Heli Patel, BS1; Linh Tran, BS2; Steven R. Feldman, MD, PhD1,3
1Center for Dermatology Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
2University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
3Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
COVID-19 is an infectious disease caused by SARS-CoV-2 that is characterized by respiratory symptoms, fever, and chills.1 While these systemic symptoms are widely known and well understood, there have also been reports of dermatological manifestations in patients with COVID-19. These manifestations include chilblain-like lesions, maculopapular lesions, urticarial lesions, necrosis, and other varicella-like exanthems.2 The pathogenesis of these lesions are not well understood, but the procoagulant and pro-inflammatory state induced by COVID-19 infections may be contributing to varied cutaneous manifestations.3 Drug interactions and concurrent hypersensitivity reactions have also been postulated.4 This review aims to compile and analyze various retrospective studies and case reports to summarize the clinical presentation of dermatological lesions associated with COVID-19 infections and suggest further areas of research.

Keywords: COVID-19, cutaneous manifestations, hypersensitivity, dermatology

Introduction

Coronavirus disease 2019 (COVID-19) has had a huge impact on global health, with well over 700 million cases reported worldwide (World Health Organization, February 2024). It is believed to originate from bats and the transmission modality is through contact and respiratory droplets.5 Once the virus enters the body, the capsid protein binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells and enters the cell through a process called endocytosis.5 After cellular entry, the virus releases its content and utilizes host machinery to replicate and produce new viral particles to be released.6 This process triggers a cytokine storm, involving interleukin (IL)-8, IL-10, IL-12, tumor necrosis factor-α, and interferon-β,6 as well as induces a pro-inflammatory and procoagulant state that has been linked to the development of skin lesions and eruptions.3 In a microscopic and immunohistologic study, Margo et al. demonstrated that purpuric skin lesions in COVID-19 patients exhibited deposition of complement proteins (C5b-9 and C4d) and inflammatory thrombogenic vasculopathic changes.3 In some cases, the presence of spike proteins was detected in the microcirculation of the skin.3 Additionally, skin manifestations may be secondary in nature, possibly due to side effects of medications or other concurrent infections.4 Another cause of skin symptoms is the pro-inflammatory state induced by COVID-19 promoting drug hypersensitivity that results in cutaneous eruptions.7 Through analyzing the literature, we provide a categorization for the different dermatological manifestations associated with COVID-19 infections: chilblain-like lesions, maculopapular lesions, vesicular eruptions, urticarial lesions, and necrosis/livedo. Histological features and clinical patterns of the lesions are also described.

Classifications

Chilblain-like Lesions

Chilblain lesions are characterized by inflammatory and swollen patches and blisters on the extremities, such as the hands and feet.8 Classically, they occur after cold exposure causing the arteries and veins to constrict.8,9 Formation of vesicles or pustules can be accompanied by edema.10 These lesions are more commonly found in young children and are correlated with lower disease severity.4,8,10 Chilblain-like eruptions seem to be the most common manifestations reported in patients with COVID-19 exposure or infection, often appearing after the presentation of other COVID-19 symptoms.9 In a nationwide prospective study in Spain analyzing 375 patient cases, 19% of the cases were associated with chilblainlike lesions in the acral areas.10 A retrospective study in France also indicated that acral chilblain-like lesions were the most common and histological examination of some of these lesions showed microthrombi.11 Histological features of chilblain lesions include perivascular lymphocytic infiltrate, microhemorrhages, necrotic keratinocytes, and lymphocytic vasculitis.8,12 In some pediatric patients, viral particles were detected in the epithelium of eccrine glands.12

Maculopapular Lesions

Maculopapular lesions are characterized by both discolored patchy rashes (macules) as well as raised lesions (papules) that span larger areas of the skin.13,14 These can occur in any part of the body, but are predominantly found on the back, abdomen, chest, and extremities.10 Rashes can vary extensively in terms of distribution, appearance, scaling, and degree of itching.14,15 Alba et al., in an analysis of 176 maculopapular cases, presented 6 further subcategorization of maculopapular lesions associated with COVID-19 infections: 1) morbilliform, 2) purpuric, 3) erythema multiforme-like eruptions, 4) pityriasis rosea-like, 5) perifollicular, and 6) erythema-elevatum diutinum.15 Morbilliform is the most common of the maculopapular lesions and is characterized by erythematous macules interspersed between areas of normal skin.15 In a histopathological examination of these lesions, researchers demonstrated the presence of perivascular dermatitis, dense lymphocyte infiltration, and, in some cases, thrombosis in vessels.16,17 Interestingly, these features are consistent with the lymphocytic vasculitis seen in immune complex and cytokine activation, which occurs in COVID-19 infections.4,16 It is also important to note that drugs can induce maculopapular rashes, so it may not be the best indicator for diagnostic purposes.4,18 Casas et al. noted that patients with maculopapular and urticarial lesions were more commonly taking drugs at the same time.10 Some of these drugs include hydroxychloroquine, azithromycin, remdesivir, and corticosteroids.4,17

Vesicular Lesions (Varicella-like Exanthem)

Vesicular lesions, also known as varicella-like exanthem, are characterized by small red vesicles that appear on the trunk and extremities.10,13 They tend to appear after respiratory COVID-19 symptoms and last a mean total of 10 days.19 A nationwide study in Spain demonstrated that vesicular lesions are more commonly seen with middle aged patients and are associated with mild severity of disease.10 Among 277 COVID-19 patients in a study, 15% developed a vesicular rash.11 Vesicular eruptions are often induced by viral infections, specifically varicella zoster virus and herpes simplex virus, but it is not known whether SARS-CoV-2 follows the same pattern due to limited studies.20 Interestingly, a prospective study demonstrated two main patterns of distribution and appearance of vesicular lesions: 1) smaller monomorphic localized lesions that were 3-4 mm and 2) diffuse larger polymorphic lesions that can be up to 7-8 mm.19 Histologically, these lesions show swollen keratinocytes, some of which exhibited necrosis and acantholysis, surrounded by fibrosis and inflammation.19 Disrupted organization of the epidermis was also a key characteristic.2 In the prospective study by Nieto et al., the majority of patients were not on medications, which suggests that these vesicular eruptions are less likely to be induced by drugs,19 This contrasts with urticarial or maculopapular eruptions, in which the pathogenesis may have a drug-related component.

Urticarial Lesions

Urticarial lesions (hives) are characterized by wheals.21 In retrospective studies from France and Spain, urticarial eruptions were seen in 9% and 19% of patients with COVID-19 infections, respectively.10,11 Most of the eruptions occurred on the face, trunks, and limbs.10,22 These lesions are often short-lasting, compared to other skin manifestations such as chilblains, maculopapular rashes, or necrotic lesions.10 Although, frequently appearing concurrently with other symptoms of COVID-19, hives can precede these other signs.10,22 Like maculopapular rashes, urticarial lesions are often drug induced, which can make it difficult to determine whether the reaction is due to the viral infection or due to the drug effect.21 Treatment with antihistamines is effective for urticarial lesions.21,22

Necrosis/Livedo

Necrotic and livedo lesions are much less common, but their presentation can signal a more severe disease course in COVID-19 patients.10 In a study of 375 patients, 7% exhibited necrotic lesions with a 10% mortality rate.10 The lesions are generally dark and can either be diffuse or localized.10 Livedo patterns are characterized by reticular reddish-blue, lace like lesions due to poor and constricted blood flow.13 Many studies categorize livedo and necrotic lesions in the same category along with other vasculitis manifestations due to similarities in the occlusive vascular pathology.10 Histopathology shows pauci-inflammatory thrombogenic vasculopathy, necrotic keratinocytes, and infiltration of lymphocytes.13,23 Other severe necrotic manifestations include skin bullae and dry gangrene, which was reported in 7 patients in 2020.24 These lesions are important to recognize due to their strong association with more aggressive and severe COVID-19 disease.10

Conclusion

There has been an increasing number of case reports illustrating the prevalence of dermatological manifestations in COVID-19 patients that are concurrent with respiratory and other systemic symptoms of COVID-19. These manifestations can be categorized into 5 broad types: chilblain-like lesions, maculopapular papular lesions, vesicular eruptions, urticarial lesions, and necrosis. Chilblain, maculopapular, and urticarial lesions are associated with milder disease, whereas necrotic lesions are seen in more severe disease courses. These lesions also have a strong association with age, in which chilblain lesions appear more commonly in younger patients and increased prevalence of necrosis/livedo in older patients.4,8,10 Viral infections (such as herpes simplex and varicella-zoster) can lead to skin symptoms, but it is still unclear whether the lesions seen in COVID-19 patients are directly the result of viral infection, concurrent illnesses, drug interactions, or other secondary causes.20 The pro-inflammatory and procoagulant state in COVID-19 infections may be implicated in the development of the skin eruptions, but this remains a topic for further investigation.

References



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