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Clinical and Histopathological Features and Potential Pathological Mechanisms of Skin Lesions in COVID-19: Review of the Literature

1
Departments of Dermatology and Clinical Pathology, University Hospital of Geneva, 1205 Geneva, Switzerland
2
Department of Clinical Pharmacology and Toxicology, University of Geneva, 1205 Geneva, Switzerland
*
Author to whom correspondence should be addressed.
Received: 24 June 2020 / Revised: 28 June 2020 / Accepted: 29 June 2020 / Published: 30 June 2020

Abstract

In recent weeks, several reports have emerged of skin lesions with different clinical presentations in COVID-19 cases. All dermatologists should be aware of these cutaneous lesions, which may be early clinical symptoms of infection. We reviewed the literature on cutaneous manifestations in the PubMed database from December 2019 and June 2020. From the cases described as case reports or series in 57 recent articles, it appears that skin lesions (i) are highly varied, (ii) may not be related to the severity of the condition and (iii) resolve spontaneously in a few days. The frequency of these lesions in COVID-19 patients varies between 1.8% and 20.4%. The major clinical forms described were maculopapular eruptions, acral areas of erythema with vesicles or pustules (pseudochilblain), urticarial lesions, other vesicular eruptions and livedo or necrosis. The lesions were mainly localized in the trunk and extremities. The majority of patients were male, aged between 4.5 and 89 years. A minority of the patients were children presenting with acral, chilblain-like lesions, papulo-vesicular eruptions or Kawasaki disease-like pediatric inflammatory multisystem syndrome. The mean duration of the lesions was a few days, but some lasting as little as 20 min and others as long as four weeks have been reported. The mean latency time in the majority of cases was between 1 and 14 days; however, in some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms. The histopathological features of these lesions also vary, corresponding to the diversity of clinical manifestations. These features underline the nature of epidermal and dermal vascular lesions—and in severe cases, microvascular injury and thrombosis—associated with COVID-19, and provide important clues to their pathological mechanisms.
Keywords: skin lesions; COVID-19; SARS-CoV-2; histopathology skin lesions; COVID-19; SARS-CoV-2; histopathology

1. Introduction

In recent weeks, there have been several published reports of COVID-19 cases with skin lesions with different clinical presentations; all dermatologists should be aware of these clinical signs. In patients with COVID-19, aggravation of previous skin lesions have been noted, and allergic reactions to the different medications used for treatment may occur. However, recently, there have been reports of skin lesions that may correspond to cutaneous manifestations of SARS-CoV-2 [1].
The characteristics of skin lesions in patients with COVID-19, as described recently in case reports or case series, are summarized in the Table 1 [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]. According to these publications, in which the majority of reported patients had Fitzpatrick skin types I–III [59], the skin manifestations of COVID-19 are highly varied and nonspecific, are not necessarily related to the severity of the condition and resolve spontaneously in a few days.
We still have a lot to learn about the cutaneous manifestations associated with this disease, and there are currently more questions than answers. It is still unclear what percentage of COVID-19 patients develops cutaneous eruptions. Although 20.4% of patients (18 out of 88) in an Italian cohort developed cutaneous abnormalities [24], they were present in only 1.8% (2 out of 1099 patients) in a Chinese cohort [10].

2. Methods

A literature search using the following strategy was performed on the PubMed database to identify eligible articles: (COVID* or coronavirus* or SARS-CoV-2*) and (dermatol* or skin* or cutaneous*). The publication date was limited to December 2019 onward. A total of 112 papers were identified in the initial search. Abstracts and full-texts of all articles were then reviewed. Reports on different cutaneous manifestations associated with COVID-19 were included in this review (67 in total, 57 of which are listed in Table 1).

3. Results and Discussion

3.1. Clinical Manifestations

Clinical manifestations are as follows (see Table 1): generalized or localized rash (erythematous, papulovesicular, maculopapular, petechial, morbilliform, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE)-like, digitate papulosquamous pityriasis rosea-like), generalized urticaria, varicelliform rash, herpes lesions (zoster), purpuric lesions (retiform purpura), livedoid lesions (livedo reticularis, livedo racemosa), acro-ischemic lesions (dry gangrene, blisters, cyanosis), erythema multiforme-like, chilblain-like lesions (COVID toes) and other lesions such as urticarial vasculitis, acute generalized exanthematous pustulosis (AGEP)-like rash, eosinophilic panniculitis, COVID mask, periorbital dyschromia, oral ulcers and COVID red half-moon nail sign. In addition, a high frequency of androgenetic alopecia has been observed in COVID-19 patients. Based on these clinical manifestations, an algorithm for the classification of COVID-19 rashes has been proposed [60].
In a recent Spanish study including 375 cases, five clinical patterns were described [41]: maculopapular eruptions (47%), acral areas of erythema with vesicles or pustules (pseudochilblain) (19%), urticarial lesions (19%), other vesicular eruptions (9%) and livedo or necrosis (6%).
The lesions are mainly localized in the trunk and extremities (hands and feet), sparing the face; however, lesions located on the face, neck, mouth and axillary folds have also been reported.
The majority of patients were male, aged between 4.5 and 89 years. A minority of patients were children (between 4.5 and 14 years) presenting with acral, chilblain-like lesions, papulo-vesicular eruptions on the trunk or pediatric inflammatory multisystem syndrome.
The mean duration of the lesions was a few days, but some lasting as little as 20 min and others as long as four weeks have been reported. The mean latency time (i.e., time to develop skin lesions after the appearance of the first typical symptoms of COVID-19) in the majority of cases was between 1 and 14 days; however, in some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms.
In the table, we have classified all reported cases according to the time of occurrence of skin lesions. In some patients, lesions appeared 2 to 5 days before the onset of COVID-19 symptoms; one such case involved an 8 year-old. The types of skin lesions in these patients were similar to those appearing up to 7 days after the onset of the first symptoms of COVID-19; this is consistent with a viral rash. In contrast, lesions appearing beyond the 7th day of ongoing COVID-19 are more vascular in nature.
COVID-19 is less frequent in children than adults (<1%), with a milder course; however, cases of pediatric inflammatory multisystem syndrome with features resembling atypical Kawasaki disease occurring several weeks after SARS-CoV-2 infection have recently been reported in children in the UK, as well as in Italy, France, Switzerland and the USA (Kawa-COVID-19) [57]. Clinical presentation includes fever, variable rash, conjunctivitis and abdominal pain, progressing to hemodynamic shock with severe myocardial involvement. Severe disease, with the need for intensive care due to myocarditis, occurred in almost half of all reported cases, with a higher risk of poor outcome for patients older than 5 years of age, and particularly for teenagers. A recent study from Italy reported a 30-fold increase in the rate of Kawasaki-like presentation during the COVID-19 pandemic among children; in many cases, nasopharyngeal swabs taken from these children were negative for COVID-19, and the association with COVID-19 infection is unclear [44].

3.2. Histopathological Features

Histopathological features have been reported in only a minority of patients in these articles (Table 1).

3.2.1. Maculopapular Eruptions

Maculopapular eruptions show superficial perivascular dermatitis with slight lymphocytic exocytosis, swollen thrombosed vessels with neutrophils, eosinophils and nuclear debris/superficial and deep perivascular dermatitis with cuffs of lymphocytes surrounding blood vessels in a vasculitic pattern/superficial perivascular vesicular dermatitis, focal acantholytic suprabasal clefts, dyskeratotic and ballooning herpes-like keratinocytes and swollen vessels with dense lymphocyte infiltration mixed with rare eosinophils in the dermis.

3.2.2. Varicella-Like Papulovasicular Exanthem

Varicella-like papulovasicular exanthems display vacuolar degeneration of the basal layer with multinucleate, hyperchromatic keratinocytes and dyskeratotic cells with no inflammatory infiltrate. According to Mahé et al., these exanthems histologically show acantholysis, intraepidermal vesicles with suprabasal clefts, prominent, “pomegranate-like” dyskeratosis and suspected viral inclusions in multinucleated cells. The authors of that report proposed the term “COVID-19-associated acantholytic rash”, rather than “varicella-like rash” [58].

3.2.3. Urticarial Lesions

Urticarial lesions show perivascular infiltrate of lymphocytes, some eosinophils and upper dermal edema. Urticarial vasculitis lesions show blood extravasation and neutrophilic perivascular inflammation with prominent karyorrhexis, some macrophages with a cytoplasm full of nuclear debris and endothelial swelling, necrosis and fibrin deposition. Some urticarial lesions show slight vacuolar-type interface dermatitis with occasional necrotic keratinocytes with no eosinophils, consistent with an erythema multiforme-like pattern.

3.2.4. Acral Chilblain-Like Lesions

In acral chilblain-like lesions, a diffuse dense lymphoid infiltrate of the superficial and deep dermis, as well as hypodermis, with a prevalent perivascular pattern and signs of endothelial activation, are observed.

3.2.5. Purpuric and Livedoid Lesions

Purpuric and livedoid lesions show thrombogenic vasculopathy accompanied by striking and extensive deposition of C5b-9 and C4d within the microvasculature.

3.2.6. Pityriasis Rosea-Like Lesions

In pityriasis rosea-like lesions, there is mild diffuse spongiosis in the epidermis and rounded spongiotic vesicles containing aggregates of lymphocytes and Langerhans cells, as well as mild papillary edema and lymphohistiocytic infiltrate in the dermis.

3.2.7. Kawasaki-Like Lesions

In Kawasaki-like lesions, findings consistent with leukocytoclastic vasculitis, including necrosis of the epidermis and most of the dermis with extravasation of erythrocytes and fibrin thrombi in the capillaries, as well as infiltration of neutrophils with nuclear debris in vessel walls, and C3 and IgA deposition in a vascular pattern in direct immunofluorescence, are observed.

3.2.8. Subcutaneous Lesions

Subcutaneous lesions show a predominantly lobular panniculitis with lymphocytes, histiocytes and many eosinophils, consistent with an eosinophilic panniculitis.

3.2.9. Pustular Lesions

Pustular lesions show a subcorneal pustule with mild focal acanthosis and spongiosis, neutrophilic exocytosis, sparse keratinocyte necrosis and a perivascular lymphocytic infiltrate with rare neutrophils and eosinophils, consistent with acute generalized exanthematous pustulosis.
In a recent report, the postmortem histology of COVID-19 patients revealed lymphocytic endotheliitis in lung, heart, kidney, liver and small intestine, a pathological picture reminiscent of what is seen in skin lesions, suggesting that SARS-CoV-2 infection facilitates the induction of endothelial inflammation in several organs as a direct consequence of viral involvement and of host inflammatory response [61].
The histopathological features of these lesions also vary, corresponding to the diversity of clinical manifestations. In maculopapular lesions, it is sometimes quite difficult to differentiate a drug reaction from a viral infection. However, the presence of multinucleated ballooning cells suggests a cytopathic effect, lending weight to the hypothesis that the lesions are due to COVID-19. For varicella-like acantholytic lesions, Grover’s disease should be eliminated by the presence of endothelial swelling and vascular damage or extensive epidermal necrosis, and a herpes infection by immunohistochemistry and cultures. The histology of chilblain lesions are quite characteristic, with dermal edema and deep lymphocytic vasculitis, and purpuric and livedoid lesions show vascular thrombosis. In Kawasaki-like lesions and urticarial vasculitis, leukocytoclastic vasculitis is observed. Other lesions such as urticaria, pityriasis rosea-like, subcutaneous and pustular lesions do not seem to be specific. These features underline the nature of epidermal (acantholysis, multinucleated ballooning keratinocytes, dyskeratosis, necrosis) and dermal vascular (lymphocytic vasculitis, endotheliitis) lesions—and in severe cases, microvascular injury and thrombosis—associated with COVID-19, and provide important clues to their pathological mechanisms.

3.3. Potential Pathological Mechanisms

The pathological mechanisms of skin lesions in COVID-19 patients remain poorly understood. Cutaneous manifestations in COVID-19 may be classified into two major groups regarding their pathomechanisms [62]:
(1)
clinical features similar to viral exanthems (an immune response to viral nucleotides)
(2)
cutaneous eruptions secondary to systemic consequences caused by COVID-19 (especially vasculitis and thrombotic vasculopathy).
The possible actions of SARS-CoV-2 on human skin and the resulting potential dermatological manifestations can be summarized as follows [63].
SARS-CoV-2 is a single-stranded RNA virus composed of 16 nonstructural proteins (NSP 1–16) with specific roles in the replication of coronaviruses (CoVs). For example, NSP3 has the ability to block the host’s innate immune response and promote cytokine expression, while NSP5 can inhibit interferon (IFN) signaling, and NSP16 avoids MAD5 (melanoma differentiation-associated gene 5) recognition, depressing innate immunity.
Some studies have shown direct T cell viral infection by the detection SARS-like viral particles and SARS-CoV-2 RNA in T lymphocytes.
In a subset of patients, overactive immune responses may induce immunopathological conditions, or “cytokine storm” (i.e., an increase in pro-inflammatory cytokines, in particular, IL-6); these cytokines could reach the skin and stimulate dermal dendritic cells, macrophages, mast cells, lymphocytes and neutrophils, and promote eruptions such as erythema, urticarial lesions, vesicles and others (JAK inhibitors for IL-6).
Complement activation (C5b-9 and C4d) by SARS-CoV-2 spike glycoproteins has been shown in retiform purpura [18]. In pseudochilblain and purpuric lesions, an obliterative microangiopathy consisting of endothelial and intensive myointimal growth with complement activation has been observed. This mechanism, together with increased vascular permeability, could contribute to obliterative vascular lumen and hemorrhage in COVID-19 patients [64].
Aerosolized uptake of SARS-CoV-2 leads to infection of the functional receptor angiotensin-converting enzyme (ACE) type II (ACE2)-expressing target cells such as alveolar type 2 or other unknown target cells. ACE2 is present in the skin in the basal layer of the epidermis, in endothelial cells of dermal blood vessels and in eccrine adnexal tissue [65]; a direct pathogenic effect of the virus in the epidermis via ACE2, leading to acantholysis and dyskeratosis, has been proposed [58]. COVID-19-endotheliitis via ACE2 could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19 [62]. SARS-CoV-2 was shown to be absent in only four studied lesional skin biopsy samples (Table 1). However, in two recent reports, its presence was confirmed by immunohistochemistry in the endothelial cells of chilblain lesions, suggesting a causal relationship between the lesions and SARS-CoV-2 [66,67]. In one of them SARS-CoV-2 particles were found in the cytoplasm of endothelial cells by electron microscopy [66]. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains, and perhaps also in a group of patients severely affected by COVID-19 presenting with microangiopathic damage [66].
In order for the virus to attach (spike protein, S) to ACE2, activation by TMPRSS2, a type II transmembrane serine protease, is needed. The TMPRSS2 gene is located on human chromosome 21; one of its significant features is that several androgen receptor elements (AREs) are located upstream of the transcription start site. The first intron COVID-19 could affect males more than females due to the relationship between TMPRSS2 and androgen levels; the greater prevalence of COVID-19 in males in Spain offers a potential clue to the role of androgens in increasing COVID-19 severity, due to the higher prevalence of androgenetic alopecia among patients [9].
A better understanding of the clinical, histopathological and pathogenetic aspects of COVID-19 in different organs, including skin, will help guide early diagnoses and treatment of this new and fatal human disease with intriguing cutaneous manifestations.

Author Contributions

G.K. and A.K. contributed to the acquisition, analysis and interpretation of data for the work, participated in original draft preparation. J.-H.S. made substantial contributions to the conception and design of the work; participated in original draft preparation, revising it critically for important intellectual content. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

In this section you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments).

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1. Clinical and histopathological characteristics of skin lesions in COVID-19 patients reported in 57 publications.
Table 1. Clinical and histopathological characteristics of skin lesions in COVID-19 patients reported in 57 publications.
Nb & SexAgeClinical FeaturesLocalization of Skin LesionsTime from 1st SymptomsMean DurationHistopathological FeaturesSARS-CoV-2 RT-PCRRef.
SwabSkin Biopsy
1 F8 yPapulovesicular skin eruptionTrunk–5 days7 daysNo biopsypositiveND[7]
1 M57 yExanthemErythematous crusted papules–2 days10 daysSuperficial perivascular vesicular dermatitis, focal acantholytic suprabasal clefts, dyskeratotic and ballooning, herpes-like keratinocytes and swollen vessels with dense lymphocyte infiltration mixed with rare eosinophils in the dermis.positiveND[8]
1 F27 yUrticarial erythematous plaquesFace and acral invol- vement–2 daysNDNo biopsypositiveND[12]
1 M68 yPainful blistersRight side of the right loin–2 daysNDNo biopsypositiveND[52]
1 F43 yDusky red, nonpruritic, nonblanching dyschromia.Periorbital skin–2 daysA few daysNo biopsypositiveND[54]
1 M50 y
1 F39 yUrticarial rashForearms–2 daysNDNo biopsypositiveND[27]
1 M71 yEntire body–a few days
1 F39 yUrticarial rashTrunk, thigh and other areas–1 dayNDNo biopsyNDND[46]
1F50 yErythematous annular and irregular wheals.Shoulders, elbow,
knee and buttocks
Onset2 daysNo biopsyNDND[47]
1F20 y
17 M 3 Fmean: 51 ySebopsoriasis (n = 1), facial herpes (n = 1), exanthem (n = 9), acral vasculitic eruption (n = 6), urticaria (n = 2) and varicelliform rash (n = 1).Face, acral sites and entire bodyOnset (n = 2), later (n = 18).NDExanthem: perivascular dermatitis and vasculitis.positiveND[38]
1 M58 yErythematous macules arranged in a morbilliform pattern.Legs, thighs, forearms, arms, shoulders, back, chest and abdomen1 day6 daysNo biopsypositiveND[23]
1 M13 yErythemato-violaceous, rounded lesions.Plantar surface of the first toe and dorsal surface of the second toe on the right and left feet, respectively2 daysAround 10 daysNo biopsynot doneND[22]
16 M
6 F
mean: 60 yVaricella-like papulovesicular exanthem.Trunk and limbs3 days8 daysVacuolar degeneration of the basal layer with multinucleate, hyperchromatic keratinocytes and dyskeratotic cells. Absence of inflammatory infiltrate.positiveND[21]
1 F59 yErythematousArms, trunk and lower limbs3 days5 daysSuperficial perivascular dermatitis with slight lymphocytic exocytosis, swollen thrombosed vessels with neutrophils, eosinophils and nuclear debris.positiveND[8]
1 M16 yErythemato-edematous, partially eroded macules and plaques.Dorsal aspects of the fingers3 daysNDEdema of the papillary dermis, superficial and deep lymphocytic infiltrate in a perivascular and strong perieccrine pattern.positiveND[40]
1 F64 ySDRIFE-like erythematous rash.Antecubital fossa, trunk and axillary folds4 days5 daysNo biopsypositiveND[19]
1 F56 yPainful ulcers with irregular margins and varying sizes in red and nonhemorrhagic background.Hard palate5 days7 daysSiffuse edema with mucosal desquamation along with granulation and ulceration under the mucosa with invasion of mononuclear cells with large and glassy nuclei.positiveND[55]
1 M75 yAnterior of the tongueND
1 M66 yPapules with pseudovesicular aspect and superficial crustsTrunk6 days10 daysExtensive epidermal necrosis with acantholysis and large multinucleated keratinocytes with ballooning degeneration in the superficial dermis, a dense perivascular lymphocytic infiltrate with some extravasated erythrocytes, neutrophils and eosinophils, dermal vessels displaying endothelial swelling with lymphocytic vasculitic alterations and endotheliitis in the absence of fibrinoid necrosis or thrombosis.positivenegative[43]
1 F32 yUrticarial rashTrunk and limbs6 daysNDPerivascular infiltrate of lymphocytes, some eosinophils and upper dermal edema.NDND[4]
1 M20 yDiffuse, morbilliform, maculo- papular rash.Trunk and extremities, sparing the face6 daysNDNo biopsypositiveND[14]
1 F55 ySmall, monomorphic vesicles of 2–3 mm diameter, often excoriated at their top.Trunk6 days11 daysScantholysis, intraepidermal vesicle, suprabasal clefts, prominent, “pomegranate-like” dyskeratosis, suspected nuclear viral inclusions and multinucleated cells.positiveND[58]
1 M55 y22 days
1 F89 yMaculesTrunk and arms7 days8 daysSuperficial and deep perivascular dermatitis with cuffs of lymphocytes surrounding blood vessels in a vasculitic pattern.positiveND[8]
5 M 1 Fmean: 15 yRed to violaceous macules and dusky, purpuric plaques.Mid- and distal- aspects of the toes7 daysNDSuperficial and deep perivascular and perieccrine lymphocytic infiltrate with junctional vacuolar change and lymphocytic vasculitis, with no evidence of thrombosis in the vessels.negativeND[33]
1 M81 yPetechial lesions initially, then hemorrhagic bullae and necrotic plaques.Fingers and toes7 daysNDPartial-thickness necrosis of the superficial portion of the epidermis and a mild inflammatory infiltrate in the papillary dermis composed predominantly of neutrophils, red blood cell extravasation and small vessel vasculitis with no thrombi, papillary dermal edema or extension of the infiltrate to the deep dermis.negativeND[34]
15NDskin rashND7 daysNDNo biopsyNDND[17]
1 M67 yTransient unilateral livedo reticularisRight anterior thigh7 days19 hNo biopsypositiveND[20]
1 F47 yRight leg10 days20 min
1NDSigitate papulosquamous eruptionPeriumbilical area, lateral side of the trunk and thighs8 days7 daysMild diffuse spongiosis in the epidermis and rounded spongiotic vesicles containing aggregates of lymphocytes and Langerhans cells, as well as mild papillary edema and lymphohistiocytic infiltrate in the dermis.positivenegative[30]
71 M
61 F
mean: 19.9 yChilblain-like (n = 95), erythema multiforme-like (n = 37)Hands and feet9.2 days8.7 daysNo biopsypositive (2 in 11)ND[5]
1 F84 yErythemato-purpuric, millimetric, coalescing macules.Periaxillary area11 daysNDNo biopsyNDND[15]
1 M32 yRetiform purpuraButtocks11 daysNDThrombogenic vasculopathy accompanied by striking and extensive deposition of C5b- 9 and C4d within the microvasculature.positiveND[18]
1 F66 yDusky purpuric patchesPalms and soles11 days
1 F40 yLivedo racemosaChest, legs and armsND
1 MNDErythematous and edematous plaques with a purpuric center.Buttocks12 daysNDPerivascular neutrophilic inflammation and blood extravasation in the dermis with endothelial swelling, necrosis and fibrin deposition.NDND[49]
1 F28 yErythematous-yellowish papules and plaques.Both heels13 daysNDNo biopsypositiveND[3]
1 M26 yErythematous, slightly edematous eruption.Malar region, neck and ears14 days6 daysNo biopsynot doneND[13]
1 F60 yDistally convex, half moon-shaped red band surrounding the distal margin of the lunula.All fingernails14 daysStill present after 1 monthNo biopsypositiveND[37]
1 F62 ySsymptomatic, nonitchy rash consisting of livedoid patches/livedoid macules.Back, abdomen and face/bilateral periorbital skin, back of the nose and frontal region14 days24 hNo biopsypositiveND[53]
1 F60 yUrticarial eruptionND16 daysNDSlight vacuolar-type interface dermatitis with occasional necrotic keratinocytes and no eosinophils.NDND[48]
42M
32F
mean: 19.6 yErythematous papules (76.4%), similar to chilblains and purpuric macules (40.54%).Hands and feet16.15 daysNDLymphocytic perivascular and perieccrine infiltrate with no vascular occlusion or intravascular thrombi.positive (1 in 11)ND[31]
6 M
6F
mean: 66.3 yItching papular exanthem.Entire body20.4 daysNDSuperficial perivascular inflammation with eosinophils (n = 1) and lichenoid pattern with eosinophils (n = 1).positiveND[39]
1 F50 ySmall, monomorphic vesicles of 2–3 mm diameter, often excoriated at their top.Trunk, upper
limbs, face
21 days10 daysAcantholysis, intraepidermal vesicle, suprabasal clefts, prominent, “pomegranate-like” dyskeratosis, suspected nuclear viral inclusions and multinucleated cells.positiveND[58]
1 F70 yDiffuse, pruritic pustular eruption.Face, trunk and upper limbs21 days30 daysSubcorneal pustules with mild focal acanthosis and spongiosis, neutrophilic exocytosis, sparse keratinocyte necrosis, and a perivascular lymphocytic infiltrate with rare neutrophils and eosinophils.NDND[36]
153M
222F
mean: 49 yMaculopapular (47%),
pseudochilblain (19%),
urticarial (19%),
vesicular (9%) and
livedo/necrosis (6%)
Extremities, Hands and feet, trunk, limbs and acral areasbefore, at the same time or after8.6 days
12.7days
6.8 days
10.4 days
ND
No biopsypositive (234 in 375)ND[41]
8 F
6 M
11 children
mean: 14 y
3 adults
mean: 29 y
Perniosis-like erythemato-violaceous papules and macules with possible bullous evolution or digital swelling or erythemato-papular targetoid lesionsFeet in eight cases, hands in four cases, both sites in two cases (elbow in one case)ND2–4 weeksAcral lesions, a diffuse dense lymphoid infiltrate of the superficial and deep dermis, as well as hypodermis, with a prevalent perivascular pattern and signs of endothelial activation/Targetoid lesions of the elbows, mild superficial perivascular dermatitis.negative (in 5)ND[25]
18NDErythematous rash (n = 14), widespread urticaria (n = 3) or varicella-like vesicles (n = 1)TrunkNDA few daysNo biopsypositiveND[24]
5NDErythematous rash (n = 2), urticaria (n = 2) and herpes lesion (n = 1)Face and the upper body (n = 4), mouth (n = 1)ND1–6 daysNo biopsypositiveND[11]
1F74 yLivedoid macules initially, then digital infarcts and ischemic necrosisThird fingertip of the left handNDNDNo biopsypositiveND[32]
2 F27 yRed-purple papulesDorsal side of fingers bilaterallyNDNDNo biopsypositiveND[2]
35 yDiffuse erythemaSubungual area of the right thumb
1 F19 yerythemato-violaceous plaquesFeet and toesNDNDNo biopsyNDND[6]
41 Mmean: 58 yAGA: 29 (71%) with clinically significant AGA and 16 (39%) with severe AGAScalpNDNDNo biopsyNDND[9]
2NDSkin rashNDNDNDNo biopsypositiveND[10]
1NDDengue-like petechial rash.NDNDNDNo biopsypositiveND[16]
1 FNDPainful erythematous patches with residual purpura.Trunk and hipsNDNDBlood extravasation and neutrophilic perivascular inflammation with prominent karyorrhexis.positiveND[49]
4NDErythematous-violaceous macules, sometimes more necrotic in appearance, even with blistering lesions.Soles of the feet, finger and/or toe pads or periungual locationNDNDNo biopsyNDND[26]
2NDUrticariaNDNDNDNo biopsypositiveND[28]
4M
3F
mean: 59 yCyanosis, skin bulla and dry gangrene.Finger/ToeNDNDNo biopsyNDND[29]
1M17 yChilblain-like lesionsToes of both feet and heelsNDNDNo biopsynegativeND[35]
10M
7F
mean: 32 yPed-violaceous, edematous, rarely necrotic lesions.Toes, feet and fingersNDNDDiffuse upper dermal edema and a dense dermal (perivascular and peri-eccrine sweat gland) lymphocytic infiltrate, endothelial cell swelling and extravasated red blood cells, thrombi, fibrin and IgM deposits in vessels.negativenegative[42]
7M
3F
mean: 7.5 yPolymorphic rashNDNDNDNo biopsy2 positive
8 negative
ND[44]
8NDMaculopapular eruption/ exanthema/Purpuric maculo-papulo-vesicular rash/Papular erythematousexanthema/Severe macular haemorrhagic eruption.Trunk/Trunk and limbs/
Trunk/Extremities
NDNDDyskeratotic cells, ballooning multinucleated cells and sparse necrotic keratinocytes with lymphocytic satellitosis/Nests of Langerhans cells within the epidermis and diffuse telangiectatic blood vessels in the upper dermis/Perivascular spongiotic dermatitis and a dense perivascular lymphocytic infiltration eosinophilic rich around the swollen blood vessels with extravasated erythrocytes/Edematous dermis with many eosinophils, cuffs of lymphocytes around blood vessels in a lymphocytic vasculitis/Intravascular microthrombi in the small dermal vessels.NDND[45]
1M68 yMorbilliform rash/Purpuric lesions/Ulcerated, purpuric plaque with retiform-livedoid borders.Trunk/Feet/ButtocksNDNDGroups of apoptotic keratinocytes in the epidermis/ND/Features consistent with a thrombotic vasculopathy.NDND[46]
1 F72 yErythematous and slightly edematous patches/Isolated typical target lesions.Trunk and upper and lower limbs/Both thighsNDNDMixed perivascular and interstitial infiltrate, including lymphocytes, granulocytes, histiocytes, plasma cells and mast cells.positiveND[50]
1 F29 yPruriginous and painful subcutaneous nodular lesions.Legs, thighs, forearms and left shoulderNDNDLobular panniculitis with lymphocytes, histiocytes and numerous eosinophils.positiveND[51]
1 F68 yPainful vesicular rash.Left side of the chest and nape of the neckNDNDNo biopsypositiveND[52]
1 M16 yPainful dusky erythematous plaques.Posterior scalpNDNDNecrosis of the epidermis and most of the dermis with extravasation of erythrocytes and fibrin thrombi in the capillaries, as well as infiltration of neutrophils with nuclear debris in vessel walls.negativenegative[56]
8 M
8 F
mean: 10 (4.5 to 12.5)Maculopapular rash in 13 (81%) patients.NDNDNDNo biopsypositive (11 in 16)ND[57]
AGA = Androgenetic alopecia. SDRIFE = Symmetrical drug-related intertriginous and flexural exanthema. ND = Not Defined.
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