Adrenaline autoinjector is underprescribed in typical cold urticaria patients
Authors: Mojca Bizjak, Mitja Košnik, Dejan Dinevski, Simon Francis Thomsen, Daria Fomina, Elena Borzova, Kanokvalai Kulthanan, Raisa Meshkova, Fernando Monteiro Aarestrup, Dalia Melina Ahsan, Mona Al‐Ahmad, Sabine Altrichter, Andrea Bauer, Maxi Brockstädt, Célia Costa, Semra Demir, Roberta Fachini Criado, Luis Felipe Ensina, Asli Gelincik, Ana Maria Giménez‐Arnau, Margarida Gonçalo, Maia Gotua, Jesper Grønlund Holm, Naoko Inomata, Alicja Kasperska‐Zajac, Maryam Khoshkhui, Aliya Klyucharova, Emek Kocatürk, Rongbiao Lu, Michael Makris, Natalya Maltseva, Maria Pasali, Marisa Paulino, David Pesqué, Jonny Peter, German Dario Ramón, Carla Ritchie, Solange Oliveira Rodrigues Valle, Michael Rudenko, Agnieszka Sikora, Nicola Wagner, Paraskevi Xepapadaki, Xiaoyang Xue, Zuotao Zhao, Dorothea Terhorst‐Molawi, Marcus Maurer
Journal: Allergy (2022)

Intramuscular adrenaline is the first-line treatment for anaphylaxis and an adrenaline autoinjector (AAI) should be carried as a first-aid measure by patients at risk.1 Cold-induced anaphylaxis (ColdA), which may result in fatality,2 is common in typical cold urticaria (ColdU), and risk factors for ColdA have recently been identified for the first time.3 As of now, it is largely unclear how often patients with ColdU (i) receive adrenaline treatment and (ii) are provided with an AAI.2 A study by Gernez et al. in the USA showed that 48% of allergy and immunology specialists prescribe an AAI to ColdU patients less than 10% of the time.4 Here, we present further results of the COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions) study,3 performed by the UCARE network.5 The study included 412 ColdU patients with whealing in response to local cold stimulation testing (i.e., typical ColdU). Concomitant chronic spontaneous urticaria was found in 10% (n = 40) of them. Of 372 patients with stand-alone ColdU, 69% (n = 258) were females and 91% adults (i.e., ≥18 years; n = 338). Their median age was 36 years (IQR 26−48). ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of the following: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms.3 It was diagnosed in 39% (n = 145) of patients. Physician collected data on baseline patient characteristics, clinical manifestations induced by different cold triggers, and answered the following: (i) "Did the patient ever receive adrenaline for the treatment of ColdU/ColdA by medical personnel or by AAI self-administration?" and (ii) "Was AAI prescribed before study enrollment?". Only 8% (n = 12) of ColdA patients had received treatment with adrenaline, and 37% (n = 54) of patients had an AAI (Table 1). Hypotension was experienced by 13% (n = 48) of patients, but only 17% (n = 8) of them received adrenaline and only 10% (n = 5) both adrenaline treatment and AAI prescription (Table S1). Patients were also categorized based on the climate of their residency (Table S2). ColdA was more common in temperate than cold climate countries (44% vs. 21%, p < 0.001) and AAI was more often prescribed in the former (30% vs. 15%, p = 0.011). The frequency of ColdA did not significantly differ between temperate and tropical countries (44% vs. 42%, p = 1.000), but AAI was more often prescribed in the former (30% vs. 12%, p = 0.038). ColdA triggered by complete cold water immersion (e.g., at beaches) was diagnosed in 29% (n = 107) of patients, but only 8% (n = 8) of them received adrenaline (Table 1). AAI was more often prescribed in patients with oropharyngeal/laryngeal symptoms than those without (37% vs. 20%, p = 0.001; Table 2). Our findings suggest that ColdA is undertreated and they call for changes in ColdU management. ColdA should be approached and treated like other types of anaphylaxis. Less than 10% of patients with ColdA received adrenaline and less than 40% of them have an AAI. ColdU patients need to be screened by specialists and non-specialists to identify those with ColdA risk factors (Table 2),3 which may also include underlying clonal mast cell disorder.6 Prescribing an AAI to patients at risk of ColdA needs to be combined with advice on avoidance of relevant cold triggers, a written treatment plan, and training and re-training in the use of the AAI. Efforts should also be made for AAIs to become accessible at public beaches and addition of ColdA in the list of indications for AAI1 shall be considered. This manuscript benefited from the support of the GA2LEN UCARE network (www.ga2len-ucare.com). We thank Laura Schwenner for providing networking. M. Bizjak has been a speaker and served on advisory boards for Novartis, outside the submitted work. S. F. Thomsen reports grants and non-financial support from Novartis, Sanofi, UCB, LEO Pharma, and Janssen, outside the submitted work. D. Fomina received honoraria from Novartis, Shire, Behring CSL and Sanofi, outside the submitted work. E. Borzova received honoraria for educational lectures from Novartis and Sanofi and research funding from GSK, outside the submitted work. K. Kulthanan reports grants from Novartis and received honoraria from Menarini and Takeda, outside the submitted work. R. Meshkova received honoraria from Novartis, outside the submitted work. S. Altrichter reports grants and personal fees from Astra-Zeneca, grants from Allakos, personal fees from Novartis, non-financial support from Moxie, grants from CSL Behring, grants from LEO Pharma, outside the submitted work. A. Bauer reports grants, personal fees and other from Novartis, personal fees and other from LEO Pharma, grants, personal fees and other from Sanofi/Regeneron, other from Amgen, other from Lilly, other from AbbVie, personal fees from Takeda, other from Pharvaris, outside the submitted work. C. Costa reports personal fees from Novartis, AstraZeneca, Menarini, Leti and Bial, outside the submitted work. R. Fachini Criado reports personal fees from Novartis, Takeda, Abbvie and Sanofi, outside the submitted work. L.F. Felipe Ensina reports personal fees from Novartis, Sanofi, Abbvie and Takeda, outside the submitted work. A.M. Giménez-Arnau reports grants and personal fees from Uriach, other from Genentech, grants, personal fees and other from Novartis, grants and personal fees from GSK, personal fees from Sanofi/Regeneron, personal fees from Amgen, personal fees from Thermo Fisher, grants from Instituto Carlos III, personal fees from LEO Pharma, personal fees from Almirall and personal fees from Avene, outside the submitted work. M. Gonçalo has been a speaker and/or advisor for Abbie, LEO Phama, Lilly, Novartis, Pfizer, Sanofi and Takeda, outside the submitted work. J.G. Holm has been a speaker for Novartis, outside the submitted work. E. Kocatürk reports personal fees from Novartis, Sanofi and Menarini, outside the submitted work. M. Makris reports personal fees from Novartis, Chiesi Hellas, AstraZeneca, Pfizer, GSK and Menarini, outside the submitted work. S. Valle reports personal fees from Novartis, Takeda, CSL Behring and Astra-Zeneca outside the submitted work. N. Wagner is or recently was a speaker and/or advisor for and/or has received research funding or is/was involved in clinical trials of/from ALK-Abelló, Novartis Pharma GmbH, Allergopharma GmbH &Co KG, Sanofi-Aventis Deutschland GmbH, Shire/Takeda, Blueprint, Abbvie GmbH & Co KG. P. Xepapadaki reports personal fees from Uriach, Novartis, Nestle and Nutricia, outside the submitted work. M. Mauer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Moxie, MSD, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach, outside the submitted work. All other authors have no conflict of interest within the scope of the submitted work. M. Bizjak initiated, entitled, and designed the COLD-CE study, collected data, performed data quality controls, and developed the manuscript. D. Terhorst-Molawi and M. Maurer contributed to study design and provided critical input to the manuscript. M. Bizjak and D. Terhorst-Molawi were principal investigators. M. Bizjak and D. Dinevski performed statistical analyses. All authors contributed to the acquisition of data, interpretation of data, and manuscript development and approved it for publication. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.