Dermatological Manifestations Associated with COVID-19 Infection

Abstract

The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causing the 2019 coronavirus disease (COVID-19) has infected millions in recent years and is a major public health concern. Various cutaneous manifestations of the COVID-19 disease have been identified. Skin is a mirror to internal disease and can be the presenting sign of COVID-19 disease. Several cutaneous manifestations can indicate severe COVID-19 disease. In the present scenario, physicians should know the various cutaneous manifestations of COVID-19 disease for early diagnosis and proper management of the disease.

Introduction

In recent years, the world is witnessing the horrors of a new viral illness caused by the novel severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) since its inception in the Wuhan province of China in December 2019. The disease was later named 2019 coronavirus (COVID-19) disease and was declared a pandemic by the World Health Organisation on March 11, 2020.[1,2] As of May 9, 2021, the global burden of the disease has increased to more than 157 million cases and more than 3 million deaths. India is accounting for 95% of the cases and 93% of deaths in the Southeast Asia region and 50% of global cases and 30% of global deaths.[3] The virus has used the angiotensin-converting enzyme-2 (ACE-2) receptor to invade human cells, and these receptors are variably expressed in various human tissues.[4] Xue et al.[5] demonstrated that ACE-2 receptors are highly expressed in keratinocytes, followed by sweat glands, suggesting that the skin is a potential target for infection by the SARS-CoV-2 virus. In this review, we describe the various cutaneous manifestations of the COVID-19 disease, its clinical significance, and the management strategy of these manifestations.

Cutaneous Manifestations of COVID-19 Disease

Preliminary data from around the world have shown a variable incidence of cutaneous manifestations in the COVID-19 disease, ranging from 0.2% from an early Chinese study to 20.4% from a study on Italian patients.[6,7] Cutaneous manifestations have been classified in various ways by various authors. Galván et al.[8] proposed a classification based on observation in 375 patients in the Spanish population, where they found five different types of lesions: maculopapular exanthem (47%), urticarial eruptions (19%), acral erythema with vesicles or pustules (19%), other vesicular eruptions (9%), and livedo or necrosis (6%). They also pointed out that the separate types of skin involvement appeared at various points of the disease course and were associated with different duration, severity, and prognosis.

In a case series of 15 patients, based on etiopathogenesis, the cutaneous features were grouped into the following categories: cutaneous vasculitides, papulosquamous and pityriasis rosea, measles-like, papulovesicular, urticarial, and cutaneous adverse drug reactions (CADR).[9] In a review of 46 articles' data with a pooled total of 998 unique patients from nine countries, the frequency of skin manifestations was up to 20.45%. The most commonly reported symptoms are chilblain‐like (40.2%), maculopapular (22.7%), and vesicular lesions (6.4%), followed by urticaria (8.9%), livedoid/necrotic lesions (2.8%), and other non-classified skin lesions (19.8%). Pain and burning were reported in at least 85 cases, and an itch was reported in at least 256 cases.[10] Freeman et al.[11] described the dermatologic manifestations in 171 COVID confirmed cases from 31 countries and found the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Klejtman described six central dermatological patterns, namely maculopapular/morbilliform, urticarial, vesicular, chilblain-like, petechiae or purpura, and livedoid, and further classified them as either inflammatory (maculopapular/morbilliform, urticarial, and vesicular) and vascular lesions (chilblain-like, petechiae/purpura, and livedoid).[12] Wang and Worswick subdivided the cutaneous manifestations into viral exanthem, urticarial, vesicular, chilblains/chilblains-like, non-chilblains vasculopathy-related, pityriasis rosea-like, erythema multiforme-like, Kawasaki/Kawasaki-like disease, and others.[13]

The salient features of the cutaneous manifestations of COVID-19 disease are listed in Table 1.

Table 1.

Prevalence of common cutaneous manifestations of the COVID-19 disease[14]

Cutaneous manifestation	Prevalence
Chilblain-like lesions	14.3-72%
Maculopapular rash	5-70%
Urticarial lesions	7-40%
Vesicular lesions	3.77-15%
Livedoid-like lesions	6%
Petechiae/Purpura	3%

Maculopapular/Morbilliform eruptions/Exanthema

A maculopapular rash has been described as the most common cutaneous manifestation in COVID-19 disease, with the prevalence ranging from 5 to 70% in various studies. These can be due to drug reactions or viral infection, most common in middle-aged or elderly patients, but have also been described in younger patients. The distribution is commonly over the trunk. The rash has been described early in the disease course in association with systemic symptoms and the latter part of the disease course, having a mean duration ranging from 8.6 to 11.6 days.[14]

Galván et al.[8] described pruritus as the most common symptom in 56% of the cases, and the maculopapular rash was associated with the more severe disease with 2% mortality. Most patients had spontaneous resolution of lesions, with a few describing secondary changes such as scaling.[13] Good response with topical corticosteroids or antihistamines and azithromycin has been described.[15] The pathophysiology of these lesions is not clear and is hypothesized to be secondary to SARS-CoV-2 infection or post-COVID immunological reaction or primary infection of skin due to viral nucleotides.[15] The histopathology varied according to the stage of the lesion; early lesions showed moderate epidermal spongiosis and perivascular lymphocytic infiltrate with eosinophils, and the late lesions showed perivascular lymphocytic infiltrate and histiocytes among collagen fibers without mucin deposits.[16]

Larrondo et al.[17] described papular-purpuric exanthem along with dermoscopic and histopathologic features. Two types of morphologies of papules were described: papules with central micropustule, dermoscopically visible as yellow globule, and papules with homogenous red‐violaceous color that under dermoscopy were seen as incomplete dark red‐violaceous rim at the edge of the papule. Histopathology showed a subcorneal pustule, acute edema, erythrocyte extravasation, and neutrophils in the papillary dermis, and a perivascular mononuclear infiltrate around superficial plexus along with endothelial swelling. These lesions were associated with elevated D-dimer and C-reactive protein.

Glick et al.[18] described a case of right-sided unilateral laterothoracic exanthem, which started with the onset of symptoms of COVID-19 disease and faded with the resolution of the symptoms. Isolated maculopapular eruption in the jawline and periauricular area has been described as a cutaneous sign of COVID-19 disease.[19]

Urticarial eruptions

Acute urticarial eruptions [Figure 1] have been described, with the prevalence ranging from 7 to 40%. They have been found most commonly in middle-aged patients; however, one case series of 26 patients described the median age to be 3 years. It can occur before, simultaneously, or after (average duration—6.8 days) the development of systemic symptoms. However, in a few cases, it occurred without any systemic symptoms. The rash predominantly involved the trunk, extremities, and face, but widespread and generalized eruptions have been described.[13,14] Galván Casas et al.[8] described pruritus to be the most common symptom in 92% of the cases and associated urticarial lesions with severe disease. Acute urticarial eruption could be drug-induced, overactivity of the immune system or a result of a direct effect of SARS-CoV-2 infection. These lesions are considered inaccurate markers for diagnosing the COVID-19 disease due to variable etiological factors.[14] Fernández-Nieto et al. biopsied a patient with urticarial rash and found the presence of perivascular infiltrate of lymphocytes, with few eosinophils and upper dermal dermal edema.[20] Almeida et al.[15] reported interface dermatitis and lymphocytic vasculitis of superficial plexus along with extravasation of red blood cells.

Figure 1.

Multiple urticarial plaques on the thigh of a moderate COVID-19-positive patient

Angioedema has been described along with urticaria in a few case reports. It was treated with antihistamines (fexofenadine, desloratadine, and diphenhydramine) with or without systemic glucocorticoids.[21,22,23] Criado et al.[24] successfully treated a case of exacerbation of chronic spontaneous urticaria with omalizumab. Rotulo et al.[25] described giant, migratory, polycyclic urticarial lesions along with acral peeling as a sign of COVID-19 disease in a pediatric patient. Nasiri et al.[26] described a case of urticarial vasculitis in a COVID recovered patient, who presented with annular and polycyclic urticarial lesions and histopathology revealed dermal edema and leukocytoclastic vasculitis. Rodriguez-Jiménez et al.[27] described a case with urticaria-like lesions as the late-onset manifestation of the COVID-19 disease, which on histopathology revealed an erythema-multiforme-like pattern: slight vacuolar-type interface dermatitis with occasional necrotic keratinocytes and no eosinophils. He stressed on histopathological correlation for characterization of cutaneous lesions in the COVID-19 disease.

Vesicular eruptions

Vesicular lesions are less common, with prevalence ranging from 3.77 to 15%. They most commonly occur in middle-aged individuals with predominant distribution on the trunk and extremities. They can be either diffuse, polymorphic, or localized, monomorphic. They can occur before, during, or after the development of systemic symptoms. The average duration of the lesions was between 8 and 10 days. Pruritus was associated with vesicular lesions and varied between 40.9 and 83.3%. These lesions are thought to be associated with the intermediate severity of the COVID-19 disease and are considered specific lesions for the disease. They can be due to immune overactivity or the cytopathic effect of SARS-CoV-2 on the endothelial cells of the dermal vessels.[14] Fernando-Nieto et al.[28] biopsied two cases and found intraepidermal vesicles, mild acantholysis, and ballooning of keratinocytes. Marzano et al.[29] reported the following pathological features from seven patients: basket-weave hyperkeratosis, slightly atrophic epidermis, vacuolar degeneration of the basal layer, multinucleate, hyperchromatic keratinocytes, and dyskeratotic cells.

Reactivation of herpes zoster has been described in the COVID-19 patient. They occur mostly during the onset of symptoms (approximately one to two weeks) but have been described before two days and after 8–10 weeks of developing symptoms. It was associated with necrotic (21% cases) and hemorrhagic (7% cases) morphologies. The most common site was trigeminal distribution in 35% of the cases. Post-herpetic neuralgia developed in 21% of the cases. They were associated with lymphopenia and a decrease in CD4+/CD8+ ratio.[30] Necrotic lesions in herpes zoster were associated with severe disease and normal lesions with mild disease.[31] The patient responded well to acyclovir and valacyclovir.[30,31]

Kitakawa et al.[32] described a case of herpes simplex infection of the lip in a young female patient. Roux et al.[33] described a case of pleuropneumonia in an infant resulting from varicella and COVID-19 infection.

Chilblain/Chilblain-like/Pernio-like lesions ('COVID toes')

The prevalence of chilblain-like lesions was found to be between 14.3 and 72% in various studies. These presented as erythematous to violaceous plaques on the acral region, mostly over fingers and toes, and were associated with pain and pruritus. Rarely, they were associated with vesicles, bulla, and pustules. These lesions were common among children, adolescents, and young adults and started after the onset of systemic symptoms with a latency period of around 1–3 weeks. However, these are being rarely described before the appearance of systemic symptoms. The lesions lasted for an average of 1–2 weeks.[13,14] Fabbrocini et al.[34] described the dermoscopic features of active and subsiding chilblain-like lesions. Active lesions showed red dots, white rosettes, white streaks over a pinkish-reddish background, white or yellow scales, yellow crusts, and focally distributed orange-yellowish structureless areas. The subsiding lesions showed red dots, rosettes (blurred as compared to active lesions), fewer white streaks over a pinkish background along with white crossed or annular line surrounded by red globular blood vessels at its periphery distributed in lines or rings, respectively, on an opaque erythematous background resembling the “Wickham striae.”

The following hypotheses have been put forward for developing chilblain-like lesions: immune dysregulation, vasculitis, vessel thrombosis, neoangiogenesis, and hypercoagulable states leading to microthrombi formation.[14] The common histopathological features include vacuolar changes in the epidermis, superficial and deep perivascular and periadnexal lymphocytic infiltrate, and dermal edema. Vascular microthrombi were reported in a few cases.[13] Santonja et al.[35] and Gambichler et al.[36] demonstrated SARS-CoV-2 spike protein in the endothelial cells of the blood vessels and eccrine cells of the sweat glands. Aschoff et al.[37] demonstrated induction of the type I interferon (IFN) pathway in lesional sections of COVID-19-associated chilblain-like lesions. These lesions typically resolved spontaneously, but in a few cases, they were treated symptomatically with topical corticosteroids and emollients.[13] Ruggiero et al.[38] used mometasone and heparin gel for the treatment of chilblain-like lesions in a pediatric patient with complete resolution of lesions in 4 days. As these lesions are not constantly seen, they should not be considered as indicators of diagnosis of the COVID-19 disease.[14]

Petechiae/Purpura-like lesions

These are less commonly described cutaneous lesions in the COVID-19 disease, with a reported incidence of 3% in one French study consisting of 277 patients. The lesions occurred diffusely or on the extremities after the symptoms of COVID-19 disease and were associated with a severe form of the disease. Proposed pathogenesis includes pauciinflammatory thrombogenic vasculopathy or deposition of complements (C5b-9 and C4d) within cutaneous microvasculature, sometimes with SARS-CoV-2 spike glycoproteins.[14] Histopathology from petechial lesion revealed parakeratosis, dyskeratotic cells, papillary dermal edema, superficial perivascular lymphocyte infiltrate, and significant red cell extravasation without thrombotic vasculopathy. Histopathology from purpuric lesions revealed thrombogenic vasculopathy with necrosis of epidermis and adnexal structures, interstitial neutrophils, and leukocytoclasia in one case and thrombosis in deep dermal vessels in the other two cases, along with deposition of C5b-9 in the vessel walls.[13] Differentials to be kept in mind while examining petechial and purpuric lesions include scurvy, drug-induced petechiae/purpura, and COVID-19 induced immune thrombocytopenic purpura.[14,39,40]

Chand et al.[41] described purpuric pressure ulcers in three cases of COVID-19 disease. Karaca et al.[42] described a case of a unilateral purpuric rash over the right inguinal region, which subsided completely with topical mometasone cream in 5 days. Wollina described a case of Schamberg-like purpuric rash with tonsillitis in a mild COVID-19 patient.[43]

Leukocytoclastic vasculitis and Immunoglobulin A (IgA) vasculitis are the most common forms of vasculitis associated with COVID-19 disease.[44,45] Atypical presentation with hemorrhagic bullous morphology in leukocytoclastic vasculitis has been described in COVID-19 patients.[46,47] Drug-induced vasculitis has to be kept in mind as a differential diagnosis of vasculitic lesions in the COVID-19 patients, as they are on multiple drugs during the presentation. The response of these lesions to oral corticosteroids is excellent.[44,45,46,47]

Livedo-like lesions

These lesions are one of the least common manifestations of the COVID-19 disease, with an incidence of 6% in one study of 375 covid confirmed cases. They were most commonly distributed over the trunk, flexor surface of the forearms, dorsal hand, and dorsal foot. The lesions coincided with the onset of the symptoms and commonly affected the elderly age group. They were associated with the severe disease with the highest mortality of all cutaneous lesions, around 10%. Hypercoagulable states leading to disseminated intravascular coagulation, macrothromboses, and microthrombi are responsible for livedo-like lesions.[14] Garcia-Gil et al.[48] described the potential role of complement C4c in the pathogenesis of livedo reticularis in the COVID-19 disease. Histological analysis revealed ectasia of small and medium-sized vessels with little or no inflammation.[15] Verheyden et al.[49] described a case of relapsing, symmetric livedo reticularis in a COVID-19 patient.

Retiform purpura lesions

These lesions occurred most commonly over the extremities and sacral/buttock area and are associated with severe COVID-19 disease.[50,51] Margo et al.[52] hypothesized that, in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response, which allows excessive viral replication with the release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation. Histopathology showed multiple thrombi occluding most of the small-sized vessels of the superficial and mid-dermis, and direct immunofluorescence showed the deposition of IgM, C3, and fibrinogen within the superficial-to-deep dermal blood vessel walls, and also C9 deposition on the vessel walls.[50] Anticoagulants were the mainstay of the treatment.[50] Rotman et al.[53] described a case of simultaneous presentation of calciphylaxis and thrombotic thrombocytopenic purpura in COVID-19 patients. Agirgol described a case of an eruptive cherry angioma with concomitant retiform purpura in a COVID-19 patient.[54]

Erythema Multiforme-like lesions

These lesions typically occurred 2–3 weeks after the onset of systemic symptoms. The lesions were smaller, less widespread, and atypical in morphology than classic erythema multiforme. Oral corticosteroid was used for treatment. Histopathological features were epidermal spongiosis, dilated vessels in the dermis with neutrophilic infiltrate, perivascular lymphocytic infiltrate, and red blood cell extravasation.[13]

Oral lesions

Iranmanesh et al.[55] described various oral manifestations in the COVID-19 disease. The most common features are aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, Kawasaki‐like, erythema multiforme‐like, mucositis, drug eruption, necrotizing periodontal disease, angina bullosa‐like, angular cheilitis, atypical sweet syndrome, and Melkerson–Rosenthal syndrome.

Nail lesions

A distally convex half‐moon‐shaped red band surrounding the distal margin of the lunula of all the fingernails appeared 2 weeks after the onset of the symptoms and persisted and became even wider a month later. This “red half-moon nail sign” represents a novel manifestation of COVID-19. The authors proposed a localized microvascular injury to the distal subungual arcade secondary to the inflammatory immune response and procoagulant state.[56] Fernández-Nieto et al.[57] described transverse leukonychia (Mee's line) in COVID-19 patient, probably due to transient matrix injury.

Hair abnormalities

Wambier et al.[58] reported a possible association of male patients with COVID-19 disease and androgenetic alopecia. “Gabrin sign” was termed to denote severe androgenetic alopecia (Hamilton-Norwood scale: 3–7), and it was hypothesized that COVID-19 patients having severe androgenetic alopecia are at risk of developing severe COVID-19 disease. Activated androgen receptor causes transcription of transmembrane protease serine 2 (TMPRSS2) gene leading to increased production of TMPRSS2, which primes SARS-CoV-2 spike protein and subsequently causes cell infection through angiotensin-converting enzyme-2 receptor.

Other forms of hair loss described in COVID-19 patients include telogen effluvium, anagen effluvium, and alopecia areata.[59,60,61]

Other lesions

Pityriasis rosea-like lesions were described to occur 3–7 days after the onset of systemic symptoms. Histopathological features in one of the cases were epidermal spongiosis, parakeratosis, nests of Langerhans cells and lymphocytes, papillary dermal edema, and a dermal infiltrate of lymphocytes and histiocytes.[13]

Gianotti et al.[62] described two cases of diffuse maculopapular rash resembling Grover's disease with the histopathology showing classic dyskeratotic cells. Sachdeva et al.[63] described a case of maculopapular itchy rash resembling Grover's disease.

Symmetrical drug‐related intertriginous and flexural exanthema (SDRIFE)‐like erythematous rash was observed in a 64‐year‐old diabetic woman from France.[64]

Ocular lesions include conjunctivitis with eyelid dermatitis[65] and periorbital dyschromia.[66]

Diffuse melanoderma of acute onset was reported from Wuhan in two severely ill Chinese doctors. The exact reason for the observed diffuse skin darkening remained unknown, but hormonal imbalance related to liver dysfunction or drug side effects were suspected, and the changes were considered reversible.[67]

Erythema nodosum-like lesions were described, which developed after the onset of systemic symptoms, and in one case, it did not respond to naproxen and subsequently responded to oral corticosteroids.[68,69,70]

Taskin et al.[71] described a case of COVID-19 disease presenting with atypical sweet's syndrome. Masson et al.[72] described angiomatous and eczematous lesions in association with the COVID-19 disease. Martinez et al.[73] described a case of acral peeling as the sole manifestation of COVID-19 in children. Development of reactive arthritis and systemic lupus erythematosus with anti-phospholipid antibody syndrome after the COVID-19 disease has been described.[74,75]

Cutaneous manifestations in the pediatric population

Just as the clinical course and outcome of COVID-19 differ in the pediatric population as compared to adults, similarly, the cutaneous manifestations also vary. The first and most commonly reported manifestation that was seen initially from Europe were chilblain-like lesions referred to as “COVID toes.”[76] In many patients, these lesions were the only manifestation of COVID-19 infection, helping the clinician to suspect infection. Subsequently, manifestations such as urticaria, morbilliform rash, erythema multiforme, and vesicular rash became common among patients of all age groups.[77]

A distinctive rise in the mucocutaneous manifestations related to Kawasaki-like illness was then noticed among children wherein 80–90% of such patients were positive for COVID-19 antibody titers. This presentation of mucocutaneous involvement along with multisystem association has since been referred to as pediatric inflammatory multisystem syndrome that has now been described in two cohort studies apart from various case series and reports.[78,79,80] Dengue-like lesions, pityriasis rosea-like, vasculitic lesions, acro-ischemia, and livedoid lesions are some rare nonspecific lesions that have also been described in children.[81]

Multisystem inflammatory system in children (MIS-C)

A particular presentation has been reported in children in Europe and North Africa, with a lesion similar to Kawasaki syndrome. According to a French series concerning 16 children with this syndrome, the skin rash was present in 81% of the patients, edema with plantar and palmar redness was present in 67% of patients, and 87% had dry lips.[82] As part of this syndrome, the skin eruption can vary, including an erythema-multiforme-like rash.[83] Maculopapular rash and ulcerated facial skin have been described in two newborns of COVID-19 infected mothers.[84]

Underrepresentation in the skin of color

The paucity of images of skin manifestations of COVID-19 in patients with darker skin is a major issue, which needs to be addressed. Given the racial disparities in COVID-19 infections and associated deaths, all manifestations of this disease must contain the broad representation of people of different races and ethnicities, as any clue, if recognized, could contribute to early diagnosis and potentially better health outcomes.[85] Lester et al.[86] examined clinical photos of COVID-19-related skin lesions for a total of 130 images and highlighted that 92% (120 of 130) showed skin types I–III, 6% (7 of 130) showed patients with type IV skin and 2% (3 of 130) could not be classified because they depicted only acral skin. No clinical images were representing Fitzpatrick type V or VI skin. Dalal et al.[87] reported dermatological manifestations in 13 patients (12.7%) from North India, 3 (2.9%) had a maculopapular rash, 2 (1.9%) had urticarial lesions, and 8 (7.8%) patients had itching without any specific cutaneous signs. Das et al.[88] described a series of patients with an erythematous-edematous type of chilblain preceded by a burning and tingling sensation. Sukhavasi et al.[89] described cutaneous manifestation in 1,065 South Indian COVID-19 positive patients and found a prevalence of 4.51%; itching and urticaria are being the most common symptoms (25%), followed by vesiculopapular rash, acral erythema, maculopapular rash, irritant contact dermatitis, aphthous ulcer, herpes zoster, purpura, and others. Goyal et al.[90] described three cases of maculopapular erythema, urticaria, and herpes zoster in type IV Fitzpatrick skin-type Indian patients.

Conclusion

To date, several skin manifestations related to COVID-19 have been reported, but additional efforts are needed to collect further data. Dermatological findings should prompt discussion between physicians and patients regarding isolation and possible testing. As a potential correlate to disease severity, prognosis, or infectibility, all healthcare professionals must be well-versed in these increasingly common cutaneous manifestations of COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.