key: cord-0969616-9wdf7pof
authors: Bogdano, Georgi; Bogdano, Ivan; Kazandjieva, Jana; Tsankov, Nikolai
title: Cutaneous adverse effects of the available COVID-19 vaccines
date: 2021-04-27
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2021.04.001
sha: 738ce01f4ffa28cd011053709b6132881637718c
doc_id: 969616
cord_uid: 9wdf7pof

Vaccination has played a crucial role in the improvement of global health. Some of the world's deadliest diseases like smallpox and rinderpest have been eradicated with the help of vaccines and many others have been restrained. The appearance of the strain of coronavirus SARS-CoV-2 and its impact on global health have made crucial the development of effective and safe vaccines for this new lethal disease. So far, there are three main types of COVID-19 vaccines in use around the world: mRNA-based vaccines, adenoviral vector vaccines, and inactivated whole-virus vaccines. Some of them have passed through phase 3 safety and efficacy trials and are widely used for prophylaxis of the coronavirus infection. A plethora of cutaneous adverse events have been reported, most of them mild or moderate injection site reactions. Some rare delayed inflammatory reactions such as "COVID arm" have been reported posing questions on their pathophysiology and their clinical importance. Some rare serious adverse events such as VIPIT and anaphylaxis have been described raising great concerns on the safety of some widely spread vaccines. More data need to be collected with further and more detailed analysis. Still, the overall risk of those severe adverse reactions remains extremely low and the benefits of the existing vaccines in combating the widespread threat of COVID-19 continue to outweigh the risk of their side effects.

Vaccination has played a crucial role in the improvement of global health (1). Smallpox, a deadly infectious disease, has been eradicated by vaccines. At the same time, there are worries about possible reactions to vaccines. The frequency of reported vaccineinduced adverse events is low and ranges between 4.8-83.0 per 100,000 doses of the most commonly used vaccines. The exact number of genuine allergic reactions to the usual vaccines is not determined, but the estimations vary 1 per 500,000 to 1 per 1,000,000 doses for most vaccines. When the vaccines contain gelatin or egg proteins as in the influenza, measles-mumps-rubella (MMR), rabies, and yellow fever, the serious allergic reactions might be more common, but still, the life-threatening cases of anaphylaxis remain rare (roughly 1 per 1,500,000 doses) (2) .

The appearance of the strain of coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and its impact on global health have made crucial the development of effective and safe vaccines for this new lethal strain (3) . Until the end of March 2021, the corona virus COVID-19 pandemic has affected 219 countries and territories, 125,000,000 people have been infected, and more than 2,700,000 have died from this virus. The SARS-CoV-2 virus consists of four structural proteins:

1. the S-spike protein (outer spiky glycoprotein), 2. an envelope protein (E), 3 . membrane glycoprotein (M), 4. nucleocapsid protein (N), which can interfere with the host's immune system, enhancing the attachment and transportation into the host cells (4) .

SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE-2) receptors, although the protease TMPRSS2 might also play a role (5) . The S protein is the main target for most of the currently available vaccines. In the mRNA vaccines, short-lived synthetically produced molecules of the RNA sequence transfected (infected by transformation) by COVID-19 virus are injected into the subject (4) . After the intramuscular injection, the transfected RNA molecules are taken by the antigen-presenting cells and this induces an immune response. The vaccine's mRNA is transferred to the ribosomes of the host cells, the spike protein is translated and exposed on the surface of the cells which later triggers the immune response. The spike protein molecules stimulate adaptive immune responses that can further identify and destroy the corresponding pathogen (6) . The mRNA is covered with lipid microvesicles (liposomes) which protect it from degradation and carry it into the human cells. As a result, mRNA vaccines mimic the natural infection with the virus, retaining only a short synthetic viral mRNA that encodes the required antigen (4) . The mRNA vaccines are easier to create and design, faster to produce, and are able to stimulate strong humoral and cellular immunity. The steps leading to the production of mRNA are simple, fast, and most importantly robust, which means that they do not depend on the mRNA sequence (7) . To date, the mRNA vaccines demonstrate the strongest efficacy against infection with the virus.

The adenoviral vector vaccines use adenoviruses from chimpanzees or gorillas to deliver a DNA gene unique to the virus which encodes the spike protein. The reason why nonhuman adenoviruses are used is to avoid the risk of pre-existing immunity against the vector and to increase their efficacy (4) . Once inside the human cell, the viral vector uses the gene and the cells' mechanism to produce the spike protein which is later displayed on the cell's surface. The exposed S protein triggers an immune response. The adenoviral vector COVID-19 vaccines show varying efficacy against infection with SARS-CoV-2 but they demonstrate strong protection from severe disease and death (8) (9) (10) .

The inactivated whole-virus vaccines are based on a living virus that has been killed or inactivated and thus is not able to cause clinical disease. These are the oldest and most studied types of vaccines so far. Inactivated virus vaccines are usually made by exposure of a virulent virus to chemical or physical agents, for example, formalin or β-propiolactone, in order to destroy infectivity while retaining immunogenicity (11) . Their major disadvantage is the need to use large amounts of antigen to obtain an adequate antibody response. These vaccines induce an immune response directed against many SARS-CoV-2 antigens, not only against the S protein. The inactivation process decreases the immunogenicity and this requires the need to use special adjuvants such as aluminum (12). Such live attenuated vaccines are employed to protect against mumps, measles, rubella, and varicella. The inactivated vaccines are not widely used for COVID-19 prophylaxis and are not entering the scope of this article.

All three types of COVID-19 vaccines can cause large spectra of vaccine-related adverse reactions. The most common side effects are limited to the injection site and are due to non-specific stimulation of inflammation.

Just as in other vaccines, the COVID-19 vaccines often cause cutaneous reactions close to the injection siteredness and swelling. (13) (Fig. 1) .

Until the end of 2020, other skin injection-site reactions, such as injection site urticaria and an injection-site maculo-papular dermatitis, have been reported for Moderna vaccine (13, 14) .

The type I IgE-mediated allergic reactions to vaccines are rarely induced by the vaccines' antigens but are usually caused by the inactive ingredients, such as egg protein, formaldehyde, gelatin, thimerosal, or neomycin (4). According to the European Medicines Agency (EMA), the excipients are constituents of a pharmaceutical form apart from the active substance. The excipients (originates from the Latin "excipere", which means to receive) are inactive substances that serve as the vehicle or medium for a drug or other active substance. Their purpose is to improve stability and absorption, to increase solubility, to influence palatability, or to create a specific appearance. Among the different excipients in the COVID-19 vaccines polyethylene glycol (PEG), present in the mRNA vaccines, is the one suspected for the induction of allergic reactions (13) . Polysorbate, which is used to improve the water solubility of drugs, may also induce allergic reactions (15) . Polyethylene glycol, which is present in the two mRNA vaccines, and polysorbate 80 found in the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca-Oxford) and Ad26.COV2.S (Janssen Pharmaceutical Companies), are the excipients blamed for allergic reactions (4).

PEG and polysorbate are components in numerous vaccines and other injectable medications (16) .

Polyethylene glycols are also known under different names such as Polikol, Carbowax TM, Oxyethylene polymer, Polyox, Ethylene Glycol polymer, Polyethylene oxide; Polyoxyethylene diol, and Macrogol. PEGs are synthesized via polymerization of ethylene oxide (17) and are widely used in medical materials (wound dressings, ultrasound gels, cleansing preparation for colon endoscopy, hydro-gels, orthopedic bone-and neurosurgical dural sealants). PEGs are also part of household products (detergents and polishes) and food additives (preservatives and supplements). Macrogols are widespread in cosmetic products such as creams, ointment bases, facial products, baby wipes, shampoos, hair gels, lipsticks, shaving creams, and oral hygiene products. Balancid Novum reflux tablet  8000 MW -Imposit throat lozenge; Malarone antimalarials; Chester packaging ultrasound gel; Effexor antidepressant tablet  20,000 MW -Some sodium alginate antacid tablets PEGylation occurs when PEGs are attached to various protein medications, allowing greater solubility for certain drugs. PEGylated drugs are common in cancer, gout, and immunotherapies PEGs are generally weak contact sensitizers (18) . Low molecular weight (LMW) (200-700kDa) PEGs are liquids, while high molecular weight (HMW) (1000-7500kDa) PEGs are solids. Usually, HMW allergens produce type I hypersensitivity, while contact sensitization is mainly reported with low molecular weight PEGs, for example, PEG 200 to PEG 400 (19) .

Various allergic reactions, such as allergic contact dermatitis, contact urticaria, and anaphylaxis, have been described. Data from the European anaphylaxis-registry with 7935 registered anaphylactic cases show that only three of them were induced by Macrogol (20) . Recently, in the anaphylaxis registry, 6 PEG cases and 1 polysorbate case have been registered, resulting in a percentage for PEG and polysorbate of 0.3% (7/2,350) for druginduced anaphylaxis (21) . There are a few cases described, concerning Macrogol induced hypersensitivities due to drugs, personal hygiene products, dental products, and lubricants.

There is no standardized diagnostic testing for suspected hypersensitivity to PEGs. Simultaneous testing to multiple PEG molecular weights or repeating positive intradermal testing should be avoided.

Cross-reactions to polysorbate 80 must be considered (23).

Polysorbate has several synonyms: Polyoxyethylene-sorbitan-20-monooleate, Polysorbate 80, Polysorbate 20, and Polyoxyethylenesorbitan monooleate. Polysorbates are a class of emulsifiers and dispersing agents derived from ethoxylated sorbitan. They are used in medicinal products (e.g., vitamin oils, vaccines, anticancer agents, and additives in tablets), cosmetics (creams, ointments, lotions), and food. Polysorbate 20 is added in brodalumab, and polysorbate 80 is added in infliximab, adalimumab, ustekinumab and secukinumab (24) .

Polysorbate 80 was identified as the causative agent for the anaphylactoid reaction of non-immunologic origin in the patients (15) .

Polysorbate 80 has been involved in isolated cases of allergy in the form of contact dermatitis caused by topical drugs, but its relevance as a contact allergen has declined during the past decades. The most commonly involved topical drugs with Polysorbate are Acyclovir and inhaled Budesonide. The most commonly involved parenteral drugs with Polysorbate are adalimumab and ustekinumab, erythropoietin and darbepoetin, and omalizumab (25) .

Polysorbates have a potential to induce urticarial and/or anaphylactoid reactions. Urticaria due to polysorbate20 in brodalumab has been described. Urticaria and/or anaphylactoid reactions could appear due to polysorbate 80 in infliximab, adalimumab, ustekinumab and secukinumab.

In most cases, a combination of skin prick, intradermal, and challenge testing with standard methodologies has been used.

Immediate hypersensitivity to PEG 3350 with cross-reactive polysorbate 80 hypersensitivity may be under-recognized in clinical practice and can be detected with skin testing (26) .

Anyone with a history of immediate allergic reaction of any severity to any component of the mRNA COVID-19 vaccines or to polyethylene glycol or polysorbate should not be vaccinated with the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (ModernaTX) vaccine. People with a history of severe allergic reactions due to any cause should be monitored for a 30-minute observation period after the application of the vaccine (4).

There is no consensus on the use of antihistamines for prophylaxis. The H 1 -receptor blockers are unable to prevent anaphylaxis. They could mask cutaneous signs and symptoms and thus might delay treatment. Antihistamines could suppress some of the allergic manifestations, such as dermatitis or itching, but they are unable to prevent death from anaphylaxis. It is important for patients with anaphylaxis to seek immediate medical care, because the only proven lifesaving treatment is epinephrine, and any delay in receiving appropriate treatment can be fatal (27) . Here, we present a modification of the decalogue of treatment proposed by the European Academy of Allergy and Clinical Immunology (28):

Recline position of the patient (Trendelenburg position) with legs up.

Volume replacement with NaCl 0.9% solution.

Inspiration support (clear airways, oxygen administration via facial mask 10 L/min.)

Emergency bronchodilation with short-acting beta 2 -agonists (SABA; e.g., Salbutamol) for severe dyspnea/wheezing; Glucagon should be applied for patients who do not respond to adrenaline due to treatment with beta-blockers.

Nebulized epinephrine and nebulized SABA.

Oral or intravenous corticosteroids (CSs) + oral or i.v. antihistamines.

Warrant anaphylaxis diagnosis by measuring mast cell tryptase 2-3 hours after the onset of the reaction.

The anaphylactic reactions to the mRNA COVID-19 vaccines are more common compared to such reactions to the other vaccines but they still remain very rare. Early safety monitoring of the Pfizer-BioNTech COVID-19 vaccine has detected 21 cases of anaphylaxis, after reported administration of 1,893,360 first doses of Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million vaccine doses administered) as well as cases of less severe nonanaphylaxis allergic reactions, based on U.S. data for December 14-23, 2020 (29) .

Other rare reactions have been reported for the mRNA-1273 (Moderna) vaccine. These include reactions to hyaluronic acid (HA) dermal fillers and delayed-type or T-cellmediated local hypersensitivity reactions, also known as "COVID arm".

The FDA brief on the mRNA-1273 (Moderna) vaccine reported reactions to dermal filler after vaccination in three patients in the experimental arm of the trial (13) . Two of these patients had facial swelling, with one reporting filler injection 6 months prior and the other one 2 weeks prior to vaccination. The third patient had only edema of the lips. In this case, the time of the filler injection was unknown, but a similar reaction has occurred after influenza vaccination in the past (30) . All reactions resolved. At the same time, two patients in the placebo group of this trial also developed facial swelling, which might indicate that other triggers apart from the vaccine or filler could have confounded the cases in the experimental group.

Immunogenic dermal filler reactions are rare, with both immediate and delayed type hypersensitivity reactions (DTR) reported and a global incidence rate of 0.8% for hyaluronic acid (HA) fillers (13) . There is a review of the cases of delayed-onset inflammatory nodules developing in people injected with HA fillers. Although delayed nodules are uncommon from HA-V (0.5%), it is important to be aware of this adverse effect and have a management protocol in place. It is the authors' opinion from the patients' responses and from the literature that these nodules are immune mediated in nature (31) . Usually, the DTRs, mediated by macrophage and T-cell interactions, develop 48 to 72 hours after injection, but sometimes they can occur weeks or months later. These reactions present with swelling and erythema at the filler site (32) or with formation of granulomas at the injection site months or even years later (33).

It has been hypothesized that DTRs develop in people with dermal fillers after certain immunogenic triggers (e.g. COVID-19 or other vaccines), because the fillers might act as adjuvants rather than direct T-cell activators, enhancing the antigen-specific immune response without triggering one on their own (13) . Genetically predisposed individuals might have a lower threshold for vaccines, infections, or other factors to trigger inflammatory reactions (33). New data indicate a higher risk of DTRs to fillers in patients with HLA subtypes B*08 and DRB1*03, with association to a predisposition for autoimmune and/or granulomatous disorders (34) . Abnormalities in acute phase reactants, C-reactive protein, fibrinogen, and low complement levels might also be involved in the reaction, probably through an autoimmune mechanism (35) . HA begins to degrade 3 to 5 months after injection, and this might cumulate unknown breakdown products that might stimulate the immune system when combined with additional triggers (31) .

A possible mechanism for the development of delayed inflammatory reaction (DIR) to hyaluronic acid (HA) dermal fillers has been proposed: this is a reaction induced by COVID-19/SARS-CoV-2 virus spike protein (36) . Although the exact mechanism of DIR is unknown, the COVID-19 spike protein may evoke a pro-inflammatory response in the location of dermal HA fillers through blockade of a cutaneous ACE2 inhibitory pathway. Whether the DIR is related specifically to the mRNA-1237 (Moderna) vaccine or is a potential adverse reaction to widespread immune surveillance following infection is to be determined.

The treatment of patients with extensive findings might include a combination of oral corticosteroids and hyaluronidase injections initially to reduce the inflammatory response, stimulate ACE2 upregulation, and eliminate the HA nidus of the inflammation (36) . The administration of oral corticosteroids to treat an active/ongoing viral infection is usually avoided in order to evade inhibition of host immune response. In the case of COVID-19, SARS-CoV-2 induces a hyperimmune response that benefits from corticosteroid administration. Based on the knowledge of the Angiotensin pathways in the body, ACE-I or angiotensin receptor blockers (ARBs) might be used in the acute phase treatment of delayed inflammatory reactions (DIR) (37) . Other possibilities of ACE-I therapy would include pretreatment to prevent DIR prior to the first vaccine dose in a patient with a longstanding history of filler placement or pretreatment of a patient prior to second vaccine dose, if a DIR develops after the first dose. Therapeutic intervention with ACE-I or ARB would not be expected to affect vaccine efficacy in a similar manner to CSs.

Other interesting but rare and non-dangerous reactions to mRNA-1273 (Moderna) vaccine against SARS-CoV-2 have been observeddelayed large local reactions, most probably T-cell-mediated hypersensitivity reactions. From the phase 3 clinical trial of the mRNA-1273 vaccine against COVID-19, there is information about immediate injection-site reactions; such reactions were observed in 84.2% of the participants after the first dose (14) . The trial also revealed that delayed injection-site reactions (defined in that trial as those with an onset on or after day 8) occurred in 244 of the 30,420 participants (0,8%) after the first dose and in 68 participants (0,2%) after the second dose. These reactions include erythema, induration, and tenderness. In most of the cases, the reactions resolved in 4 to 5 days.

Recently, there have been observed delayed large local reactions with variable appearance to mRNA-1273 vaccine, with a median onset on day 8 (range, 4 to 11) after the first dose (38) . The reactions are also known as "COVID arm." (Fig.2 ) In a series of 12 patients with such reactions, these appeared near the injection site after complete resolution of the initial local and systemic manifestations associated with the vaccination. Five of the reactions were grade 3 plaques (>10cm in diameter). Some of the patients had coexisting systemic adverse effects, including 2 persons with additional skin findings. Most of the patients were treated symptomatically with ice and antihistamines, some of them received corticosteroids (topical, oral, or both), and 1 patient was given antibiotic therapy for supposed cellulitis. The signs and symptoms resolved in a median of 6 days after onset (range 2 to 11) (38) . The authors' suspicion of delayed-type hypersensitivity reaction was supported by skinbiopsy specimens taken from a patient with a delayed large local reaction who was not among the 12 patients described by this team. The specimens revealed superficial perivascular and perifollicular lymphocytic infiltrates with rare eosinophils and scattered mast cells. The injection-site reactions and the delayed type hypersensitivity reactions are not contraindications to subsequent vaccination, so all 12 patients were encouraged to receive the second dose and complete their mRNA-1273 vaccination course. Half of these 12 patients did not have recurrence of large local reactions, 3 of them had reactions similar to the initial ones, and 3 subjects had recurrent reactions of lower grade than the initial ones. The median onset of cutaneous symptoms after the second dose (day 2; range, 1 to 3) was earlier compared to that after the first dose.

The mass vaccination campaign against COVID-19 is progressing and different skin changes, including delayed local reactions, are more likely to appear. These adverse reactions are not serious and should not discourage people to complete the vaccination.

Adenoviral vector vaccines (ChAdOx1 nCoV-19 (AstraZeneca-Oxford), Gam-COVID-Vac (Gamaleya National Centre of Epidemiology and Microbiology), Ad26.COV2.S (Johnson and Johnson's Janssen Pharmaceutical Companies), Ad5-nCoV (CanSinoBIO)) have shown reasonably good safety profile. Some recent concerns that vaccination with ChAdOx1 nCoV-19 (AstraZeneca-Oxford) is linked to thromboembolic events (39) and the precautionary move of several European countries (Denmark, Norway, Iceland, Austria, Estonia, Lithuania, Luxembourg, Italy, Latvia) that have suspended use of this vaccine, have led to an issue of a statement by the European Medicines Agency that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (ChAdOx1 nCoV-19 (AstraZeneca-Oxford) (40) . The overall risk of blood clots of the vaccine is very low, and its benefits in combating the widespread threat of COVID-19 continue to outweigh the risk of side effects (41) . Physicians should be aware for potential Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT), which might be a rare adverse event following the AstraZeneca COVID-19 vaccine. The reaction seems to be similar to heparininduced thrombocytopenia (HIT) or drug-induced cutaneous vasculitis which can have a very demonstrative cutaneous involvement (42) .

Some findings of VIPIТ are present on the skin such as a petechial eruption, erythema and edema of the extremity with pallor and coldness. This may occur together with some systemic symptoms like persistent and severe headache, focal neurologic symptoms, seizures, blurred vision, shortness of breath, chest or abdominal pain, providing be a valuable sign for a condition that is potentially fatal and should not be misdiagnosed (43) .

The cutaneous adverse effects of the ChAdOx1 nCoV-19 are once again primarily injection site reactions. No serious adverse reactions to this vaccine occurred during the trials, and the majority of adverse events reported were mild or moderate in severity, and all were self-limiting (9, 44, 45) . One study has described only one case of rosacea as an unrelated adverse effect and moderate pruritus as a related adverse effect apart from multiple mild solicited adverse local reactions such as pain, redness, warmth, itch, swelling, induration, tenderness (44) . The phase 2/3 trial following the study has shown similar results with most of the reported local and systemic adverse events classified as mild to moderate in severity (45) . In another study with a larger cohort combining four randomized controlled trials in Brazil, South Africa, and the UK, there was only one case of cellulitis observed (46) . Delayed inflammatory reactions are rarely reported mainly in mRNA type vaccines such as mRNA-1273 vaccine (Moderna, Cambridge MA), and BNT162b2 vaccine (Pfizer/BioNTech, New York, NY) (36, 38) . The only known case of a suspected delayed inflammatory cutaneous reaction after ChAdOx1 nCoV-19 vaccine has been described in a 68 years old woman with a history of localized scleroderma and appearance of highly pruritic, erythematous papular eruption, located within the limits of the morphea lesions, subsequently spreading to different areas of the body. This started on the 3 rd day following the first administration of the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) (47) (Fig. 3) .

The only available clinical trial of Ad26.COV2.S (Johnson and Johnson's Janssen vaccine) showed no serious cutaneous adverse effects. The most frequent injection site reaction was erythema followed by swelling. Both were mild and self-limiting (48) . EMA's safety committee PRAC has initiated a review of a safety signal based on four serious cases of unusual blood clots with low blood platelets post-vaccination with this vaccine with one fatality (40) . Recently, CDC and FDA have reviewed data about six potential cases of a rare and severe type of cerebral venous sinus thrombosis (CVST) in combination with thrombocytopenia in individuals after receiving the Ad26.COV2.S vaccine. They have issued a recommendation for a pause in the use of the vaccine, pending further and more detailed analyses of this rare but severe adverse effect is fulfilled. Because there is a similarity to heparin-induced thrombocytopenia (HIT), heparin is considered potentially dangerous and should be avoided in the treatment of this condition (49) . Some authors consider the use of intravenous immunoglobulin (IVIG) to treat this serious reaction (50) .

The Russian vaccine Gam-COVID-Vac (Gamaleya National Centre of Epidemiology and Microbiology), also known as SputnikV is heterologous, consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). The first phase 1/2 trial based on the data of only 76 healthy participants has shown similar results to those of the other adenoviral vaccines with a good safety profile and no severe adverse reactions. Mild local adverse events were observed such as pain and itch in the injection site as well as hives in 1 patient (51).

The phase 3 trial Gam-COVID-Vac vaccine gave a far more detailed picture of the safety profile. This study included a total of 21,977 healthy adult volunteers aged at least 18 years. Of those participants, only 12296 received both doses and were included in the general safety analysis due to violation of the restrictions imposed and lack of data verification in their case report form (8) . In the vaccine group, they have reported several cutaneous adverse reactions such as extremity abscess in 1 patient, allergic skin reactions in 6 patients and skin rash in 12 patients, petechial rash in 1 patient, itch in 4 patients, acneiform dermatitis in 1 patient, eczema in 2 patients and alopecia in 2 patients (8) . Four deaths occurred during this study -three in the vaccine group and one in the placebo group. None were considered related to the vaccine. Both phase 1/2 and phase 3 studies do not provide detailed information on mild and moderate adverse events which makes it difficult to evaluate the possible cutaneous side effects.

The Chinese vaccine Ad5-nCoV (CanSinoBIO) has one dose-escalation, single-center, open-label, non-randomized, phase 1 trial with 195 recruited individuals of which only 108 have been sequentially enrolled and assigned to receive the vaccine (52) . In this trial, only mild injection site adverse reactions such as pain, induration, redness and swelling were reported with no severe adverse reactions. A subsequent randomized, double-blind, placebo-controlled, phase 2 trial with 508 eligible participants has shown a similar safety profile as the previous trial. Apart from the mild injection site reactions some unsolicited cutaneous and mucosal adverse reactions have been reported such as noninfective gingivitis, buccal ulcerations, oral Herpes simplex infection, lymphadenopathy, and oral hypoesthesia (10) .

Finding and describing the cutaneous adverse reactions of the available COVID-19 vaccines has proved to be a challenging and difficult task. Injection site reactions presenting on the skin are among the most frequent adverse events, most of them mild or moderate, usually self-limited and without serious consequences. Delayed inflammatory reactions are less frequent but mysterious with no clear vision on the potential mechanisms leading to their appearance. Serious adverse events like VIPIT and anaphylaxis are of course the most important part of every safety and efficacy trial and the main topic of this article. Most of them are systemic adverse reactions with frequent cutaneous symptoms which may be the first manifestation and the key for the diagnosis leading to a timely and potentially life-saving treatment. Further vigilance for severe adverse reactions is mandatory after the beginning of the worldwide spread of the vaccines. The cutaneous findings are a very important part of this vigilance since they might be the first symptoms to detect. Their importance is frequently underestimated, and sometimes they are unreported in the clinical trials or considered irrelevant. 

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High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review. Expert review of hematology

Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Probably the low number or absence of skin biopsies is due to the mild or moderate local or systemic reactions which resolve quickly only with the help of antihistamines or topical corticosteroids. In our case of "COVID arm" the patient initially agreed to give material for biopsy but the reaction was over (dissipated) until the time/appointment for the procedure.