A rapid review of the prevalence and onset of urticaria triggered by COVID-19 vaccine [version 1; peer review: awaiting peer review]

Background: The Coronavirus Disease 2019 (COVID-19) vaccine is essential to reduce the spread of this disease virus and is very effective at preventing patients with severe symptoms of the disease from dying. As of February 2022, more than 10 billion doses of the COVID-19 vaccine have been administered worldwide, and at least 60% of the world's population have received the first dose of the vaccine. The increasing number of populations receiving the COVID-19 vaccine has increased reports of post-immunization follow-up events, one of which is urticaria. This study aimed to determine the prevalence and onset of urticaria due to the administration of the COVID-19 vaccine. Methods: This study used a rapid review method based on previous research on the prevalence and onset of urticaria due to the COVID-19 vaccine. The articles were obtained from the PubMed and Google Scholar databases. The inclusion criteria were articles containing data on the prevalence and onset of urticaria due to the COVID-19 vaccine, published from December 2020 – January 2022


Introduction
Coronavirus Disease 2019 (COVID-19) is a disease caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 was first identified in December 2019 in Wuhan, China, and spread rapidly until the World Health Organization (WHO) declared this disease a pandemic on March 11, 2020. 1 COVID-19 is easily transmitted between humans through aerosols, droplets, and direct contact. SARS-CoV-2 was also found in the feces of patients with COVID-19, so the fecal-oral route could potentially transmit this virus. 2,3 This easy transmission is what causes COVID-19 to spread quickly.
The WHO and the Centers for Disease Control and Prevention (CDC) recommend preventive measures to protect people from the transmission of 5 Precautions that can be taken include maintaining a minimum distance of 1 meter from other people, wearing masks, avoiding crowds, frequently washing hands with soap, covering coughs and sneezes, staying at home when sick, and getting the COVID-19 vaccine immediately. The COVID-19 vaccine is essential to reduce the spread of this disease virus and is very effective in preventing patients with severe symptoms of the disease from dying. 4,6 According to WHO data and Pharmaceutical Technology, as of February 2022, more than 10 billion COVID-19 vaccines have been administered worldwide, and at least 60% of the world's population have received the first dose of the vaccine. 7, 8 The most widely used vaccines in several countries are ChAdOx1 nCov-19 (Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech) from the 33 vaccines that have been distributed worldwide.
The increasing number of COVID-19 vaccines being administered worldwide has led to reports of side effects from administering the vaccine. The presence of side effects, such as adverse reactions and contraindications, is one of the reasons individuals hesitate to receive the vaccine. This doubt is a challenge for global health today. 9 Several studies have reported the incidence of urticaria after patients received the COVID-19 vaccine. Cugno et al. showed the presence of urticaria after the BNT162b2 vaccine was administered in less than 2% of cases and increased to more than 6% of cases in subjects taking ACE inhibitors. 10 McMahon et al. stated that of 23 cases of urticaria after administration of the mRNA-1273 vaccine (Moderna), both at the first and second doses, only 2 cases had urticaria appearing in less than 24 hours. 11 The results of the review of Avallone et al. stated that 10.89% of the 5,941 skin cases after the COVID-19 vaccine were urticaria. 12 This study aimed to examine the prevalence and onset of urticaria due to the administration of COVID-19 vaccine by summarizing existing research data.

Methods
This study used a rapid review method that summarized data on the prevalence and onset of urticaria due to the administration of the COVID-19 vaccine based on existing scientific publications using the PubMed and Google Scholar databases. The PICO search strategy is depicted in the Extended data. 14 The inclusion criteria were all articles containing data on the prevalence and onset of urticaria due to the COVID-19 vaccine published from December 2020 to January 2022, not limited in the study design. The exclusion criteria were articles that were not full text, incomplete data, and not in language. English or Indonesian language. Three reviewers (DAMO, IF and ADK) independently extracted the following data: first author, publication year, research design, sample size, adverse reaction prevalence and onset, allergic history, comorbidities, vaccine types and dosage. From the studies remaining for the analysis, three reviewers (DAMO, IF, and ADK) independently extracted outcome data and recorded the information on a standardised report form using Google Sheet.
The risk assessment of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist tools adapted to each assessed article's study design. 13 There are several assessment categories with answers that can be 'Yes', 'No', 'Unclear', or 'Not Applicable'. Item 'Yes' counted as 1, 'No' and 'Unclear' were 0, and 'Not Applicable' was not included in the assessment. Articles with a score of at least 50% were included in the study. Two reviewers (IF and ADK) independently evaluated the quality of the included studies. Disagreements were resolved by discussion and adjudicated by a third reviewer (DAMO).

Results
The search results and article selection are shown in Figure 1. From the search results through the PubMed and Google Scholar databases, 82 articles were obtained from the PubMed database and 186 articles from the Google Scholar database, totaling 268 research articles that matched the search keywords. Then, a duplication check was done using the EndNote X8 application, and the duplicated articles were removed, resulting in 264 articles. Next, the authors screened titles, inclusion and exclusion criteria, and abstracts that matched the aims of this research. A total of 232 articles were excluded because these were articles that were not published in the range of December 2020 to January 2022, were not full text, used a review method, were not in English or Indonesian, and were abstracts of articles that did not discuss urticaria or cutaneous reactions due to the COVID-19 vaccine. If the results of the abstract screening were doubtful, the manuscript screening was still done to see if there are data on the prevalence or onset of urticaria. The results of the screening left 32 articles that were in accordance with the aims of this study. Furthermore, the authors reviewed the 32 articles to check for data on the prevalence or onset of acute urticaria due to the COVID-19 vaccine. The article was excluded in the absence of data for calculating the prevalence or onset of acute urticaria after administering the COVID-19 vaccine. From this check, 20 articles were obtained that were included in the rapid review.
The risk assessment of bias in this study used the JBI Critical Appraisal Checklist following the study design of each article. The authors used a checklist for prevalence studies for the cohort study design because they are more relevant to this study. A total of 4 articles used a checklist for cross-sectional studies, 4 articles used a checklist for prevalence studies, 5 articles used a checklist for study case reports, and 7 articles used a checklist for case series studies. Articles with a value of 50% or more were included in this study. Based on the risk assessment of bias using the JBI Critical Appraisal Checklist on the 20 articles, the lowest score was 62.5%, and the highest was 100%. See Extended data for more information. 14 This study used all of the 20 articles, consisting of 7 articles containing prevalence only, 11 articles containing only onset data, and 2 articles containing prevalence and onset data.

Prevalence
A total of 9 articles contained prevalence data ( Table 1). The study designs of these articles included 1 case series, 1 letter, 4 cohort prospective observational studies, and 3 cross-sectional studies. The research was conducted in several countries: Italy, Spain, Poland, Japan, Iran, USA, and Sri Lanka. A total of 7 articles used health workers as samples. The sample age range for the entire article was 16 to 76 years. Cohort prospective and cross-sectional articles had more female samples than males, with the percentage of female from 60% to 87.7%. There were a history of allergies and atopic history in the study samples used, including drug allergies (antibiotics, non-steroid anti-inflammatory drugs/NSAID, others), food allergies (shellfish, eggs, milk, fish, peaches, kiwi, buckwheat, others), history of anaphylaxis, allergy to vaccines other than COVID-19 vaccines, bronchial asthma, atopic dermatitis, allergic rhinitis, and urticaria. There were 7 types of vaccines reported in the 9 articles, namely BNT162b2 in 8 articles, mRNA-1273 in 3 articles, ChAdOx1 nCoV-19 in 4 articles, Sputnik V in 1 article, BBIBP-CorV in 1 article, BBV152 in 1 article, and Cuba-Pasteur in 1 article.   A total of 2 articles used first dose vaccine only, 1 article used second dose vaccine only, and 6 articles used first and second dose vaccine. The total sample of these 9 articles was 21,747, with the incidence of urticaria after the COVID-19 vaccine being 150 events and the prevalence range was between 0.035% to 3.2%. The other 7 articles showed the prevalence from lowest to highest, 0.17%, 0.18%, 0.51%, 0.6%, 0.96%, 1.2%, and 1.81%.

Onset
There were 13 articles containing onset data ( Table 2). The articles consist of several different study designs, including 1 cross-sectional, 1 registry-based study, 5 case series, 2 case reports, and 4 letters. The research was conducted in several countries, including Spain, USA, Thailand, Germany, Italy, and Portugal. The age range of the sample who experienced urticaria after the COVID-19 vaccine from the 13 articles was 26 to 76 years. The incidence of urticaria after the COVID-19 vaccine in females was 107, and 25 for males. There were a history of allergies and atopic history in the sample who experienced urticaria after the COVID-19 vaccine, such as drug allergies (antibiotics, NSAIDs, others), food allergies (shellfish, pickles, others), venom hypersensitivity, history of anaphylaxis, vaccine allergy other than COVID-19 vaccine, asthma, atopic dermatitis, allergic rhinitis, chronic rhinitis, urticaria, and psoriasis. A total of 8 articles mentioned the incidence of urticaria after the BNT162b2 vaccine with a total of 56 events, 6 articles mention the incidence of urticaria after the mRNA-1273 vaccine with a total of 47 events, 3 articles mention the incidence of urticaria after the ChAdOx1 nCoV-19 vaccine with a total of 22 events, and 1 article mentions the incidence of urticaria after CoronaVac vaccine with 7 urticaria events. Of the 13 articles included in this study, 132 occurrences of urticaria occurred after the COVID-19 vaccine. A total of 26 urticaria events after the COVID-19 vaccine had an onset within 24 hours, 103 urticaria events after 24 hours, and 3 urticaria events of unknown onset. The onset of urticaria in the 13 articles ranged from 5 minutes to 10 days (Table 2 and Table 3).

Discussion
The prevalence of urticaria due to the COVID-19 vaccine was found in a total of 9 articles used in this study. Bianchi et al., 15 Anton Girones et al., 16 and Wentrys and Stopyra 17 described cases of urticaria in their study as having an immediate onset (onset within 4 hours). Pourani et al. 18 and Grieco et al. 19 stated that all cases of urticaria in their study occurred with an onset of more than 24 hours. Bianchi et al., with the lowest prevalence of urticaria (0.035%) in this study, may be due to only looking at the direct incidence of urticaria and having the most significant number of research samples. 15 Research by Anton Girones et al. showed a higher prevalence rate (0.18%) but it was relatively low compared to other studies that only looked at the incidence of direct urticaria with smaller samples. 16 The study of Wentrys and Stopyra, although it also only looked at direct urticaria, had a higher prevalence rate (1.2%), probably because half of the sample in this study had a history of anaphylaxis, and the sample size of this study was the lowest. 17 Pourani et al., who had the highest prevalence (3.2%) in this review, may be due to this study not only looking at immediate urticaria but also delayed urticaria (onset of more than 4 hours). 18 This high prevalence of urticaria is in accordance with the research of McMahon et al. 11 and Català et al. 20 that observed delayed urticaria occurred more frequently than immediate urticaria.
Urticaria is an allergic reaction resulting from activating skin mast cells. 21 Allergic reactions to vaccines are more often associated with excipients than with the active components of the vaccine itself. Allergic reactions caused by vaccines may originate from the following pathophysiological mechanisms 22,23 : mast cell activation and degranulation due to IgE/antigen complexes, complement system-induced activation and degranulation of mast cells, direct activation of Masrelated G protein-coupled receptor X2 (MRGPRX2) by pseudo allergens, type IV hypersensitivity or delayed reactions. Several components are suspected to be potential allergens in the COVID-19 vaccine. These components are excipients in the vaccine, namely polyethylene glycol (PEG) in the BNT162b2 and mRNA-1276 vaccines, trometamol in the mRNA-1276 vaccine, and PEG derivatives such as polysorbate 80 in the ChAdOx1 nCoV-19 vaccine. 24 The onset of urticaria due to the COVID-19 vaccine from 13 articles used in this study showed mixed results with an onset range of 5 minutes to 10 days. Statistical analysis was not performed because of the considerable variation in the data between articles. The CDC divides urticaria reactions after the COVID-19 vaccine into immediate urticaria (occurring within 4 hours) and delayed urticaria (starting more than 4 hours). 25 Of the 13 onset articles in this study, at least 15 of the 133 urticaria events were direct urticaria. Immediate urticaria may represent a type I hypersensitivity reaction (≤4 hours), whereas delayed urticaria may represent a pseudoallergenic reaction (>4 hours but ≤24 hours) and type IV hypersensitivity (>48 hours). Hypersensitivity reactions to COVID-19 vaccine excipients, such as PEG, have been suggested as possible causes of urticaria, but this has not been proven, and the mechanism of the reaction (immediate and delayed) remains to be elucidated. 26 An interesting observation in the research of Pitlick et al. was that half of the patients have had COVID-19 before. 26 It can be hypothesized that these patients develop a memory T-cell response to the components of the COVID-19 virus. An alternative explanation may be a delayed T cell response to vaccine components or excipients. A similar hypothesis was also stated by Triwatcharikom et al., who speculated that the urticarial rash that occurred in some patients following the CoronaVac vaccine might not be due to an allergic reaction to the vaccine excipient but could occur in sensitive subjects as a result of a cross-reactive immune response to the COVID-19 viral spike protein present from the previous infection. 27 McMahon et al. mentioned cases of skin symptoms reported in their study, such as urticaria, angioedema, and morbilliform eruptions, which may not be due to an allergic reaction to the vaccine but are related to the body's immune response or immunological reaction to NSAIDs commonly used for pain and fever after vaccination. 11 It is essential to differentiate between immediate and delayed urticaria because immediate urticaria requires a risk assessment for subsequent doses of vaccine. 25 The ages who received the vaccine from the 20 articles in this study ranged from 16 to 76 years. Cugno et al. mentioned a higher risk of urticaria/angioedema in females and subjects aged 45-49. 10 In all articles with subjects more than 2 persons and also divides the sexes from urticaria subjects, 10,11,19,20,26,27 it can be seen that the female subjects suffer from urticaria more than the males. This is in accordance with the research of Alhumaid et al. that found the risk factors for anaphylactic and non-anaphylactic reactions (including urticaria) to the SARS-CoV-2 mRNA vaccine were female and a previous history of atopy. 28 Sensitization to PEG is more common in females due to frequent exposure to products containing PEG, such as skin exposure to cosmetics or the use of drugs such as contraceptives use. Other possible explanations include hormonal differences, such as estrogen's role, which may be an essential factor in allergic, immunologic responses. Català et al. mentioned that 80.2% of reactions that occurred in females might indicate significant differences or reporting bias. 20 The female immune system may be more reactive to the SARS-CoV-2 protein, resulting in lower susceptibility to disease and higher reactivity to the vaccine. Another reason may also be selection bias because most study subjects who received the vaccine were health workers and female.
Manilgama et al. stated that in their study, a history of anaphylaxis, drug, or food allergy had no significant association with current vaccine-induced allergy or anaphylaxis. 29 This is in contrast to Alhumaid et al. who summarized the most frequently identified risk factors for anaphylactic and non-anaphylactic reactions to the SARS-CoV-2 vaccine, namely female gender and history of atopy. 28 Previous history of anaphylaxis and comorbidities such as asthma, allergic rhinitis, atopic and contact eczema/dermatitis, psoriasis, and cholinergic urticaria. Cugno et al. found that the risk of developing urticaria/angioedema after vaccination with BNT162b2 in subjects taking ACE inhibitors was three times higher than in subjects not taking ACE inhibitors. 10 The proposed mechanism may be an increase in bradykinin, a vasoactive peptide that induces vascular permeability and is catabolized by ACE.
Of the 9 articles containing prevalence data, apart from Cugno et al., the other eight articles included the incidence of urticaria in each type of vaccine. BBV152 has the highest prevalence, which was 5%. 15 Hayashi et al.'s research was conducted on health workers who wanted to get a vaccine. 31 The vaccination was given in two doses to each patient, but one patient did not receive the second dose due to shortness of breath on the first dose. Allergic reactions were observed 15 minutes after administration of the vaccine dose (30 minutes for those requiring additional attention). If there was an adverse reaction, it was reported to the chiefs of each department with their reporting system. Follow-up bias may be considered. Research subjects Grieco et al. consisted of 74% of health workers and 26% of patients referred to the Department of Dermatology and Allergy. 19 Research seems to be conducted with its reporting system. The subjects of Cugno et al. were health workers. 10 Acute reaction data were collected through a short-structured questionnaire about all types of reactions that occurred after the vaccination schedule was completed. Although the data were collected by questionnaire and not by clinical diagnosis, the research subjects in the form of health workers were believed to have a more reliable symptom assessment than the general population. The subjects in the Wentrys and Stopyra study were patients who had a history of anaphylaxis and who did not have a history of anaphylaxis. 17 In this study, patients were monitored for 60 minutes after vaccination. Each patient was contacted by telephone a week after vaccination to collect data on the potential for other allergic reactions. Any unwanted symptoms that occurred during monitoring in the department or within a week of dosing were evaluated for potential allergic reactions. 17 This rapid review is still very limited due to the small number of articles. Also, the analysis was only descriptive, so reliable statistical data were not produced. Most of the samples in the articles in this study were health workers, so they may not be able to represent the general population. Although the risk assessment of article bias was done using the JBI Critical Appraisal Tools, this study could not avoid bias because only one person did the assessment.

Conclusion
The prevalence rate of urticaria in the population given the COVID-19 vaccine from 9 reviewed articles ranged from 0.035% to 3.2%. The time of onset of urticaria in the population given the COVID-19 vaccine ranged from 5 minutes to 10 days.
Further research to see more reliable quantitative data can be done by improving the quality of the methodology, such as adding search keywords, using statistical analysis/meta-analysis to determine prevalence and onset rates quantitatively, and increasing the number of investigators and search databases.

Data availability
Underlying data No data are associated with this article.