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Medical Journal Review

June 2020

WAO Reviews – Editors' Choice

The Editors’ Choice comes to you from Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI. They select articles for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases, and whenever possible, for their accessibility to everyone.

Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: A nationwide cohort study of the global SABINA programme
Nwaru BI, Ekström M, Hasvold P, Wiklund F, Telg G, Janson C.
European Respiratory Journal 2020;55(4):1901872.
https://doi.org/10.1183/13993003.01872-2019

In this study by Nwaru and colleagues, the authors explored Swedish national registries of asthma patients aged 12–45 years with two or more prescription fills of drugs for obstructive lung disease during 2006–2014 to see if short-acting beta agonist (SABA) overuse was associated with poor outcomes. SABA overuse was defined as filling of more than two SABA canisters in a 1-year baseline period following inclusion. The authors stratified SABA use into 3–5, 6–10 and ⩾11 canisters per baseline-year and relied upon Cox regression to examine associations between SABA use and exacerbation (hospitalizations and/or oral corticosteroid claims) and mortality. This analysis included 365,324 asthma patients (mean age 27.6 years; 55% female); average follow-up was 85.4 months. 30% overused SABA, with 21% filling 3–5 canisters per year, 7% filling 6–10 canisters per year and 2% filling ⩾11 canisters per year. They found that an increasing number of filled SABA canisters was associated with increased risk of exacerbation, as follows. 3–5 canisters: hazard ratio (HR) 1.26 (95% CI 1.24–1.28); 6–10 canisters: 1.44 (1.41–1.46); and ⩾11 canisters: 1.77 (1.72–1.83), compared to two or fewer canisters per year. Higher SABA use was associated with incrementally increased mortality risk (2564 deaths observed), as follows. 3–5 canisters: HR 1.26 (95% CI 1.14–1.39); 6–10 canisters 1.67 (1.49– 1.87); and ⩾11 canisters: 2.35 (2.02–2.72) compared to two or fewer canisters per year. Overall, these findings reinforce the importance of following SABA usage, as this should provide a key to improving asthma management.

Sialylation of immunoglobulin E is a determinant of allergic pathogenicity
Shade KTC, Conroy ME, Washburn N, Kitaoka M, Huynh DJ et al.
Nature. 2020; Published online ahead of print (20 May).
https://doi.org/10.1038/s41586-020-2311-z

Although it is known that IgE is required for allergies, it is not understood why total and allergen-specific IgE concentrations do not consistently correlate with allergic disease. Furthermore, it is well established that glycosylation of IgG dictates its effector function and has disease-specific patterns; however, it is not known whether IgE glycans differ in disease states or affect biological activity. In this study, Shade et al., examine whether glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies can provide further aid, finding an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuated effector-cell degranulation and anaphylaxis in several models of allergic disease. Therapeutic interventions — including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor FcεRI, and administering asialylated IgE — markedly reduce anaphylaxis. The authors suggest that utilizing the IgE–sialylation axis presents a compelling diagnostic and therapeutic strategy.

Bruton’s tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis
Dispenza MC, Krier-Burris RA, Chhiba KKD, Undem BJ, Robida PA, Bochner BS
Journal of Clinical Investigation 2020; Published online ahead of print (2 June)
https://doi.org/10.1172/jci138448

Presently, no known therapy can prevent anaphylaxis. Bruton’s tyrosine kinase (BTK) is an enzyme thought to be essential for high-affinity IgE receptor (FcεRI) signaling in human cells. In this study by Dispenza and colleagues, the authors hypothesize that BTK inhibitors (BTKi’s) would prevent IgE-mediated responses including anaphylaxis. Through in vitro studies, they showed that irreversible BTKi’s broadly prevented IgE-mediated degranulation and cytokine production in primary human mast cells and blocked allergen induced contraction of isolated human bronchi. To address their efficacy in vivo, they created a novel humanized mouse model of anaphylaxis that does not require marrow ablation or human tissue implantation. After a single intravenous injection of human CD34 + cells, NSG-SGM3 mice supported the population of mature human tissue-resident mast cells and basophils. These mice showed excellent responses during passive systemic anaphylaxis using human IgE to evoke selectively human mast cell and basophil activation, and response severity was controllable by altering the amount of allergen used for challenge. Pretreatment with just two oral doses of the BTKi acalabrutinib completely prevented moderate IgE-mediated anaphylaxis in these mice and also significantly protected against death during severe anaphylaxis. These data suggest that BTKi’s may be able to prevent anaphylaxis in humans by inhibiting FcεRI-mediated signaling.

A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection
Casanova JL, Su HC, COVID Human Genetic Effort.
Cell 2020; Published online ahead of print (13 May).
https://doi.org/10.1016/j.cell.2020.05.016

SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. In this commentary by the COVID Human Genetic Effort, the authors highlight that studies of outliers (those uninfected despite viral exposure vs healthy young patients with life-threatening disease) present a unique opportunity to reveal human genetic determinants of infection and disease.

Nasal gene expression of angiotensin-converting enzyme 2 in children and adults
Bunyavanich S, Do A, Vicencio A.
JAMA 2020; Published online ahead of print (20 May).
https://doi.org/10.1001/jama.2020.8707

It well known that very few children suffer from significant coronavirus disease, and some hypothesize that this lower risk may be due to differential expression of angiotensin-converting enzyme 2 (ACE2), the receptor that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for host entry. This study investigated ACE2 gene expression in the nasal epithelium of children and adults through a retrospective examination of nasal epithelium from 305 individuals aged 4 to 60 years encountered within the Mount Sinai Health System. Individuals were balanced with regard to sex (48.9% male), demonstrating an age-dependent ACE2 gene expression in nasal epithelium, with ACE2 gene expression lowest (mean log2 counts/million, 2.40; 95% CI, 2.07-2.72) in younger children (n = 45) and increased with age, with mean log2 counts/million of 2.77 (95% CI, 2.64-2.90) for older children (n = 185), 3.02 (95% CI, 2.78-3.26) for young adults (n = 46), and 3.09 (95% CI, 2.83-3.35) for adults (n = 29). Overall, this study demonstrates an age-dependent expression of ACE2 in nasal epithelium, the first point of contact for SARS-CoV-2 and the human body. The authors suggest that lower ACE2 expression in children relative to adults may help explain why COVID-19 is less prevalent in children, but is should be noted that a limitation of this study was that the samples did not include individuals older than 60 years.

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