key: cord-1046773-5mtddxpz authors: Sun, Qisi; Fathy, Ramie; McMahon, Devon E.; Freeman, Esther E. title: COVID-19 Vaccines and the Skin: The landscape of cutaneous vaccine reactions worldwide date: 2021-05-31 journal: Dermatol Clin DOI: 10.1016/j.det.2021.05.016 sha: c9697360425a7d3c6c091f31e74e8b245f32a2f4 doc_id: 1046773 cord_uid: 5mtddxpz In 2021, we entered a new phase of the COVID-19 pandemic. As mass vaccinations are underway and more vaccines are approved, it is increasingly important for dermatologists to recognize potential cutaneous adverse events. In this article we review the dermatologic manifestations of COVID-19 vaccines worldwide as reported in clinical trial data and summarize additional observational reports of skin reactions to COVID-19 vaccines. Early-onset local injection reactions were the most common cutaneous side effects observed in clinical trials, while delayed injection reactions were the most common cutaneous side effect reported outside of clinical trials. Understanding the landscape of cutaneous manifestations to COVID-19 vaccines is key to providing appropriate vaccine guidance. While studies varied in their reporting of characteristics, most of the delayed large local reactions were mild and transient with few recurrences after the second dose. All delayed large local reactions reported in the non-trial literature resolved within 11 days. In McMahon et al., only 11 subjects developed reactions after both doses; all were mRNA-1273 vaccine recipients, and reactions after the second dose were frequently smaller in size with an earlier onset at a median of two days. 4 Six of the 12 patients who received the mRNA-1273 vaccine in Blumenthal et al. had recurrent reactions that were of lesser severity than those after the first dose and also appeared at a median of two days. 23 24 The morphology of these delayed large local reactions ranged from erythematous targetoid patches to large plaques. 4, 24 In two studies of mRNA-1273 vaccine recipients, lesion diameters ranged from 5 cm to 19.5 cm, with seven of the 16 lesions labeled as grade 3 plaques (10 cm in diameter). 23, 25 Histology of these skin lesions revealed superficial and deep perivascular lymphocytic infiltrates with rare eosinophils and scattered mast cells, confirming a delayed-type, T-cell-mediated hypersensitivity reaction. 23, 24, 26 To date, no such findings have been reported with other non-mRNA COVID-19 vaccines and the exact etiology is still unknown. However, a delayed hypersensitivity reaction to polyethylene glycol (PEG), an J o u r n a l P r e -p r o o f allergen, may be one explanation since both BNT162b2 and mRNA-1273 vaccines contain this excipient. 25 Treatment has not been necessary; most reactions are mild and resolve spontaneously. While some patients were treated with ice, antihistamines, pain-relievers and glucocorticoids (topical, oral, or both), others received no intervention. 4, 23, 24, 26, 27 However, some patients received unnecessary antibiotics due to concern of cellulitis or other infections, highlighting the need for more providers to recognize that these delayed large local reactions are benign and not a contraindication to the second dose. Morbilliform and maculopapular exanthems have been described in 43 subjects across three observational studies (Table 3) . Of these 43 individuals, 21 (49%) received the BNT162b2 vaccine and 22 (51%) received the mRNA-1273 vaccine (Table 3) . Of these cases, 11 (four associated with mRNA-1273; seven associated with BNT162b2) had been submitted to the Vaccine Adverse Event Reporting System (VAERS) and labeled by the Centers for Disease Control and Prevention (CDC) as part of an anaphylaxis reaction. 28 Among the cases not characterized as anaphylaxis, most rashes occurred within two to three days after injection and resolved within a week. One recipient of the BNT162b2 vaccine developed a pruritic, maculopapular exanthem that persisted for more than a month. This patient, who had no significant past medical history or drug allergy, erupted in an erythematous rash over J o u r n a l P r e -p r o o f 30% of his body, including the face, trunk, upper extremities and thighs but sparing the oral and genital mucosa. 29 Histological examination revealed lymphocytic perivascular infiltrates, consistent with maculopapular toxidermia. 29 Despite a lack of other systemic manifestations, the patient developed concomitant liver injury with slightly elevated aspartate transaminase (AST) and gamma-glutamyl transferase (GGT) enzymes. 29 Given the persistence of this exanthem, the patient was advised to avoid the second dose, and gradually the rash and elevated liver enzymes improved with corticosteroids. 29 Another BNT162b2 vaccine recipient developed a pruritic morbilliform rash across his lower back 48 hours after injection; the rash self-resolved within 24 hours. 30 Upon receiving the second dose, he developed a recurrent and more robust morbilliform eruption involving not only the lower back but also flanks, proximal extremities and upper back. 30 This rash also resolved within 24 hours without intervention. Notably, morbilliform rashes have been reported in several cases of COVID-19 infection in both pediatric and adult populations. 31-34 Histological examination of such cases have revealed spongiosis and mild dermal perivascular lymphocytic infiltrates, suggesting an immune-mediated etiology rather than a direct viral effect. 35 Therefore, while the exact mechanism of COVID-19 vaccine-induced morbilliform rashes is still unknown, it is plausible that these cutaneous manifestations are also the result of an immune activation. Urticaria is defined as wheals (hives) that typically resolves within 24 hours. 36 It can either present as part of immediate hypersensitivity reactions, defined by the CDC as onset J o u r n a l P r e -p r o o f within four hours after injection, or occur as similar reactions four hours after injection. 37 This delineation is important to recognize as the former are potential contraindications to the second dose. There are 55 cases of urticaria among the six observational reports in non-trial literature (Table 3) . Of these 55 individuals, 30 (55%) received the BNT162b2 vaccine and 25 (45%) received the mRNA-1273 vaccine (Table 3) . Of these cases, 11 (one associated with mRNA-1273; 10 associated with BNT162b2) had been submitted to the Vaccine Adverse Event Reporting System (VAERS) and labeled by the Centers for Disease Control and Prevention (CDC) as part of an anaphylaxis reaction. 28 In contrast, in an analysis of 414 COVID-19 dermatology registry cases, none of the 40 urticaria reactions (17 associated with BNT162b2, 23 associated with mRNA-1273) were classified as an immediate hypersensitivity rash. 4 One female patient in Park et al. developed pruritic urticaria on her extremities and face within three minutes after administration of the BNT162b2 vaccine. 38 However, history and test results demonstrated a baseline proclivity to allergic reactions and revealed a previously undiagnosed, underlying cholinergic urticaria. 38 Given that she felt overheated while waiting in line for the dose, the anaphylaxis likely arose from heat-induced rather than vaccine-induced cholinergic urticaria. As such, she received the second dose in a cool, temperature-controlled room without incident. 38 This case illustrates that categorically denying patients a second dose based solely on an anaphylactic reaction may erroneously prevent patients from reaping the benefits of immunization, as not all cases of anaphylaxis are directly vaccine-related. Delayed inflammatory reactions (DIRs) to dermal hyaluronic acid (HA) fillers HA fillers are increasingly resistant to biodegradation, resulting in longevity and more DIRs to these implants. Among the known triggers of DIRs to fillers include viral illness, lowquality products, dental procedures, influenza vaccines and most recently, COVID-19 vaccines. 4, 39, 40 To date, 15 cases have been reported across three observational studies. Of these reports, 11 (73%) are associated with the mRNA-1273 vaccine and four (27%) are associated with the BNT162b2 vaccine (Table 3 ). In many cases, DIRs occurred to fillers that had been injected over a year or two before COVID-19 vaccination. 40 These reactions developed rapidly, often within 24 to 48 hours and presented as swelling and inflammation focused around areas previously treated with fillers. 39, 40 Most cases were recalcitrant to antihistamines, hyaluronidase and acetaminophen. 39, 40 However, a novel mechanism for these reactions has been proposed, generating a potential pathogenesis-based treatment. Previous research revealed high expression of angiotensin converting enzyme (ACE) 2 receptors in adipose tissue, where most fillers are injected. 40 These receptors are targeted by the SARS-CoV-2 spike protein and the resulting interaction in the skin releases a pro-inflammatory cascade, which may explain the DIRs to HA fillers seen in COVID-infection. 41 By blocking the production of angiotensin II and thus reducing the substrate for ACE2, ACE inhibitors (ACE-I) in effect promote an anti-inflammatory response. 39, 40 Indeed, upon initiation with oral lisinopril, all DIRs resolved completely within J o u r n a l P r e -p r o o f 24-72 hours. 39, 40 Despite the success of ACE-Is in treating DIRs, further research on the proposed mechanism of action is warranted. Important factors to consider when treating these reactions with ACE-Is include lab tests to assess for metabolic disturbances, especially if a patient is on medications that could interact with ACE-Is. 39, 40 Given that treatment of DIRs to HA fillers do not require a long course of ACE-Is, a brief discontinuation of concurrent drugs may suffice. Pernio-like lesions have been observed in COVID-19 infected individuals since the beginning of the pandemic. 42, 43 Only recently have they also been associated with COVID-19 vaccines. Of the 10 cases described across three observation studies, six (60%) were associated with the BNT162b2 vaccine, and the rest were associated with the mRNA-1273 vaccine. Pernio-like lesions tend to present as painless, erythematous and violaceous papules and macules on the hands and feet, with some cases exacerbated by cold exposure. 44, 45 Histopathological examinations of these vaccine-associated lesions reveal dense, perivascular lymphocytic infiltrates in the superficial-to-deep dermis, confirming the pernio diagnosis. 44, 45 With topical corticosteroids, these lesions can resolve in a week to one month. 44, 45 J o u r n a l P r e -p r o o f The appearance of pernio lesions not just during COVID-19 infection but also postvaccination suggests that the vaccines and SARS-CoV-2 activate a similar immune pathway. While the mechanism is still unclear, these findings suggest that the pernio lesions seen in COVID-19 infection and post-vaccination may be less directly related to viral effects. Reports of other cutaneous reactions include early-onset local injection site reactions, erythromelalgia, erythema multiforme (EM), lichen planus, varicella zoster and herpes simplex reactivation, pityriasis rosea-like reactions and petechial rash and purpuric rash (Table 3) . Local injection site reactions occurring within three days of vaccination were the second most common skin manifestations observed in the analysis of 414 COVID-19 dermatology registry cases. 4 Of the 202 cases of local injection site reactions, 186 (92%) were attributed to the mRNA-1273 vaccine. 4 These findings were also widely reported in clinical trial data, but less frequently discussed in non-trial literature, likely because this pattern of reactogenicity is commonly observed in other vaccines. 46 Some reactions such as erythromelalgia, erythema multiforme and pityriasis rosea mimic known cutaneous manifestations of COVID-19 infection. Of the 14 reports of erythromelalgia, planus, as well as petechial and purpuric rash, the latter of which has been associated with thrombocytopenia after the mRNA-1273 vaccine. 48 As of April 2021, over 1 billion COVID-19 vaccine doses have been administered worldwide. 49 Although these vaccines are instrumental against the pandemic, important knowledge gaps remain, such as our understanding of the mechanistic relationship between these vaccines and their associated cutaneous side effects. COVID-19) Dashboard Vaccines for COVID-19 The UK has approved a COVID vaccinehere's what scientists now want to know Cutaneous Reactions Reported after Vaccination: A Registry-Based Study of 414 Cases COVID-19 vaccine tracker Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebocontrolled, phase 1/2 clinical trial. The Lancet Infectious Diseases Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. The Lancet Infectious diseases Safety and efficacy of the vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Challenges Faced by Female Healthcare Professionals in the Workforce: A Scoping Review World Health O. Gender equity in the health workforce: Analysis of Your Health Care is in Women's Hands. United States Census Bureau Sex differences in immune responses Sex and Gender Impact Immune Responses to Vaccines Among the Elderly The evolution of greater humoral immunity in females than males Sex and Gender Differences in the Outcomes of Vaccination over the Life Course Delayed Large Local Reactions to mRNA Vaccine against SARS-CoV-2 Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers COVID arm": A reaction to the Moderna vaccine Delayed Large Local Reactions to mRNA Vaccines COVID Arm": very delayed large injection site reactions to mRNA COVID-19 vaccines Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine -United States Cutaneous manifestation of COVID-19 in images: a case report Morbilliform Rash: An Uncommon Herald of SARS-CoV-2 Morbilliform exanthem associated with COVID-19 Cutaneous manifestations in patients with coronavirus disease 2019: clinical and histological findings Vaccine-associated hypersensitivity Centers for Disease C. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States Anaphylaxis After the Covid-19 Vaccine in a Patient With Cholinergic Urticaria COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a Pernio-like skin lesions associated with COVID-19: A case series of 318 patients from 8 countries Emerging Evidence of the Direct Association Between COVID-19 and Chilblains Pernio after COVID-19 Vaccination New-onset chilblains in close temporal association to mRNA-1273 The how's and what's of vaccine reactogenicity Pityriasis rosea, COVID-19 and vaccination: new keys to understand an old acquaintance Purpuric Rash and Thrombocytopenia After the mRNA-1273 (Moderna) COVID-19 Vaccine Coronavirus (COVID-19) Vaccinations. Online: Our World in Data