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Cutaneous Manifestations in Adult Patients with COVID-19 and Dermatologic Conditions Related to the COVID-19 Pandemic in Health Care Workers

Purpose of Review COVID-19 (coronavirus viral disease 2019), due to the novel SARS-CoV-2, may present with different types of cutaneous manifestations of varying pathophysiology. During the ongoing pandemic, publications reporting dermatologic findings in COVID-19 continue to emerge. Recent Findings Cutaneous vasculopathy and microthrombus-related changes including acral and sacral lesions, retiform purpura, livedo reticularis, and cutaneous vasculitis are notable findings in adult patients. Other exanthems include urticaria or angioedema, morbilliform/maculopapular exanthems, erythema multiforme, and vesicular eruptions. Increased recognition of these findings, especially those consistent with cutaneous microthrombi or vasculitis, is of particular importance. Additionally, occupational dermatologic disease related to extended personal protective equipment (PPE) use, such as skin damage and irritant or allergic contact dermatitis (ACD), represents another emerging problem amidst the pandemic. Summary In this review, we highlight the various cutaneous manifestations associated with COVID-19 in adult patients and occupational dermatitis in health care workers (HCWs) caring for this patient population.

SARS-CoV-2 can purportedly induce cutaneous manifestations via direct viral binding or secondarily through various allergic-immunologic mediated mechanisms [7]. Binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor facilitates viral entry into epithelial cells, primarily in the upper respiratory mucosa. The ACE2 receptor is also expressed in the cutaneous/subcutaneous and vascular tissues and thus may contribute to dermatologic findings in SARS-CoV-2 infection [8]. COVID-19 dermatologic manifestations can be classified into (1) viral exanthems as an immune response to viral nucleotides or (2) systemic immunologic consequences of SARS-CoV-2 such as vasculopathy or micro-thrombotic skin lesions [9]. Viral exanthems encompass urticaria/angioedema, maculopapular or morbilliform rashes, vesicular eruptions, and erythema multiforme. Vasculitic-type lesions include chilblain-like acral lesions, sacral ulcerations, purpuric lesions, and vasculitis, ischemic, or necrotic lesions. Evidence suggests that cytokine release, coagulation pathway derangement, and complement-mediated microvascular injury play a role in the pathology of this latter group [10,11]. Medication-induced hypersensitivity exanthems and petechiae in the setting of acquired thrombocytopenia represent other cutaneous findings. Table 1 summarizes the classification of dermatologic manifestations observed in adults with COVID-19.
New literature on COVID-19 cutaneous manifestations is continuously available. It is likely that dermatologic findings are either under-recognized or under-reported, especially in subclinical disease. The American Academy of Dermatology (AAD) COVID-19 Registry was created in an effort to gather information on COVID-19 cases and better define accompanying cutaneous lesions [12]. Preliminary results on 171 confirmed cases have been published and with increasing data the medical community can expect a greater understanding on the incidence and course of exanthems associated with SARS-CoV-2 infection [13]. In this review, we summarize reports and reviews on the varied cutaneous manifestations observed in adult patients with COVID-19 as well as the dermatologic conditions in HCWs pertaining to extended PPE use and scrupulous hand hygiene practices during the pandemic. Interspersed throughout this manuscript, we briefly describe cases from our own institutional experience. Table 2 summarizes select publications of cutaneous manifestations that had accompanying histologic examination, notated throughout the text.
At our institution, we observed two cases of histaminergicangioedema in the setting of confirmed SARS-CoV-2 infection. Both middle-aged adult patients had mild-to-moderate COVID-19 respiratory disease: one presented with profound lip and eyelid angioedema while the other experienced an episode of generalized facial angioedema with flushing and pruritus. There was a concern for azithromycin-related reaction in the latter which was subsequently disproven. These cutaneous-limited reactions rapidly responded to antihistamine treatment.
Urticaria or angioedema in the setting of viral infection may be attributed to direct mast cell degranulation. Increased levels of cytokine IL-6 stimulate mast cells, resulting in activation and subsequent degranulation, leading to urticaria and/ or angioedema [7,49]. Another proposed mechanism includes the deposition of antigen-antibody complexes with complement activation and subsequent mast cell degranulation [49]. Immediate hypersensitivity due to medication must be considered in the differential diagnosis of acute urticaria/angioedema, especially if a temporal association between drug administration and urticaria/angioedema onset is apparent [41]. Non-sedating anti-histamines represent the preferred treatment for isolated acute urticaria/angioedema not part of a systemic anaphylactic reaction.

Maculopapular Exanthems
Maculopapular or morbilliform appearing exanthems can emerge during viral infections (i.e., EBV, HHV-6, HIV-1) in the presence or absence of medications, secondary to an immunologic response to viral antigens, and are mostly benign with a self-limited course. Maculopapular exanthems are characterized by erythematous, blanching scattered to confluent lesions that can be distributed throughout the body, with prominence for the chest, back, abdomen, and extremities. Maculopapular exanthem seems to be the most common cutaneous manifestation associated with COVID-19, occurring in 22-47% of cases [3,4,13]. Reports associated with SARS-CoV-2 infection have varied clinical descriptions such as development at disease onset or as a later manifestation with negative repeat SARS-CoV-2 RT-PCR, suggesting a potential drug-induced etiology [2,3,5,[14][15][16][50][51][52][53][54][55]. These exanthems may be pruritic or non-pruritic. Reymundo and colleagues reported on 7 adult patients without recent medication use who primarily developed truncal exanthems later on in the course of SARS-CoV-2 infection [16]. Histologic findings are varied ( Table 2). Galván Casas et al. noted that maculopapular exanthems were associated with more severe COVID-19 disease and a 2% mortality rate [3••]. Topical corticosteroids and liberal moisturization for skincare represent mainstays of treatment. Severe erythroderma or extensive body surface area involvement may require systemic steroid therapy.

Erythema Multiforme
Erythema multiforme is characterized by macules, papules, and classic target lesions with a predominance to occur on the distal extremities. Mucosal involvement and systemic symptoms such as fever and arthralgias may be accompanying features. Associated with viral infections in the majority of cases, erythema multiforme has been observed in the setting of COVID-19 disease [17,57].  (Table 2). A report of erythema multiforme major with mucosal involvement also exists [58]. Furthermore, there is an overlap of erythema multiforme-like lesions with non-evanescent urticarial eruptions and atypical palmar plaques [18,59].

Vesicular Eruptions
Vesicular rashes usually manifest as small, fluid-filled lesions on an erythematous base. In the cohort analyzed by Galván Casas and colleagues, vesicular eruptions with distinct monomorphic lesions primarily on the trunk or limbs were observed in 9% of cases [ [3,61]. It is unclear whether or not these lesions are due to Herpesviridae viral reactivation.

Pityriasis Rosea
Largely considered self-limited, pityriasis rosea manifests during human herpes virus reactivation. One report describes an erythematous and scaly annual plaque on the forearm starting 3 days after the onset of COVID-19 pneumonia, followed by generalized, pruritic papular and plaque-like lesions in a classic pityriasis rosea trailing collaret pattern [62]. A digitate papulosquamous, pityriasis rosea variant eruption was described in an elderly patient in another report [21]. It has been suggested that a robust immunologic-inflammatory response to SARS-CoV-2 can cause endogenous viral reactivation leading to pityriasis rosea [63].

Cutaneous Lesions Due to Vasculopathy or Micro-Thrombi
Based on autopsy findings, SARS-CoV-2 infection causes both macrovascular and microvascular thrombi in organ system vasculature including the cardio-pulmonary, renal, central nervous, and integumentary systems [64][65][66]. One proposed mechanism involves a cytokine storm reaction in which macrophage-induced inflammation leads to a pro-thrombotic state [67]. Purpuric or vasculitic skin manifestations due to SARS-CoV-2 infection include a spectrum of chilblains-like acral lesions, sacral "ulcers," cutaneous small vessel vasculitis (CSSV), retiform purpura, livedo eruptions, and cutaneous ischemia/necrosis. The pathophysiology of these lesions is likely varied or multi-factorial including cutaneous microthrombi, vascular injury due to viral ACE2 receptor binding, or disseminated intravascular coagulation (DIC).
Chilblain-like lesions occur in adult patients with COVID-19 disease in 19-40% of cases [3,4,23]. Acral lesions present as asymmetric, self-limited, painful, erythematous to violaceous papules or plaques in an acral distribution with predominance for the feet [22,27,71]. Some may have associated bullous eruption or digital swelling [22,25]. A description of 74 cases of acral lesions among pediatric and adult patients reported variable findings from erythematous to purpuric macules or papules [24•]. It is important to note that many patients were not subject to cold exposure nor had underlying disorders associated with pernio. Overall, pernio lesions are usually found in patients with less severe COVID-19 disease. The preliminary results published by the AAD found that 16% of patients with pernio lesions were hospitalized [13]. Chilblains may affect younger adults and tend to present later in the disease course, lasting for an approximate mean of 13 days [3••]. Mid to high potency topical corticosteroids can be considered in the management of acral lesions, particularly if they are pruritic or painful. Overall, acral lesions tend to resolve over the course of several weeks [25]. Although chilblain-like lesions during the COVID-19 pandemic are reportedly common, SARS-CoV-2 infection was not detected or not tested for in some cases [23][24][25]70]. Some patients had cough and fever prior to the onset of acral lesions, whereas many had no COVID-19 symptoms and some had negative nasopharyngeal and rectal SARS-CoV-2 RT-PCR swabs; the authors suggested that patients had brief, asymptomatic COVID-19 infection prior to the onset of skin lesions [22]. Chilblain-like acral eruptions with asymptomatic or mild COVID-19 disease was also reported in a series of adolescents/young adults [72]. In a retrospective observational French study of patients with skin lesions encountered during an approximate 3-week pandemic period, acral lesions were observed in 51% (n = 142/277) of pediatric and adult patients, some of which had positive SARS-CoV-2 RT-PCR testing [23•]. Of all the cutaneous manifestations associated with COVID-19 disease, acral lesions may represent a comparatively more specific finding that could aid in the diagnosis of asymptomatic cases [3••].
The pathogenesis of acral chilblain-like lesions remains unclear. Several proposed mechanisms include cutaneous microthrombi, acquired coagulopathy, or CD8+ T lymphocyte endothelial cell cytotoxicity [23,25]. Of note, SARS-CoV-2 viral particles were detected via electron microscopy in endothelial cells of lesional skin biopsies in pediatric patients, suggesting that chilblains are the result of vascular damage [73•]. An exaggerated innate immune response involving interferon cytokine signaling may be part of the pathogenesis [74•]. Histopathologic findings are noted in Table 2.

Sacral Ulcers
Sacral "ulcers" represent a peculiar finding in COVID-19 that require heightened awareness among medical providers, as they are distinct from sacral decubitus ulcers. Risk factors for the development of sacral decubitus ulcer include immobility and prolonged bed rest, incontinence, poor nutrition, diabetes, and vascular disease. Similar to other institutions, we have noted cases of sacral lesions and ulcerations in patients with critically ill, multi-organ system COVID-19 disease [26,35]. Sacral ulcerations may present with purpuric lesions, violaceous induration, livedoid plaques, and eschars ( Table 2). The pathogenesis is hypothesized to be multifactorial including a combination of systemic coagulopathy, cutaneous ischemia, and pressure-induced deep tissue injury. Figure 1 depicts a slow healing, sacral "ulcer" in a middleaged adult patient with a prolonged and complicated course of COVID-19 pneumonia including intubation for respiratory failure. Wound care consultation is warranted in these cases as some sacral ulcerative lesions require local debridement and removal of devitalized tissue. Specialized care must be taken to ensure that patients do not develop subsequent bacterial infection leading to sepsis.

Cutaneous Small Vessel Vasculitis
Cutaneous small vessel vasculitis (CSVV) is mostly mediated by immune complex deposition in the small vessels and subsequent complement-mediated inflammation and tissue destruction. CSVV is generally attributed to infection or medications, presenting as palpable purpura and/or non-blanching petechiae without extra-cutaneous organ involvement. Associated observations include urticaria, ulcerations, or hemorrhagic bullae. Several cases of CSVV associated with acute SARS-CoV-2 infection exist; findings include purpuric lesions or erythematous urticaria-like papules with central purpura or hyperpigmentation localized to the lower extremities or in a cranial-caudal distribution [28,29,35,67,75]. Vasculitic lesions may be painful and tend to appear during the latter part of active disease. Histopathological findings are listed in Table 2.
Medication-induced or hypersensitivity vasculitis is part of the differential diagnosis of CSVV. In one case, a 57-year-old woman developed a pruritic, erythematous maculopapular exanthem which progressed to painful, non-blanchable, purpuric plaques on the trunk and extremities [76]. She had received amoxicillin, ibuprofen, and metamizole; these medications were discontinued and the patient was successfully treated with topical and systemic steroids. Similarly, an adult man with COVID-19 developed a cranial-caudal, pruritic, erythematous urticarial eruption with central hyperpigmentation. Based on biopsy results and clinical features, the authors suggested a possible medication-induced urticarial vasculitis [30].

Livedo Reticularis and Racemosa
Livedo reticularis or racemosa is defined by a mottled, lace-or net-like vascular pattern of erythematous to violaceous discoloration associated with ischemia of the cutaneous capillaries. Compared with other cutaneous findings in COVID-19, livedo reticularis seems less common (2.3%) but associated with more severe disease and possibly greater mortality [3,4,77]. Livedo eruptions are described in multiple case reports potentially due to inflammation caused by SARS-CoV-2 binding to vascular endothelium (Table 2) [31,33,77,78]. Patients may be at risk for massive systemic thromboembolic events and multi-organ involvement [34,77].

Ischemic and Necrotic Lesions
Ischemic lesions and necrosis of the fingers and toes are reported in critically ill patients with COVID-19 [79]. Laboratory markers indicating disseminated intravascular coagulation (DIC) were observed in 4 of 7 patients with acral dry gangrene; the mortality rate was 71%. Other reports describe fatal cases of COVID-19 in patients who had a necrotic ulcer on the sole and dry gangrene of the digits, toes, and nose with clinical DIC [80,81].

Other Cutaneous Findings in Adults with COVID-19
Petechiae and Purpura Associated with Thrombocytopenia SARS-CoV-2 may cause thrombocytopenia by several mechanisms including bone marrow suppression, consumptive coagulopathy, immune-mediated platelet destruction, or cytokine release syndrome [82]. Petechiae and purpura associated with mild to profound levels of thrombocytopenia, including cases of immune thrombocytopenic purpura (ITP) during COVID-19 disease, have been noted [83][84][85][86][87]. Several therapies including immunoglobulin replacement and eltrombopag were administered. Purpura with or without associated thrombocytopenia may also represent evolution of maculopapular exanthem or a feature of purpuric vasculitis as described in the above sections [20••].

Symmetrical Drug-Related Intertriginous and Flexural Exanthema
Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) represents a cutaneous reaction to systemic drug administration, with a unique distribution and morphology. An SDRIFE-like case was reported in a woman with COVID-19 who developed an erythematous rash on the bilateral antecubital fossae, trunk, and axillary folds; she had only been in receipt of paracetamol [52]. Another case report describes an atypical SDRIFE case in a 73-year-old woman with confirmed SARS-CoV-2 infection who developed erythema on the axillae, antecubital fossae, and trunk and medial thighs [36]. Although there were no clinically evident pustules, histopathologic examination suggested AGEP and she had received azithromycin and hydroxychloroquine (Table 2).

Acute Generalized Exanthematous Pustulosis
Acute generalized exanthematous pustulosis is a rare, medication-induced, severe cutaneous adverse reaction with a mortality rate upwards of 5%. An elderly patient with COVID-19 pneumonia who had received treatment with lopinavir/ ritonavir and hydroxychloroquine developed a diffuse, pruritic pustular eruption on the extremities and trunk; targetoid lesions were also present [37]. Other reports of acute generalized exanthematous pustulosis (AGEP) attributed to hydroxychloroquine in the setting of SARS-CoV-2 infection, including fatal cases, have also been described [38,88]. Table 2 lists histopathologic findings.

Occupational Dermatitis
The PPE recommendations for direct encounters of patients with SARS-CoV-2 infection include a respirator facemask, eye protection (goggles or face shield), gloves, and isolation gowns. Occupational dermatitis among HCWs represents an emerging problem amidst the COVID-19 pandemic. According to data from China, 74% of HCWs (n = 280/376) reported adverse skin reactions due to PPE use and hand hygiene practices, including xerosis, desquamation, erythema, papules, and maceration [89]. Female sex, PPE usage for more than 6 h daily, and increased hand washing frequency were significant risk factors [89]. Other publications report similar findings among HCWs [90,91]. Both irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD), particularly due to frequent hand washing or alcohol-based sanitizer and extended or repeated PPE use, can occur. Pressure injuries and skin damage attributed to facemask and goggle use are other major harms incurred by HCWs.

Irritant Contact Dermatitis
ICD accounts for approximately 80% of all contact dermatitis, developing on sites exposed to irritant agents which activate the innate immune system inflammatory response causing direct skin damage. Hand hygiene represents a hallmark of SARS-CoV-2 transmission prevention. Several organizations promote the practice of frequent hand washing with surfactant-containing detergents or cleansing with alcoholbased sanitizers [92]. Increased handwashing frequency translates to increased exposure to water and detergents, which can cause local epidermal barrier dysfunction and keratinocyte impairment. Surfactants deplete protective lipids and ceramides from the skin. In turn, physical barrier disruptions increase skin permeability and susceptibility to physical or chemical irritants.
Hand dermatitis induced by frequent hand washing includes a spectrum of findings: cutaneous xerosis, dyshidrotic eczema, and ICD especially in patients with underlying atopic dermatitis (AD) [93]. The distribution may be localized to the finger webs and finger tips or involve the wrist and dorsal or ventral aspects of the hand. Repeated use of alcohol-based sanitizers can quickly lead to skin dryness and subsequent ICD. Beiu and colleagues reported on hand ICD and eczema flare due to frequent hand washing in the context of COVID-19 [93]. Prolonged and/or frequent glove wearing in the setting of compromised skin integrity can further exacerbate hand dermatitis due to an added inflammatory response. Although frequent hand washing may be unavoidable for HCWs during the pandemic, applying a skin emollient or protectant can mitigate symptoms [93]. The AAD recommends application of a petrolatum-containing moisturizer between hand washings and whenever practical, especially while not working or overnight in order to reduce transepidermal water loss [94].
Facemask-induced itch seems to be prevalent (19.6% of 1393 persons) according to a self-questionnaire study conducted in Poland [95]. Some patients who reported sensitive skin and AD were at significantly greater risk of pruritus; whether these patients have a tendency to develop ICD or ACD remains a subject of investigation. The application of disinfectants to face masks has been associated with retroauricular ICD [96]. Similar to hand dermatitis, management of other ICD involves basic skin care with moisturizing creams, the use of emollients or skin protectants when feasible, and avoidance of irritant substances.

Allergic Contact Dermatitis
ACD represents a T lymphocyte-mediated, delayed-type hypersensitivity reaction of the skin due to previous sensitization to a hapten contact allergen. Acute ACD manifests as pruritic, erythematous, eczematous-appearing plaques, with papule, vesicle or bullous formation in moderate-to-severe cases. Chronic ACD tends to have scaling, fissures, or lichenification. There are thousands of contact sensitizers,; however, those likely most relevant to facemask-induced ACD include textile dyes and preservatives. Patch testing represents the gold standard in diagnosing ACD. We have evaluated two HCWs with moderate-to-severe facial ACD who exhibited positive patch test (PT) to textile dye mix. Figure 2 illustrates peri-auricular ACD related to surgical mask wear and positive PT reaction to textile dye mix at the 72-h reading.
Other identified contact allergens include polyurethanes (toluene-2,4-diisocyanate, 4,4′-diaminodiphenylmethane, hexamethylene diisocyanate) and formaldehyde-releasing preservatives (formaldehyde, 2-bromo-2-nitropropane-1,3-diol) [97,98]. Trace amounts of formaldehyde can be present in polypropylene masks as a degradation by-product [99]. A polyurethane sponge lined within a KN95 facemask was implicated in ACD involving the nasal bridge and zygomatic arches [97]. Retro-auricular ACD due to facemask ear loops composed of different materials including thermoplastic elastomer, rubber, and latex has been described [96]. Other potential allergens contained within PPE include rubber accelerators (thiuram, carbamates), other preservatives ( m e t h y l d i b r o m o g l u t a r o n i t r i l e , q u a t e r n i u m -1 5 , imidazolinylurea), paraphenylenediamine, and aluminum [100]. Upon identification of a relevant contact allergen through patch testing, the mainstay of ACD management is avoidance of that particular substance. ACD treatment may require topical and/or systemic corticosteroid therapy depending on the dermatitis severity.

Skin Damage
Skin damage associated with PPE use, especially N95 facemasks and goggles, among HCWs is prevalent, as high as 97% in one study (n = 526/542) [90•]. Various types of skin damage reported include skin desquamation, maceration, fissures, erosions, and ulcers on the cheeks, forehead, and nasal bridge [89,90]. The European Task Force on Contact Dermatitis recommends the use of hydrocolloid dressings at pressure points on the face and ears to reduce friction as well as restricting prolonged duration of PPE use when possible [101]. Caution must be advised on the use of any product placed between the skin and a N95 respirator as the tight seal required for mask efficacy must not be compromised [102]. Recommendations from the AAD include applying a liquid sealant to relevant contact areas and allowing it to fully dry before N95 mask wear [94].

Conclusions
In summary, SARS-CoV-2 has been associated with several different cutaneous manifestations, likely of varying pathophysiology, some preceding COVID-19 symptomatology and others occurring during active disease or later in the course. Adult patients exhibiting COVID-19 cutaneous manifestations may demonstrate a range of illness severity. Some findings are cutaneous-limited and benign, likely due to an immunologic response to the virus itself, while vasculopathy or thrombotic-type lesions may harbor extra-cutaneous, life-threatening systemic involvement. Given the varied rashes associated with COVID-19 and their respective differential diagnoses, cutaneous manifestations related to SARS-CoV-2 infection can represent a diagnostic dilemma. A pathognomonic dermatologic finding in COVID-19 is not currently apparent. Urticaria, angioedema, maculopapular exanthems, erythema multiforme, and petechiae seem to be nonspecific while purpuric and cutaneous vasculitic findings could aid in the diagnosis and portend more severe disease. Thus, heightened awareness and timely recognition of dermatologic findings in COVID-19 are important. Additionally, HCWs may suffer deep tissue injury or dermatitis including ACD due to extended or repeated PPE use. Continued research and reporting will more precisely determine the incidence, underlying pathophysiology, potential prognostication, and optimal treatments of cutaneous manifestations in COVID-19 disease.

Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant to this manuscript.