key: cord-0810090-06bk900s
authors: Pitlick, Mitchell M; Sitek, Andrea N; D'Netto, Michael E; Dages, Kelley N; Chiarella, Sergio E; Gonzalez-Estrada, Alexei; Joshi, Avni Y; Park, Miguel A
title: Utility and Futility of Skin Testing to Address Concerns Surrounding mRNA COVID-19 Vaccine Reactions
date: 2021-11-16
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2021.11.006
sha: 96b887a3e1bec4394b8f69d90df298173db0c69f
doc_id: 810090
cord_uid: 06bk900s

Background The mechanism of COVID-19 vaccine hypersensitivity reactions is unknown. COVID19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. Objective To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first mRNA COVID-19 vaccine dose and patients with a history of polyethylene glycol (PEG) allergy who have not yet received a COVID-19 vaccine dose. Methods In this multi-center, retrospective review, COVID-19 vaccine and/or vaccine excipient skin testing was performed in patients referred to one of three large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. Results 129 patients underwent skin testing, which was positive in 12 patients (9.3%). 101 patients received a COVID-19 vaccine after skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of the 6 patients with positive skin testing who received a COVID-19 vaccine after skin testing. The remaining 11 patients experienced minor allergic symptoms following COVID-19 vaccination, none of which required treatment beyond antihistamines. Conclusion The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggests a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing if necessary. Based on these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.

The mechanism of COVID-19 vaccine hypersensitivity reactions is unknown. COVID19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown.

Objective:

To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first mRNA COVID-19 vaccine dose and patients with a history of polyethylene glycol (PEG) allergy who have not yet received a COVID-19 vaccine dose.

In this multi-center, retrospective review, COVID-19 vaccine and/or vaccine excipient skin testing was performed in patients referred to one of three large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance.

129 patients underwent skin testing, which was positive in 12 patients (9.3%). 101 patients received a COVID-19 vaccine after skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of the 6 patients with positive skin testing who received a COVID-19 vaccine after skin testing. The remaining 11 patients experienced minor allergic symptoms following COVID-19 vaccination, none of which required treatment beyond antihistamines. vaccines. 3 All these numbers are higher than the historically quoted rate of vaccine induced anaphylaxis (1.3 cases per million doses), which has partially contributed to vaccine hesitation. 4, 5 Aside from anaphylaxis, less severe immediate and delayed reactions to the mRNA vaccines have been reported. [6] [7] [8] The mechanisms and culprits of all these reactions remain unclear. Vaccine excipients including polyethylene glycol (PEG, found in the mRNA COVID-19 vaccines) and polysorbate (found in the adenovirus vector COVID-19 vaccine) have been proposed as possible culprits, although the evidence supporting this is currently lacking. [9] [10] [11] [12] [13] Guidelines for skin testing with nonirritating concentrations of polysorbate are available, and expert opinion suggested an algorithm utilizing them in the evaluation of mRNA COVID-19 vaccine reactions. 9, 14, 15 Nonirritating concentrations of the Pfizer-BioNTech COVID-19 vaccine have also been published. 16 Multiple professional organizations and expert opinions have stressed the need for a systematic approach to COVID-19 vaccine reactions, investigation into the mechanisms of reaction, limiting the over-diagnosis of vaccine anaphylaxis, and safely vaccinating the maximum number of individuals in a rapid fashion. [17] [18] [19] [20] [21] [22] There have been multiple reports describing excipient skin testing in the evaluation of mRNA COVID-19 vaccine reactions, which have largely shown a low rate of skin test positivity and high rate of subsequent vaccine tolerance. [23] [24] [25] These results have raised concerns regarding the utility of excipient skin testing in the evaluation of COVID-19 vaccine reactions. Areas that have not been as rigorously studied include the utility of COVID-19 vaccine skin testing and COVID-19 vaccinecomponent skin testing in patients with a prior PEG or polysorbate allergy who have yet to receive a vaccine.

In this study, we describe a large cohort of over 100 patients who underwent excipient and/or vaccine skin testing in the evaluation of an mRNA COVID-19 vaccine reaction or for evaluation of PEG and/or polysorbate allergy prior to receiving a COVID-19 vaccine.

In this multicenter, retrospective review, skin testing was performed in adult patients referred to the Mayo Clinics based in Rochester, Minnesota, Scottsdale, Arizona, and Jacksonville, Florida from 1/14/21 to 7/14/21. Patients were separated into 2 cohorts: those who had a possible allergic reaction to one of the mRNA COVID-19 vaccines and those who reported a prior PEG or polysorbate allergy and had not yet received a COVID-19 vaccine dose.

The clinical need for skin testing and test selection was provider-determined at the time of evaluation. Skin testing to PEG 3350 (MiraLAX™), methylprednisolone acetate (PEG-containing), methylprednisolone sodium (control), triamcinolone acetonide (polysorbate 80-containing), Prevnar™ (polysorbate 80-containing), Havrix™ (polysorbate 20-containing), Flublok™ (polysorbate 20-containing), fresh polysorbate 20 compound, Pfizer-BioNTech COVID-19 vaccine, Moderna COVID-19 vaccine, and Janssen COVID-19 vaccine was performed with methods partially adapted from previously published guidelines and reports (Table 1) . 9, 23 Following skin testing to the components of the COVID-19 vaccines and/or COVID-19 vaccines, patient charts were reviewed to determine if they had received and tolerated a COVID-19 vaccine. Demographic characteristics including atopic and non-atopic comorbidities were collected along with details of the index reaction. Reaction symptoms were defined both by time of onset (<4 hours: immediate, 4 hours: delayed) and by body system involved (cutaneous, upper airway, lower airway, cardiovascular, gastrointestinal, other). Anaphylaxis was defined using Brighton criteria. 26, 27 Each case was reviewed independently by two of the authors (MMP and MED) if there was discordance in the assigned Brighton classification, the case was adjudicated by a third author (ANS). The primary outcome was tolerance of any COVID-19 vaccine following skin testing, which was defined as the absence of patient-reported allergic symptoms following vaccination.

Data were analyzed using BlueSky Statistics Software v7.2 (BlueSky Statistics LLC, Chicago, IL, USA). Statistical comparisons were made between two groups: those who tolerated a subsequent vaccine dose and those who had allergic symptoms with a subsequent vaccine dose. Continuous variables between groups were compared using either ANOVA or independent group t tests. Proportions of categorical variables between groups were compared using Fisher's exact test. Results were deemed significant when a two-sided p-value was less than .05.

One hundred twenty-nine patients underwent skin testing. Fifty-five had a history of a reaction to a dose of an mRNA COVID-19 vaccine, and 74 had a prior history of PEG or polysorbate allergy without having received a COVID-19 vaccine. In each of these groups, patients were separated based on outcome of post-skin testing vaccination (tolerated, experienced symptoms, or deferred). A flow diagram of patient testing and outcomes is shown in Figure 1 .

Demographic characteristics are shown in Table 2 . The majority of patients were female (80%) and white (83.6%). The most common allergic co-morbidities were patient-reported drug allergy (60%) and anaphylaxis (29%) followed by asthma and food allergy (25.5% each). There was a significantly higher proportion of patients with prior COVID-19 infection in those who had symptoms with their second COVID-19 vaccine dose compared to those who did not (57.1% vs 8.3%, p=.008). Otherwise, there was no significant differences between groups.

Details regarding the index reaction are shown in Table 2 . 72.7% (40/55) of patients had experienced symptoms following their first dose of the Pfizer-BioNTech COVID-19 vaccine with the other 27.3% (15/55) being evaluated for symptoms following their first dose of the Moderna vaccine. 74.5% (41/55) of reactions were immediate with 65.5% (36/55) occurring within 1 hour of vaccination. Cutaneous symptoms were most common, occurring in 78.2% of patients, with no significant differences in symptomatology between groups. Four patients (7.3%) experienced Brighton class 1 reactions, but there was no significant difference in reaction severity (based on Brighton classification) between groups. There was no significant difference in treatment required for the index reaction between groups.

Four patients had positive skin test results, all of which were to polysorbate containing products (Table 3 ). There was no significant difference in skin test positivity between groups.

Eleven patients had mRNA COVID-19 vaccine skin prick testing with one also undergoing intradermal testing, all of which were negative.

78.2% of patients tested (43/55) chose to receive their second dose, all of whom except one received the same vaccine as their index reaction ( Table 2) . 83.7% (36/43) of patients tolerated their second dose with no allergic symptoms. Of the 7 patients who experienced allergic symptoms with the second dose, only one had a positive skin test (triamcinolone acetonide), and none received any treatment beyond antihistamines. Of the 36 patients that tolerated their second dose, 6 (16.7%) received pre-treatment with antihistamines compared to 2 of the 7 that had symptoms with their second dose (28.6%). There was no significant difference in subsequent vaccine tolerance or days between vaccine doses between those that received the Pfizer-BioNTech COVID-19 vaccine compared to the Moderna COVID-19 vaccine.

Demographic characteristics are shown in Table 4 . The majority of patients were female (87.8%) and white (91.9%). The most common allergic co-morbidities were patient-reported drug allergy (100%) and non-COVID-19 vaccine allergy (35.1%) followed by allergic rhinitis (31.1%) and asthma (29.7%) each. Thirty-seven (50%) patients reported a history of reaction to a PEG containing medication, and 17 (23.0%) patients reported a prior reaction to a polysorbate containing medication. The remainder of patients were referred due to either a history of multiple drug allergies or prior reactions to unknown vaccines. 46% of patients had documented evidence of prior tolerance of polysorbate containing vaccines. There were no significant differences between groups.

Details regarding the index reaction are shown in Table 4 . 59.5% (44/74) of reactions were immediate (with 33 occurring within 1 hour of exposure), 9.5% were delayed, and timing was unknown in the remaining 31.0%. Cutaneous symptoms were most common, occurring in 68.9% of patients, with no significant differences in symptomatology between groups. There were no significant differences in severity of reaction among the groups, with a majority of patients experiencing Brighton class 5 reactions (75.7%) and 5 patients (6.8%) experiencing Brighton class 1 reactions. Seven patients reported receiving epinephrine for their index reaction (9.5%), but many patients did not recall what treatment they required (45.9%). There were no significant differences in type of treatment or rates of emergency room visits/hospitalization between the groups.

Skin testing performed with results are shown in table 5 Three of those 4 were able to receive their second dose of the same vaccine with no allergic symptoms, with the remaining patient opting to undergo graded vaccine administration when it is able to be arranged. Ten of 11 patients who received the Janssen vaccine were recommended to do so because of their reported history of PEG allergy, with two of those patients having a positive PEG and/or Pfizer-BioNTech COVID-19 vaccine skin test. None of these patients experienced allergic symptoms with vaccination. There was no significant difference in vaccine tolerance between any of the groups.

This is one of the largest reports to date of utilization of excipient and vaccine skin testing in the evaluation of both mRNA COVID-19 vaccine reactions and patients who have deferred vaccination due to a prior reported history of PEG or polysorbate allergy. Previous reports have provided suggestions for excipient skin testing in these groups, but subsequent reports have largely been confined to the use of excipient skin testing in those with reactions to the first dose of an mRNA COVID-19 vaccine, the utility of which is questionable. 9, 23, 24 This report is unique in its evaluation of skin testing in patients who have yet to receive a vaccine but report a PEG or polysorbate allergy and in its use of vaccine for skin testing.

Several findings from this study deserve attention. First, in 129 patients tested, there were only 12 who had positive tests (9.3%). Additionally, of the 101 patients who proceeded with receiving a vaccine dose subsequent to testing, 90 were able to tolerate it without allergic symptoms with the other 11 patients experiencing mild symptoms that were either self-limited or treated with antihistamines. The overall rate of tolerance was slightly higher in those with a prior PEG or polysorbate allergy compared to those with reactions to the first dose of an mRNA COVID-19 vaccine (93.1% vs 83.7%). These findings are similar to a recent report of 80 patients with first vaccine dose reactions where 14 were skin test positive (18%) and 62/70 (88.6%) were able to tolerate a subsequent vaccine dose without significant allergic symptoms. 24 In our cohort, patients with positive PEG skin testing were able to tolerate a subsequent mRNA vaccine dose with no symptoms, but some patients with negative skin testing had symptoms with subsequent vaccine doses. This raises concerns regarding the sensitivity and specificity of excipient skin testing in this population as well as the role of PEG in adverse reactions to the mRNA vaccines. Allergy to PEG-containing laxatives and medications confirmed by skin testing has previously been reported in the past, with a recent review showing an estimate of 4 cases of PEG anaphylaxis per year between 2005 and 2017. 14, 15, 28, 29 While an early single case report showed positive PEG skin testing in a patient with anaphylaxis to the Pfizer-BioNTech COVID-19 vaccine, larger cohorts, including this one, have shown extremely low rates of PEG skin test positivity in patients with reactions to mRNA COVID-19 vaccines, including those with anaphylaxis. 13, 23, 24 This suggests that non-PEG or non-IgE mediated mechanisms such as complement activation related pseudoallergy may account for some of these reactions. 11, 22 In addition to the overall low rate of skin test positivity, another interesting aspect of this report is that 8 of the 12 patients who tested positive did so only for polysorbate containing products. Polysorbates are derived from PEGs and found in a large number of injectable medications and existing vaccines. 9, 30, 31 Additionally, polysorbate 80 is an excipient in the Janssen COVID-19 vaccine, but not in the mRNA COVID-19 vaccines from Pfizer-BioNTech or Moderna. Given prior reports of skin test cross-reactivity to polysorbate 80 in patients with PEG allergy, there was initial concern and caution from the CDC regarding administration of PEG containing mRNA vaccines to patients with polysorbate allergy. 15, 32 However, clinical reactivity to polysorbate 80 is uncommon, with only one report of skin test proven hypersensitivity to a polysorbate 80 containing vaccine previously reported. 33 We have previously reported a case of biphasic anaphylaxis following the first dose of the Pfizer-BioNTech COVID-19 vaccine in a patient with positive skin testing to multiple polysorbate containing products, but negative testing to PEG and the Pfizer-BioNTech COVID-19 vaccine. 34 Aside from excipient skin testing, this report is one of the largest to date reporting on the use of COVID-19 vaccine skin testing. While non-irritating concentrations for intradermal testing with the Pfizer-BioNTech COVID-19 vaccine have been reported, our report primarily utilized skin prick testing (only two patients underwent intradermal vaccine testing) due to institutional restrictions. 16 Of the 24 skin prick tests performed (17 Pfizer-BioNTech, 5 Moderna, 2 Janssen) only one test to the Pfizer-BioNTech COVID-19 vaccine was positive. This patient had not yet received any COVID-19 vaccine, and following testing received the Janssen vaccine without any allergic symptoms. Choosing or altering a vaccine platform based on skin testing either as a screening tool prior to vaccination or in response to a first dose vaccine reaction has been suggested and reported, although the necessity and efficacy of it has not been proven. 3, 9, 24, 30 An over-emphasis on this technique may result in delayed vaccination in resource-limited areas.

Although general practice parameters exist regarding the use of vaccine skin prick and intradermal testing in the evaluation of vaccine hypersensitivity, the validity of these modalities for mRNA COVID-19 vaccines remains unproven and will require more further evaluation. 35 It should be noted that even in the case of true COVID-19 vaccine or excipient hypersensitivity with positive skin testing, subsequent vaccination can still be possible. While using an alternative vaccine platform (i.e. Janssen vaccination in a patient with mRNA vaccine hypersensitivity) is an option and previously discussed, using a graded dosing regimen for a subsequent dose of the same vaccine that may have caused a reaction is also an option, as discussed in vaccine allergy practice parameters. 35 Given the lack of knowledge regarding efficacy of mixed vaccine platform use, graded dosing using the same vaccine may be an attractive option, although the efficacy of this is also unproven in terms of vaccine response.

Graded dosing regimens for the Moderna vaccine in patients who experienced an allergic reaction with their first dose have been published, and one of the authors has also used graded dosing regimens for the Pfizer vaccine in two patients with Pfizer COVID-19 vaccine-induced anaphylaxis (AGE, unpublished data, August 24, 2021). 36 While this strategy may be limited by patient access to an allergist, it is important to stress that excipient and vaccine skin testing, if used, should not be to label patients as unable to receive a vaccine, but to potentially identify those who require an alternative dosing scheme or vaccine type.

Our data is similar to a recent multicenter study that evaluated 189 patients with an immediate hypersensitivity (including anaphylaxis) to their first dose of an mRNA COVID-19 vaccine and showed that all 159 patients that chose to receive their next dose were able to tolerate it, with only 32 experiencing minor self-limited allergic symptoms. 25 These reports showing a high rate of subsequent mRNA COVID-19 vaccine tolerance in spite of immediate hypersensitivity or anaphylaxis with the first dose is encouraging and should be included in the medical decisionmaking discussion with patients when contemplating vaccine doses. An emphasis should be placed on the high tolerance rate of subsequent vaccine doses in our COVID-19 vaccine reaction cohort even when the majority of the immediate reactions occurred within 1 hour, a time frame that may be more concerning to some individuals. This data can be used to address COVID-19 vaccine hesitancy that may still exist in both patients and health-care providers.

Weaknesses of our study include its retrospective nature and limited standardization in the approach of different providers to the use of skin testing in these clinical situations, which limits our ability to provide a robust, systematic review of its utility. Additionally, there is the potential for recall bias among the patients, particularly among those who presented for evaluation due to a prior PEG or polysorbate allergy prior to receiving any vaccine.

In summary, we demonstrated a low rate of skin test positivity in patients evaluated for potential allergic reactions to the first dose of an mRNA COVID-19 vaccine and in patients with a previous history of PEG or polysorbate allergy prior to receiving any COVID-19 vaccine. There was a high rate of COVID-19 vaccine tolerance following evaluation, regardless of skin test result. This report shows that excipient skin testing may be of minimal value in the evaluation of these patients. COVID-19 vaccine skin testing with offering of subsequent graded vaccine dosing according to established vaccine allergy guidelines may be the most reasonable and cost-effective strategy moving forward, although more study is needed to determine this. Other: Headache, extremity tingling, lightheaded, abnormal taste, hearing/vision decrease, rhinorrhea, palpitations without heart rate change ∑ Brighton Classification: All cases of anaphylaxis (represented by class 1-3) must have sudden onset of symptoms and rapid symptom progression with classification based on a certain combination symptoms as follows (see reference for list of symptoms that fulfill major/minor criteria): Class 1: ≥1 major dermatologic criteria AND ≥1 cardiac and/or respiratory major criteria Class 2: 4 ways to meet class 2: 1. ≥1 dermatologic major criterion AND ≥1 cardiac and/or respiratory minor criteria 2. ≥1 respiratory major criterion AND ≥1 cardiac major criterion 3. ≥1 respiratory major criterion AND ≥1 minor criterion from a different system (dermatologic, cardiac, GI, lab) 4. ≥1 cardiac major criterion AND ≥1 minor criterion from a different system (dermatologic, respiratory, GI, lab) Class 3: 2 ways to meet class 3: 1. ≥1 respiratory minor criterion AND ≥1 minor criterion from at least 2 different systems (dermatologic, cardiac, GI, lab) 

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Figure 1. Flow Diagram of Patient Evaluation, Testing and Outcome