Dermatological Side Effects of SARS-CoV-2 Vaccinations

Introduction

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a novel RNA virus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected and taken the lives of millions worldwide, rendering a global health crisis. Based on the highly contagious nature of the virus, mask mandates and social distancing laws were put in place to control the transmission of the disease. At the same time, scientists launched large-scale, worldwide, clinical trials with unprecedented rapidity in an effort to demonstrate safety and efficacy of vaccines in preventing virus transmission.

On December 2, 2020, the United Kingdom Medicine and Health Regulatory Agency (MHRA) approved the first, two-dose mRNA vaccine labeled BNT162b2, also known as the Pfizer-BioNTech COVID-19 vaccine, to be administered for emergency use in humans.¹ Soon after, several other vaccines were authorized for emergency use worldwide, leading to a total of thirteen vaccines to date.² In late December 2020, mRNA vaccines, BNT162b2 and mRNA-1273 (Moderna) were approved for emergency use in the United States by the Food and Drug Administration.³

To limit the gravity of illness of this highly contagious virus, mass vaccinations have commenced. However, a significant obstacle confronted by the health care community has been hesitancy to receive vaccines.^4,5 By accurately identifying adverse cutaneous vaccine reactions and providing timely education on prognosis and treatments, dermatologists may play a key role in reducing unnecessary anxiety and easing vaccine hesitancy.

During the clinical trial phase, the most common adverse skin-related side effect was a local cutaneous reaction. However, it is important to note that the clinical trials excluded individuals on immunosuppressive therapies.⁶ This exclusion criterion encompassed patients who suffer from chronic autoimmune skin diseases, including those who are on immunosuppressive or immunomodulatory therapies for these conditions. Therefore, the increasing vaccination rates in this population that were previously excluded in the clinical trials have revealed increased post-vaccination adverse skin reactions.⁶ This article will review the current reported adverse dermatological side effects (Table 1) and recommendations for management following SARS-CoV-2 vaccination.

Methods

Embase and PubMed databases were used to identify published articles in English pertaining to the dermatological side effects of the COVID-19 vaccine. This review includes case reports, case series, retrospective studies, and other review articles. Search terms included a combination of SARS-CoV-2 vaccine with dermatology, skin, varicella zoster, psoriasis, bullous pemphigoid, pemphigus vulgaris, vasculitis, Stevens-Johnson Syndrome, anaphylaxis, and vitiligo.

Results

Cutaneous reactions reported during clinical trials

Clinical trial data have been published on 11 of the 13 authorized COVID-19 vaccines. During the clinical trials, the most common cutaneous eruption was a local injection site reaction, with onset of 7 days after injection. Of the patients that experienced a local injection site reaction, 88% of patients had resolution of symptoms within 48 hours. Delayed large local reactions (DLLR) were most notable during the phase III clinical trial of the Moderna vaccine, with usual onset within 8 days following injection of either the first or second dose. However, it was not specified whether patients who reacted to the first dose also experienced a reaction after receiving the second dose.⁷

Other cutaneous eruptions reported in clinical trials included “allergic, atopic, contact dermatitis, eczema, exfoliative rash, hypersensitivity reaction, injection site urticaria, papular urticaria, and vesicular eruptions.”⁷ Only 3 reported cutaneous reactions were labeled as “severe.” These reactions included acute hypersensitivity with urticaria, severe unspecified rash, and severe cellulitis.⁷

Cutaneous reactions reported in the real-world setting

Delayed Large Localized Reactions (DLLR)

Following the clinical trials, the most common real-world cutaneous reaction was a DLLR which was experienced by 350 participants (7%) over 6 studies.⁷ The DLLRs were mild and resolved within 11 days. While the etiology of the delayed T cell-mediated hypersensitivity is unclear, polyethylene glycol (PEG), found in both Moderna and Pfizer, is a possible culprit. These DLLRs are considered self-limited, and patients should continue with normal vaccination schedule. There was no mention of pretreatment recommendations for preventative measures.⁷

Morbiliform Exanthems

Morbilliform and maculopapular exanthems were identified in 43 patients across 3 studies. Histological evaluation demonstrated spongiosis and mild dermal perivascular lymphocytic infiltrates, which proposes the etiology to be an overactive immune system rather than a direct effect caused by the viral product.⁷

Urticaria

Urticaria is another cutaneous reaction that was noted in 55 participants across 6 observational studies.^8–12 One patient had also developed pruritic urticaria within minutes following injection of the Pfizer vaccine. However, this patient was found to have underlying cholinergic urticaria and waited a long time in the heat, so it was concluded that the patient may have experienced heat-induced urticaria rather than a vaccine-induced urticaria.^7,12

Filler Reactions

Patients with hyaluronic acid fillers were found to have delayed inflammatory reactions following COVID-19 vaccination. Hyaluronic acid fillers are often used for soft tissue augmentation. COVID-19 vaccine can now be added as a trigger after 15 cases of delayed inflammatory reactions were noted across 3 observational studies.^11,13,14 The proposed mechanism for this reaction was explained by the fact that adipose tissues have high levels of angiotensin-converting enzyme-2 (ACE-2) receptors and this is where hyaluronic acid fillers are usually administered. The SARS-CoV-2 spike protein is also a substrate for ACE-2 receptors, which likely generated the delayed immune response. The recommendation is to treat patients with hyaluronic acid fillers with a short course of ACE inhibitors before COVID-19 vaccination to limit the inflammatory response.^13,15

Pernio and “COVID Toes”

Pernio eruptions were identified in 10 cases, all of which resolved within one week to one month using topical corticosteroids.⁷ Notably, similar lesions were also commonly noted amongst patients who had COVID-19 infection.¹⁶ With the SARS-CoV-2 infection, pernio-like lesions were labeled as “COVID toes.”¹⁶ Sun et al. found that these were the most common cutaneous side effects reported during the clinical trials and in the real world setting of COVID-19 vaccination up to April of 2021, only a few months after the vaccine was authorized for emergency use.⁷

Lesort et al. reported another “COVID toes” case following mRNA vaccination. Their report supports the idea that the mechanistic cause of the pernio-like lesions is the activation of an immune pathway rather than the viral product itself. The report describes an 82-year-old female with a history of psoriasis, treated with methotrexate, presenting with painful lesions on both hands and feet onset 24 hours after the first dose of the Pfizer vaccine. The physical exam findings revealed macular, violaceous, and erythematous lesions isolated to the fingers and toes. Laboratory findings, including inflammatory markers and autoimmune tests, were normal. Histology showed partly necrotic epidermis overlying a dense lymphocytic infiltrate forming aggregates around blood vessels, eccrine sweat glands, and occasionally around the nerves. Direct immunofluorescence of the frozen skin biopsy and serological testing for SARS-CoV-2 were both negative. The patient tested positive for a vaccinal anti-S antibody and the interferon signature suggesting immune reactivation to the vaccine rather than a direct, viral cytopathogenic cause.¹⁷

“COVID arm”

Patients were also noted to experience rare, delayed local skin reactions following administration of mRNA vaccines identified by the CDC as “COVID arm”. In August 2021, Hoff et al. reported 11 cases of “COVID arm” out of 6,821 participants administered the Moderna vaccine. The lesions were noted to occur after the initial local and systemic symptoms had resolved and were described as diffuse, poorly demarcated urticarial eruptions presenting 3-12 hours post-vaccine injection. Four out of 11 patients required treatment with oral antihistamines and topical corticosteroids and all patients had complete relief of symptoms within 4 days. The mechanism of these skin reactions following vaccination remains unclear and is hypothesized to be a dermal hypersensitivity reaction. Recommendations for the management of “COVID arm” is to continue with scheduled vaccinations.¹⁸

Erythema Multiforme

While delayed local cutaneous reactions following COVID-19 vaccination were commonly noted, de novo eruptions or new-onset lesions of erythema multiforme (EM) have also been reported at a much lower frequency.¹⁹ Three cases of EM following vaccination with the first dose of Moderna were reported in the retrospective review of a registry including 414 patients by McMachon et al.; however, the specific patient presentations were not discussed.¹¹

Lavery et al. report the first case of EM flare-up following administration of the Pfizer vaccine. The case involves a 58-year-old female with prior history of EM who developed a cutaneous eruption of erythematous, concentric targetoid plaques on her bilateral palms and soles twelve hours after receiving the first dose of the Pfizer vaccine and reoccurred after receiving the second dose. Treatment with topical clobetasol led to improvement in symptoms. The mechanism of reactivation is hypothesized to be via an increase in cytokines and IFN-γ, which targets the epidermal cells, ultimately leading to cell death and detachment at the dermo-epidermal junction.¹⁹

Lopes et al. report another case in which a 75-year-old male presented with edematous targetoid lesions on extremities, trunk, and face 5 days after receiving the second dose of CoronaVac, an inactivated SARS-CoV-2 vaccine.²⁰ Histologic findings revealed lymphohistiocytic infiltrate surrounding the superficial dermal vessels. He was treated with topical corticosteroids and oral antihistamines. While the exact etiology of this EM eruption was not definitive, the CoronaVac vaccine was thought to be the trigger based on the timing and the absence of other identifying events. It is hypothesized that a component of the CoronaVac vaccine may trigger the activation of a Type III or IV hypersensitivity reaction, similar to EM.²¹

The first reported onset of EM following the second dose of Pfizer vaccine was reported by Bonino et al. A 91-year-old female had presented with skin lesions at the injection site six days after second dose vaccination with Pfizer. Large discrete plaques with erythematous borders were identified at the injection site, trunk, and extremities. There was no fever or mucosal involvement. Biopsy demonstrated lymphocytic infiltrate obscuring the dermo-epidermal junction with hydropic changes and dyskeratosis of keratinocytes not confined to the basal layer. The patient was admitted because of the extent of the lesions and was treated with topical corticosteroids. Over a week, the lesions gradually subsided leaving residual hyperpigmentation.²²

A case of nevocentric erythema multiforme was reported in a 27-year-old female 3 days after receiving the Pfizer vaccine. The lesions were erythematous, ring-shaped plaques surrounding many melanocytic nevi. On microscopy, reticular or globular pigment patterns surrounded the plaques. Her skin eruption was completely resolved after two weeks of treatment with 10mg of Cetirizine and skin emollients. There were no residual skin changes to the pre-existing nevi, which suggests a benign and self-limiting course. Scharf et al. described that the mechanism is thought to be similar to that of post-herpetic nevocentric EM.²³

Rowell’s Syndrome

A case of Rowell’s syndrome was identified in a patient after Pfizer vaccination. Rowell’s syndrome is a rare condition involving both rheumatological and EM cutaneous manifestations. Gambichler et al. described a case of an elderly woman presenting with circular erythematous macules and papules one day after receiving the Pfizer vaccine. Skin biopsies revealed an atrophied epidermis and liquefactive degeneration along the dermo-epidermal junction associated with premature abnormal keratinization of basal keratinocytes consistent with EM. Serology showed speckled antinuclear autoantibodies as well as anti-Ro/SSA, and anti-La/SSB antibodies. These findings associated with unspecific direct immunofluorescence and a negative SARS-CoV-2 swab were clinically consistent with a diagnosis of Rowell’s syndrome. Cutaneous symptoms gradually improved after treatment with a systemic prednisolone taper. In this case, polyethylene glycol (PEG) from the vaccine was hypothesized to serve as the antigen activating the T cell-mediated pathway.²⁴

Reactivation of Varicella Zoster Virus

Varicella-zoster virus (VZV), classified as a DNA human herpes virus, is the cause of Varicella and Herpes Zoster and commonly establishes latency in the dorsal root ganglia.²⁵ Several case reports have been published about the reactivation of VZV after COVID-19 vaccination. A systematic review by Triantafyllidis et al. described a total of 91 cases out of 12 eligible studies that reported VZV reactivation on average of 5.8 days following COVID-19 vaccination.²⁶ Moreover, 13% of the total patients were diagnosed with an autoimmune condition and 10% of the total patients were on immune suppressive therapies. While the skin lesions were scattered among various dermatomes, many eruptions described in the studies were anatomically located along the mammary region. Most cases required monotherapy with either Valacyclovir or Acyclovir, while some patients received fusidic acid in addition.²⁷

The eruption of VZV following COVID-19 vaccination may seem unusual, as mRNA vaccines induce and boost the T cell response, while VZV reactivation typically occurs in an immunocompromised state.²⁶ This paradox is explained by the hypothesis that VZV-specific CD8+ T cells become transiently unable to eliminate VZV in the setting of COVID-19 vaccination due to the large increase in naïve CD8+ T cells. Additionally, changes in toll-like receptors among vaccinated individuals potentiate pro-inflammatory cytokines, which may decrease antigen expression in immune cells, thereby contributing to herpes zoster reactivation.²⁶

Psoriasis

Psoriasis is a chronic, inflammatory skin disease mediated by T lymphocytes.^28,29 Onsun et al. reported a case of a 72-year-old male with chronic plaque psoriasis maintained on topical treatments who presented with fever and psoriasiform eruption 4 days after receiving CoronaVac, an inactivated SARS-CoV-2 vaccine. Diffusely erythematous plaques with desquamation and coalescing pustules covered the whole body. Laboratory findings included elevated acute-phase reactants, negative COVID-PCR test, and normal peripheral blood smear. Histopathology was consistent with pustular psoriasis. Based on the temporal association to CoronaVac administration and no recent changes to medications or infections, the vaccination was the deemed to be the cause of the constellation of symptoms. The patient was initially treated with 25mg/d of acitretin which was ineffective. The treatment was switched to 5mg/kg of IV infliximab, which led to the complete resolution of symptoms.²⁹

The first case of a de novo pustular psoriasis involved a 66-year-old woman who experienced a generalized biopsy-consistent pustular psoriasis 3 week after receiving the Covishield vaccine, an adenovirus viral vector vaccine. The patient was treated with topical steroids and acitretin 20mg once daily. While Onsun et al. reported ineffective control with acitretin,²⁹ this patient responded very well. Acitretin is a preferred treatment for psoriatic exacerbations in this setting to minimize the risk of immunosuppression.³⁰

Two additional cases of psoriasis after the Covishield vaccine were reported in India.⁶ The first patient, a 56-year-old woman with a history of psoriasis which was in remission for 6 months, had a flare-up of psoriatic lesions 1 week after receiving her first dose of Covishield and exacerbated lesions after the second dose. The other case described a 65-year-old male who presented with psoriasis plaques covering nearly a third of his body surface areas ten days after receiving the Covishield vaccine. These patients were treated with Apremilast, antihistamines, and topical emollients, leading to improvement of symptoms.⁶

Perna et al. and Pesqué et al. reported cases of psoriasis following vaccination with viral messenger RNA, including Pfizer and Moderna.^31,32 Perna et al. described a middle-aged man with prior history of psoriasis maintained only with moisturizers, who presented with progressive skin eruptions 5 days after receiving the Pfizer vaccine.³¹ On post-vaccination day 8, the rash worsened, and the patient developed malaise. Skin biopsies showed psoriasiform dermatitis with intraepidermal neutrophilic pustules thereby confirming the diagnosis of acute general pustular psoriasis. Due to the patient’s worsening presentation, he was admitted and treated with intravenous fluids, 4 mg/kg/d of cyclosporine, and a single dose of 5mg/kg Infliximab. He had improvement of his symptoms and was discharged home with secukinumab.

Pesqué et al. described the case of a 30-year-old female with chronic plaque psoriasis who experienced a flare up 10 days after receiving the Moderna vaccine.³² The scaly, desquamative plaques arose primarily in the region where the vaccine was injected. The second case was a 72-year-old male with a prior history significant only for multiple myeloma who presented with biopsy-consistent psoriatic plaques on his trunk and extremities six days after receiving the second dose of the Moderna vaccine. Both patients in these cases were treated with topical steroids and topical calcipotriol with complete resolution of their symptoms.^31,32

COVID-19 vaccines are hypothesized to act as a trigger for psoriasis by overstimulating plasmacytoid dendritic cells (pDC) leading to a massive increase in the production of interferon-1 (IFN-1).³³ This is the hallmark pathway for IFN-driven inflammatory diseases, including psoriasis.^29,32,33 The recommendation is that patients with psoriasis and autoimmune conditions should be vaccinated.^29,32

Vitiligo

Vitiligo is an acquired pigment disease characterized by the absence or destruction of melanocytes in the skin.³⁴ Abdullah et al. further described multiple complex pathogenic factors that contribute to epidermal melanocyte loss - the leading hypothesis is that vitiligo is an immune-mediated inflammatory disorder. The mechanistic pathway by which COVID-19 vaccines trigger vitiligo may be described by Awada et al.'s explanation – the activation of pDC and subsequent production of IFN plays a significant role in the pathogenesis of not only psoriasis but also vitiligo.^33,35

There have been two cases of vitiligo reported after mRNA vaccine administration. The first case is a 58-year-old male with history of ulcerative colitis maintained on azathioprine and sulfasalazine who presented with vitiligo on the face one week after administration of the Pfizer vaccine.³⁶ The second case was a 61-year-old woman who presented with clinically evident vitiligo on the anterior neck several days after first dose vaccination with Moderna. There was worsening after the second dose with spread to other parts of her body.³⁷ One patient was treated with tacrolimus who had no response.³⁶ The other patient was treated with an unspecified topical calcineurin inhibitor in addition to phototherapy and the response is unknown.³⁷

Aktas et al. and Kaminetsky et al. discussed the importance of considering risks and benefits when approving treatments or vaccines for patients. While other commonly reported adverse side effects from COVID-19 vaccination are typically self-limited, vitiligo can be a disfiguring skin disorder that can pose significant stress on a patient’s psychosocial well-being.^36,37 However, given the low incidence of this adverse effect, COVID-19 vaccination was still encouraged by the authors.³⁷

Lichen Planus

Piccolo et al. reported a case of a 64-year-old woman with chronic patches of vitiligo on the dorsal aspect of both hands who developed pruritic papules with secondary excoriations on both dorsal hands five days after receiving the Pfizer vaccine. The lesions exacerbated after administration of the second dose. Dermoscopic evaluation showed Wickham striae and histopathology findings confirmed the diagnosis of lichen planus (LP). The patient was undergoing treatment with topical and systemic corticosteroids at the time of publication; therefore, treatment outcomes were not reported.³⁸

Another case involved a 56-year-old female with a history of lichen planus who presented with an eruption of biopsy-consistent lichen planus across several anatomical areas 48 hours after the second dose of the Pfizer vaccine.³⁹ She was treated with high-potency topical corticosteroids. Merhy et al. reported an otherwise healthy 56-year-old female who developed biopsy-consistent lichen planus on the trunk 1 week after receiving the Pfizer vaccine.⁴⁰ The proposed hypothesis of lichen planus eruption following COVID-19 vaccination involves enhanced Th1 response inducing various cytokines.⁴⁰

Bullous Pemphigoid

Tomayko et al. reported the first 12 cases of new-onset bullous pemphigoid (BP) following COVID-19 vaccination. They described a group of patients with no prior history of BP or autoimmunity who developed inflammatory vesicles and bullae on average 7 days after administration of the first or second dose of COVID-19 mRNA vaccine.³ Nine out of 12 patients had received the Pfizer vaccine. The cutaneous bullae were not at the injection site, and skin biopsies demonstrated subepidermal separation with dermal infiltrates of eosinophils. Eight out of the 12 patients were diagnosed with BP based on direct immunofluorescence with or without salt split skin analysis and/ or serum BP180-IgG ELISA. Three of the remaining 4 patients not meeting diagnostic criteria had a negative immunologic test result, and one patient did not have immunologic testing. After treatment with topical corticosteroids, doxycycline, nicotinamide, and systemic corticosteroids, the blistering lesions resolved within an average of 3 weeks in 7 out of the 12 patients. The other 5 patients continued to have bullae at the time the paper was published.³

Additionally, in a case series of bullous eruptions following COVID-19 mRNA vaccination, Damiani et al. reported 3 cases in patients with prior history of BP, who were in remission. The first case described a 63-year-old female who had previously been treated with oral prednisone 6 months prior and developed a flare up on blisters on her trunk three days after receiving the first dose of the Moderna vaccine. The other case was of an 84-year-old male who was in remission of BP for 4 years after treatment with oral prednisone and azathioprine. Two weeks after administration of the Moderna vaccine, he developed cutaneous eruptions of mild blisters on his trunk that did not necessitate systemic corticosteroids. However, after receiving the second dose of the Moderna vaccine 28 days later, the lesions worsened and dispersed more widely throughout including to his oral cavity. The last case described an 82-year-old female with BP in remission for three years after treatment with oral prednisone and mycophenolate mofetil. Three days after receiving the Pfizer vaccine, she experienced a flare-up of blisters on her arms and legs. All patients were treated with oral prednisone and reached a stable resolution of their eruptions. They all were able to receive both doses of mRNA vaccinations without other cutaneous reactions.⁴¹

Pemphigus Vulgaris

In their case series, Damiani et al. also reported two patients with prior history of pemphigus vulgaris (PV) whose conditions exacerbated following mRNA vaccination. The first case was a 40-year-old male who had been in remission for one year after treatment with Rituximab. Three days after the administration of the Moderna vaccine, the patient developed blisters on his back and upper limbs. He was treated with oral prednisone in addition to mycophenolate mofetil, with an improvement in his symptoms. The second case reported an 80-year-old male who also was in remission one year after treatment with oral prednisone and mycophenolate mofetil. Three days after he received the Pfizer vaccine, the patient developed severe blisters on his back. Treatment with oral prednisone was sufficient to control his symptoms. Both reported cases by Damiani et al. were able to receive their booster doses of mRNA vaccination without complications or other side effects.⁴¹

Furthermore, Solimani et al. describe the first case of a 40-year-old female who had newly developed PV after COVID-19 vaccination.⁴² The patient was an otherwise healthy female who presented with painful erosions in the oral mucosa, trunk, and back five days after administration of the first dose of the Pfizer vaccine. She was found to have high titers of autoantibodies against desmoglein 3 and desmoglein 1, and histological and direct immunofluorescence findings were consistent with PV. The patient was treated with oral prednisone and azathioprine, which ceased her blistering and depleted the autoantibody production.

Sneddon-Wilkinson Disease (Subcorneal pustular dermatosis)

Sneddon-Wilkinson Disease, also known as subcorneal pustular dermatosis (SPD), is a type of neutrophilic dermatosis characterized by sterile pustules. There was a single case report of Sneddon Wilkinson after COVID-19 vaccination (McCoy, T. (2021). Sneddon Wilkinson Disease following COVID -19 Vaccination [manuscript submitted for publication]). The case report described a 21-year-old male with no history of SPD who developed pustular eruptions consistent with SPD 8 days following his second dose of the Moderna COVID-19 vaccine. Histology findings from a punch biopsy showed subcorneal pustules and mild spongiosis with perivascular infiltrate, consistent with the clinical presentation of coalesced pustules with some “half-and-half” pustules consistent with a diagnosis of SPD. He was treated with prednisone 50 mg once daily for seven days and triamcinolone acetonide 0.1% ointment two times daily with resolution of his symptoms.

Undifferentiated Bullous Eruption

There was one case of a severe, bullous eruption following vaccination with the Moderna vaccine. A 66-year-old male with no prior dermatological diseases presented with fever, myalgias, and a painful blistering rash onset 24 hours after receiving the second dose of the Moderna vaccine. The patient’s trunk, abdomen and lower extremities were covered by painful violaceous lesions. There was progression of the blisters into large flaccid bullae, although mucous membranes, palms, soles, and joints were spared. Serum antibodies to bullous pemphigoid were within the normal limit. Histopathology of a skin lesion from the anterior thigh revealed extensive necrosis of the epidermis and some infiltrates of lymphocytic inflammation. Based on this histology and the absence of mucosal involvement, the diagnosis was thought to be a bullous drug eruption with features of SJS. The bullae were drained, and the patient was treated with supportive, topical wound care in addition to high dose oral prednisone.⁴³

While the exact pathological link between bullous diseases and COVID-19 vaccination is still unclear, it is hypothesized to be due to the boosted T cell and B cell response that results in eruptions of blistering disease.⁴²

Sweet Syndrome

Sweet syndrome is a neutrophilic dermatosis that usually occurs following a nonspecific infection in either the respiratory or GI tract. This condition is described to be a hypersensitivity reaction, thus commonly triggered by autoimmune diseases, infections, and vaccinations.⁴⁴ Capassoni et al. report a rare case of a 37-year-old otherwise healthy female who developed Sweet syndrome after COVID-19 vaccination. Four days after receiving the Covishield vaccine, the patient developed partially coalescing, vesicular lesions on the face, thighs and feet described as having a center of necrosis surrounded by a halo. In addition to her rash, she experienced arthritis of the metacarpophalangeal joints, pitting edema in the distal extremities, myalgias, and neuropathic foot pain. While pending evaluation of her acute condition, the patient was started on 125mg infusion of methylprednisolone succinate followed by an oral tapering dose of prednisone. On laboratory evaluation, she was noted to have elevated CRP and neutrophils. Histological evaluation found a neutrophilic pustular dermatitis with a necrotizing neutrophilic infiltrate. Additionally, immunohistochemistry was positive for neutrophils and histiocytes-macrophages. Based on these findings and negative immunofluorescence, this case was classified as Sweet syndrome. With systemic corticosteroid treatment, the patient had complete resolution of her dermatological eruptions. However, her myalgias, fatigue, and neuropathic foot pain persisted and an electromyographic study demonstrated inflammation in the tibialis anterior muscle and on repeat serology, the patient was found to have positive ANA with borderline positivity of anti-Pm/scl-75 antibodies. Thus, the patient was further diagnosed with polymyositis due to an autoimmune reaction following COVID-19 vaccination. The recommended treatment was IVIG. Capassoni et al. suggested that in some patients with a predisposition, vaccination may induce an autoimmune response similar to how natural infection with SARS-CoV-2 may initiate an autoimmune reaction.⁴⁵

Darier’s Disease

Darier’s disease is a genetic disease caused by a mutated gene that normally encodes the SERCA2 calcium pump in the endoplasmic reticulum. The dermatological manifestations of this condition include hyperkeratotic papules and plaques in seborrheic or intertriginous regions.⁴⁶ Darier’s disease may be triggered by sun exposure, friction, or recent infection.⁴⁷

Elbæk et al. describe the case of a 47-year-old female with a prior history of Darier’s disease which was previously verified by histology. The patient had been in remission for ten years. Two days after receiving the first dose of the Covishield vaccine, the patient developed systemic flu-like symptoms associated with dyskeratotic papules located mostly on the anterior trunk and lower back. She was treated with topical corticosteroids and salicylic acid. Over the next few weeks, response to treatment was minimal, so oral isotretinoin was added, and this demonstrated clinical improvement. However, the second dose of vaccine was not given because the Danish Medical Agency halted use of the Covishield vaccine. It is unclear why COVID-19 vaccination triggered Darier’s disease.⁴⁷ A potential explanation may be the increase in proinflammatory cytokines after vaccination, including IL-6 and IL-8. These cytokines have previously been involved in the genes that code for the SERCA calcium channels in human keratinocytes.

Research has shown drugs that are effective for Darier’s disease modulate ATP2A2 mRNA expression and IL-6 and IL-8 have an important role in regulating ATPA2 and ATP2C1 expression in homeostasis and inflammation of the skin.²⁰ Normally, UVB suppresses mRNA levels of both ATP2A2 and ATP2C1 in normal human epidermal keratinocytes.²⁰ The addition of anti-IL-6 antibodies to the cell culture inhibited the UVB-induced suppression of mRNA of ATP2A2 and ATP2C1.²⁰ However, suppression of ATP2A2 and ATP2C1 mRNA levels were slightly enhanced while incubated with anti-IL8 antibodies.²⁰ The specific pro-inflammatory cytokines known to increase following COVID-19 vaccination were INF-γ and IL-2.⁴⁷

Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) is a severe cutaneous adverse drug reaction that is very rarely reported post-vaccination. Dash et al. described the only reported case of SJS following COVID-19 vaccination in a 60-year-old man who presented with skin rash, fever and oral ulcerations three days after administration of the first dose of the Covishield vaccine. On initial medical evaluation, the patient was started on paracetamol and levocetirizine; however, his symptoms worsened. Days later, the patient was noted to have multiple purpuric macules all over the body with erythema surrounding the lesions. There were large sheets of necrosed skin over the front and back of the patient’s trunk with some of the areas that had formed bullae. He additionally had mucosal involvement described as oral erosions, hemorrhagic crusting over the lips, and redness with slight discharge from his eyes. On the histological evaluation of his skin lesion, there was orthokeratosis with epidermal atrophy, some intraepidermal infiltration of lymphocytes and neutrophils with moderate spongiosis and scattered degenerated apoptotic keratinocytes with extravasation of the erythrocytes in the dermis. This histopathology in association with the clinical presentation lead to the diagnosis of SJS. However, because the symptoms worsened after treatment with paracetamol, it is not clear whether the onset of SJS was related to the vaccine as the presence of paracetamol may be a confounder.⁴⁸ The patient was treated with 300mg of oral cyclosporine and his symptoms resolved after 7 days. Due to this severe adverse drug reaction and risk of reoccurrence, the second dose of the vaccine was deferred.

Dash et al. described two factors in COVID-19 vaccines that may cause the severe cutaneous eruptions, which are virotypes and excipients. In the case described, SJS was thought to be caused by the virotype since severe delayed-type hypersensitivity to any other components of the vaccine was not identified. Furthermore, virotypes on the surface of keratinocytes lead to a CD8+ T- lymphocyte reaction towards epidermal cells and result in apoptosis of keratinocytes and the detachment of the dermoepidermal junction. This causes SJS in genetically prone individuals.⁸

This pathway further suggests that the Covishield vaccine triggered the immune response leading to keratinocyte damage. While SJS is a severe, life-threatening reaction, this is an exceedingly rare complication. Importantly, the concomitant exposure to paracetamol further adds to the uncertainty, as paracetamol has been a noted cause of SJS in other reports.^48,49 Thus, COVID-19 vaccination is still recommended, as the benefits outweigh this risk.⁵⁰

Vasculitis

Cohen et al. reported a case of a 46-year-old female who developed a leukocytoclastic vasculitis flare after the COVID-19 vaccine.⁵¹ The patient did not have any flares for 2 years until she received the BNT162b2 mRNA COVID-19 vaccine. Two days after receiving the vaccine, she experienced a mild exacerbation of her palpable purpuric papules on both of her lower legs. The vasculitis stabilized and then was exacerbated 2 days after the second dose of the vaccine. The patient’s biopsy-proven vasculitis was successfully treated with a prednisone taper. Although the vaccine caused a flare up of a preexisting leukocytoclastic vasculitis, a case report has shown a new onset case after the vaccine. A healthy 33-year-old man experienced a widespread violaceous eruption that began 3 days after his first dose of the inactivated COVID-19 vaccine. The biopsy confirmed IgA vasculitis without systemic involvement. He was prescribed topical mometasone furoate twice daily with partial resolution.⁵²

Pityriasis rubra pilaris

A 31-year-old man presented with pruritic salmon to erythematous scaly plaques on the upper trunk, upper and lower extremities for about 2 months. Within 10 days of him receiving the first dose of SARS-CoV-2 with the AstraZeneca vaccine, he experienced a skin rash on his abdomen and face that progressed to the dorsum, upper and lower limbs. Histopathology was consistent with pityriasis rubra pilaris. He was treated with isotretinoin 30 mg daily and emollients for 3 months with total remission.⁵³

Conclusion

SARS-CoV-2 is a novel virus whose contagious transmission through respiratory droplets⁴ has caused a global pandemic, COVID-19. While vaccines are a principal instrument in controlling the pandemic, there have been reported cases of adverse dermatological side effects. These side effects are generally hypothesized to stem from vaccine-driven T cell and cytokine activation. It remains unclear which patients are at risk. Further research is needed to elucidate underlying mechanisms, which may well differ depending on the type of vaccine technology administered.

In this article, we have reviewed the adverse side effects following COVID-19 vaccination (Table 2). The most common dermatological side includes a self-limited local injection site, and the rarest and most severe reported side effect was one case of SJS, although concomitant exposure to a medication was also implication. While there is some correlation between the COVID-19 vaccine and inducing or exacerbating dermatological conditions including psoriasis, vitiligo, lichen planus, and bullous skin diseases, overall, the adverse dermatological side effects of the COVID-19 vaccine are mostly self-limiting, or completely resolved with a short course of oral steroids. Most patients were able to receive all scheduled vaccines, despite induced or exacerbated dermatological disease.

It is imperative for dermatologists and all health care providers to be aware of these emerging reactions, especially due to increases in vaccine hesitancy. Patients who are concerned or unaware of vaccine side effects may delay scheduled booster doses, thereby slowing down the efforts to tame the pandemic.⁷ Overall, the benefits of vaccination outweigh the risks; therefore health care workers should continue to encourage vaccine completion and address any concerns regarding adverse side effects. In addition, dermatologic adverse events are rare, treatable, and in general have not been seen as severe enough to prompt avoidance of vaccine or booster regimens.

Declaration of Interest

Najiba Afzal, Adrianne Pan, and Anastasia Shakhbazova declare that they have no conflicts of interest. Raja Sivamani is a scientific advisor for LearnHealth, Arbonne, and Codex Labs and a Consultant/Honoraria for Burt’s Bees, Galderma, Novozymes, Nutrafol, Abbvie, Leo, Incyte, Sanofi, UCB, Sun and Regeneron Pharmaceuticals.

Funding

No funding was received for this study

Ethics Approval

Not required for this review.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material (Data Transparency)

Not applicable.

Author Contributions

Study conception, literature search, analysis, manuscript draft, critical revisions: [Najiba Afzal]; critical revisions: [Adrianne Pan]; Study conception, critical revisions: [Anastasia Shakhbazova]; critical revisions: [Raja Sivamani].

All authors reviewed and approved the final version of the manuscript.