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Medical Journal Review

December 2021

WAO Reviews – Editors’ Choice

Articles are selected for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases by Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, WAO Reviews Editor.

Evaluation of pharmacologic treatments for H1 antihistamine-refractory chronic spontaneous urticaria: A systematic review and network meta-analysis
Nochaiwong S, Chuamanochan M, Ruengorn C et al
JAMA Dermatology 2021;157(11):1316-1327

The comparative benefits and harms of all available treatments for H1 antihistamine–refractory chronic spontaneous urticaria (CSU) have not been established. Thus, the objective of this study was to evaluate the efficacy of treatment options among patients with H1 antihistamine–refractory CSU. The authors pursued standard literature analysis relying upon two investigators who independently extracted study data according to the predefined list of interests and then utilized a random-effects model to calculate the network estimates reported as standardized mean differences and odds ratios with corresponding 95% CIs. The primary outcomes included changes in urticaria symptoms from baseline and unacceptability of treatment (all-cause dropouts). Twenty-three randomized clinical trials with 2480 participants met criteria and these compared 18 different interventions or dosages vs placebo. The standardized mean differences for change in urticaria symptoms were −1.05 (95% CI, −1.37 to −0.73) for ligelizumab, 72 mg; −1.07 (95% CI, −1.39 to −0.75) for ligelizumab, 240 mg; −0.77 (95% CI, −0.91 to −0.63) for omalizumab, 300 mg; and −0.59 (95% CI, −1.10 to −0.08) for omalizumab, 600 mg. No significant differences in treatment unacceptability were observed. With respect to benefits and harms, the network estimates illustrated that the most efficacious treatments were achieved with ligelizumab, 72 or 240 mg (large beneficial effect) and omalizumab, 300 or 600 mg (moderate beneficial effect). Overall, this meta-analysis suggests that the biologic agents ligelizumab, 72 or 240 mg, and omalizumab, 300 or 600 mg, can be recommended as effective treatments for patients with CSU who have had an inadequate response to H1 antihistamines. The authors note that head-to-head trials with high methodologic quality and harmonized design and outcome definitions are needed to help inform subsequent international guidelines for the management of CSU.

The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1
Li H, Xiao Y, Li Q et al
Cancer Cell 2021; Published online ahead of print (24 November)

The authors note that reinvigoration of antitumor immunity remains an unmet challenge and thus performed a retrospective analysis of cancer patients who took antihistamines during immunotherapy treatment demonstrating a significantly improved survival. They further found that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. The authors conclude that pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.

Biologics for asthma and allergic skin diseases in children
De Keyser HH, Chipps B, Dinakar C
Pediatrics 2021;148(5):e2021054270

This wonderful comprehensive review explores use of biologic agents for asthma and allergic skin diseases, including urticaria and atopic dermatitis in children.

Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy
Jakwerth CA, Chaker AM, Guerth F et al
Clinical and Experimental Allergy 2021;51(12):1577-1591

Several microRNAs (miRs) have been touted as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. To better understand their potential impact, Jakwerth and colleagues investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without allergen-specific immunotherapy (AIT) by analyzing sputum samples of healthy controls (HC), AIT-treated and -untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) using miR microarray and whole-transcriptome microarray analysis of the same samples. Two hundred and fifty-nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. On the other hand, the opposite picture was seen in the induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics on AIT. Of these 4 miRs, miR-3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Furthermore, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL-13 levels, inflammatory cell load, sputum eosinophils, and symptom burden. This indicates that the prostaglandin E3 receptor might mediate AIT effects through suppression of the PGE2-PTGER3 axis.

Automatic screening of self-evaluation apps for urticaria and angioedema shows a high unmet need
Antó A, Maurer R, Gimenez-Arnau A et al
Allergy 2021;76(12):3810-3813

In this letter, the authors stress that there is a major unmet need in chronic urticaria (CU) and recurrent angioedema (RAE), specifically a lack of suitable apps for patients to (a) self-evaluate their disease activity, impact, and control, (b) improve the self-management of their condition by recognizing important triggers of exacerbation, comorbidities, and consequences of their disease, and (c) optimize their therapy including allergic comorbidities. The authors stress that apps that allow patients to achieve these goals are needed globally. It is hoped that such apps may improve the management of CU and RAE patients and may also serve as important tools for CU and RAE research.

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