Cutaneous Manifestations in Patients With COVID-19

A Preliminary Review of an Emerging Issue

A.V. Marzano; N. Cassano; G. Genovese; C. Moltrasio; G.A. Vena

The British Journal of Dermatology. 2020;183(3):431-442.

Abstract and Introduction

Abstract

Background: The infection caused by the recently identified SARS-CoV-2, called coronavirus disease-19 (COVID-19), has rapidly spread throughout the world. With the exponential increase of patients worldwide, the clinical spectrum of COVID-19 is being better defined and new symptoms are emerging. Numerous reports are documenting the occurrence of different cutaneous manifestations in patients with COVID-19.

Objectives: To provide a brief overview of cutaneous lesions associated with COVID-19.

Methods: A literature search was performed in the PubMed, Scopus and Web of Science databases up to 30 April 2020. This narrative review summarizes the available data regarding the clinical and histological features of COVID-19-associated skin manifestations.

Results: The literature reports showed a great heterogeneity in COVID-19-associated cutaneous manifestations, as well as in their latency periods and associated extracutaneous symptoms. Pathogenic mechanisms are unknown, although the roles of a hyperactive immune response, complement activation and microvascular injury have been hypothesized. Based on our experience and the literature data, we subdivided the reported cutaneous lesions into six main clinical patterns: (i) urticarial rash; (ii) confluent erythematous–maculopapular–morbilliform rash; (iii) papulovesicular exanthem; (iv) chilblain-like acral pattern; (v) livedo reticularis–livedo racemosa-like pattern; and (vi) purpuric 'vasculitic' pattern. These six patterns can be merged into two main groups: the first – inflammatory and exanthematous – includes the first three groups listed above, and the second includes the vasculopathic and vasculitic lesions of the last three groups.

Conclusions: The possible presence of cutaneous findings leading to suspect COVID-19 puts dermatologists in a relevant position. Further studies are needed to delineate the diagnostic and prognostic values of such cutaneous manifestations.

Introduction

A novel zoonotic enveloped RNA virus of the family Coronaviridae, which has been named 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2), was identified in hospitalized patients with pneumonia in Wuhan, China, in December 2019. The infection caused by the virus, called coronavirus disease-19 (COVID-19), has rapidly spread throughout the world, becoming pandemic in early March 2020.^[1]

The clinical spectrum of COVID-19 is rather heterogeneous, ranging from unapparent or mild symptoms to critical fatal forms with respiratory failure, septic shock or multiorgan dysfunction. The clinical features at onset of illness vary, but, over the disease course, patients present mainly with fever and respiratory symptoms. However, various signs and symptoms can occur, and among the most common are fever, cough, fatigue, anorexia, shortness of breath, sputum production, myalgia, dyspnoea, rhinorrhoea, ageusia, anosmia, pharyngodynia, headache and chills.^[1] With the exponential increase of infected patients worldwide, the clinical characteristics of COVID-19 are being better defined and new symptoms are emerging.

In most of the early reports from China, cutaneous lesions were not generally included in the COVID-19 clinical spectrum, apart from a few exceptions. For instance, Guan et al. described skin rash in 0·2% of 1099 hospitalized patients, without specifying clinical patterns or further details.^[2] Hoehl et al. observed a faint rash and minimal pharyngitis in one traveller returning from Wuhan to Germany in February 2020 who tested positive for SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of her throat swab.^[3] Subsequently, a case of COVID-19 presenting with purpuric lesions mimicking dengue has been reported.^[4] In Iran, the clinical findings of COVID-19 found in a 15-day-old neonate were fever, lethargy, respiratory distress without cough and cutaneous mottling.^[5]

Another report, which analysed a series of 88 patients with COVID-19 to describe the rate and type of skin lesions, drew the attention of the scientific community to COVID-19-associated cutaneous manifestations.^[6] In all of these patients, history of intake of any new drug in the previous 15 days was excluded. Cutaneous manifestations developed in 18 patients (20%) either at the onset of the disease (n = 8) or after admission (n = 10), and consisted of erythematous rash (n = 14), widespread urticaria (n = 3) and chickenpox-like vesicles (n = 1). The trunk was the most frequently affected area, and itch was mild or absent. Skin lesions usually disappeared in a few days and did not show any apparent correlation with COVID-19 severity.

Subsequently, various reports of skin manifestations in patients with COVID-19 have been published. It should be kept in mind that, at the beginning of this vast outbreak, the rapidly increasing rate of infected patients and the parallel multitude of severe and critical patients could have hampered systematic skin assessments. Therefore, cutaneous lesions are likely to have been underestimated for obvious reasons, including the paucity of dermatology consultations in this group of patients.^[7] Moreover, cutaneous lesions may have been neglected as their duration can be very short and local symptoms can be minimal or absent. The difficulty in determining the actual prevalence of COVID-19-associated skin manifestations has also been linked to the fact that in some countries only patients with respiratory illness or requiring hospitalization are screened.^[8]

The aim of our article is to provide a brief overview of the cutaneous manifestations associated with COVID-19, accepting the preliminary nature of such data.

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Abstract and Introduction
Methods
Results
Conclusions
References
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Table 1. Case reports of exanthems and inflammatory eruptions in patients with COVID-19
Study	Sex, age (years) Relevant history (if present)	Clinical features of skin lesions	Respiratory and other relevant symptoms or signs in relation to the onset of skin lesions	Treatments for COVID-19	Outcome of skin lesions
Henry⁹	Female (27)	Pruritic urticarial rash	Prodromal odynophagia; concomitant arthralgia; chills, chest pain and fever (up to 39·2 °C) 48 h after the onset of skin lesions	Paracetamol	Slow improvement (n.s.)
Fernandez-Nieto¹⁰	Female (32)	Urticarial rash	COVID-19 symptoms (n.s.) started 6 days before	Hydroxychloroquine and azithromycin	Improvement after 5 days
Quintana-Castanedo¹¹	Male (61)	Mildly itchy urticarial exanthem	Concomitant body temperature of 37·3 °C. No symptoms (RT-PCR performed due to epidemiological link)	None	Disappearance after 7 days
van Damme¹²	Male (71) Obesity, DM, AH, OSAHS, RF on dialysis, previous stroke, hypercholesterolaemia	Urticarial rash	Concomitant fever and general weakness. Progressive deterioration up to respiratory failure and death	n.s.	Improvement
van Damme¹²	Female (39)	Pruritic generalized urticarial rash	Concomitant fever (38·3 °C) with chills, myalgia and headache, then rhinorrhoea, mild dry cough, dyspnoea; later anosmia and ageusia	n.s.	Gradual improvement
Lu¹³	One case (n.s.)	Urticarial rash	Mild dry cough started a few days before	Ribavirin and interferon	n.s.
Morey-Olivé¹⁴	Male (6)	Erythematous, nonpruritic maculopapular exanthem	Low-grade fever 2 days before	None	Disappearance after 5 days
Morey-Olivé¹⁴	Female (2 months)	Urticaria-like exanthem	Concomitant low-grade fever	None	Disappearance after 5 days
Rivera-Oyola¹⁵	Male (60) Mitral valve replacement, paroxysmal atrial fibrillation, depression	Asymptomatic erythematous maculopapular rash on the back, flanks, groin and upper thighs becoming purpuric 1 week later	Low-grade fever (38 °C), myalgias, fatigue, mild cough 3 days before	None	n.s.
Rivera-Oyola¹⁵	Female (60)	Generalized, pruritic urticarial rash	Low-grade fever (38·2 °C), myalgias, fatigue, mild cough, gastrointestinal symptoms started 9 days before	None	Disappearance after a few days
Amatore¹⁶	Male (39)	Nonpruritic erythematous, oedematous, annular and circinate fixed plaques on upper limbs, chest, neck, abdomen and palms	Concomitant fever (39 °C). Pulmonary findings suggestive of COVID-19 on CT scan without respiratory symptoms	Hydroxychloroquine	Disappearance after 8 days
Najarian¹⁷	Male (58)	Pruritic diffuse morbilliform rash	Cough, pain in legs and hands shortly before; no fever	Azithromycin and benzonatate	Disappearance after a few days
Hunt¹⁸	Male (20)	Nonpruritic diffuse, morbilliform rash, sparing the face	Concomitant fever; initial signs suggestive of an upper respiratory infection, with pneumonia diagnosed 6 days later	n.s.	n.s.
Avellana Moreno¹⁹	Female (32)	Generalized, pruritic morbilliform rash (petechial and erythematous maculopapular lesions and a scaly reaction on the 4th day)	Fever, myalgia, asthenia 6 days before; later cough, diarrhoea	Paracetamol	Disappearance after the 4th day (n.s.)
Genovese²⁰	Female (8)	Asymptomatic papulovesicular (varicella-like) rash on the trunk	Mild cough started 3 days before. Mild transient thrombocytopenia. Mild fever 2 days after the onset of skin lesions	None	Disappearance after 7 days
Mahé²¹	Female (64) DM	Erythematous symmetrical flexural rash (antecubital folds, then trunk and axillary folds)	Prodromal fever (up to 40 °C) and asthenia (4 days before); concomitant cough with confirmation of interstitial pneumonia and persistent fever	Paracetamol from fever onset until day 16	Disappearance after 5 days (day 9 of the disease)
Ahouach²²	Female (57)	Diffuse erythematous blanching maculopapular lesions, with symptoms (burning sensation) only on the palms	Fever (39 °C) 2 days before. Concomitant dry cough. Typical thorax CT scan findings	Paracetamol	Disappearance within 9 days
Estébanez²³	Female (28)	Pruritic erythematous-yellowish papules on both heels (13 days after being tested), becoming plaques 3 days later	Initially dry cough, nasal congestion, fatigue, myalgias and arthralgias without fever, then diarrhoea, ageusia and anosmia	Paracetamol for a few days	n.s.
Jimenez-Cauhe²⁴	Female (84) AH, dyslipidaemia	Flexural erythematous-purpuric macules, mildly pruriginous, mainly in the periaxillary area (on the 3rd hospital day)	Respiratory symptoms requiring hospitalization 11 days before	Hydroxychloroquine and lopinavir/ritonavir	n.s.
Joob⁴	One case (n.s.)	Petechial rash, misdiagnosed as dengue	Presence of thrombocytopenia. Further presentation of respiratory problems requiring referral to a tertiary medical centre (other information not given)	n.s.	n.s.
Diaz-Guimaraens²⁵	Male (48) AH	Mildly pruritic, maculopapular and petechial rash, with periflexural distribution	Fever (up to 39 °C) 3 days before, along with chest pain and shortness of breath. Hospitalization for pneumonia	Hydroxychloroquine, lopinavir/ritonavir and azithromycin	Disappearance after 5 days
Sanchez²⁶	n.s. (elderly) AH, DM, peripheral artery disease, RF	Digitate papulosquamous eruption on the trunk, upper limbs and thighs (on the 2nd hospital day)	Fever, fatigue, dyspnoea 1 week before hospitalization for acute respiratory distress. Death	n.s.	Disappearance within 7 days
Gianotti²⁷	Female (59)	Widespread erythematous macules on the arms, trunk and lower limbs (on the 3rd hospital day)	Bilateral interstitial pneumonia requiring hospitalization	Lopinavir/ritonavir, heparin and levofloxacin	Improvement within 5 days
	Female (89)	Erythematous papular exanthem on the trunk and arms (on admission)	Fever and cough started 7 days before	Ceftriaxone and azithromycin	Improvement after 8 days
	Male (57)	Widespread pruritic eruption of erythematous macules and papules	Fever, headache, cough and arthralgia 2 days after the onset of the rash	Levofloxacin and hydroxychloroquine	Improvement after 10 days

AH, arterial hypertension; CT, computed tomography; DM, diabetes mellitus; n.s., not specified; OSAHS, obstructive sleep apnoea–hypopnoea syndrome; RF, renal failure; RT-PCR, real-time reverse-transcriptase polymerase chain reaction.

Table 2. Case reports of vasculopathic skin lesions in patients with COVID-19
Study	Sex, age (years) Relevant history (if present)	Clinical features of skin lesions	Respiratory symptoms and other relevant findings	Treatments for COVID-19
Manalo²⁸	Male (67)	Nonpruritic LR-like livedoid patch on the right thigh. Disappearance after 19 h	Low-grade fever, nasal congestion, postnasal drip, cough, shortness of breath 7 days before; concomitant weakness and transient haematuria	n.s.
Manalo²⁸	Female (47) CD, HT, past portal vein thrombosis	Asymptomatic LR-like rash on right leg immediately after sunlight exposure (10 days after testing positive). Disappearance after 20 min	Previous appearance of mild headache, sinus pressure, anosmia and fever (up to 37·9 °C)	n.s.
Alramthan²⁹	Female (27)	Red–purple papules on the dorsal aspect of fingers bilaterally in both cases (also subungual erythema in the right thumb in the second case)	No symptoms	None
Alramthan²⁹	Female (35)		No symptoms	None
Kolivras³⁰	Male (23) Psoriasis (secukinumab stopped 1 month before)	Violaceous, infiltrated and painful plaques on the toes and lateral aspects of the feet	Low-grade fever (37·7 °C) and dry cough 3 days before	None
Magro³¹	Male (32) OASA, anabolic steroid use (current use of testosterone)	After 4 days on ventilator support, retiform purpura with surrounding inflammation on buttocks	Fever, cough, then dyspnoea up to acute respiratory failure (elevated D-dimer and INR, normal PTT and platelet count)	Mechanical ventilation, hydroxychloroquine, azithromycin, remdesivir
	Female (66)	On hospital day 11, dusky livedoid patches on palms and soles bilaterally	Fever, cough, diarrhoea, chest pain for 9 days. Hypoxaemia on admission. Comatose state after further 3 days (low platelet count, high D-dimer, normal INR and PTT)	Hydroxychloroquine, enoxaparin, intubation, renal replacement
	Female (40)	Mildly purpuric reticulated eruptions on the chest, legs and arms (livedo racemosa)	Dry cough, fever, myalgias, diarrhoea for 2 weeks and progressive dyspnoea. Then severe reduction of left ventricular function, respiratory failure, shock (elevated D-dimer and INR, normal platelet count and PTT)	Intubation

CD, coeliac disease; HT, Hashimoto thyroiditis; INR, international normalized ratio; LR, livedo reticularis; n.s., not specified; OASA, obesity-associated sleep apnoea; PTT, partial thromboplastin time.

Table 3. Histopathological features of cutaneous manifestations found in patients with COVID-19
Study	Clinical form	Main histopathological features
Fernandez-Nieto¹⁰	Urticarial rash	Upper dermal oedema
Fernandez-Nieto¹⁰	Urticarial rash	Perivascular infiltrate of lymphocytes and some eosinophils
Amatore¹⁶	Urticarial figurate lesions	Lichenoid and vacuolar interface dermatitis
		Mild spongiosis and dyskeratotic basal keratinocytes
		Papillary dermal oedema with superficial perivascular lymphocytic infiltrate and occasional neutrophils
Ahouach²²	Erythematous maculopapular rash	Slight spongiosis and basal cell vacuolation
Ahouach²²	Erythematous maculopapular rash	Mild perivascular lymphocytic infiltrate
Gianotti²⁷	Erythematous eruption	Superficial perivascular dermatitis with slight lymphocytic exocytosis
		Presence of a small thrombus in a vessel in the mid dermis
		Swollen thrombosed vessels with neutrophils, eosinophils and nuclear debris patchily distributed in the dermis
	Erythematous papular exanthem	Superficial and deep perivascular dermatitis
		Cuffs of lymphocytes surrounding blood vessels in a vasculitic pattern
		In the mid dermis extravasated red blood cells from damaged vessels
	Erythematous papular eruption	Superficial perivascular vesicular dermatitis, with features reminiscent of Grover disease
		Focal acantholytic suprabasal clefts
		Dyskeratotic and ballooning herpes-like keratinocytes
		Presence of a nest of Langerhans cells within the epidermis
		Patchy bandlike infiltration with occasional necrotic keratinocytes and minimal lymphocytic satellitosis
		In the dermis, swollen vessels, with dense lymphocyte infiltration, mixed with rare eosinophils
Sanchez²⁶	Papulosquamous eruption	Focal parakeratosis in the epidermis
		Mild spongiosis, with a few spongiotic vesicles containing lymphocytes and Langerhans cells
		Papillary dermal oedema with moderate superficial lymphohistiocytic infiltrate
Diaz-Guimaraens²⁵	Maculopapular and petechial rash	Focal parakeratosis and isolated dyskeratotic cells
		Focal papillary dermal oedema and superficial perivascular lymphocytic infiltrate
		Extravasated red cells
		No signs of thrombotic vasculopathy
Rivera-Oyola¹⁵	Erythematous maculopapular rash with purpuric evolution	Mild perivascular infiltrate of predominantly mononuclear cells in the superficial dermis
		Scattered foci of hydropic changes in the epidermis and slight spongiosis
		Minimal acanthosis and focal parakeratosis
Marzano³⁴	Varicella-like lesions (n = 7)	Features compatible with viral exanthem
Recalcati⁴¹	Targetoid nonacral lesions (n = 2)	Mild superficial perivascular dermatitis
	Perniosis-like lesions on the fingers (n = 2)	Diffuse dense dermal–hypodermal lymphoid infiltrate with a prevalent perivascular pattern
	Perniosis-like lesions on the fingers (n = 2)	Signs of endothelial activation
Kolivras³⁰	Chilblain-like lesions	Epidermal basal vacuolar alteration and scattered necrotic keratinocytes
		Superficial and deep lichenoid, perivascular and perieccrine infiltrate of lymphocytes and occasional plasma cells
		Presence of some nuclear debris without neutrophils
		Plump endothelial cells in the venules surrounded by lymphoplasmacytic infiltrate
		Absence of intraluminal thrombi or fibrin within venule walls
Magro³¹	Retiform purpura	Thrombogenic vasculopathy
		Extensive necrosis of the epidermis and adnexal structures
		Interstitial and perivascular neutrophilia with prominent leucocytoclasia (IHC: extensive deposits of C5b-9 within the microvasculature)
	Palmoplantar livedoid patches	Superficial vascular ectasia and occlusive arterial thrombus within the deeper dermis
	Palmoplantar livedoid patches	Absence of inflammation (IHC: extensive vascular deposits of C5b-9, C3d and C4d throughout the dermis, with marked deposition in an occluded artery)
	Livedo racemosa	Modest perivascular lymphocytic infiltrate in the superficial dermis along with deeper-seated small thrombi within rare venules of the deep dermis, in the absence of a clear vasculitis (IHC: significant vascular deposits of C5b-9 and C4d)