NHS Digital. Daily mean temperature at 1 km×1 km resolution was retrieved from the UK Met Office. The authors focused on lag 0–3 days and employed a case–crossover study design and fitted Bayesian hierarchical Poisson models accounting for possible confounders (rainfall, relative humidity, wind speed, and national holidays). After accounting for confounding, they found an increase of 1.11% (95% credible interval: 0.88% to 1.34%) in the asthma hospitalization risk for every 1°C increase in the ambient summer temperature. The effect was highest for males aged 16–64 (2.10%, 1.59% to 2.61%) and during the early years of our analysis.  Interestingly, they found evidence of a decreasing linear trend of the effect over time. Overall, this study provides evidence of an association between warm temperature and hospital admission for asthma. The effect has decreased over time with potential explanations including temporal differences in patterns of heat exposure, adaptive mechanisms, asthma management, lifestyle, comorbidities, and occupation.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases
Metz M, Kolkhir P, Altrichter S, Siebenhaar F et al
Allergy 2023; Published online ahead of print (22 August)

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, the authors  explore: (1) the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Distinction between rhinitis alone and rhinitis with asthma using interactomics
Aguilar D, Lemonnier N, Melén E et al
Scientific Reports 2023;13(1):13125 (12 August) 10.1038/s41598-023-39987-6

The concept of “one-airway-one-disease”, coined over 20 years ago, may be an over-simplification of the links between allergic diseases. Genomic studies suggest that rhinitis alone and rhinitis with asthma are operated by distinct pathways. In this Medal (Mechanisms of the Development of Allergy) study, Augilar and colleagues leveraged the information of the human interactome to distinguish the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone and rhinitis with asthma. The authors found significant differences in the topology of the interactomes and in the pathways associated to each phenotype. In rhinitis alone, identified pathways included cell cycle, cytokine signaling, developmental biology, immune system, metabolism of proteins and signal transduction. In rhinitis and asthma multimorbidity, most pathways were related to signal transduction. The remaining few were related to cytokine signaling, immune system or developmental biology. Toll-like receptors and IL-17-mediated signaling were identified in rhinitis alone, while IL-33 was identified in rhinitis in multimorbidity. On the other hand, few pathways were associated with both phenotypes, most being associated with signal transduction pathways including estrogen-stimulated signaling. The only immune system pathway was Fery-mediated MAPK activation. Overall, the authors suggest that rhinitis alone and rhinitis and asthma/multimorbidity should be considered as two distinct diseases.

Food allergen sensitization on a chip: The gut-immune-skin axis
Janssen R, de Kleer JWM, Heming B et al
Trends in Biotechnology 2023; Correct proof (12 August)

The global population is growing, rapidly increasing the demand for sustainable, novel, and safe food proteins with minimal risks of food allergy. In vitro testing of allergy-sensitizing capacity is predominantly based on 2D assays. However, these lack the 3D environment and crosstalk between the gut, skin, and immune cells essential for allergy prediction. Organ-on-a-chip (OoC) technologies are promising to study type 2 immune activation required for sensitization, initiated in the small intestine or skin, in interlinked systems. Increasing the mechanistic understanding and, moreover, finding new strategies to study interorgan communication is of importance to recapitulate food allergen sensitization in vitro. In this paper, Janssen and colleagues outline recently developed OoC platforms and discuss the features needed for reliable prediction of sensitizing allergenicity of proteins.

Current state and prospects of artificial intelligence in allergy
van Breugel M, Fehrmann RSN, Bügel M et al
Allergy 2023; Published online ahead of print (16 August)

As noted by the authors of this paper, van Breugel and colleagues note that the field of medicine is witnessing an exponential growth of interest in artificial intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy. In this review the authors explore the fundamental concepts of AI and critically discuss its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. They provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide clinicians in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. The authors conclude by suggesting that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.

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