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Medical Journal Review

March 2022

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.

Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study
Greuter T, Straumann A, Fernandez-Marrero Y et al
Allergy 2022; Published online ahead of print (29 January)

In this study by Greuter et al, the authors attempt to characterize and classify an eosinophilic esophagitis (EoE) variant group who have symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm2 (<15/hpf) in esophageal biopsies and absence of gastro-esophageal reflux disease (GERD). Clinical, endoscopic, (immuno)-histological, and molecular features were determined and compared with EoE, gastroesophageal reflux disease (GERD), and healthy controls. In a group of 69 such patients, in which endoscopic abnormalities were found in 53.6%, they found EoE-like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non-specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed—in contrast to EoE—no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE-typical Th2-response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, they found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE-like (characterized by eotaxin-3 expression), non-specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression). Overall, all of these EoE variants were clinically and histologically active conditions, despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype.

Evaluation of budesonide-formoterol for maintenance and reliever therapy among patients with poorly controlled asthma: A systematic review and meta-analysis
Beasley R, Harrison T, Peterson S et al
JAMA Network Open 2022;5(3):e220615 (1 March)

The Global Initiative for Asthma (GINA) recommends two alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid (ICS)-formoterol as both maintenance and reliever (SMART) or ICS-long-acting β2-agonist (ICS-LABA) as maintenance plus short-acting β2-agonist (SABA) as reliever. In order to understand optimal intervention better, the authors performed a systematic review and meta-analysis that compared budesonide-formoterol by SMART with maintenance ICS-LABA plus SABA reliever with the primary outcome being the first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression. They examined whether switching to SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance ICS-LABA plus SABA reliever among patients with poorly controlled asthma. Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). The authors found that switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation – with a 29% reduced risk compared with stepping up to step 4 ICS-LABA maintenance plus SABA reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85). These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance ICS-LABA plus SABA reliever therapy.

Delayed allergic skin reactions to vaccines
Aquino MR, Bingemann TA, Nanada A, Maples KM
Allergy & Asthma Proceedings 2022;43(1):20-29 (1 January)

In this literature review, the authors focused on delayed reactions to vaccines, examining possible causative agents and providing practical information on how to diagnose, evaluate with patch testing, and manage subsequent dose administration. They note that most delayed hypersensitivity reactions to vaccines include cutaneous manifestations, which vary from local persistent pruritic nodules to systemic rashes. The onset is usually within a few days but there can be a delay of weeks. Several excipients have been identified that have been implicated in delayed vaccine reactions, including thimerosal, formaldehyde, aluminum, antibiotics, and gelatin. Treatment with antihistamines, topical corticosteroids, or systemic corticosteroids alleviates symptoms in most patients. It is important to note that these reactions are generally not contraindications to future vaccination. However, for more severe reactions, patch testing for causative agents can be used to aid in diagnosis and approach further vaccination.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Sparreman Mikus M, Kolmer J, Andersson LI et al
European Respiratory Journal 2022; 59(2):2100142 (17 February)

In this study, the authors identified plasma biomarkers associated with asthma phenotypes by applying a new proteomic panel to samples from two well-characterized cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, chronic obstructive pulmonary disorder (COPD) subjects, and healthy controls (HCs). The applied antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. They found in U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β, and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained, following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.

Epithelial and sensory mechanisms of nasal hyperreactivity
Velasco E, Delicado-Miralles M, Hellings PW et al
Allergy 2022; Published online ahead of print (17 February)

In this review by Velasco and colleagues, the authors explore how nasal hyperreactivity may be the result of three different mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. They describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and suggest that there remains a need to identify thermal, chemical, and mechanical sensors determining hyperreactivity in humans. They discuss research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics, stressing that understanding of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis in precision medicine.

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