key: cord-0894466-3d7bfhi1
authors: Seirafianpour, Farnoosh; Pourriyahi, Homa; Gholizadeh Mesgarha, Milad; Pour Mohammad, Arash; Shaka, Zoha; Goodarzi, Azadeh
title: A systematic review on mucocutaneous presentations after COVID‐19 vaccination and expert recommendations about vaccination of important immune‐mediated dermatologic disorders
date: 2022-04-11
journal: Dermatol Ther
DOI: 10.1111/dth.15461
sha: 1376e0fcfee5121ab54d8c61c415f51dd6064f30
doc_id: 894466
cord_uid: 3d7bfhi1

With dermatologic side effects being fairly prevalent following vaccination against COVID‐19, and the multitude of studies aiming to report and analyze these adverse events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a thorough body of information about these post‐COVID‐19 immunization mucocutaneous reactions. To achieve this goal, a comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar on July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID‐19 vaccine administration were retrieved using the following keywords: COVID‐19 vaccine, dermatology considerations and mucocutaneous manifestations. A total of 917 records were retrieved and a final number of 180 articles were included in data extraction. Mild, moderate, severe and potentially life‐threatening adverse events have been reported following immunization with COVID vaccines, through case reports, case series, observational studies, randomized clinical trials, and further recommendations and consensus position papers regarding vaccination. In this systematic review, we categorized these results in detail into five elaborate tables, making what we believe to be an extensively informative, unprecedented set of data on this topic. Based on our findings, in the viewpoint of the pros and cons of vaccination, mucocutaneous adverse events were mostly non‐significant, self‐limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers could be of great importance to provide those at higher risks and those with specific worries of flare‐ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra‐indications.

The global impact of the Coronavirus Disease 2019 (COVID-19) pandemic does not need to be underscored. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly throughout the world and left tragic consequences, and vaccination appears to be a mainstay for overcoming this contagious calamity. Many candidate vaccines have been developed against SARS-COV-2, using different vectors and methods of production, which fall into different vaccine types. To name a few: accelerated pace of vaccine production, distribution, and administration, several steps of vaccine development were condensed and got fast-tracked which increased the probability of unsolicited adverse reactions, warranting further attention to the potential side effects of these vaccines, 42, 43 and an international effort to report the observed reactions, through the Vaccine Adverse Event Reporting System (VAERS), 44 or other registries. Previous studies have revealed the main side effects to include localized pain, swelling or redness at the injection site, along with constitutional or COVID-like symptoms, mostly comprised of generalized weakness, myalgia, headache, fever and chills, joint pain, nausea, and diarrhea. 45 Of note, mucocutaneous adverse events encompass a large number of post-vaccination reactions: local injection site reactions as previously mentioned, delayed large local reactions, morbilliform rashes, urticaria, erythema multiforme, delayed inflammatory reactions to dermal fillers, erythromelalgia, lichen planus, varicella-zoster, herpes simplex, pityriasis rosea, petechiae, purpura, and mimickers of COVID-19 infection cutaneous manifestations (e.g., pernio or chilblains), which have predominantly been insignificant and self-limited. 46 

With dermatologic side effects being fairly prevalent after COVID vaccination, and the multitude of studies aiming to report and analyze these events, the need for an extensive investigation on previous studies seemed urgent, in order to provide a comprehensive body of information about these post-COVID-19 immunization mucocutaneous reactions.

Therefore, the main objective of this qualitative systematic review is to recapitulate and categorize the clinical characteristics of mucocutaneous reactions following COVID vaccination, provide an update on the state of underlying mucocutaneous diseases after vaccination, their diagnoses and biopsies, therapeutic strategies, patients' outcomes, and further integrated guidance for approach to patients who have previously experienced these side effects or flares of underlying diseases with other vaccines.

We have also tried to classify experts' recommendations and consensus guidelines on COVID-19 vaccination in those with immunemediated dermatologic disorders, allergic disorders, along with systemic disorders with probable mucocutaneous presentations, for example, autoimmune inflammatory rheumatic diseases (AIIRD); as these disorders could be underlying factors that may affect vaccine immunogenicity, either by themselves, or indirectly, with the use of immunosuppressive and immunomodulatory treatment for their control. Being knowledgeable and updated on the non-critical, critical or potentially life threatening mucocutaneous adverse effects of COVID-19 vaccine and the mutual effects of vaccination and dermatologic disorders on each other is a must for dermatologic, as well as general medical practice today, and we hope the present article provides a stepping stone to that aim.

This study is the first systematic review that thoroughly assesses all aspects of the various dermatological concerns regarding COVID-19 vaccination, condensing the results of all study types with a detailed categorization of the results.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to conduct and report this review. 48 

A comprehensive electronic search was performed through the international databases including Medline (PubMed), Scopus, Cochrane, Web of science, and Google scholar from the beginning to July 12, 2021, and all articles regarding mucocutaneous manifestations and considerations after COVID-19 vaccine administration were initially retrieved using the following major keywords and their MeSH terms: COVID-19 vaccine, dermatology considerations and mucocutaneous manifestations. The search strategy is illustrated in Appendix S1 of supplement file. In addition, a manual search through the references of included reviews was conducted to identify any missing related studies. Two researchers separately performed the search and screening, and the details of each step in the search and screening process is provided in our PRISMA flow diagram, 49 

Our inclusion criteria were studies or reports on any dermatology- 

After duplication removal of the primary search results, two reviewers independently screened the title and abstract of retrieved articles based on the above eligibility criteria. They then separately studied the full-text of the selected studies in detail, for evaluation of eligibility and data extraction. In case of disagreement, they discussed the subject and if they did not reach a consensus, another researcher expert in the field joined the discussion. The data extraction sheet 

A total of 917 articles were retrieved from all databases and 248 duplicates were identified and removed. A total of 669 articles went through title and abstract screening. From those, 388 articles were excluded, including 7 animal studies, 16 trial protocols, 21 systematic reviews, 78 non-recommendation narrative reviews, 109 non-"vaccine related AEs" studies, and 157 non-"dermatologic AEs" studies. The remaining281 articles were selected for full text screening. From those, 101 studies were excluded, including 7 trial protocols, 28 non-"vaccine related AEs" studies, 30 non-"dermatologic AEs" studies, 18 RCTs without specification of cutaneous AEs, and 18 recommendation narrative reviews with no consensus opinion or guideline. Also, references of 20 retrieved narrative and systematic reviews, comprised of 152 articles, were manually screened for any missing articles and 7 related articles from those were also added to our included papers.

F I G U R E 1 PRISMA flow diagram of the study Finally, a total of 180 studies were included in our data extraction and descriptive synthesis, including 65 case reports, 10 case series, 41 RCTs, 27 analytical studies, and 37 recommendations or guidelines.

In total, 116 cases were included in the case reports table from a total of 65 articles, as depicted in Table 1 

Hypersensitivity reaction type 1 (n = 14)

A total of 14 patients were incorporated in the section of type 1 hypersensitivity reaction.

• Urticaria (n = 5) Isolated urticaria occurred in 5 patients (mean age: 30.8 years, F/M: 4) in a range of 5 min to 8 h after inoculation (100% BNT162b2; 100% 1st dose), 80% had an allergic background and they were mainly treated by antihistamines and then oral corticosteroids.

• Flushing (n = 3)

Three patients experienced Flushing of the face (mean age: 48 years, all female) in a range of 5-30 min after inoculation (100% BNT162b2; 100% 1st dose). Two had an allergic background and 1 was treated with antihistamines.

• Angioedema (n = 3)

Three patients (mean age: 35 years, F/M:2) presented with angioedema within 10 min to 24 h of immunization (66.7% BNT162b2 and 33.3% mRNA-1273; 100% 1st dose). For two patients, no treatment was conducted and for the other one antihistamines and corticosteroids were prescribed and symptom relief was achieved in 24 h.

• Anaphylaxis (n = 3)

Three patients encountered anaphylaxis (mean age: 27.3 years, F/M:2) all of whom had an allergic background and developed symptoms pertaining to anaphylaxis, with systemic reactions such as tachycardia, tachypnea, dysphagia, dyspnea, severe chills, dysphagia, the feeling of a slurred mouth and hoarseness, wheezing and throat pruritus, along with mucocutaneous reactions such as diffuse maculopapular rash, urticaria, diaphoresis, palate pruritis, generalized rash and pruritus, sudden onset of rash followed by urticaria and angioedema in a span of a few minutes to 5 h after vaccination (66.7% BNT162b2 and 33.3% mRNA-1273; 100% after 1st dose).

They were diagnosed as Biphasic anaphylaxis, Severe allergic reaction and Level 1 Anaphylaxis. Resolution was achieved 6 h to 1 day after the onset of symptoms using steroids, antihistamines, one patient was treated with an Epinephrine injection and Sodium Succinate, and one was given oxygen.

In the generalized eruptions section, we considered patients with miscellaneous presentations and diagnoses who could not be further categorized in other groups. A total of 21 patients were included (mean age: 55.14 years, F/M:1.63)(57.1% BNT162b2, 19% mRNA-1273, 14 .3% ChAdOx1 nCoV-19, 9.6% Ad26.COV2.S; 66.7% after 1st dose, 14 .3% after 2nd dose, 14.3% after both doses and 4.7% dose not mentioned).

Among the more distinguished presentations were:

• Steven-Johnson syndrome was a diagnosis of a patient (male, 60-year-old) who presented with fever, oral ulceration, eye congestion, erosions over the glans, and multiple purpuric macules all over the body with perilesional erythema which progressed to necrosis after 3 days of immunization (ChAdOx1 nCoV-19, 1st dose); resolution of his symptoms was achieved in 7 days on oral cyclosporine. • Lichen planus or lichenoid reactions (n = 2)

Lichen planus was a medical history of 2 patients (mean age: 51.5 years, F/M:1) who encountered their disease relapse after 1.5 days on average of their immunization (100% BNT162b2, 50% after 1st dose, and 50% after 2nd dose). • Ulcerative colitis (UC) (n = 1)

A 28-year-old male with history of UC for 10 years, and hyper eosinophilic syndrome (HES) for 5 years (which were both well controlled under vedolizumab and cyclosporin), experienced vesicular skin rash, oral aphthosis and hemorrhagic diarrhea 4 days following his 1 st dose of BNT162b2, which was treated with daily 1 gr of sulomedrol for 3 days and prednisone 60 mg/day.

• BCG scar local skin inflammation (n = 2)

Two patients (mean age: 29.5 years, both female) experienced BCG scar local skin inflammation after 1.75 days of their 2nd injection (50% BNT162b2 and 50% mRNA-1273; 50% after 1st dose, 50% after both doses) and it resolved within 3 days on average with paracetamol use.

• Radiation recall phenomenon (n = 3)

Three patients with a medical history of malignancy (mean age: 

We included a total of 41 RCTs as depicted in Table 3 , having enrolled a cumulative number of 160,464 participants who received vaccines, with a cumulative mean age of 38.28 years (weighted average age from 40 studies), 51.53% of them being women.

The included articles consist of phase 1 (n = 11), phase 2 (n = 3), phase 1/2 (n = 17), phase 2/3 (n = 3) and phase 3 (n = 6) trials, along with 1 study on all three phases. Table 3 .

We must bear in mind that the earlier expeditious vaccination with mRNA vaccines and their larger number of RCT participants is also reflected in the net number of observed side-effects, as the number of participants in RCTs on mRNA vaccines (70, 277) , is almost comparable to the number of participants in the collective rest of the vaccine RCTs (90, 353) . This earlier jumpstart in mRNA vaccination also warrants more time for researchers to observe the side effects.

We believe that these reasons have led to the larger number of studies on mRNA vaccines and therefore when evaluating the different vaccine categories, the relative risk of side-effects should be compared between the groups, not the number of reported cases or articles.

A total of 27 observational articles, consisting of case-control, cohort and cross-sectional studies were included, with a total population of 467,577 participants, as illustrated in 69, 70 Gam-COVID-Vac (n = 683), 71 and BBIBP-CorV (n = 89). 56 In addition, seven studies reported combined results on more than one vaccine, collectively comprised of 9851 participants. Five of these studies were on BNT162b2 and mRNA-1273, [72] [73] [74] [75] [76] one study with the addition of ChAdOx1 nCoV-19 to the two previous vaccines, 77 and one study with BNT162b2 and ChAdOx1 nCoV-19. 78 We categorized the studies base on the vaccines administered in Table 4 .

A total of 37 articles regarding recommendations, guidelines and consensus opinion of experts on COVID vaccination in specific groups, such as those with underlying dermatologic or autoimmune disorders (with worries of potential flare-ups 79, 80 ) , those with allergies, and those on immunosuppressive, immunomodulatory or biologic therapies (with worries of inefficient immunization 79, 81 ) , along with articles on certain precautions to be taken with regard to possible anaphylaxis or vaccine-induced thrombotic thrombocytopenia (VITT) were found and their key points were extracted, as highlighted in Table 5 . • Typically vaccinated at least 4 weeks before RTX infusion. Individuals who are actively receiving RTX:

• Often vaccinated 12-20 weeks after completion of a treatment cycle,so there is a 4-week or longer period prior to next their infusion (assuming dosing every 6 months) to mount an immune response (this is the common pattern for influenza vaccines and could be used for COVID vaccination as well)

Concerns of the effect of RTX on immune response after vaccination • Before getting the change to vaccinate, encourage careful use of anti-CD20 (RTX) therapy for skin diseases.

• When vaccines are available, consider vaccination 12-20 weeks after the completion of a treatment cycle, or extending RTX dosing intervals

• Extending RTX dosing intervals to enhance the immune response after vaccination should be weighed against the risk of disease recurrence.

• Although vaccine response may be attenuated, and may have lower rates in RTX recipients, it can be quantified with titers, which may then be helpful for further decisions to revaccinate patients.

Siegel, C. A.

• Patients with IBD should be vaccinated against COVID as soon as possible.

• Patients with IBD are at the same risk of COVID as the general population.

• Patients with IBD, whether or not receiving immune-modifying therapies, can safely receive all non-live vaccinations for any vaccine-preventable illness. If on immune they should not receive live virus vaccines.

• Do not defer vaccination for a patient with IBD receiving immune-modifying therapies.

• Inform patients that they will mount an immune response to vaccination, however, vaccine efficacy may be blunted when receiving systemic corticosteroids.

Patients with IBD receiving Infliximab infusions can receive non-live vaccinations:

• on the day of their infusion • or in mid-cycle with no reduction in efficacy and safety of vaccination. Patients can be vaccinated during induction or maintenance of biologic therapies irrespective of timing within their treatment cycle. Thyssen, J.P. AD is not a contraindication to vaccination • recommend a case-by-case approach considering the specific drug and vaccine product

• recommend to strictly follow guidelines and decisions issued by the local and national health authorities in each country

• Suggest at least 3 weeks between the two COVID-19 vaccine doses AD worsening is unlikely after vaccination, as the vaccination response is mainly skewed toward T helper cell 1.

The risk of AD flares and loss of AD control increases if the systemic AD therapy is withheld or reduced in dose for longer than 3 weeks. Most clinicians pause these therapies as follows:

• JAK-inhibitors and CYSP from the vaccination day until 1 week after • history of anaphylaxis to a vaccination or parenteral monoclonal antibody preparation

• Mast cell disease (systematic mastocytosis) Vaccination contraindications:

• prior allergic reaction to the vaccine itself or to its components such as PEG

In these cases, vaccination should be proceeded as normal:

• 25 Klimek, L.

• Immediate-or late-type allergy, or anaphylaxis to one or more ingredients of the vaccine or to substances that are cross-reactive to them

• Patients with an anaphylactic reaction to the first dose of vaccine In case of (supposed) allergic reactions to vaccination, an allergological work-up in a specialized center is indicated. 26 Klimek, L. Oldenburg, J.

• The positive effects of vaccination with ChAdOx1 nCoV-19 outweigh the negative effects, so its administration is welcome to be resumed in Germany.

• Considering the immunogenesis of thrombosis in intracranial veins or other atypical locations, patientswith a history of thrombosis and/or known thrombophilia do not have a higher risk for this specific and very rare complication with ChAdOx1 nCoV-19.

• Flu-like symptoms (joint and muscle pain or headache) persisting for 1 to 2 days after vaccination are a common side effect and not a cause for concern

• If side effects persist or recur more than 3 days after vaccination (dizziness, headache, visual disturbances, nausea, vomiting, shortness of breath, acute pain in chest, abdomen, or extremities), further medical diagnostics should be carried out to clarify a thrombosis

• Anticoagulation is necessary to treat the thrombosis. While heparins are contraindicated in (autoimmune) HIT, IV anticoagulation with heparins is likely possible in confirmed VIPIT.

• Diagnostics for HIT/VIPIT should be ordered before administering IVIG, since high-dose IVIGs may lead to false-negative test results.

• There is no indication for routine thromboprophylaxis with anticoagulants or antiplatelet agents following vaccination with ChAdOx1 nCoV-19.

• Regardless of (autoimmune) HIT/VIPIT test results, alternative causes of thrombocytopenia and/or thrombosis must be considered and further clarified, including: thrombotic microangiopathies ITTP or atypical HUS, APS, paroxysmal nocturnal hemoglobinuria, and underlying hematological malignancies Concerns of thromboses after ChAdOx1 nCoV-19 Labs: CBC with PLT count, blood smear, D-dimers, further imaging in indicated (cranial MRI, ultrasound, chest and abdomen CT).

• In the case of thrombocytopenia and/or evidence of thrombosis (regardless of previous exposure to heparin): antibodies against the PF4/heparin complex • In case of a negative screening test: an HIT-like cause of thrombosis/thrombocytopenia can be ruled out.

• In case of a positive screening test for PF4/heparin antibodies: order classical HIPA assayor SRA, as a functional confirmatory test;

• if positive: establishment of the diagnosis of autoimmune HIT (in the absence of previous heparin exposure)

• if negative: order a modified HIPA assay; if positive: establishes the diagnosis of VIPIT

• Patients receiving oral anticoagulation (e.g., for AF, VTE): continue treatment during and after vaccination.

• Patients with no indication for oral anticoagulation at significant risk of VTE: thromboprophylaxis over several days may be indicated individually, in case of severe flu-like symptoms with fever and immobilization

• Until (autoimmune) HIT is ruled out: anticoagulation with heparins should be avoided, alternated to danaparoid, argatroban, direct oral anticoagulants, and possibly fondaparinux (with very specific considerations)

• The authors of this guidance document advise against the use of LMWH or fondaparinux for thromboprophylaxis, as it cannot be safely ruled out that these IV anticoagulants foster the production of platelet-activating antibodies.

• As an off-label alternative, general measures (exercise, fluid replacement, compression stockings) + prophylactic doses of direct oral anticoagulants (rivaroxaban 10 mg once daily or apixaban 2.5 mg BD), maybe be considered.

• Collected data does not support the concern for a higher risk of adverse reactions following soft tissue filler injections associated with COVID vaccination, compared to other previously described triggers or the default of adverse reactions following soft tissue filler injections

Concerns of reactions to fillers NM NM 36 Rice, S. M.

• Emerging reports of delayed-type hypersensitivity reactions (DTRs) to facial fillers after COVID vaccination may cause patients to become confused by potential side effects and possibly postpone vaccination as a result.

• Vaccination must be encouraged and patients should be informed about the temporary and treatable nature of these side effects.

• Do not discourage patients with a history of treatment with dermal fillers from vaccination A time frame should be suggested:

• longer than 2 weeks between vaccination and filler procedures, dental procedures or for with recent infections,

• potentially longer windows for those with risk factors such as prior sensitivity to dermal fillers, autoimmune disorders, or those on immunomodulatory medications

Concerns of DTRs to fillers Dilution of fillers with saline or lidocaine or use of non-HA fillers around the time of vaccination may also be suggested to minimize the risk of DTRs

In case of facial swelling lasting longer than 48 h: treat with antihistamines, steroids, and/or hyaluronidase, with resolution both alone or in combination, without altering the vaccine efficacy ACE-Is(lisinopril) have been recommended (not strongly) for the treatment of facial edema following COVID-19 vaccination

In case of symptoms after first vaccine dose, manage the side effects, reassure the patient and advise them to obtain their second dose, with pretreatment considerations (including antihistamines), and instruct them to present to the emergency department if a more severe reaction is suspected 37 Rice, S. M. Pre-vaccine counseling in cosmetic patients seeking fillers:

• Patients with allergies, history of injection site reactions, or urticaria may benefit from antihistamines and topical medications.

• COVID-19 vaccine-related planning (procedures could be planned with a time window to minimize the risk of reactions), along with screening for dental procedures and the herpes simplex virus importance, so that with concrete knowledge, vaccination is not hindered by hesitancy through false beliefs about the extension or prevalence of adverse events or worries of flare-ups or inefficient immunization, and that critical or potentially fatal adverse reactions are safely avoided.

We extracted any side effects of COVID-19 vaccines reported in these studies with a special emphasis on mucocutaneous manifestations, comorbidities, lesion characteristics, time of onset, location, and duration of reactions, along with vaccine types, and further details regarding dosage, conjugated materials and age groups for the RCTs.

It is important to mention that studies with no mucocutaneous manifestations were not included in our systematic review. Also, among the studies we did include, we did not extract the data on groups or subgroups that had no mucocutaneous reactions to the vaccines, so the results and numbers presented here are only on groups with mucocutaneous side effects.

Regarding the case reports and case series, we would like to also emphasize the importance of reporting registries and helping the medical community gather data on more unsolicited adverse events related to vaccination, that were perhaps less commonly observed in the initial trials, and through this cumulative international effort to report these events, many less solicited adverse reactions are now well-known and clinicians are well aware of their potential emergence, and as expressed earlier, many guidelines, consensus recommendations and position papers have been written since.

Regarding the RCTs, the most common side effect among all trials These side effects were sometimes more common in lower dose groups or younger age groups, which is an interesting observation.

There was the same pattern with the primer and booster doses where sometimes side effects were more common after the booster doses and sometimes after the primers, so the trials' results were not all in the same direction on this matter. Among patients' comorbidities were obesity, hypertension, diabetes, history of or current COVID-19, metabolic and endocrine conditions, allergies and hypersensitivities, asthma, cardiac and pulmonary conditions, psychiatric disorders, joint and back pain, positive HIV, malignancy and autoimmune illnesses.

Moving on to safety assessments, most studies had observed the side effects within 7 days after vaccination, others extending the watch period to 14, 21, 28, or more days.

Regarding the analytical observational studies, a wide range of side effects after vaccination were reported in the studies. Among these studies, the most common reaction after COVID-19 vaccination was local adverse events such as injection site pain and numbness.

Apart from local events, systematic reactions such as fatigue followed by fever, myalgia, headache, bone pain, joint pain represented as the most common symptoms. Other mild adverse effects such as nausea, sweating, dizziness, diarrhea, vomiting, taste disturbance, itchy scratchy throat, insomnia, spasm, migraine, nasal obstruction, and rhinolalia were also observed in the reported results. To further categorize the reported adverse events, they mostly fell into seven groups; musculoskeletal, gastrointestinal, cardiovascular, neurological, respiratory, allergic reactions, and mucocutaneous symptoms. The mucocutaneous reactions ranged a broad spectrum from mild local reactions including swelling, redness, pruritus, rash, urticaria, and burning sensa- were hypertension, prior COVID-19, diabetes mellitus, cardiovascular disorders, autoimmune, rheumatologic or allergic disorders, malignancies, obesity, and anaphylaxis. 47, 57, 59, 65, 67, [70] [71] [72] [73] [74] 78, 118, [136] [137] [138] [139] In addition, less common co-morbidities including asthma, thyroid disorder, psychological distress, hepatologic disease, and ophthalmologic disease were also mentioned in these studies.

Regarding the recommendations and guidelines for vaccination in specific groups, a generally positive view toward vaccination was expressed, inviting most groups to vaccinate, while having the necessary precautions in mind, and clarifying the contra-indications so those with higher risks could safely avoid any severe adverse reactions or modify their vaccination and/or treatment schedules to achieve peak immunization, all the while having their underlying diseases under control.

In some cases, a true causality between proposed adverse events and vaccination was not concluded. In these situations, we relied on the authors' original statement, while considering patient's past medical history, notably previous allergic/hypersensitivity reactions to other vaccines or drugs, and the temporal course between vaccine administration and onset of the eurptions. Based on provided evidence, in patients with no alternative underlying source for the adverse eurptions, and in case the onset of reactions were compatible with our experience and current literature, usually occurring from 2-3 days to 3-4 weeks, a vaccine induced adverse reaction was ascertained.

The authors of this study have worked on various clinical aspects of COVID-19, COVID-19 vaccination and dermatology [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] 140, 141 and it seems that this hot topic could answer some questions and concerns about the most encountered specific disorder in the field of dermatology.

We hope the present article provides its audience with the stateof-the-art knowledge that is essential in today's standard of care regarding the mucocutaneous adverse reactions following COVID-19

vaccination.

Mild, moderate, severe, and potentially life-threatening adverse events have been reported following immunization with COVID-19

vaccines. It appears that although in the assessment of the pros and cons of vaccination, mucocutaneous adverse events could be one of the causes of vaccine hesitancy, they are nonetheless mostly non-significant, self-limiting reactions, and for the more uncommon moderate to severe reactions, guidelines and consensus position papers can be of great importance to provide those at higher risks and those with specific worries of flare-ups or inefficient immunization, with sufficient recommendations to safely schedule their vaccine doses, or avoid vaccination if they have the discussed contra-indications.

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COVID-19 vaccines and the skin: the landscape of cutaneous vaccine reactions worldwide

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Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine

Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine -United States

Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US

Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial

Safety monitoring of the Janssen (Johnson & Johnson) COVID-19 vaccine -United States

Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines

Side effects reported by jordanian healthcare workers who received covid-19 vaccines

Prevalence of COVID-19 vaccine side effects among healthcare Workers in The Czech Republic

Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers

POS1248 safety profile of Pfizer-BioNTech Covid-19 vaccine in patients with rheumatic diseases: preliminary assessment

Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID symptom study app in the UK: a prospective observational study

Safety of new mRNA vaccines against COVID-19 in severely allergic patients

Adverse reactions following the first dose of ChAdOx1 nCoV-19 vaccine and BNT162b2 vaccine for healthcare workers in South Korea

Can reactogenicity predict immunogenicity after COVID-19 vaccination?

Adverse reactions to Pfizer-BioNTech vaccination of healthcare workers at Malta's state hospital

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study

First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland

Safety of chadox1 ncov-19 vaccine: independent evidence from two eu states

Adverse events following immunization associated with coronavirus disease 2019 vaccination reported in the mobile vaccine adverse events reporting system

Determining the frequency of serious adverse reactions of inactive SARS-COV-2 vaccine

Safety of an inactivated SARS-CoV-2 vaccine among healthcare workers in China

Active monitoring of early safety of sputnik V vaccine in

SARS-CoV-2 vaccine and thrombosis: an expert consensus on vaccine-induced immune thrombotic thrombocytopenia

Spanish Society of Nephrology Council. COVID-19 vaccination among Spanish nephrologists: acceptance and side effects

Safety of the first dose of mRNA SARS-CoV-2 vaccines in patients with rheumatic and musculoskeletal diseases

COVID-19 mRNA vaccines are generally safe in the short term: A vaccine vigilance real-world study says

Delayed large local reactions to mRNA Covid-19 vaccines in blacks, indigenous persons, and people of color

The incidence and severity of post-vaccination reactions after vaccination against COVID-19. Vaccines (Basel)

Self-reported realworld safety and reactogenicity of COVID-19 vaccines: a vaccine recipient survey

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bonemarrow transplantation -A systematic review of randomized trials, observational studies and case reports

Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases

Methotrexate and glucocorticoids, but not anticytokine therapy, impair the immunogenicity of a single dose of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic inflammatory arthritis

American College of Rheumatology Guidance for COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases: version 1

COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: clinical guidance of the Korean college of rheumatology

A recommended paradigm for vaccination of rheumatic disease patients with the SARS-CoV-2 vaccine

Updated APLAR consensus statements on care for patients with rheumatic diseases during the COVID-19 pandemic

Recommendations for COVID-19 vaccination in people with rheumatic disease: developed by the Singapore chapter of rheumatologists

The COVID-19 vaccine landscape: what a rheumatologist needs to know

National Psoriasis Foundation COVID-19 task force guidance for management of psoriatic disease during the pandemic: version 2-advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments

Psoriasis and psoriatic arthritis in the context of the COVID-19 pandemic: A plenary session from the GRAPPA 2020 annual meeting

Anti-COVID-19 measurements for hidradenitis suppurativa patients

Toward a COVID-19 vaccine strategy for patients with pemphigus on rituximab

SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting

COVID-19 vaccination of patients with allergies and type-2 inflammation with concurrent antibody therapy (biologicals) -A position paper of the German Society of Allergology and Clinical Immunology (DGAKI) and the German Society for Applied Allergology (AeDA)

Risk of severe allergic reactions to COVID-19 vaccines among patients with allergic skin diseases -practical recommendations. A position statement of ETFAD with external experts

European task force on atopic dermatitis: position on vaccination of adult patients with atopic dermatitis against COVID-19 (SARS-CoV-2) being treated with systemic medication and biologics

COVID-19 vaccination in mastocytosis: recommendations of the European Competence Network on mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM)

Adverse cutaneous and mucous reactions from anti SARS-CoV-2 vaccines: recommendations from the Italian Society of Dermatology (SIDeMaST)

Allergic reactions to COVID-19 vaccinations -what ENT doctors should know

COVID-19 vaccination: recommendations for management of patients with allergy or immune-based diseases

Insights from American College of Allergy, asthma, and immunology COVID-19 vaccine task force: allergic reactions to mRNA SARS-CoV-2 vaccines

Severe allergic reactions to the COVID-19 vaccine-statement and practical consequences

Sars-cov-2 vaccination and anaphylaxis: recommendations of the french allergy community and the Montpellier world health organization collaborating center

Immunologically relevant aspects of the new COVID-19 vaccines-an ÖGAI (Austrian Society for Allergology and Immunology) and AeDA (German Society for Applied Allergology) position paper

Practical recommendations for the allergological risk assessment of the COVID-19 vaccination -a harmonized statement of allergy centers in Germany

COVID-19 vaccineassociated anaphylaxis: a statement of the world allergy organization anaphylaxis committee

COVID-19 vaccine-associated anaphylaxis and allergic reactions: consensus statements of the KAAACI Urticaria/angioedema/anaphylaxis working group

Practical handling of allergic reactions to COVID-19 vaccines: A position paper from German and Austrian allergy societies AeDA, DGAKI, GPA and ÖGAI

Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA: position statement of the German allergy societies: medical Association of German Allergologists (AeDA), German Society for Allergology and Clinical Immunology (DGAKI) and Society for Pediatric Allergology

How to manage COVID-19 vaccination in immune-mediated inflammatory diseases: an expert opinion by IMIDs study group

An evidence-based guide to SARS-CoV-2 vaccination of patients on immunotherapies in dermatology

SARS-CoV-2 (COVID-19) vaccination in dermatology patients on immunomodulatory and biologic agents: recommendations from the Australasian medical dermatology group

COVID-19 vaccine and biologics: an impending dilemma

Recommendations and guidance for steroid injection therapy and COVID-19 vaccine administration from the American Society of Pain and Neuroscience (ASPN)

Diagnosis and management of vaccine-related thrombosis following AstraZeneca COVID-19 vaccination: guidance statement from the GTH

Global recommendations on COVID-19 vaccines and soft tissue filler reactions: A survey-based investigation in cooperation with the International Society for Dermatologic and Aesthetic Surgery (ISDS)

COVID-19 vaccine reactions in dermatology: "filling" in the gaps

The art of prevention: COVID-19 vaccine preparedness for the dermatologist

Cutaneous manifestations and considerations in COVID-19 pandemic: A systematic review

N-acetylcysteine and coronavirus disease 2019: may it work as a beneficial preventive and adjuvant therapy? A comprehensive review study

Cytokine storm and probable role of immunoregulatory drugs in COVID-19: a comprehensive review

Geriatric challenges in the new coronavirus disease-19 (COVID-19) pandemic: A systematic review

A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients

Patients with specific skin disorders who are affected by COVID-19: what do experiences say about management strategies? A systematic review

Systemic retinoids in the COVID-19 era-are they helpful, safe, or harmful? A comprehensive systematized review. Iranian

Treatment of COVID-19 with pentoxifylline: could it be a potential adjuvant therapy?

A comprehensive review on COVID-19 infection and comorbidities of various organs

Histopathologic survey on lung necropsy specimens of 15 patients who died from COVID-19: A large study from Iran with a high rate of anthracosis

A systematic review of the histopathologic survey on skin biopsies in patients with Corona virus disease 2019 (COVID-19) who developed virus or drug-related mucocutaneous manifestations

Histopathologic changes and cellular events of organs systems in COVID-19

Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID-19 patients

The effect of influenza vaccine on severity of COVID-19 infection: an original study from Iran

The effect of opium on severity of COVID-19 infection:an original study from Iran

Pansclerotic morphea following COVID-19: A case report and review of literature on rheumatologic and non-rheumatologic dermatologic immune-mediated disorders induced by SARS-CoV-2

Severe and life-threatening COVID-19-related mucocutaneous eruptions: A systematic review

A systematic review on efficacy, safety, and treatment-durability of low-dose rituximab for the treatment of pemphigus: special focus on COVID-19 pandemic concerns

Safety of new MRNA vaccines against COVID-19 in severe allergic patients

A systematic review of clinical studies on mucocutaneous manifestations of COVID-19: virus-related and drug-related

Mucocutaneous adverse effects following COVID-19 vaccination: a comprehensive review of the literature with a presentation of some cases from Iran

First reported case of delayed-type hypersensitivity reaction to non-hyaluronic acid polycaprolactone dermal filler following COVID-19 vaccination: A case report and a review of the literature

Predictors of critical COVID-19 in an Iranian population: age and disabilities play a special role

Simultaneous occurrence of cerebral venous sinus thrombosis and immune thrombocytopenic Purpura in a patient with a history of COVID-19 infection

A systematic review on mucocutaneous presentations after COVID-19 vaccination and expert recommendations about vaccination of important immunemediated dermatologic disorders

The authors would like to express their gratitude to the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) for their technical and editorial assistance.

The authors declare no conflicts of interest.

All authors contributed to the preparation and finalization of this article.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0002-1249-4429