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Skin Manifestations Associated With COVID-19: Current Knowledge and Future Perspectives
Skin Manifestations Associated With COVID-19: Current Knowledge and Future Perspectives
Angelo Valerio Marzano a, b
a Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; b Department of
Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; c Department of Medical Surgical
Keywords Introduction
COVID-19 · Cutaneous manifestations · SARS-CoV-2
In December 2019, a novel zoonotic RNA virus named
“severe acute respiratory syndrome coronavirus 2” (SARS-
Abstract CoV-2) was isolated in patients with pneumonia in Wuhan,
Background: Coronavirus disease-19 (COVID-19) is an ongo- China. Since then, the disease caused by this virus, called
ing global pandemic caused by the “severe acute respiratory “coronavirus disease-19” (COVID-19), has spread through-
syndrome coronavirus 2” (SARS-CoV-2), which was isolated out the world at a staggering speed becoming a pandemic
for the first time in Wuhan (China) in December 2019. Com- emergency [1]. Although COVID-19 is best known for
mon symptoms include fever, cough, fatigue, dyspnea and causing fever and respiratory symptoms, it has been report-
hypogeusia/hyposmia. Among extrapulmonary signs asso- ed to be associated also with different extrapulmonary
ciated with COVID-19, dermatological manifestations have manifestations, including dermatological signs [2]. Whilst
been increasingly reported in the last few months. Summa- the COVID-19-associated cutaneous manifestations have
ry: The polymorphic nature of COVID-19-associated cutane- been increasingly reported, their exact incidence has yet to
ous manifestations led our group to propose a classification, be estimated, their pathophysiological mechanisms are
which distinguishes the following six main clinical patterns: largely unknown, and the role, direct or indirect, of SARS-
(i) urticarial rash, (ii) confluent erythematous/maculopapu- CoV-2 in their pathogenesis is still debated. Furthermore,
lar/morbilliform rash, (iii) papulovesicular exanthem, (iv) chil- evidence is accumulating that skin manifestations associ-
blain-like acral pattern, (v) livedo reticularis/racemosa-like ated with COVID-19 are extremely polymorphic [3]. In this
pattern, (vi) purpuric “vasculitic” pattern. This review sum- regard, our group proposed the following six main clinical
marizes the current knowledge on COVID-19-associated cu- patterns of COVID-19-associated cutaneous manifesta-
taneous manifestations, focusing on clinical features and tions in a recently published review article: (i) urticarial
therapeutic management of each category and attempting rash, (ii) confluent erythematous/maculopapular/morbil-
to give an overview of the hypothesized pathophysiological liform rash, (iii) papulovesicular exanthem, (iv) chilblain-
mechanisms of these conditions. © 2020 S. Karger AG, Basel like acral pattern, (v) livedo reticularis/racemosa-like pat-
Erythematous- Reticular
Erythematous Erythematous Violaceous papules,
Wheals violaceous macules erythematous-
macules and papules papules and vesicles ulceration
and patches violaceous macules
tern, (vi) purpuric “vasculitic” pattern (shown in Fig. 1) [2]. ia-like eruptions have been subsequently described in
Other authors have attempted to bring clarity in this field, other cohort studies. Galván Casas et al. [4] stated that
suggesting possible classifications of COVID-19-associated urticarial rash occurred in 19% of their cohort, tended to
cutaneous manifestations [4–6]. Finally, distinguishing no- appear simultaneously with systemic symptoms, lasted
sological entities “truly” associated with COVID-19 from approximately 1 week and was associated with medium-
cutaneous drug reactions or exanthems due to viruses oth- high severity of COVID-19. Moreover, itch was almost
er than SARS-CoV-2 remains a frequent open problem. always present [4]. Freeman et al. [10] found a similar
Herein, we have striven to provide a comprehensive prevalence of urticaria (16%) in their series of 716 cases,
overview of the cutaneous manifestations associated with in which urticarial lesions predominantly involved the
COVID-19 subdivided according to the classification by trunk and limbs, relatively sparing the acral sites. As
Marzano et al. [2], focusing on clinical features, histo- shown in Table 1, urticaria-like signs accounted for 11.9%
pathological features, hypothesized pathophysiological of cutaneous manifestations seen in an Italian multicen-
mechanisms and therapeutic management. tric cohort study on 159 patients [unpubl. data]. Urticar-
ial lesions associated with fever were reported to be early
or even prodromal signs of COVID-19, in the absence of
Urticarial Rash respiratory symptoms, in 3 patients [11–13]. Therefore,
the authors of the reports suggested that isolation is need-
Clinical Features and Association with COVID-19 ed for patients developing such skin symptoms if COV-
Severity ID-19 infection is suspected in order to prevent possible
It is well known that urticaria and angioedema can be SARS-CoV-2 transmission [11–13]. COVID-19-related
triggered by viral and bacterial agents, such as cytomega- urticaria occurred also in a familial cluster, involving 2
lovirus, herpesvirus, and Epstein-Barr virus and myco- patients belonging to a Mexican family of 5 people, all in-
plasma. However, establishing a cause-effect relationship fected by SARS-CoV-2 and suffering also from anosmia,
may be difficult in single cases [7, 8]. Urticarial eruptions ageusia, chills and dizziness [14]. Angioedema may ac-
associated with COVID-19 have been first reported by company COVID-19-related urticaria, as evidenced by
Recalcati [9] in his cohort of hospitalized patients, ac- the case published in June 2020 of an elderly man present-
counting for 16.7% of total skin manifestations. Urticar- ing with urticaria, angioedema, general malaise, fatigue,
2 Dermatology Genovese/Moltrasio/Berti/Marzano
DOI: 10.1159/000512932
Table 1. Prevalence of different clinical patterns in the main studies on COVID-19-associated cutaneous manifestations
First author (total size of study population) Number of patients Number of patients with Number of patients Number of patients Number of patients Number of patients
with urticarial confluent erythematous/ with papulo-vesicular with chilblain-like with livedo reticularis/ with purpuric
rash (%) maculopapular/ exanthem (%) acral pattern (%) racemosa-like “vasculitic”
morbilliform rash (%) pattern (%) pattern (%)
Galván Casas [4] (375) 73 (19) 176 (47) 34 (9) 71 (19) 21 (6)
Freeman [10] (716) 55 (8.1) 115 (16.1) 49 (7.2) 422 (62) 46 (6.4) 51 (7.1)
Askin [29] (52) 7 (13.5) 29 (55.8) 3 (5.8) 1 (1.9) 0 8 (15.4)
De Giorgi [20] (53) 14 (26) 37 (70) 2 (4) 0 0 0
Unpublished data from an Italian
multicentric study (159) 19 (11.9) 48 (30.2) 29 (18.2) 46 (28.9) 4 (2.5) 13 (8.2)
fever and pharyngodynia [15]. Urticarial vasculitis has al. [4], for 44% of the skin manifestations included in the
also been described in association with COVID-19 in 2 study by Freeman et al. [10], who further subdivided this
patients [16]. group of cutaneous lesions into macular erythema (13%),
morbilliform exanthems (22%) and papulosquamous le-
Histopathological Findings sions (9%), and for 30.2% of the cutaneous manifestations
Histopathological studies of urticarial rashes are scant. included in the unpublished Italian multicentric study
In a 60-year-old woman with persistent urticarial erup- shown in Table 1. The prevalence of erythematous rash
tion and interstitial pneumonia who was not under any was higher in other studies, like that published by De
medication, Rodriguez-Jiménez et al. [17] found on his- Giorgi et al. [20] in May 2020, in which erythematous
topathology slight vacuolar interface dermatitis with oc- rashes accounted for 70% of total skin manifestations. In
casional necrotic keratinocytes curiously compatible with the series by Freeman et al. [10], macular erythema, mor-
an erythema multiforme-like pattern. Amatore et al. [18] billiform exanthems and papulosquamous lesions were
documented also the presence of lichenoid and vacuolar predominantly localized on the trunk and limbs, being
interface dermatitis, associated with mild spongiosis, dys- associated with pruritus in most cases. In the same series,
keratotic basal keratinocytes and superficial perivascular these lesions occurred more frequently after COVID-19
lymphocytic infiltrate, in a biopsy of urticarial eruption systemic symptoms’ onset [21]. The clinical picture of the
associated with COVID-19 (Fig. 2). eruptions belonging to this group may range from ery-
thematous confluent rashes to maculopapular eruptions
Therapeutic Options and morbilliform exanthems. Erythematous lesions may
Shanshal [19] suggested low-dose systemic corticoste- show a purpuric evolution [21] or coexist from the begin-
roids as a therapeutic option for COVID-19-associated ning with purpuric lesions [22]. Erythematous papules
urticarial rash. Indeed, the author hypothesized that low- may also be arranged in a morbilliform pattern [23]. In a
dose systemic corticosteroids, combined with nonsedat- subanalysis of the COVID-Piel Study [4] on maculopapu-
ing antihistamines, can help in managing the hyperactiv- lar eruptions including also purpuric, erythema multi-
ity of the immune system in COVID-19, not only to con- forme-like, pityriasis rosea-like, erythema elevatum
trol urticaria, but also to improve possibly the survival diutinum-like and perifollicular eruptions, morbilliform
rate in COVID-19. exanthems were the most frequent maculopapular pat-
tern (n = 80/176, 45.5%) [24]. This study showed that in
most cases lesions were generalized, symmetrical and
Confluent Erythematous/Maculopapular/ started on the trunk with centrifugal progression. In the
Morbilliform Rash same subanalysis, hospital admission due to pneumonia
was very frequent (80%) in patients with a morbilliform
Clinical Features and Association with COVID-19 pattern [24]. In this group, the main differential diagno-
Severity ses are represented by exanthems due to viruses other
Maculopapular eruptions accounted for 47% of all cu- than SARS-CoV-2 and drug-induced cutaneous reac-
taneous manifestations in the cohort of Galván Casas et tions.
c d
Fig. 2. Histopathological features of the main cutaneous patterns associated with COVID-19. a Urticarial rash.
b Confluent erythematous maculopapular/morbilliform rash. c Chilblain-like acral lesions. d Purpuric “vascu-
litic” pattern.
4 Dermatology Genovese/Moltrasio/Berti/Marzano
DOI: 10.1159/000512932
case series of 22 patients published in April 2020 [28]. nent acantholysis and dyskeratosis associated with the
In this article, it was originally described as “varicella- presence of an unilocular intraepidermal vesicle in a su-
like” due to resemblance of its elementary lesions to prabasal location. Based on these histopathological find-
those of varicella. However, the authors themselves un- ings, the authors refused the term “varicella-like rash”
derlined that the main clinical features of COVID- and proposed a term which was more suitable in their
19-associated papulovesicular exanthem, namely trunk view: “COVID-19-associated acantholytic rash.” Histo-
involvement, scattered distribution and mild/absent pathological findings of another case of papulovesicular
pruritus, differentiated it from “true” varicella. In this eruption revealed extensive epidermal necrosis with ac-
study, skin lesions appeared on average 3 days after sys- antholysis and swelling of keratinocytes, ballooning de-
temic symptoms’ onset and healed after 8 days, without generation of keratinocytes and signs of endotheliitis in
scarring sequelae [28]. The exact prevalence of papulo- the dermal vessels [33]. Acantholysis and ballooned ke-
vesicular exanthems is variable. Indeed, in a cohort of ratinocytes were found also by Fernandez-Nieto et al.
375 patients with COVID-19-associated cutaneous [31] in 2 patients.
manifestations [4], patients with papulovesicular exan- The differential diagnosis with infections caused by
them were 34 (9%), while they were 3 out of 52 (5.8%), members of the Herpesviridae family has been much de-
1 out of 18 (5.5%) and 2 out of 53 (4%) in the cohorts bated. Tammaro et al. [34] described the onset of numer-
published by Askin et al. [29], Recalcati [9] and De ous, isolated vesicles on the back 8 days after COVID-19
Giorgi et al. [20], respectively. In the Italian multicen- diagnosis in a Barcelonan woman and reported on 2 pa-
tric study shown in Table 1, papulovesicular rash ac- tients from Rome presenting with isolated, mildly pru-
counted for 18.2% of skin manifestations. Further- ritic erythematous-vesicular lesions on their trunk, spec-
more, even if papulovesicular exanthem tends to in- ulating that these manifestations might be due to viruses
volve more frequently the adult population, with a belonging to the Herpesviridae family. On the other hand,
median age of 60 years in the study by Marzano et al. classic herpes zoster has been reported to complicate the
[28], also children may be affected [30]. Galván Casas course of COVID-19 [35].
et al. [4] reported that vesicular lesions generally in- The controversy regarding the role of herpesvirus in
volved middle-aged patients, before systemic symp- the etiology of papulovesicular exanthems fuelled an in-
toms’ onset in 15% of cases, and were associated with tense scientific debate. Indeed, some authors raised the
intermediate COVID-19 severity. Fernandez-Nieto et question whether papulovesicular exanthem associated
al. [31] conducted a prospective study on 24 patients with COVID-19 could be diagnosed without ruling out
diagnosed with COVID-19-associated vesicular rash. varicella zoster virus and herpes simplex virus with
In this cohort, the median age (40.5 years) was lower Tzanck smear or polymerase chain reaction (PCR) for the
than that reported by Marzano et al. [28], and COV- Herpesviridae family in the vesicle fluid or on the skin
ID-19 severity was mostly mild or intermediate, with [36, 37]. In our opinion, even if seeking DNA of Herpes-
only 1 patient requiring intensive unit care support. In viridae family members is ideally advisable, clinical diag-
our cohort of 22 patients, a patient was hospitalized in nosis may be reliable in most cases, and the role of herpes
the intensive care unit and 3 patients died [28]. Vesicu- viruses as mere superinfection in patients with dysfunc-
lar rash, which was generally pruritic, appeared after tional immune response associated with COVID-19
COVID-19 diagnosis in most patients (n = 19; 79.2%), needs to be considered [38]. To our knowledge, SARS-
with a median latency time of 14 days [31]. Two differ- CoV-2 has not been hitherto isolated by means of reverse
ent morphological patterns were found: a widespread transcriptase PCR in the vesicle fluid of papulovesicular
polymorphic pattern, more common and consisting of rash [33, 31].
small papules, vesicles and pustules of different sizes,
and a localized pattern, less frequent and consisting of Therapeutic Options
monomorphic lesions, usually involving the mid chest/ No standardized treatments for COVID-19-related
upper abdominal region or the back [31]. papulovesicular exanthem are available, also given that it
is self-healing within a short time frame. Thus, a “wait-
Histopathological Findings and-see” strategy may be recommended.
Mahé et al. [32] reported on 3 patients with typical
COVID-19-associated papulovesicular rash, in which
the histological pattern of skin lesions showed promi-
Histopathological and Pathophysiological Findings Clinical Features and Association with COVID-19
Chilblain-like lesions share many histopathological fea- Severity
tures with idiopathic and autoimmunity-related chilblains, Livedo describes a reticulate pattern of slow blood
including epidermal necrotic keratinocytes, dermal edema, flow, with consequent desaturation of blood and bluish
6 Dermatology Genovese/Moltrasio/Berti/Marzano
DOI: 10.1159/000512932
cutaneous discoloration. It has been divided into: (i) li- Therapeutic Options
vedo reticularis, which develops as tight, symmetrical, In view of the absence of significant therapeutic op-
lace-like, dusky patches forming complete rings sur- tions for livedo reticularis/racemosa-like lesions associ-
rounding a pale center, generally associated with cold- ated with COVID-19, a “wait-and-see” strategy may be
induced cutaneous vasoconstriction or vascular flow dis- suggested.
turbances such as seen in polycythemia and (ii) livedo
racemosa, characterized by larger, irregular and asym-
metrical rings than seen in livedo reticularis, more fre- Purpuric “Vasculitic” Pattern
quently associated with focal impairment of blood flow,
as it can be seen in Sneddon’s syndrome [66]. Clinical Features and Association with COVID-19
In our classification, the livedo reticularis/racemosa- Severity
like pattern has been distinguished by the purpuric “vas- The first COVID-19-associated cutaneous manifesta-
culitic” pattern because the former likely recognizes a oc- tion with purpuric features was reported by Joob et al.
clusive/microthrombotic vasculopathic etiology, while [76], who described a petechial rash misdiagnosed as den-
the latter can be more likely considered the expression of gue in a COVID-19 patient. Purpuric lesions have been
a “true” vasculitic process [2]. Instead, the classification suggested to occur more frequently in elderly patients
by Galván Casas et al. [4] merged these two patterns into with severe COVID-19, likely representing the cutaneous
the category “livedo/necrosis”. manifestations associated with the highest rate of COV-
In a French study on vascular lesions associated with ID-19-related mortality [4]. This hypothesis is corrobo-
COVID-19, livedo was observed in 1 out of 7 patients rated by the unfavorable prognosis observed in several
[43]. In the large cases series of 716 patients by Freeman cases reported in the literature [77, 78].
et al. [10], livedo reticularis-like lesions, retiform purpura The purpuric pattern reflects the presence of vasculitic
and livedo racemosa-like lesions accounted for 3.5, 2.6 changes probably due to the direct damage of endothelial
and 0.6% of all cutaneous manifestations, respectively. In cells by the virus or dysregulated host inflammatory re-
the multicentric Italian study, livedo reticularis/racemo- sponses induced by COVID-19.
sa-like lesions accounted for 2.5% of cutaneous manifes- These lesions are likely to be very rare, representing
tations (Table 1). 8.2% of skin manifestations included in the Italian multi-
The pathogenic mechanisms at the basis of small blood centric study shown in Table 1. In their case series of 7
vessel occlusion are yet unknown, even if neurogenic, mi- patients with vascular skin lesions related to COVID-19,
crothrombotic or immune complex-mediated etiologies Bouaziz et al. [43] reported 2 patients with purpuric le-
have been postulated [67]. sions with (n = 1) and without (n = 1) necrosis. In the se-
Livedo reticularis-like lesions are frequently mild, ries by Freeman et al. [10], 12/716 (1.8%) and 11/716
transient and not associated with thromboembolic com- (1.6%) cases of patients with palpable purpura and den-
plications [68, 69]. On the contrary, livedo racemosa-like gue-like eruption, respectively, have been reported.
lesions and retiform purpura have often been described Galván Casas et al. [4] reported 21 patients with “livedo/
in patients with severe coagulopathy [60–72]. necrosis,” most of whom presenting cutaneous signs in
concomitance with systemic symptoms’ onset.
Histopathological and Pathophysiological Findings Purpuric lesions may be generalized [79], localized in
The histopathology of livedoid lesions associated with the intertriginous regions [80] or arranged in an acral dis-
COVID-19 has been described by Magro et al. [73], who tribution [81]. Vasculitic lesions may evolve into hemor-
observed in 3 patients pauci-inflammatory microthrom- rhagic blisters [77]. In most severe cases, extensive acute
botic vasculopathy. The same group demonstrated that in necrosis and association with severe coagulopathy may be
the thrombotic retiform purpura of patients with severe seen [78]. Dermoscopy of purpuric lesions revealed the
COVID-19, the vascular thrombosis in the skin and in- presence of papules with incomplete violaceous rim and
ternal organs is associated with a minimal interferon re- a central yellow globule [82].
sponse permitting increased viral replication with release
of viral proteins that localize to the endothelium inducing Histopathological Findings
widespread complement activation [74], which is fre- When performed, histopathology of skin lesions
quent in COVID-19 patients and probably involved in showed leukocytoclastic vasculitis [77, 79], severe neutro-
the pathophysiology of its clinical complications [75]. philic infiltrate within the small vessel walls and in their
Urticarial rash Itching urticarial rash predominantly Intermediate Vacuolar interface Low-dose systemic
involving the trunk and limbs; angioedema severity dermatitis associated with corticosteroids
may also rarely occur superficial perivascular combined with
lymphocytic infiltrate nonsedating
antihistamines
Confluent erythematous/ Generalized, symmetrical lesions starting from Intermediate Superficial perivascular Topical
maculopapular/morbilliform the trunk with centrifugal progression; severity lymphocytic and/or corticosteroids for
rash purpuric lesions may coexist from the onset or neutrophilic infiltrate mild cases;
develop during the course of the skin eruption systemic
corticosteroids for
severe cases
Papulovesicular exanthem (i) Widespread polymorphic pattern consisting Intermediate Prominent acantholysis and Wait and see
of small papules, vesicles and pustules of severity dyskeratosis associated with
different sizes; (ii) localized pattern consisting unilocular intraepidermal
of papulovesicular lesions, usually involving vesicles in a suprabasal
the mid chest/upper abdominal region or the location
back
Chilblain-like acral pattern Erythematous-violaceous patches or plaques Asymptomatic Perivascular and Wait and see
predominantly involving the feet or, to a lesser status periadnexal dermal
extent, hands. Pain/burning sensation as well lymphocytic infiltrates
as pruritus were commonly reported
symptoms
Livedo reticularis/ Livedo reticularis-like lesions: mild, transient, Livedo reticularis- Pauci-inflammatory Wait and see
racemosa-like pattern symmetrical, lace-like, dusky patches forming like lesions: microthrombotic
complete rings surrounding a pale center. intermediate vasculopathy
Livedo racemosa-like lesions: large, irregular severity; livedo
and asymmetrical violaceous annular lesions racemosa-like
frequently described in patients with severe lesions: high severity
coagulopathy
Purpuric “vasculitic” pattern Purpuric lesions may be generalized, arranged High severity Leukocytoclastic vasculitis, Topical
in an acral distribution or localized in the severe perivascular corticosteroids for
intertriginous regions. Purpuric elements may neutrophilic and mild cases;
evolve into hemorrhagic blisters, possibly lymphocytic infiltrate, systemic
leading to necrotic-ulcerative lesions presence of fibrin and corticosteroids for
endothelial swelling severe cases
The correlation between severity of COVID-19 systemic symptoms and skin manifestations has been inferred mainly from the study by Freeman et al.
[10].
8 Dermatology Genovese/Moltrasio/Berti/Marzano
DOI: 10.1159/000512932
tions is likely to be still incomplete, and it is expected that Key Message
new entities associated with this infection will be de-
Although COVID-19-associated cutaneous manifestations
scribed. have been increasingly reported, their pathophysiological mecha-
nisms need to be extensively explored. The conditions may be dis-
tinguished in six clinical phenotypes, each showing different his-
Conclusion topathological patterns.
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DOI: 10.1159/000512932