Cutaneous Manifestations in the Context of SARS-CoV-2 Infection (COVID-19)

Abstract

The coronavirus 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had enormous health, economic, and social consequences. The clinical spectrum of cutaneous manifestations observed in patients with COVID-19 is both heterogeneous and complex. To date, reports have identified 5 main categories: acral lesions, vesicular rashes, urticarial rashes, maculopapular rashes, and livedoid and necrotic lesions. However, these will probably be modified as new information comes to light. Cutaneous manifestations associated with COVID-19 probably reflect the activation of pathogenic pathways by the virus or a response to inflammatory processes, vascular or systemic complications, or even treatments. Familiarity with the cutaneous manifestations of COVID-19 may enable early diagnosis or help guide prognosis.

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ARTICLE IN PRESS
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Actas
Dermosifiliogr.
2020;xxx(xx):xxx---xxx
NOVELTIES
IN
DERMATOLOGY
Cutaneous
Manifestations
in
the
Context
of
SARS-CoV-2
Infection
(COVID-19)夽
J.M.
Carrascosa,∗V.
Morillas,
I.
Bielsa,
M.
Munera-Campos
Servicio
de
Dermatología,
Hospital
Universitari
Germans
Trias
i
Pujol,
Universitat
Autònoma
de
Barcelona,
Badalona,
Barcelona,
Spain
Received
12
May
2020;
accepted
22
August
2020
KEYWORDS
COVID-19;
SARS-CoV-2
infection;
Skin;
Acral
lesions;
Blister;
Urticaria;
Exanthema;
Livedoid
lesions;
Viral
diseases
Abstract
The
coronavirus
2019
(COVID-19)
pandemic,
caused
by
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
has
had
enormous
health,
economic,
and
social
conse-
quences.
The
clinical
spectrum
of
cutaneous
manifestations
observed
in
patients
with
COVID-19
is
both
heterogeneous
and
complex.
To
date,
reports
have
identified
5
main
categories:
acral
lesions,
vesicular
rashes,
urticarial
rashes,
maculopapular
rashes,
and
livedoid
and
necrotic
lesions.
However,
these
will
probably
be
modified
as
new
information
comes
to
light.
Cutaneous
manifestations
associated
with
COVID-19
probably
reflect
the
activation
of
pathogenic
pathways
by
the
virus
or
a
response
to
inflammatory
processes,
vascular
or
systemic
complications,
or
even
treatments.
Familiarity
with
the
cutaneous
manifestations
of
COVID-19
may
enable
early
diagnosis
or
help
guide
prognosis.
©
2020
Published
by
Elsevier
Espa˜
na,
S.L.U.
on
behalf
of
AEDV.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
PALABRAS
CLAVE
COVID-19;
SARS-CoV-2;
Piel;
Acral;
Vesículas;
Manifestaciones
cutáneas
en
el
contexto
de
la
infección
por
SARS-CoV-2
(COVID-19)
Resumen
La
pandemia
por
SARS-CoV-2
ha
causado
un
gran
impacto
desde
el
punto
de
vista
sanitario,
económico
y
social.
La
semiología
dermatológica
se
ha
demostrado
heterogénea
y
compleja.
En
la
actualidad
se
han
definido
cinco
grupos
principales
de
manifestaciones
cutáneas
asociadas
a
la
COVID-19:
lesiones
acrales,
exantemas
vesiculares,
erupciones
urticariales,
exan-
temas
maculopapulares
y
lesiones
livedoides/necróticas.
Sin
embargo,
es
probable
que
esta
夽Please
cite
this
article
as:
Carrascosa
JM,
Morillas
V,
Bielsa
I,
Munera-Campos
M.
Manifestaciones
cutáneas
en
el
contexto
de
la
infección
por
SARS-CoV-2
(COVID-19).
Actas
Dermosifiliogr.
2020.
https://doi.org/10.1016/j.ad.2020.08.002
∗Corresponding
author.
E-mail
address:
jmcarrascosac@hotmail.com
(J.M.
Carrascosa).
1578-2190/©
2020
Published
by
Elsevier
Espa˜
na,
S.L.U.
on
behalf
of
AEDV.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
ADENGL-2442;
No.
of
Pages
9

ARTICLE IN PRESS
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2
J.M.
Carrascosa
et
al.
Urticaria;
Exantema;
Livedo;
Virosis
clasificación
se
modifique
en
el
futuro.
La
clínica
cutánea
es
probablemente
el
reflejo
de
dis-
tintas
vías
patogénicas
con
implicación
variable
de
la
infección
vírica,
del
proceso
inflamatorio,
de
las
complicaciones
vasculares
o
sistémicas
de
la
enfermedad
o
incluso
de
los
tratamientos
administrados.
El
conocimiento
de
las
manifestaciones
cutáneas
puede
permitir
un
diagnóstico
precoz
o
incluso
servir
como
marcador
pronóstico.
©
2020
Publicado
por
Elsevier
Espa˜
na,
S.L.U.
en
nombre
de
AEDV.
Este
es
un
art´
ıculo
Open
Access
bajo
la
licencia
CC
BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
In
December
2019,
cases
of
pneumonia
of
unknown
origin
were
reported
in
Wuhan,
China.
These
were
subsequently
found
to
be
caused
by
a
new
pathogen,
severe
acute
respi-
ratory
syndrome
coronavirus
2
(SARS-CoV-2),
isolated
from
the
lower
respiratory
tract
of
affected
patients.1
This
is
the
third
time
in
the
last
few
decades
that
a
coro-
navirus
endemic
in
animal
species
has
made
the
jump
to
humans.1Prior
to
these
jumps,
coronaviruses
(HCoVs)
alfa
(HCoV-229E
and
HCoV-NL63)
and
beta
(HCoV-JHKU1,
HCoV-
OC43)
had
been
identified
as
endemic
in
humans.
In
2002,
there
was
an
outbreak
in
China
of
a
coronavirus
that
caused
severe
acute
respiratory
syndrome
(SARS).
The
virus
was
named
SARS-CoV,
and
mortality
was
reported
at
around
10%.
In
2012,
a
respiratory
syndrome
caused
by
a
coronavirus
from
the
Middle
East
(MERS-CoV)
was
identified
in
Saudi
Arabia.
In
this
case,
the
mortality
was
35%.
SARS-CoV-2
is
the
new
member
of
this
group.
Disease
associated
with
the
virus
is
denoted
coronavirus
disease-19
(COVID-19),
thus
avoiding
any
geographical
qualification.
The
virus
propagated
out
of
control
and
the
outbreak
was
declared
a
pandemic
by
the
World
Health
Organization
(WHO)
in
March
2020.
The
most
frequent
manifestations
of
infection
with
SARS-
CoV-2
include
fever,
dry
cough,
and
dyspnea;
less
frequent
are
odynophagia,
gastrointestinal
symptoms,
and
anosmia
or
ageusia.
A
high
proportion
of
patients
develop
pneumonia,
often
bilaterally,
and
this
may
lead
to
respiratory
failure
and
the
need
for
respiratory
support
in
more
than
6%
of
cases.2
Around
30%
will
require
admission
to
hospital,
and
5%
to
10%
will
need
admission
to
intensive
care
units
(ICUs).
Mortality
varies
widely,
from
around
2%
to
somewhat
greater
than
10%
in
some
countries,3and
it
appears
higher
in
older
individ-
uals
and
those
with
comorbidities
and
marked
respiratory
compromise.
Infection
can
also
occur
without
symptoms
or
with
very
mild
symptoms,
and
patients
with
these
forms
are
probably
potent
vectors
helping
to
spread
infection.
Pathogenesis
From
the
pathogenic
point
of
view,
the
immune
response
triggered
by
infection
with
SARS-CoV-2
may
result
in
harmful
effects,
such
as
endothelial
cell
dysfunction
and
activation
of
coagulation
pathways;
this
may
explain
the
cardiovascu-
lar
and
thrombotic
complications
that
affect
a
subgroup
of
patients.4
The
corona
(or
crown)
of
this
virus
is
formed
from
protruding
glycoproteins
that
form
spikes.
These
struc-
tures
are
what
enables
the
virus
to
establish
itself
in
the
host.
The
infection
process
occurs
by
binding
to
receptors
of
angiotensin
converting
enzyme
2
(ACE2),
a
membrane
protein
expressed
in
the
cardiovascular
system,
kidneys,
gastrointestinal
system,
and
lungs.
This
enzyme
is
impli-
cated
in
activation
of
the
renin-angiotensin-aldosterone
system
(RAAS).
ACE2,
in
normal
conditions,
counteracts
the
activity
of
the
ACE
enzyme
by
reducing
the
amount
of
angiotensin
II
(vasoconstrictor)
and
increasing
the
vasodila-
tory
metabolites
of
the
RAAS.
According
to
preliminary
data,
when
SARS-CoV-2
infection
occurs,
ACE2
appears
to
be
downregulated
and
this
process
is
implicated
in
the
devel-
opment
of
acute
lung
lesions.5Contact
between
these
2
proteins
(spikes
on
the
virus
and
ACE2)
permits
anchor-
ing
via
the
transmembrane
protease,
serine
2
(TMPRSS2)
enzyme,
setting
in
motion
a
molecular
cascade
by
which
the
virus
is
able
to
enter
the
cells.
The
main
target
is
the
respiratory
tract,
and,
in
particular,
the
alveoli,
where
binding
to
the
ACE2
receptors
on
pneumocytes
occurs.
Alveolar
epithelial
cells
and
macrophages
release
proinflam-
matory
cytokines
that
attract
neutrophils
and
macrophages.
In
normal
conditions,
these
are
components
of
immune
pro-
tection.
However,
in
some
patients,
the
immune
response
is
pathogenic
or
dysregulated,
with
exaggerated
release
of
IL-1␤,
IL-6,
and
IFN-␥;
epithelial
cell
apoptosis;
and
increased
vascular
permeability.
These
events
may
lead
to
the
development
of
SARS,
in
which
obliteration
of
the
alveoli,
formation
of
typical
hyaline
membranes,
and
hyper-
plasia
of
type
II
pneumocytes
have
been
observed.
The
terms
coined
for
this
exaggerated
inflammation
are
cytokine
storm
or
cytokine
release
syndrome.
Blood
workup
often
shows
lymphopenia,
with
elevated
values
for
inflammatory
indicators
(C-reactive
protein,
ferritin,
d-dimer,
IL-6,
and
procalcitonin).2
In
addition,
the
pattern
of
tissue
damage
observed
in
lung
samples
and
some
skin
samples
taken
from
patients
with
severe
COVID-19
suggest
occlusive
microvascular
damage
mediated
by
complement
activation
of
both
the
alterna-
tive
pathway
and
the
lectin-associated
pathway.
Capillary
damage
has
been
found
with
extensive
deposition
of
the
C5b-9
membrane
attack
complex,
C4d,
and
mannose-
binding
lectin-associated
serine
protease
2
(MASP2)
in
the
lungs.
There
have
also
been
reports
of
a
pattern
of
microvas-
cular
thrombotic
disease
mediated
by
complement
in
the
skin
of
patients
similar
to
that
seen
in
livedo
racemosa
lesions
and
retiform
purpura,
with
C5b-9
and
C4d
deposi-
tion.
Activation
of
these
mechanisms
and
interference
in

ARTICLE IN PRESS
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Cutaneous
Manifestations
in
the
Context
of
SARS-CoV-2
Infection
(COVID-19)
3
ACE2
function
in
target
tissues
due
to
viral
action
leads
to
an
increase
in
angiotensin
II,
associated
with
greater
inflam-
mation
and
oxidative
stress.
The
release
of
these
reactive
oxygen
species
and
interference
in
antioxidant
activity
may
increase
complement
activiation.6
Skin
Manifestations
Articles
published
at
the
start
of
the
pandemic
in
China
considered
skin
manifestations
as
a
minor
and
nonspecific
sign,
with
rash
reported
in
0.2%
of
patients.7However,
this
observation
may
presumably
have
been
conditioned
by
the
lack
of
dermatologists
caring
for
patients
affected
by
COVID-
19
at
the
start
of
the
outbreak.
Recalcati,8who
was
a
dermatologist,
observed
skin
manifestations
in
20.4%
of
a
group
of
88
patients
with
COVID-19;
in
some
cases,
these
manifestations
were
present
from
the
start
whereas
oth-
ers
appeared
during
or
after
admission
to
hospital.
Hedou
et
al.,9in
response
to
the
aforementioned
article,
reported
skin
lesions
attributable
to
COVID-19
in
4.9%
of
patients
with
a
positive
polymerase
chain
reaction
(PCR)
test
result
in
a
series
of
103
patients.
However,
the
real
incidence
of
skin
manifestations
in
infection
by
SARS-CoV-2
is
not
known,
bearing
in
mind
that
at
the
time,
the
focus
was
on
patients
with
severe
signs
or
symptoms,
and
diagnosis
was
made
in
many
patients
with
no
or
limited
symptoms
following
a
tele-
phone
call
by
the
patient
to
the
primary
care
physician,
without
any
face-to-face
visits,
and
therefore
no
skin
exam-
ination
(Table
1).
Fernández-Nieto
et
al.10 reported
difficulties
facing
der-
matologists
for
taking
samples
and
even
clinical
images
in
a
pandemic
that
requires
rigorous
isolation
measures,
and
this
is
a
barrier
to
conducting
reliable
epidemiological
studies.
For
these
procedures,
transparent
bags
can
be
considered
both
for
transporting
photographic
equipment
and
the
tools
necessary
for
taking
biopsies.
The
COVID-19
pandemic
repre-
sents
a
completely
new
scenario
for
dermatologists,
and
this
situation
may
be
prolonged,
depending
on
how
the
pandemic
progresses.
The
recent
article
by
Galván
et
al.,11 supported
by
the
Spanish
Academy
of
Dermatology
and
Venereology
(AEDV),
reported
heterogeneous
and
complex
skin
manifestations
associated
with
COVID-19
infection.
The
authors
studied
a
group
of
375
patients
prospectively
enrolled
in
several
Span-
ish
hospitals
for
2
weeks
during
the
peak
of
the
pandemic.
They
identified
5
main
clinical
patterns
related
to
COVID-19:
acral
areas
of
erythema
with
vesicles
or
pustules
(pseu-
dochilblain
pattern)
(19%),
vesicular
rashes
(9%),
urticarial
lesions
(19%),
maculopapular
lesions
(47%),
and
livedo
or
necrosis
(6%).
The
following
paragraphs
describe
the
most
important
clinical
features
and
diagnostic
and
prognostic
implications
in
patients
with
SARS-CoV-2
infection.
Acral
or
Acroischemic
Lesions
The
acral
pseudochilblain
pattern
of
lesions,
reported
by
Galván
et
al.11 as
acral,
erythematous,
and
edematous
lesions,
with
formation
of
vesicles
and
pustules,
are
per-
haps
the
most
characteristic
skin
lesions
associated
with
the
SARS-CoV-2
pandemic.
The
description
and
reporting
Figure
1
Acral
pseudochilblain
papule.
of
these
lesions
initially
occurred
outside
academic
cir-
cles
in
an
informal
fashion
in
medical
or
dermatological
social
media,
based
on
shared
images
from
family
members,
acquaintances,
and
colleagues.
The
first
case
published
reported
an
adolescent
aged
13
years
who
developed
pur-
puric
lesions
on
the
feet
prior
to
developing
systemic
symptoms
such
as
fever,
muscle
pain,
and
headache,
in
a
family
with
suspected
cases
of
COVID-19
infection
at
the
time
the
pandemic
in
Italy
was
spreading
rapidly.12 How-
ever,
no
specific
microbiological
studies
were
performed.
In
the
article,
the
authors
mentioned
the
existence
of
an
epidemic
of
similar
lesions
in
children
with
suspected
COVID-
19
in
Italy.
In
the
series
by
Galván
et
al.,11 the
pattern
of
pseudochilblain
lesions
was
the
second
most
common
skin
manifestation
(19%).
They
developed
in
young
patients,
gen-
erally
late
on
in
the
course
of
the
disease,
and
were
present
for
a
period
of
12.7
days,
in
general,
in
patients
with
mild
disease
or
asymptomatic
individuals.
These
lesions
were
described
as
painful
(32%)
or
itchy
(30%).
From
the
clinical
point
of
view,
the
pseudochilblain
pat-
tern
of
lesions
consists
of
macules,
papules,
or
plaques,
often
about
a
millimeter
in
size,
and
usually
with
a
clearly
defined
border
in
the
metatarsophalangeal
area,
although
the
whole
of
the
finger
or
toe
can
be
involved
(Fig.
1).
Often,
only
some
fingers
or
toes
are
affected
while
others
com-
pletely
lack
any
involvement,
and
at
times,
these
lesions
may
be
accompanied
by
lesions
in
the
palmar
and
plantar
region.
They
usually
affect
the
feet
and,
to
a
lesser
degree,
the
hands.
Initially
purpuric
or
bluish,
they
can
form
blisters
or
scabs
during
the
course
of
the
disease;
at
times,
they
may
resemble
multiform
erythema13 or
vasculitis;
in
fact,
some
authors
recognize
a
multiform
erythema
type
subgroup,13---15
with
targetoid
or
atypical
target
lesions,
which
can
be
asso-
ciated
with
lesions
in
extensor
areas,
such
as
the
elbows.
In
cases
with
histological
study,
a
lymphocytic
infiltrate
is
reported
in
the
superficial
and
deep
dermis,
of
perivascu-
lar
predominance,
occasionally
associated
with
edema
and
signs
of
endothelial
activation.14 Keratinocyte
necrosis
and
perieccrine
reinforcement
may
be
present.15
Alramthan
and
Aldaraji,16 reporting
2
clinical
cases
in
young
adults,
proposed
the
hypothesis,
not
con-

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4
J.M.
Carrascosa
et
al.
Table
1
Characteristics
of
the
Skin
Manifestations
Described
in
Association
With
SARS-Cov-2
Infection.
Acral
or
Acroischemic
Lesions
Vesicular
and
Chickenpox-Like
Lesions
Urticarial
Rash
Maculopapular
Rash
Livedoid
or
Necrotic
Lesions
Frequency
19%
9%
19%
47%
6%
Site
Acral.
Asymmetric
Feet
>hands
5%
other
sites
Trunk
(∼100%)
±limbs
(∼20%)
No
facial
or
mucosal
involvement
Predominance
on
the
trunk,
proximal
to
the
limbs.
Symmetric
Trunk
Region
proximal
to
the
limbs
No
mucosal
involvement
Predominance
of
acral
region
and
region
distal
to
the
legs
Regions
with
greater
hydrostatic
pressure
or
lower
regions
Symptoms
Asymptomatic
(∼1/3),
painful
(∼1/3),
or
itchy
(∼1/3)
Mild
or
asymptomatic
pruritus
(∼2/3),
pain
or
burning
sensation
Almost
constant
pruritus,
of
variable
intensity
Pruritus
(>2/3),
mild
to
moderate
Pain,
burning
Characteristics
Macules,
papules,
plaques,
or
nodules
Erythematous
to
purpuric
Small-sized
vesicles.
Disperse
Monomorphic
Erythematous
and
edematous
papules
and
plaques
Erythematous
macules
and
papules,
often
confluent
Ischemic
or
necrotic
lesions,
often
diffuse
Possible
subtypes
and
variants
2
possible
patterns:
•
Pseudochilblain
lesions
(>70%)
in
the
digital
region.
Region
distal
from
the
fingers
or
toes.
Edematous.
Possible
formation
of
vesicles,
pustules,
and
scabs
•
Multiform
erythema-like
pattern
(approx.
30%).
Plaques
(heels)
and
palms.
Erythematous,
confluent
macules
or
papules,
with
possible
blistering.
No
formation
of
typical
targetoid
lesions
and
less
extensive
than
multiform
erythema
•
Generally,
disperse
lesions.
Resemble
other
viral
rashes
•
They
may
have
hemorrhagic
content,
be
of
larger
size,
or
show
diffuse
coverage
of
extensive
areas
•
Less
often,
predominantly
acral
vesicles
or
pustules
Cases
have
been
reported
of
acral
and
facial
involvement
Forms
have
been
described
with
perifollicular
predominance,
of
the
pityriasis
rosea
and
flexural
type
that
resemble
SDRIFE
In
some
cases,
craniocaudal
progression
has
been
reported
From
forms
that
resemble
livedo
reticularis
or
racemosa
to
areas
of
retiform
purpura,
hemorrhagic
blisters,
diffuse
ischemia,
or
gangrene
involving
the
distal
regions
Demographic
profile
Adolescents
or
young
adults
No
significant
differences
between
sexes
Adults,
middle
age
(30---40
years)
No
significant
differences
between
sexes
Adults,
middle
age
(40---50
years)
No
significant
differences
between
sexes
Adults,
middle
age
(30---50
years)
No
significant
differences
between
sexes
Middle
aged
and
elderly
adults
No
significant
differences
between
sexes

ARTICLE IN PRESS
+Model
Cutaneous
Manifestations
in
the
Context
of
SARS-CoV-2
Infection
(COVID-19)
5
Table
1
(Continued)
Acral
or
Acroischemic
Lesions
Vesicular
and
Chickenpox-Like
Lesions
Urticarial
Rash
Maculopapular
Rash
Livedoid
or
Necrotic
Lesions
Lag
with
respect
to
respiratory
or
systemic
manifestations
Late
onset
Early
onset.
After
a
few
days
of
respiratory
and
systemic
manifestations
(15%
before
other
symptoms)
Early
onset.
Accompanies
respiratory
or
systemic
manifestations,
or
precedes
them
Accompanies
respiratory
or
systemic
manifestations,
or
appears
a
few
days
later
Accompanies
respiratory
or
systemic
manifestations,
or
sometimes
with
late
onset
Positive
for
PCR/serology
<50%
(possibly
associated
with
late
onset)
In
favor:
clinical
and
epidemiological
evidence,
positive
contacts
Frequent,
probably
>50%
Frequent,
probably
>50%
Frequent,
probably
>50%
Very
frequent,
probably
>75%
Mean
duration
(days)
of
the
rash
12.7
(±8)
10.4
(±9.3)
6.8
(±7.8)
8.6
(±6.8)
9.4
(±5.4)
Prognosis
It
appears
to
be
associated
with
milder
disease
(acral
ischemic
lesions
in
patients
with
DIC
are
excluded
from
these
cases)
Moderate
severity
Recovery
without
any
scarring
Variable
Cases
ranging
from
mild-moderate
severity
to
death
as
the
outcome
(2%
mortality)
Severe
cases,
some
with
death
as
the
outcome
(10%
mortality)
Proposed
treatments
Topical
corticosteroids,
alone
or
in
combination
with
topical
antibiotics
Watch-and-wait
Oral
antihistamines
Topical
corticosteroids,
oral
antihistamines,
oral
corticosteroids
Support
measures
Anticoagulation
measures
Main
references
11,13---18
11,19
11,21---23
11,25,30,31
6,34,35
firmed
with
histology
in
their
own
cases,
that
for-
mation
of
hyaline
thrombi
in
small
caliber
vessels
of
different
organs
observed
in
autopsies
of
patients
could
explain
the
pseudochilblain
characteristics
of
the
lesions.
Fewer
than
half
the
cases
had
microbiological
or
sero-
logical
test
results
available
(specific
PCR
or
rapid
antibody
test
for
IgM/IgG).
In
general,
when
assessed,
laboratory
abnormalities
or
elevations
have
generally
been
lacking
in
measures
of
inflammation
such
as
D-dimer,
C
reactive
pro-
tein
(CRP),
or
lactate
dehydrogenase
(LDH),
indicative
of
poor
prognosis
for
this
disease.
The
strongest
evidence
of
association
with
viral
infection
was
therefore
that
presen-
tation
occurred
during
the
pandemic
(and
in
a
different
context
to
that
of
chilblains,
in
the
warmer
months
than
when
they
usually
appear)
and
a
history
in
the
family
envi-
ronment
or
personal
situation
consistent
with
infection.
The
authors
suggested
these
negative
results
were
due
to
the
late
development
of
these
lesions
in
the
course
of
the
dis-
ease;
the
low
sensitivity
of
the
tests
used,
which
has
led
to
mass
recall
of
some
batches;
and
the
rapid
disappearance
of
antibodies.11,15
Docampo-Simón
et
al.,17 in
the
first
prospective
study
of
skin
manifestations,
found
a
positive
PCR
result
in
only
1
of
the
38
samples
tested.
In
addition,
due
to
the
afore-
mentioned
technical
reasons
(time
since
infection,
false
negatives),
the
authors
considered
the
possibility
that
this
manifestation
simply
has
nothing
to
do
with
COVID-19.
Other
possible
explanations
could
be
a
traumatic
origin
during
lock-down
or
even
the
concurrent
expansion
of
another
virus,
such
as
parvovirus
B19.
This
possible
relation
with
the
lock-down
period,
and
not
necessarily
with
COVID-19,
has
also
been
suggested
in
a
recent
series
with
similar
results.18
During
the
worst
weeks
of
the
pandemic,
we
saw
patients
with
these
characteristics
almost
on
a
daily
basis
in
our
clinics.
From
both
the
clinical
and
epidemiological
point
of
view,
the
characteristics
are
consistent
with
those
described
above.
Most
of
our
patients
were
young,
asymptomatic
or
with
mild
symptoms,
and
not
one
of
them
had
a
serious
complication
associated
with
COVID-19.

ARTICLE IN PRESS
+Model
6
J.M.
Carrascosa
et
al.
Figure
2
Disperse
monomorphic
papulovesicles
on
the
trunk.
Vesicular
and
Chickenpox-Like
Lesions
In
8
Italian
centers,
clinical
data
were
collected
from
patients
with
COVID-19,
with
microbiological
confirmation
by
RT-PCR
from
a
nasopharyngeal
swab
and
with
no
history
of
medications
that
could
have
triggered
chickenpox-like
lesions.
In
total,
the
study
included
22
patients,
mainly
males,
with
a
mean
age
of
60
years.
The
lag
from
the
onset
of
symptoms
of
COVID-19
to
development
of
skin
manifesta-
tions
was
relatively
short,
3
days
(range,
2
to
12
days).
Most
patients
presented
with
the
full
clinical
manifestations
of
the
disease,
with
general
and
respiratory
manifestations.19
Vesicular
lesions,
usually
monomorphic,
appear
early
on
and
may
at
times
precede
other
symptoms
(in
15%
of
patients),11 although
in
most
cases,
up
to
79.2%
in
a
series
of
24
patents
reported
by
Fernandez-Nieto
et
al.,20 they
occur
at
the
onset
of
other
symptoms.
There
is
involve-
ment
of
the
trunk
in
almost
all
cases
and
in
20%
the
limbs
are
also
affected
(Fig.
2).
Exceptionally,
facial
and
mucosal
involvement
have
been
reported.
The
skin
lesions
are
barely
symptomatic,
but
when
they
do
cause
symptoms,
these
are
usually
mild
itching
and,
to
a
lesser
extent
pain
or
burn-
ing
sensation.11,19 Although
the
lesions
may
be
disperse,
an
extensive
disseminated
pattern
is
more
frequent,
75%
according
to
Fernandez-Nieto
et
al.
In
some
patients,
the
legs
may
be
affected,
or
the
lesions
may
present
with
hemorrhagic
content
or
be
large,
with
a
diffuse
distribu-
tion.
The
mean
duration
of
skin
symptoms
is
10.4
days
(±9.3).11 In
cases
in
which
a
biopsy
was
obtained,
the
findings
were
described
as
consistent
with
viral
infection,
showing
vacuolar
abnormalities
and
abnormal
maturation
of
keratinocytes,
as
well
as
larger,
multinucleated
ker-
atinocytes,
and
dyskeratosis.19 There
have
been
no
reports
of
presence
of
SARS-Cov-2
confirmed
with
positive
PCR
in
biopsies
of
skin
lesions.
Urticarial
Rash
Henry
et
al.21 reported
the
case
of
a
female
patient
who
developed
an
urticarial
rash,
accompanied
by
odynophagia
and
arthralgia,
before
developing
the
full
clinical
manifes-
tations
of
COVID-19.
Van
Damme
et
al.22 reported
a
further
2
cases
of
urticarial
rash
as
the
first
clinical
manifestation
of
COVID-19,
although
microbiological
confirmation
of
infec-
tion
was
only
obtained
in
1
of
those,
and
in
both
cases
the
Figure
3
Maculopapular
rash
in
a
patient
with
COVID-19
asso-
ciated
with
bilateral
pneumonia,
who
received
different
drugs.
Differential
diagnosis
with
respect
to
toxicoderma
is
difficult.
skin
manifestations
preceded
pyrexia.
One
of
the
patients
developed
severe
respiratory
failure,
leading
to
death.
Urticarial
rash
accounts
for
19%
of
skin
manifestations
in
COVID-19.
In
general,
these
skin
manifestations
become
evident
more
or
less
at
the
same
time
as
other
general
and
respiratory
symptoms.
Lesions
occur
predominantly
on
the
trunk,
and
involvement
of
the
face
and
hands
is
fre-
quent,
with
resolution
in
approximately
7
days.11 In
one
of
the
cases
reported,
histological
study
showed
edema
of
the
upper
dermis
and
perivascular
lymphocytic
infiltration,
with
some
eosinophils
present.10 Although
such
lesions
may
be
associated
with
worse
prognosis
in
some
patients,11 this
is
a
nonspecific
rash,
and
it
has
been
reported
in
patients
with
a
favorable
clinical
outcome
and
those
with
limited
symptoms.23
There
is
probably
a
certain
degree
of
variability
in
the
way
in
which
rashes
are
reported
as
urticarial
maculopapu-
lar
because,
in
the
cases
described,
it
is
not
specified
whether
the
lesions
follow
a
transient
course
or
not.
These
are
nonspecific
rashes
in
which
it
is
difficult
to
establish
a
solid
relationship
with
viral
infection,
bearing
in
mind
that
the
patients
who
present
with
these
lesions
have
often
received
a
range
of
treatments
such
as
antiviral
agents,
antibiotics,
hydroxychloroquine,
anticoagulants,
and
sup-
port
treatments,
and
these
could
also
trigger
skin
reactions
(Fig.
3).
In
fact,
in
a
histological
study,
some
cases
of
vac-
uolar
interface
dermatitis
were
observed
with
occasional
necrotic
keratinocytes,
findings
more
reminiscent
of
a
mul-
tiform
erythematous
pattern.24
Maculopapular
Rash
This
group
of
lesions
includes
a
heterogeneous
group
of
rashes
that,
considered
together,
and
given
the
difficulty
of
further
subclassification,
account
for
47%
of
the
skin
manifestations
in
patients
with
COVID-19.11 At
times,
these
rashes
may
be
accompanied
by
a
petechial
component

ARTICLE IN PRESS
+Model
Cutaneous
Manifestations
in
the
Context
of
SARS-CoV-2
Infection
(COVID-19)
7
Figure
4
Nonspecific
rash,
with
perifollicular
distribution
in
a
patient
with
COVID-19.
Figure
5
Multiform
erythema-like
eruption
in
a
patient
with
SARS-CoV-2
infection.
or
with
macules
or
more
extensive
areas
with
a
purpuric
appearance.
In
other
cases,
the
lesions
have
a
markedly
perifollicular
distribution
(Fig.
4)
with
variable
degrees
of
scaling,
some
of
which
have
been
reported
as
simi-
lar
to
pityriasis
rosea.25 Infiltrated
papules
have
also
been
observed;
these
are
pseudovesicular
lesions
or
similar
to
erythema
elevatum
diutinum
or
multiform
erythema,
and
they
may
occasionally
be
pruritic
(Fig.
5).26 A
markedly
craniocaudal
development
has
also
been
reported,
with
involvement
of
the
folds
but
without
the
palmoplantar
region
or
the
mucosa
being
affected.27,28
Jimenez-Cauhe
et
al.29 reported
the
case
of
a
female
patient
who
developed
a
coalescent
erythematous-purpuric
rash
about
a
millimeter
in
size,
with
a
flexural
distribution
predominantly
in
the
periaxillary
region.
The
authors
con-
sidered
the
difficulty
of
associating
the
skin
manifestations
with
viral
infection
in
view
of
its
nonspecific
appearance
and
concomitant
medication
use.
Other
authors
have
reported
the
appearance
of
rash
that
resembles
the
typical
skin
involvement
of
symmetrical
drug-related
intertriginous
and
Figure
6
Periaxillary
exanthematous
eruption
similar
to
SDRIFE.
Figure
7
Livedoid
rash
with
a
transient
course
on
the
trunk
of
a
patient
with
severe
COVID-19.
flexural
exanthema
(SDRIFE),
possibly
associated
with
viral
infection,
given
that
the
rash
resolved
despite
continued
use
of
the
drug.30 We
have
also
observed
a
similar
distribution
in
our
own
patients
(Fig.
6).
From
the
histological
point
of
view,
a
range
of
features
have
been
reported
within
the
group
of
maculopapular
rashes,
such
as
a
perivascular
inflammatory
infiltrate
with
discrete
lymphocytic
exocytosis,
marked
ves-
sel
dilatation
in
the
superficial
and
medial
dermis,
as
well
as
lymphocytic
vasculitis.31,32
There
is
limited
additional
information
in
these
patients
regarding
the
timing
with
respect
to
other
clinical
man-
ifestations
or
its
prognostic
or
diagnostic
value.
In
most
cases,
maculopapular
rashes
appear
either
at
the
same
time
as
the
characteristic
respiratory
symptoms
or
a
few
days
later.11,28,32,33 However,
in
our
hospital,
we
have
detected
more
or
less
generalized
maculopapular
rashes,
in
some
cases
similar
to
multiform
erythema,
in
young
patients
with
a
history
of
mild
or
even
no
symptoms,
although
with
epi-
demiological
evidence
of
infection
with
SARS-CoV-2
and
these
resemble
those
that
can
be
seen
in
other
viral
infec-
tions.
Livedoid
or
Necrotic
Lesions
Livedoid
or
necrotic
lesions
are
relatively
uncommon,
accounting
for
6%
of
skin
lesions
in
the
series
reported

ARTICLE IN PRESS
+Model
8
J.M.
Carrascosa
et
al.
by
Galván
et
al.11 These
are
lesions
usually
reported
in
elderly
patients
with
prior
comorbidities
and
with
severe
forms
of
COVID-19
infection.
They
are
considered
sec-
ondary
to
vascular
micro-occlusion
and
acral
ischemia
due
to
general
deterioration
in
the
patient’s
state
and/or
the
coagulation
disorders
attributed
to
COVID-192,5 (Fig.
7).8
However,
in
some
patients,
episodes
have
been
reported
of
patchy
livedo
reticularis
that
presented
over
the
course
of
minutes
or
hours,
of
an
uncertain
nature
and
a
benign
course.35
In
the
histological
study
of
cutaneous
purpuric
lesions,
a
pauci-inflammatory
thrombogenic
vasculopathy
has
been
found,
with
C5b-9
and
C4d
deposits,
and
localization
of
viral
particles,
leading
to
suspicion
of
the
presence
of
a
catastrophic
microvascular
lesion
caused
by
complement
activation.6
Conclusions
The
SARS-CoV-2
pandemic
has
had
a
major
impact
from
the
healthcare,
economic,
and
societal
point
of
view,
and
will
probably
lead
to
lasting
changes
in
our
generation.
Considered
initially
as
of
little
relevance,
the
dermatolog-
ical
manifestations
have
proved
to
be
varied
and
complex.
Recent
efforts
to
characterize
cutaneous
involvement
in
patients
with
COVID-19,
implemented
in
a
study
conducted
quickly
and
rigorously
in
a
full
health
emergency,
has
iden-
tified
5
main
groups
of
lesion
(acral,
vesicular,
urticarial,
maculopapular
and
livedoid/necrotic
lesions).11 Although
these
manifestations
are
considered
a
reflection
of
differ-
ent
pathogenic
pathways,
with
a
variable
implication
of
the
viral
infection,
inflammatory
processes,
and
vascular
and
systemic
complications
of
the
disease,
there
is
a
substantial
knowledge
gap
in
many
aspects.
Thus,
it
cannot
be
ruled
out
that
acral
lesions,
reported
as
characteristic
given
the
epi-
demiological
evidence
rather
than
microbiological
tests
in
most
cases,
may
not
be
directly
related
to
COVID-19.
Exten-
sive
urticarial
or
maculopapular
rashes,
often
described
in
symptomatic
or
even
hospitalized
patients,
may
be
linked
in
many
cases
to
drugs
able
to
trigger
them,
such
as
hydroxychloroquine
or
antibiotics,
administered
during
the
COVID-19
pandemic
despite
limited
evidence
of
their
effec-
tiveness.
Finally,
the
heterogeneous
set
of
maculopapular
rashes
consistent
with
viral
infection,
multiform
erythema,
or
SDRIFE,
may
be
associated
with
other
etiologic
agents
neglected
during
the
pandemic,
as
in
many
cases,
microbi-
ological
or
serologic
confirmation
of
SARS-CoV-2
infection
is
lacking.
Thus,
in
the
panorama
of
lesions
associated
with
COVID-19,
for
the
most
part,
priority
in
the
international
literature
during
the
peak
of
the
pandemic
was
given
to
rapid
publication,
even
though
the
description,
support,
or
methodological
rigor
were
not
ideal.
Familiarity
with
the
skin
manifestations
may
allow
not
only
greater
investiga-
tion
into
aspects
still
little
known
in
COVID-19,
but
also
may
help
a
more
rapid
diagnosis
and
even
serve
as
a
prognostic
marker.
Conflicts
of
Interest
The
authors
declare
that
they
have
no
conflicts
of
interest.
Acknowledgments
We
would
like
to
thank
Doctors
Aram
Boada,
Isabel
Bielsa,
María
Blanco,
Ferran
Ballescà,
Juli
Bassas,
Elena
del
Alcázar,
Gonzalo
Castillo,
Carlos
Ferrándiz,
María
José
Fuente,
Adrià
Plana,
Nina
Richarz,
Verónica
Mora,
Arantxa
Arrieta,
and
Ane
Jaka,
with
whom
the
authors
have
worked
and
shared
knowledge
during
the
peak
of
the
COVID-19
pandemic.
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