key: cord-0685542-roqcelbw authors: DAVILA-FERNANDEZ, Galicia; SANCHEZ-MORENO, Gema Vanesa; MADRIGAL-BURGALETA, Ricardo title: SENSITIZATION TO TROMETAMOL IN PATIENTS WITH DELAYED LOCAL REACTIONS AFTER ADMINISTRATION OF THE MODERNA mRNA‐1273 VACCINE AGAINST SARS‐CoV‐2 date: 2022-05-03 journal: J Allergy Clin Immunol Pract DOI: 10.1016/j.jaip.2022.04.026 sha: 2a5e8492c0df0d17f92bff9c343452639b24a3fa doc_id: 685542 cord_uid: roqcelbw nan There are no potential conflicts of interest for any of the authors regarding this article. There 28 are no financial interests, and there have been not any provision of study materials by their 29 manufacturer for free or at a discount from current rates. protein of the SARS-CoV-2 virus. Each 0.5-ml dose contains 100 µg of this highly purified 42 mRNA encapsulated in lipid nanoparticles, as well as the excipients PEG2000 DMG and 43 trometamol, both of which have been associated with immediate and nonimmediate 44 reactions to other drugs(1-3). 45 The skin reaction that has come to be known as "COVID arm" is considered a mild adverse 46 effect of the vaccine, which consists of erythema, induration, and pruritus at the injection 47 site. It occurs some 8 days after administration of the first dose of the Moderna vaccine and 48 some 2 days after the second dose(3). Remarkably, this reaction has been observed less 49 frequently with the Pfizer vaccine, which does not contain trometamol(1-2). Therefore, we 50 decided to assess the role of a possible sensitization to trometamol in patients experiencing 51 this type of reaction to the Moderna SARS-CoV-2 vaccine. 52 We conducted a prospective pilot study including all healthcare professionals referred to us 53 from our hospital's vaccination hubs between February and April 2021. We selected those 54 patients presenting with nonimmediate local reactions that could be considered large 55 (reddened and edematous plaques > 10 cm in diameter) and happening over 6 hours after 56 injection and on the injection site (3-5). We planned to recruit a rate of 2:1 controls:cases 57 from a pool of healthy hospital staff who had received vaccination with no reactions. The 58 study and informed consents were approved by our hospital's Ethics Committee. 59 The data recorded in the clinical history included atopy, previous adverse drug reactions, 60 previous tolerance of vaccines and contrast media, and PCR-confirmed previous infection by 61 SARS-CoV-2. 62 All patients and controls underwent skin prick testing (SPT) and intradermal testing (IDT) 63 with the Moderna vaccine and excipients (see table 1 ). Skin testing was performed and 64 interpreted as per European Academy of Allergy and Clinical Immunology (EAACI) 65 guidance(5). Moreover, all underwent patch testing with a standard contact allergen series 66 (TRUE-TEST®) and trometamol 10% aq. 67 Drug challenge with the Moderna vaccine was performed in an allergy-dedicated area for 68 drug challenges with expert staff, resources to treat severe anaphylaxis, allergist on-site, and 69 rapid access to intensive therapy unit, following EAACI guidelines for drug provocation 70 testing. Given the characteristics of these reactions, the chosen protocol for these patients 71 was a one-step administration of a full dose of the vaccine, mimicking real-life administration 72 as per EAACI guidance(5). 73 A total of 7 patients met the inclusion criteria, and all of them had reacted to the 74 administration of the first dose of the Moderna vaccine against SARS-CoV-2 (see figure E1 75 for a photograph of a reaction). 76 All the patients were women (median age 52 years, ranging from 46 to 56). Four of them had 77 a history of atopy (hay fever), and all had previously tolerated the influenza vaccine and 78 were up to date with their vaccine schedule without incident. Four of the 7 patients had had 79 SARS-CoV-2 between 8 and 12 months before being vaccinated. The median time to onset 80 of the local reaction was 7 days (ranging from 6 to 9 days) after the first dose of the vaccine. 81 Median duration of the reaction was 96 hours (ranging from 72 to 144 hours). See their third dose booster, which could be an unconfirmed factor for better tolerance. 108 Trometamol is used as an excipient in the pharmaceutical industry and as a pH stabilizer for 109 improving the solubility and stability of various substances (eg, contrast media, vaccines, 110 eye drops, cosmetics)(6). Although widely used, trometamol has rarely been involved in 111 allergic reactions. In addition, its role in such reactions has not been assessed. the administration of gadolinium(7). The reaction was caused by hypersensitivity to 117 trometamol, which was confirmed by a positive intradermal test result (0.01 mg/ml). The 118 results were negative in controls. 119 The skin reaction known as "Covid arm" has mainly been observed with the Moderna 120 vaccine and not the Pfizer vaccine (1-3) . Therefore, even if there are likely multiple causes 121 for this type of reaction, sensitisation to trometamol could be responsible for some cases of 122 "Covid arm". All our cases and none of our controls were positive to trometamol on skin 123 testing, supporting this hypothesis. 124 give false negatives given the lower concentration of trometamol, whereas skin testing with 149 trometamol alone might be more sensitive, but the sample size is too small to draw definitive 150 conclusions. 151 The results of this pilot study in a subset of healthcare professionals from our local hospital 152 is limited by the small sample size and the unexplained heterogeneity in the timings for the 153 skin testing positivity. However, these promising data seem to identify trometamol as a 154 culprit allergen for these reactions and justify further studies in a larger population. 155 The positivity of skin testing with nonirritant concentrations in all patients suggests that a 156 hypersensitivity to trometamol could play a role in some patients experiencing nonimmediate 157 large local reactions to the Moderna vaccine. Interestingly, these patients will suffer an 158 earlier onset but milder, local reaction on each reexposure. However, they can safely receive 159 further doses with alleviating measures such as antihistamines and topical steroids in case 160 of a reaction, with only a subset of patients needing oral steroids. 161 162 J o u r n a l P r e -p r o o f Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-170 based study of 414 cases Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2 Subcutaneous immunotherapy with aeroallergens: safety profile assessment Vaccination and 178 allergy: EAACI position paper, practical aspects Contact allergy to trometamol Anaphylaxis to trometamol excipient in gadolinium-based contrast agents for 183 clinical imaging Safety 185 Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With 186 Immediate Reactions to the First Dose The Beauty of Simplicity: Delayed-Type Hypersensitivity Reaction to Measure Cellular 190 Immune Responses in RNA-SARS-Cov-2 Vaccinated Individuals. Vaccines (Basel) SPT and IDT with the Moderna vaccine (sequentially, 1/100 -1/10). SPT with polyethylene 199 glycol (Roxall, Germany, magistral pharmaceutical preparation to reach 0.1%, 1%, and 200 10%). SPT and IDT with trometamol (Tris 36.34% solution for infusion 20 ml ampoules Sigma-Aldrich/Merck, Germany, magistral pharmaceutical preparation to 203 reach 0.004 mg/ml). Trometamol and Tween 80 were tested in 15 control patients