key: cord-0748314-bwct1gwz
authors: Wolfson, Anna R.; Robinson, Lacey B.; Li, Lily; McMahon, Aubree E.; Cogan, Amelia S.; Fu, Xiaoqing; Wickner, Paige; Samarakoon, Upeka; Saff, Rebecca R.; Blumenthal, Kimberly G.; Banerji, Aleena
title: First Dose mRNA COVID-19 Vaccine Allergic Reactions: Limited Role for Excipient Skin Testing
date: 2021-06-22
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.06.010
sha: e415601f7d532765ebee8f2ac731facd8d02cb8e
doc_id: 748314
cord_uid: bwct1gwz

Background CDC states that a severe or immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine is a contraindication for the second dose. Objective To assess outcomes associated with excipient skin testing after a reported allergic reaction to mRNA COVID-19 vaccine dose one. Methods We identified a consecutive sample of patients with reported allergic reactions after the first dose of mRNA COVID-19 vaccine who underwent allergy assessment with skin testing to polyethylene glycol (PEG) and, if appropriate, polysorbate 80. Skin testing results in conjunction with clinical phenotyping of the first dose mRNA COVID-19 vaccine reaction guided second dose vaccination recommendation. Second dose mRNA COVID-19 vaccine reactions were assessed. Results 80 patients with reported first dose mRNA COVID-19 vaccine allergic reactions (n=65, 81% immediate onset) underwent excipient skin testing. 14 (18%) had positive skin tests to PEG (n=5) and/or polysorbate 80 (n=12). Skin testing result did not impact tolerance of second dose in patients with immediate or delayed reactions. Of 70 (88%) patients who received their second mRNA COVID-19 vaccine dose, 62 (89%) had either no reaction or a mild reaction managed with antihistamines, but two patients required epinephrine. Three patients with positive PEG-3350 intradermal (methylprednisolone) testing tolerated second dose mRNA COVID-19 vaccination. Refresh Tears caused non-specific irritation. Conclusion Most individuals with a reported allergic reaction to dose one of the mRNA COVID-19 vaccines, regardless of skin test result, received the second dose safely. More data are needed on the value of skin prick testing to PEG (Miralax) in evaluating patients with mRNA COVID-19 vaccine anaphylaxis. Refresh Tears should not be used for skin testing.

been an important focus of investigation with recent limited supportive evidence. 10 Furthermore, 139 the utility of skin testing to PEG and polysorbate 80 was unclear but experts suspected excipient 140 skin testing to have a high positive predictive value and a low negative predictive value. 11 Our risk stratification algorithm 13 uses clinical history with skin testing to PEG and/or 147 polysorbate to evaluate higher risk individuals who report a history of an immediate allergic 148 reaction to a first dose of mRNA COVID-19 vaccine. Herein, we report the outcomes of 149 individuals referred for reported allergic reactions to a first dose of mRNA COVID-19 vaccine 150 that completed skin testing and followed our initial published skin testing guidance. 13 We review 151 patient and reaction characteristics with skin testing findings along with second dose vaccine 152 outcomes that motivate an updated approach to individuals who present following a reported 153 allergic reaction to the first dose of mRNA COVID-19 vaccine. This cohort included consecutive patients referred for an in-person allergy/immunology excipient 157 skin testing visit which occurred at MGB between January 6 and March 3, 2021 after a first dose 158 mRNA COVID-19 vaccine reaction. In-person visits occurred after initial allergy/immunology 159 telemedicine visits with clinical phenotyping and risk stratification. All included patients 160 received their first mRNA vaccine dose at an MGB vaccination clinic with second doses 161 scheduled at the vaccination clinics associated with the MGB academic medical centers: 162

Massachusetts General Hospital (MGH) or Brigham and Women's Hospital (BWH). 163

We recommended excipient skin testing to all patients who reported symptoms concerning for an 164 IgE-mediated allergy within 4 hours of vaccination. Patients with symptoms consistent with an 165 allergic reaction which was delayed (occurring more than 4 hours after vaccination but before 166 day 3 post vaccination) may also have proceeded to excipient skin testing, especially if the 167 symptoms were more severe or patient preference using shared decision-making. For patients 168 who reported symptoms which were potentially IgE-mediated but subjective (e.g., globus or itch 169 without rash), the decision to proceed to skin testing was also based on shared decision-making 170 considering patient preferences. Interested and eligible patients were referred for an in-person 171 excipient skin testing appointment at either MGH or BWH. Approximately 14% of patients with 172 first dose mRNA COVID-19 vaccine reactions were referred for in-person excipient skin testing 173 using our algorithm. 13 174 175 At MGH, PEG skin testing was performed using Miralax, a laxative containing 176 epicutaneous and methylprednisolone acetate (containing PEG-3350 only 13 ) intradermally 177 (Table E1) . 13 If methylprednisolone acetate was positive, methylprednisolone sodium succinate 178 J o u r n a l P r e -p r o o f was used as a control to exclude methylprednisolone as the cause of allergy. At We used excipient skin testing alone --without mRNA COVID-19 vaccine skin testing --which 191 has since been described, 15,16 as we did not have access at the time to mRNA COVID- 19 vaccine 192 for skin testing purposes and the mRNA COVID-19 vaccines were the first vaccines of their 193 kind. It was not apparent that any prior vaccine guidance 17 could be accurately applied to these 194 vaccines and there was initial concern that dilution could degrade mRNA so it could not be used 195 as a skin testing product nor as a graded challenge. 18 196 197 Due to concern which arose during this study for irritant skin testing reactions to Refresh Patients were predominantly female (89%) and white (78%) with mean age 40.9 ±13.6 years. 249

Past medical history included a history of non-anaphylactic IgE mediated food allergy (n=29, 250 36%), asthma (n=25, 31%), anaphylaxis to medications, foods, venom or latex (n=22, 28%), 251 allergic rhinitis (n=20, 25%), polysorbate allergy (n=5, 6%), atopic dermatitis (n=4, 5%), and 252 PEG allergy (n=2, 3%) ( Figure 1a ). All polysorbate 80 positive individuals were 276 positive on skin testing to Refresh Tears (n=12), which was found to be an irritant in 13 of 25 277 (52%) non-allergic controls ( Table E3) Overall, 66 (83%) patients were skin test negative and 60 (91%) of these patients went on to 300 receive their second dose of the vaccine, 45 (75%), ultimately had the second dose of the vaccine 301 without recurrent symptoms. Among the 65 patients who reported an immediate allergic reaction 302 to the first dose of mRNA COVID vaccine, 57 (88%) were skin test negative, 52 (80%) received 303 their second dose of the vaccine, and 39 (75%) had no symptoms with the second dose. There 304 were 13 (25%) patients who were skin test negative but reacted to the second dose of the 305 vaccine, and their most common symptoms were cutaneous (n=11) but 4 (31%) patients were 306 seen in the Emergency Department and 2 (15%) received epinephrine ( Table 3) . 307

Among the 15 individuals who reported a delayed reaction after the first dose of mRNA 308 COVID-19 vaccine, 9 (60%) were skin test negative and 8 (89%) received their second vaccine 309 dose; 6 of 8 (75%) tolerated the second dose without reaction. Two patients who were skin test 310 negative but reacted to the second dose of the vaccine reported the following symptoms: one had 311 mild swelling of throat, tongue, and eyes, pruritus without rash on face and chest, no treatment 312 was sought; one had pruritus and erythema of arms, with pruritus of lips and neck, treated with 313 antihistamines. antihistamines for patients with mild symptoms such as delayed urticaria, but try to restrict use of 363 glucocorticoids that may an unfavorable immunologic effect. 25 Fourth, in our experience to date, 364 PEG skin testing was of limited utility (n=5 with positive skin tests), and should only be 365 considered in specific cases, e.g. patients with convincing history of anaphylaxis to mRNA 366 COVID-19 vaccine or recently to oral PEG-containing medications. Lastly, methylprednisolone 367 acetate or PEG intradermal skin testing did not provide additional information to guide safety of 368 second dose mRNA COVID-19 vaccination as patients (n=3) with positive skin testing to this 369 tolerated the vaccine, in our experience. We thus suggest that, when PEG excipient testing is 370 warranted, epicutaneous testing to Miralax (PEG3350) alone is adequate. 10, 11, 12 In our 371 experience, consistent with rare true cases of anaphylaxis to the COVID-19 mRNA vaccines, 372

Miralax skin testing was positive in one patient with symptoms consistent with anaphylaxis. This 373 patient did not receive a second dose of COVID-19 vaccine so the positive predictive value of 374

Miralax skin testing remains unknown. 10,26 (Figure E1) . 375

The cause of mRNA COVID-19 vaccine allergic reactions remains unclear and may be 376 multifactorial, but one case report linked PEG as a possible allergen 10 and an improved 377 understanding of the role for excipient skin testing to PEG in individuals with a history of 378 anaphylaxis to mRNA COVID-19 vaccines is still needed. While we were able to calculate the 379 NPV for PEG skin testing and tolerance with dose two, we were unable to calculate sensitivity, 380 specificity, and/or positive predictive value. There were two patients who reported histories of 381 being allergic to PEG (reported after their first dose mRNA COVID-19 vaccine reaction). Due to the high rate of skin test positivity to Refresh Tears, which was used as a source of 394 polysorbate 80 in the BWH study population, we tested a new control group (Table E3) . 395

Approximately half of the non-allergic controls had positive skin test results suggesting that 396

Refresh Tears is likely causing an irritant, or false positive, skin test reaction. These findings 397 prompted us to modify our initial algorithmic approach and also to contact all MGB patients with 398 positive skin tests to Refresh Tears to modify our initial advice and encourage mRNA COVID-399 19 vaccination. None of the patients with positive skin tests to Refresh Tears that received the 400 second dose of the mRNA COVID-19 vaccine developed an allergic reaction, but three patients 401 had subjective symptoms and were treated with antihistamines only. 402

Vaccine hesitancy is an important issue that may be exacerbated by adverse and/or allergic 403 symptoms after the first dose of the mRNA COVID-19 vaccine, and we are eager to reassure our 404 patients regarding the vaccine's safety in order to encourage vaccination. 27 In our cohort of 405 individuals referred for skin testing, 10 out of 80 have not received their second dose of mRNA 406 J o u r n a l P r e -p r o o f COVID-19 vaccine, although only 2 were advised by our group to not receive mRNA COVID-407 19 vaccine (a third patient received Janssen vaccine). The reasons for incomplete vaccination are 408 not clear, but may include vaccine administration logistics, unclear benefit of second dose 409 vaccination, and/or concern about having a recurrent allergic or adverse reaction. 28 The allergist 410 may not be able to address all these barriers, but the allergist can acknowledge them, 29 and, 411 based on these data, provide reassurance around receiving the second dose if the clinical history 412 is low risk. 12, 13, 16, 30 The allergist also has an important role in helping to correctly recognize and 413 treat allergic reactions, so allergist-observed second dose vaccinations may help reassure our 414

Recently, the CDC added guidance allowing Janssen COVID-19 vaccine at least 28 days after an 416 allergic reaction to a first dose of mRNA COVID vaccine, broadening our patients' options. 5 The 417

Janssen COVID-19 vaccine contains the excipient polysorbate 80 but not PEG and therefore 418 could be administered without skin testing to PEG in patients concerned about PEG allergy. 419 Janssen COVID-19 vaccine could also be considered in an individual with a history of PEG 420 allergy or PEG skin test positivity but a negative polysorbate 80 skin test or tolerance of vaccine 421 with polysorbate 80 (Figure 2) . Reassuringly, to date, the rate of allergic reactions to the 422 Janssen vaccine appears exceedingly low. 31 One patient in our cohort who had reported an 423 immediate allergic reaction to Moderna, then had positive skin testing to methylprednisolone 424 acetate and Refresh Tears has subsequently tolerated the Janssen vaccine. This is an important 425 option for our high-risk patients with possible PEG allergy. 426

The limitations of our study include generalizability as our study population was a referred 427 population consisting of MGB patients evaluated by a specialist. The majority of our patients 428 J o u r n a l P r e -p r o o f were white females, which was likely a reflection of the overrepresentation of white females in 429 the healthcare worker population in the Boston area. The demographics may limit 430 generalizability across demographics although these demographics closely match those reported 431 nationally. 3,6,7 These data are subject to information bias as we do not know why some 432 individuals chose not to receive their second dose of the vaccine, even when the allergist advised 433 that it was safe to proceed. Given that proceeding to a second mRNA COVDI-19 vaccine dose 434 was not at random, we acknowledge that there is a bias in calculation of an NPV. However, 435 while NPV could be calculated given that only 9% of skin test negative patients did not receive 436 dose two, we were unable to calculate PPV given that 40% of skin test positive patients did not 437 receive dose two and sample size was just 5. Another limitation is that symptoms were self-438

reported. Although we intended to only use excipient skin testing in high risk individuals, some 439 individuals reported minor and subjective symptoms (e.g. itch, globus, diziness); including these 440 symptoms in our analysis may have made it more difficult to ascertain the association of 441 excipient skin testing with true mRNA COVID-19 vaccine allergy. However, the inclusion of 442 these patients was due to patient preference and shared decision-making. 443

Overall, our initially published risk stratification protocol 13 allowed safe second dose mRNA 444 COVID-19 vaccination for the vast majority of individuals despite a reported first dose allergic 445 reaction. We have since learned that excipient skin testing may be of little utility in the 446 assessment of these reactions, particularly in individuals without anaphylaxis. More data are 447 needed to identify whether PEG skin prick testing after a reaction clinically consistent with 448 severe anaphylaxis to mRNA COVID vaccine is predictive of a reaction with subsequent mRNA 449 https://www.janssenlabels.com/emergency-use-authorization/Janssen+COVID-556

19+Vaccine-Recipient-fact-sheet.pdf. Accessed April 13, 2021. 557 558 559 Figure 1 : Patients who were skin tested due to symptoms after mRNA COVID-19 vaccination 560 that were concerning for an allergic reaction. A: All patients. B: Patients with immediate allergic 561 reactions. C: Patients with delayed allergic reactions 562 * 3 patients who had positive skin testing to both PEG and polysorbate are represented in the PEG 563 category only in this figure. 564 † 1 patient did not receive the next dose in the series and instead received Janssen. 565 ‡ 2 patients had a grade 0 reactions. 1 patient had a grade 1 reaction. 566 § 3 patients had a grade 0 reaction. 9 patients had a grade 1 reaction, and 3 patients had a grade 2 567 reaction. 568 ǁ 2 patients who had positive skin testing to both PEG and polysorbate are represented in the PEG 569 category only for the purpose of this figure. 570 ¶ 1 patient did not receive the next dose in the series and instead received Janssen. 571 # 1 patient had a grade 0 reaction. 1 patient had a grade 1 reaction. 572 ** 2 patients had a grade 0 reaction. 8 patients had a grade 1 reaction. 3 patients had a grade 2 573 reaction. 574 † † 1 patient who had positive skin testing to both PEG and polysorbate is represented in the PEG 575 category only for the purpose of this figure. 576 ‡ ‡ 1 patient had a grade 0 reaction. 577 § § 1 patient had a grade 0 reaction. 1 patient had a grade 1 reaction. 578 579 Figure 2 : Management of patients who present with symptoms concerning for an allergic 580 reaction to the first dose of mRNA COVID-19 vaccine. Use of Janssen vaccine (if available) 581 may be appropriate following allergic reaction to the first dose of mRNA COVID-19 vaccine if 582 allergy evaluation is not feasible or due to shared decision-making between patient and 583 physician. 584 585 586 J o u r n a l P r e -p r o o f Miralax 1:10 (SPT) 0 (0) 0 (0) 0 (0) Miralax 1:1 (SPT) 0 (0) 0 (0) 0 (0) Depo-Medrol 0.4mg/mL (IDT) 3 (4) 2 (3) 1 (7) Depo-Medrol 4mg/mL (IDT) 1 (1) 1 (2) 0 (0) Refresh Eye Drops 1:1 (SPT) 0 (0) 0 (0) 0 (0) Refresh Eye Drops 1:100 (IDT 10 (13) 5 (8) 5 (33) Refresh Eye Drops 1:10 (IDT) 2 (3) 1 (2) 1 (7) * Immediate was defined as 4 or fewer hours. 47 (72%) were within 1 hour, with a median of 10 minutes (IQR: 5,15) † Delayed was defined as more than 4 hours. 11 (73%) were within 24 hours ‡ Medication 9 (14), Food 6 (9), Venom 2 (3) § Medication 3 (20), Food 2 (13) ǁ Hives, rash, itching, swelling (not throat), flushing ¶ Wheezing, chest tightness, shortness of breath, cough # Tachycardia, hypotension ** Gastrointestinal upset, diarrhea, vomiting, nausea † † Throat swelling, hoarseness, globus ‡ ‡ Tingling (n=14, 22%), lightheaded (n=4, 6%), chest pain (n=1, 2%), feeling hot (n=1, 2%), and syncope (n=1, 2%), red eye (n=1, 2%). Patients may have more than one symptom. § § Sneezing (n=1, 7%), tingling (n=1, 7%). Patients may have more than one symptom. 

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