by Dr. Shahrzad Alimohammadi and Edited by Dr. Christopher M. Cirino

The Coronavirus (COVID-19) pandemic erupted in early December 2019 and spread worldwide in the ensuing months. SARS-CoV-2 causes mild to severe respiratory infections and gastrointestinal, neurological, and dermatological complications (Li et al. 2020; Singh et al. 2021). Skin manifestations in COVID may appear in different ages and stages (Singh et al. 2021; Xue et al. 2021). This article will outline key skin findings of the disease process.

Introduction: COVID Pandemic: A New Disease

SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus within the Betacoronavirus group. Unlike other outbreaks, never before have we faced a spillover virus with the extent of global spread as SARS-CoV-2. Through the pandemic, physicians have witnessed disease presentations unique to this virus. Here is a YHF link to what occurred when the disease jumped species to human beings.

Disease manifestations include fever, cough, shortness of breath, sputum production, headache, runny nose, sore throat, in addition to some novel cutaneous manifestations (Singh et al. 2021). 

The virus interacts with human cells via an essential cell surface receptor known as the angiotensin-converting enzyme 2 (ACE2). The fusion enables it to invade and infect cells. Disease manifestations follow tissue inflammation and damage of cells carrying this receptor.  

SARS-CoV-2 begins with an infection in the respiratory tract first. It then infects several other body organs such as the small intestine, kidneys, testis, thyroid gland, heart, and adipocytes, which highly express ACE2. In contrast to mentioned organs, the blood and vascular system, bone marrow, spleen, and brain express the lowest ACE2 while lungs, the liver, colon, adrenal glands, and bladder express medium levels of ACE2 (Li et al. 2020). Research suggests that a significant cell type in the skin, the keratinocytes, express higher levels of ACE2 receptors. 

The infection presents with myriad skin manifestations. The awareness of skin features may even allow a physician to come up with a diagnosis. The overlap of the COVID-19 with the skin brings to light the ways in which the body manifests systemic disease (Xue et al., 2021).

Cutaneous COVID-19 Manifestations

Skin manifestations in COVID-19 infection are broad. Although their relevance is ever-increasing, the incidence, characterization, and pathogenesis are not yet fully known. The main findings fall into seven major categories: maculopapular, urticarial (hives), chilblain, vesicular, purpura, or petechiae, along with livedoid (Klejtman 2020). Additionally, the multisystem inflammatory syndrome in children (MIS-C) from COVID may have skin manifestations (Ely and Seabury Stone 2010; Singh et al. 2021). If you are not familiar with these terms, we will explore each of them in greater detail, including photos.

Major COVID-19 skin 

1. Maculopapular (measle-like or morbilliform)
2. Urticarial (hives)
3. Chilblain
4. Vesicular (small, fluid-filled blisters)
5. Purpura (dark, large, purple findings)
6. Petechia (small, purplish-red lesions)
7. Livedo (mottled, purplish, net-like findings)

Maculopapular (MP) Lesions:

These lesions are the most common skin manifestation in COVID-19 patients. They usually occur from viral infections or reactions to medications (Ely and Seabury Stone 2010; Singh et al. 2021). The prevalence varies from 5 to 70% of cases. They primarily occur in middle- or advanced-age; some younger adults can also develop maculopapular lesions. MP lesions typically start on the trunk but can spread to the extremities. (Galván Casas et al. 2020; de Masson et al. 2020; Rubio-Muniz et al. 2020).

A deeper look:

Urticarial Lesions

Urticarial rashes also occur in COVID-19 cases. The rash can range from scattered hives to more severe reactions, such as angioedema (swelling of the tongue and lips.) Urticaria is a slightly raised rash or wheal, followed by intense itchiness (Diotallevi et al., 2020). The prevalence varies from 7 to 40% and ranges in age, mainly affecting the middle-aged (Galván Casas et al. 2020; de Masson et al. 2020; Rubio-Muniz et al. 2020). 

Urticarial lesions show up on the trunk and limbs. They can either be localized, e.g., the face, or generalized (Askin et al. 2020; Dalal et al. 2020; Galván Casas et al. 2020; de Masson et al. 2020). Histopathological features report the possible presence of perivascular infiltrates of lymphocytes along with few eosinophils as well as upper dermal edema (Fernandez-Nieto et al. 2020b)

Typically urticarial lesions resolve after the offending trigger (Singh et al. 2021). Viral, bacterial, and antiparasitic infections, in addition to immunoglobulin-E-mediated allergic reactions after specific food, medication, or insect bites, may trigger these manifestations (Radonjic-Hoesli et al., 2018). Urticaria can be self-limiting, usually not lasting more than four to six weeks. On the other hand, in about 5% of the population, it can be recurrent and persist for more than six weeks (Radonjic-Hoesli et al., 2018). Steroids and antihistamines can help in severe cases (Singh et al., 2021).

Similar to the maculopapular lesions, urticarial lesions occur in the background of anti-COVID-19 therapies. Therapies include chloroquine, lopinavir/ritonavir, nitazoxanide, corticosteroids, baricitinib, checkpoint inhibitors, and several others. There conceivably could erupt from an overactive immune system and cytokine storm (Singh et al. 2021). 

Chilblain-like Lesions

Chilblain lesions, or pernio, are inflammatory skin lesions that have distinguishing features. The skin shows purple or red lesions similar to those in systemic lupus erythematosus (SLE), an autoimmune disorder, or some patients with Raynaud’s syndrome (Singh et al., 2021). They present mainly as erythematous-violaceous papules, macules, or even nodules, typically found on the feet and hands on the toes and fingers, respectively, i.e., an acral distribution (Singh et al. 2021).

The findings of pernio, acral-like, or chilblain-like lesions in a patient with COVID-19 became known as “COVID Toes.” The incidence of chilblains lesions is around 63% (of 505 cases), while other studies reported an incidence of 14.3% to 72%, mainly in younger adults and adolescents. 

Researchers believe that chilblains occur after vasoconstriction, vasospasm, and inflammation. Low tissue oxygen may be part of the disease. Treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), vasodilators, and topical corticosteroids (Cappel and Wetter 2014; Singh et al. 2021).

Vesicular Lesions

Vesicles are clear, fluid-filled sacs below the epidermis, less than 1 cm. They may develop in clusters. Multiple factors, such as medications, heat, disorders such as contact dermatitis (AD), autoimmune diseases, and viral infections, can lead to these lesions. Among viral infections, herpes simplex virus, varicella-zoster, echovirus, and Coxsackievirus might display this manifestation (Drago et al., 2017).

The presence of vesicles in COVID-19 is not as common as other skin manifestations, with a prevalence ranging from 3.77% to 15%. They typically are found on the trunk (Singh et al., 2021).

A Deeper Look:

Petechiae and Purpura

Petechiae are less than 2 mm in diameter and have red-purple spots. If they exceed 2 mm, they are classified as purpura. Such subdermal hemorrhages may be associated with several disorders such as thrombocytopenia, platelet dysfunction, vascular integrity loss, or coagulation defects. Rashes such as these occur with viral infections. Other examples include enterovirus, dengue virus, or parvovirus B19 (Caputo et al. 2020; McGrath and Barrett 2021).

Purpuric manifestations are less frequent in COVID-19 patients and have been reported in around 3% of the cases and commonly in middle-aged patients recovering from COVID-19. These lesions mainly appear on limbs along with distal extremities (de Masson et al. 2020).

Petichiae and Purpura Pathology

An example of purpura is retiform, or net-like. The histopathological features are characterized by significant interstitial and perivascular neutrophilia with prominent leukocytoclasia. Petechiae are a pauci-inflammatory thrombogenic vasculopathy. However, these lesions might also appear from medications tried on patients with COVID-19, such as camostat mesylate (Magro et al. 2020).

Livedoid Eruption Lesions:

Livedo Reticularis (LR) is a transient or persistent cutaneous manifestation exclusively with a reddish-bluish to purplish reticular (net or lace-like) pattern and mottled discolorations. Benign symptoms such as cutis marmorata (physiological) or other idiopathic conditions fall into “benign LR.” Livedo racemosa (LRC) applies to lesions with more significant pathology. LRCs are considered permanent with a higher widespread display on the body with irregular shapes when compared to LRs (Sajjan et al., 2015).

LR prevalence is rare compared to the rest of the skin manifestations reported in COVID-19. Similar to other cutaneous lesions, LRs are commonly present on the trunk, dorsal hands and foot, and flexor surface of forearms (Bouaziz et al. 2020; Caselli et al. 2020; Galván Casas et al. 2020).

LR etiology correlates to the hypercoagulability in COVID-19 infection cases. The lesions result from a disturbance in skin blood supply and poor tissue oxygenation. As studies reveal, severe COVID-19 patients had higher D-Dimer and fibrin degradation levels as well as prothrombin time, suggesting coagulation abnormalities. Disseminated Intravascular Coagulopathy (DIC) or large vessel clots may be responsible for severe cases. However, in less severe cases, the formation of microthrombi due to inflammatory cytokines or ACE2 entry into cells may be associated with LR presence (Manalo et al. 2020; Tang et al. 2020).

Multisystem Inflammatory Syndrome in Children (MIS-C):

There were several children with the multisystem inflammatory syndrome (MIS-C) with Kawasaki disease features and positive SARS-CoV-2 antibodies. As of September 2021, the US Health Department reports that 4,661 children have had MIS-C.  

There are some overlapping features of Kawasaki disease and toxic shock syndrome in children suffering from COVID-19. However, some differences exist between adolescents and older children, including heart conditions and abdominal symptoms (Ebina-Shibuya et al., 2020).

Discussion

The COVID-19 pandemic represents the emergence of the SARS-2 Coronavirus as a cause of infection in humans. The disease continues to spread globally and impact health systems all around the world. Although there are many previous and forthcoming studies on skin disease in COVID-19, many questions remain regarding the pathogenesis and treatment of these conditions. In addition to cardiovascular and respiratory complications, COVID-19 infection can also manifest with several types of cutaneous lesions, some of which may facilitate its diagnosis. 

References:

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