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\begin{document}

\title{SARS-CoV-2, COVID-19, skin and vascular system - what do we know so far?}



\author[1]{Natalija Novak}%
\author[1]{Wenming Peng}%
\author[2]{Mirjam Naegeli}%
\author[3]{Christina Galvan}%
\author[2]{Isabel Kolm-Djamei}%
\author[2]{Charlotte Brüggen}%
\author[1]{Beatriz Cabanillas}%
\author[4]{Peter Schmid-Grendelmeier}%
\author[5]{Alba Catala}%
\affil[1]{University of Bonn}%
\affil[2]{University Hospital Zurich}%
\affil[3]{Mostoles University Hospital}%
\affil[4]{University of Zurich Hospital}%
\affil[5]{Hospital Plato}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
The pandemic condition Coronavirus-disease (COVID-19), caused by the
novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can
take asymptomatic, mild, moderate, and severe courses. COVID-19 affects
primarily the respiratory airways leading to dry cough, fever, myalgia,
headache, fatigue, and diarrhea and can end up in interstitial pneumonia
and severe respiratory failure. Different clinical symptoms caused by
involvement of organs outside the respiratory system have been also
described. Interestingly, reports about the manifestation of various
skin lesions and lesions of the vascular system in some subgroups of
SARS-CoV-2 positive patients as such features outside the respiratory
sphere, are rapidly emerging. However, knowledge about prevalence and
pattern of skin involvement, time of onset, predilection, and its direct
or indirect relation to SARS-CoV-2 is still limited. In order to update
information gained, we provide a systematic overview of the skin lesions
described in COVID-19 patients, discuss potential causative factors and
describe differential diagnostic evaluations.%
\end{abstract}%



\sloppy


\textbf{Introduction}

\emph{The story behind the virus with the crown}

Coronaviruses belong to a large group of related viruses, named
coronavirus family, which can infect humans and animals and lead to
diseases of the airways, the gut, liver, and the nervous system. Some
members of coronavirus family may infect the upper airways with rather
mild courses and others - as severe acute respiratory syndrome
coronavirus SARS-CoV-2 -- may affect the lower respiratory airways with
pneumonia and fatal courses (Table 1) (\textbf{1, 2} ).

Belonging to the \selectlanguage{greek}β-\selectlanguage{english}Coronavirus genus, SARS-CoV-2 is the pathogen that
causes the new infectious respiratory disease, termed as coronavirus
disease 19 (COVID-19), which emerged in December 2019, in Wuhan (Hubei
province, China) first and later turned to be a global pandemic
(\textbf{2} ). SARS-CoV-2 displays 79\% nucleotide identity with
SARS-CoV and 51.8\% nucleotide identity with MERS-CoV, but most
importantly shares 96\% identity across the entire genome with a bat
coronavirus, which is supposed to be the natural origin of SARS-CoV-2
(\textbf{1, 3, 4} ).

As other coronaviruses, SARS-CoV-2 is an enveloped, positive-sense
single-stranded RNA virus with spikes that protrude from the virus
surface resembling a crown or ``corona'' (Fig. 1). Most importantly, the
spike (S) protein of coronaviruses is essential for viral infection of
host cells. During the virus entry procedure, the S protein engages its
cellular receptor, angiotensin-converting enzyme 2 (ACE2), which
facilitates viral attachment to the cell surface of target cells. As a
next step, the engaged S protein is further primed by the cellular
serine protease (Transmembrane Protease Serine 2) TMPRSS2, which
mediates membrane fusion and viral entry into the cells (Fig. 1)
(\textbf{5, 6} ). Importantly, as the efficiency of ACE2-S interaction
largely determines SARS-CoV transmissibility (\textbf{7-9} ), the
expression of ACE2 receptors represents a major risk factor for the
vulnerability to SARS-CoV-2 infection. In humans, the ACE2 receptors are
expressed by CD8\textsuperscript{+} T cells (\textbf{10} ), resting and
activated natural killer (NK) cells (\textbf{10} ), alveolar epithelial
cells of type II (\textbf{11} ), vascular endothelial cells, macrophages
and adipocytes (\textbf{12} ). The nose and the nasal epithelium plays
an important role for infection and viral spreading (\textbf{13, 14} ).
High ACE2 expression has also been demonstrated on epithelial cells of
the oral mucosa, in particular the tongue, so that this receptor might
provide an entry route for the virus and designates the oral cavity as a
potential organ at high risk for viral spreading from one individual to
the other (\textbf{15} ). Tissue distribution of the \emph{ACE2} gene
includes the small intestine, testis, kidneys, heart, thyroid, and
adipose tissue with relatively high expression (\textbf{12} ). It has
been recently demonstrated that the inflammatory cytokines interferon
(IFN)-\selectlanguage{greek}α\selectlanguage{english}2 and IFN-\selectlanguage{greek}γ \selectlanguage{english}increase the expression of ACE2 and is supposed that
tissue inflammation may modulate the receptor expression and thereby
change the risk of immune cells to be infected by SARS-CoV-2
(\textbf{14} ). So far, a positive correlation of \emph{ACE2} gene
expression to CD8\textsuperscript{+} cells in the skin has been
shown\textbf{12} ).

Binding of SARS-CoV-2 to ACE2 downregulates its expression and impacts
thereby on its main function, the regulation of the renin-angiotensin
system. This downregulation leads to a dysregulation of the balance of
soluble factors, electrolytes, blood pressure combined with an increase
of vascular permeability and lung inflammation (\textbf{1} ). Usually,
virus-specific T cells recruited to the site of inflammation eliminate
the virus with neutralizing antibodies generated from B cells and
macrophages and prevent thereby virus spreading in an immunocompetent
individual (\textbf{1, 16} ). However, inflammation-induced cell death
of infected cells and damage-released molecular patterns might induce
proinflammatory cytokines and chemokines and recruitment of inflammatory
cells to the lung (Fig. 2). Thus, the lung tissue damage caused by
SARS-CoV-2 infection and replication, may thereby destroy step-wise the
lung structure with the development of pulmonary fibrosis by
transformation of adipocytes into myofibroblasts (\textbf{17} ). The
knowledge accumulated from SARS and MERS, together with current clinical
observations from COVID-19 patients, suggest that type-I IFN-mediated
antiviral responses and activation of both CD4\textsuperscript{+} Th1
and CD8\textsuperscript{+} cytotoxic T lymphocytes (CTLs) result in
viral clearance in SARS-CoV-2 infected subjects with mild symptoms.
However, insufficient initiation of antiviral immune responses,
increased production of inflammatory cytokines, as well as lung
infiltration of monocytes and neutrophils, contribute to a cytokine
storm in SARS-CoV-2 positive patients (\textbf{18, 19} ). Moreover, the
cytokine storm elicited from the overproduction of pro-inflammatory
mediators such as interleukin (IL)-1, IL-6, IL-12, and tumor necrosis
factor (TNF)-\selectlanguage{greek}α, \selectlanguage{english}not only leads to increased vascular permeability and
inflammation in the lung (\textbf{18, 19} ) but may reach other organs
through the vascular system. In the worst case, this might induce injury
of multiple other organs including the cardiac, renal or hepatic system
(Fig. 2) (\textbf{1} ). This cascade of events might lead despite
intensive care and a lot of other measures initiated, to fatal courses
and death, in particular in elderly patients and individuals with
pre-existing diseases.

\textbf{SARS-CoV-2 infection and COVID19}

Transmission and symptoms

Transmission of SARS-CoV-2 is mediated mainly via respiratory droplets
from an infected person (\textbf{20, 21} ). Of note, SARS-CoV-2 positive
patients emit respiratory droplets in high numbers during speaking,
which remain in the air up to 8-14 minutes (\textbf{22} ). The average
incubation time until the onset of COVID-19 is 4-11 days (\textbf{23} ).
The immune responses resulting from SARS-CoV-2 infection vary broadly
and range from asymptomatic courses, over mild, moderate to severe
courses with a need for hospitalization and intensive care. Typical
symptoms of COVID-19 include dry cough, fever, myalgia, headache,
anosmia and ageusia (\textbf{24} ). Depending on the severity of the
disease, even other organ systems such as the gastrointestinal tract,
the liver, the renal system as well as the cardiac system might be
involved and become symptomatic as well (Fig. 3).

Factors associated with poor prognosis

\emph{Comorbidities}

Skin lesions might at least in part or completely result from the
reactivation or aggravation of pre-existing skin diseases such as
urticaria, autoimmune disease or other diseases with SARS-CoV-2 and
soluble mediators and immune mechanisms induced both in the organs
involved and systemically in the blood (\textbf{25} ). Comorbidity rate
increases the rate of mortality of COVID-19 with cardiovascular
diseases, hypertension, diabetes mellitus and obesity being major risk
factors (\textbf{26} ). Sine adipocytes express ACE2 and might serve as
a reservoir for SARS-CoV-2, this fact might explain in part the higher
risk of obese patients (\textbf{17} ).

\emph{Gender and sex hormones}

Circulating plasma levels of ACE2 have been demonstrated to be higher in
men with heart failure than in women and might indicate higher tissue
expression of the SARS-CoV-2 entry receptor in man as a risk factor for
more fatal courses of COVID-19 (\textbf{27} ). The expression of ACE2 in
the myocard is regulated by androgen in mouse models (\textbf{28, 29} ).
Male mice with hypertension had higher ACE2 expression, which was
reduced after orchiectomy. These data indicate that testosterone might
negatively impact on the risk for COVID-19.

In a study on patients with asthma, male gender, African Americans race
and history of diabetes mellitus, was associated with higher expression
of ACE2 and TMPRSS2 in sputum cells of patients with asthma (\textbf{30}
).

Whether gender differences in terms of nature and frequency of the skin
lesions exist, needs to be elucidated in further studies.

However, several gender differences in relation to virus responses and
responses to viral vaccines have been described in the past. These
include higher susceptibility of men to infectious diseases or stronger
antibody titers inducible by a number of different types of vaccines in
women as opposed to men. Moreover, plasmacytoid dendritic cell-mediated
type I IFN responses have been demonstrated to be stronger in women than
in men, another factor of putative importance for viral clearance even
in the context of SARS-CoV-2 infections (\textbf{31, 32} ). Higher
susceptibility, need for hospitalization, longer duration of the disease
and higher rate of mortality in men versus women has been also described
for other virus infections such as with influenza virus (\textbf{33} ).
Together, these observations point to SARS-CoV-2 specific as well as
general differences in viral immunity in man versus women.

\emph{Age, ethnic and genetic risk factors and senescence of the immune
system}

In the context of SARS-CoV-2 age seems to be one of the highest
predictors of the probability to get infected as well as of the extent
of symptoms and severity of COVID-19. One reason besides a higher number
of comorbidities and drugs take in the group of elder patients might be
that ACE2 expression increases with age (\textbf{34} ). Younger age
groups seem to be not only at lower risk but maybe even protected from
infection or severe viral spreading within the body. This could be
managed for example by the presence of cross-reactive antibodies derived
from other rather mild coronavirus infections in the past and an
immunocompetent viral defense system at different immunologic levels.
Another reason might be the presence of allelic variants interfering
with the binding of the S-protein of SARS-CoV-2 to ACE2 and putative
protection of the carriers from SARS-CoV-2 infection (\textbf{35} ). In
contrast, higher allele frequencies of variants in the \emph{ACE2}coding
gene region, which go along with higher ACE2 expression in the tissue,
have been observed in populations from east Asia (\textbf{36} ) and
might indicated a specific risk, related to ethnic groups.

Finally, senescence of the immune system with lower antigen response of
T and B cells from elder individuals as well as weaker effector
functions and limited number of CD8\textsuperscript{+} memory cells
capable to react do different pathogens might among other factors play a
role for attenuated virus clearance and lower number of
anti-inflammatory cytokines and mediators, innate immune regulatory
proteins or regulatory cell mechanisms in higher age groups (\textbf{37,
38).}

Skin lesions observed in relation to SARS-CoV-2

Besides the typical symptoms described above, more and more reports
about skin lesion and lesions of the vascular system observed in
patients tested positive for SARS-CoV-2 and patients suspected to be
infected by SARS-CoV-2 are coming up in countries all over the world
(\textbf{39, 40} ). The percentage of patients with skin lesions varies
from lower than 1\% to up to 20\% of all SARS-CoV-2 patients and has to
be estimated exactly in systematic studies on this issue.

The spectrum of skin lesions in SARS-CoV-2 patients described and
published so far contain skin lesions occurring in other infectious and
viral diseases such as maculopapular-exanthema, vesicular exanthema or
urticarial eruptions (\textbf{39, 41-46} ). Furthermore, the skin
lesions might also be related to virus induced or indirectly induced
vascular dysfunctions, such as livedo reticularis, petechiae or
cutaneous acro-ischemia (\textbf{39-42, 47} ). Chilblain lesions have
been described as well (\textbf{48-50} ). Considering frequency, most
reports exist on maculopapular exanthema/vesicular exanthema,
urticarial, and chilblain lesions (\textbf{41} ). Less reports exist on
acro-ischemia or livedo reticularis and other skin lesions.

Based on the largest collection of skin lesions from patients from
Spain, lesions have been recently categorized into 5 main groups
(\textbf{41} ) summarized in Fig. 4A-E.

\begin{enumerate}
\tightlist
\item
  Vesicular eruptions, predate in about 15\% COVID-19 symptoms or occur
  with symptoms, last 10-12 days and go along with COVID-19 with
  intermediate severity, patients affected are middle aged and lesions
  are accompanied by moderate itch (Fig. 4A).
\item
  Maculopapular exanthema manifests together with COVID-19 symptoms,
  often in more severe cases with a mortality rate up to 2\%, lasts 7-9
  days and is in over 50\% of the cases accompanied by itch (Fig. 4B).
\item
  Urticarial eruptions occur at the same time as other symptoms in more
  severe COVID-19 cases are accompanied by itching and last 6-8 days
  (Fig. 4C).
\item
  Livedo or necrosis and other vasculitis forms tend to occur in older
  and more severe cases, with relatively high mortality (up to 10\%) and
  the onset was together with COVID-19 symptoms (Fig. 4D).
\item
  Chilblain was observed in younger patients with mild or even
  asymptomatic courses, the onset is late, duration 12-14 days and in
  one third are the lesions accompanied by pain and itch (\textbf{22-23}
  ) (Fig. 4E).
\end{enumerate}

Methods

Since it is quite difficult to verify, in which context the skin lesions
occur in terms of SARS-CoV-2 infections, we would like to summarize in
the next few sections current knowledge about the pathophysiologic
background of virus-induced and drug-induced lesions of the skin and the
vascular system.

Data for this Review were identified by searches of MEDLINE, Current
Contents, PubMed, and references from relevant articles using the search
terms ``SARS-CoV-2'', ``COVID-19'', ``skin'', ''vascular system``,
''virus (infection)`` and ''drug hypersensitivity reaction``. Only
articles published in English between 1995 and 2020 were included.

Possible pathogenic mechanisms involved for skin manifestations

\emph{Viral rashes}

Viral exanthema is defined as a skin rash, which is sometimes associated
with an enanthem and goes along with fever and other systemic symptoms
(\textbf{51, 52} ). In this context, it is important to notice that also
the ACE2 receptor has been described to be expressed in the oral cavity
(\textbf{11} ), lesions of the mucous membranes have not been reported
so far to occur very frequently together with skin lesions in SARS-CoV-2
positive cases,

In principle, skin manifestation of viral infections can derive by

\begin{enumerate}
\tightlist
\item
  direct inoculation of the virus,
\item
  dissemination or reactivation of the virus from another site or
\item
  interaction of the virus with the immune system in general and related
  cellular and humoral immune responses including virus-specific
  lymphocytes and antibodies (\textbf{51} ).
\end{enumerate}

The onset of the skin lesions in relation to viremia and general
symptoms can help to understand the pathophysiologic mechanisms behind
the lesions in COVID-19 patients. In the case of skin lesions precede
general symptoms or might even be the only sign for a putative
infection, they might serve as important early indicators of the disease
or indicator for asymptomatic virus carriers. On the other hand-side,
skin symptoms, which occur quite late during infection or even after
resolution of main symptoms might indicate a lack of viral clearance and
cascades of immune responses induced by the virus .

Viremia often predates the typical COVID-19 symptoms and virus-specific
virology might be both, false negative or false positive due to
cross-reactivity to other members of the coronavirus family, but could
provide important information about acute or previous infection by the
analysis of virus-specific IgM and IgG. Nucleotide testing of tissue
specimens is highly sensitive and specific, but stability of samples and
RNA, contamination, and other issues may occur and limit information
gained, so that even part of smear taken from the mouth remain false
negative (\textbf{52} ).

\emph{1.1 Virus induced maculopapular exanthema}

Although skin biopsies are rarely taken from viral skin lesions, because
the features observed are mostly not very specific, biopsies might be an
option to differentiate viral exanthema from drug-induced exanthema in
COVID-19 patients, in these cases it is essential to do the differential
diagnosis and rule out the pharmacological cause.

To distinguish infectious exanthema from exanthema induced by
drug-hypersensitivity reactions, histologic features and immunologic
changes in the skin might help to diagnostically differentiate both
entities.

Immunologic features of maculopapular virus exanthema known so far are
summarized in Fig. 5A. Typical histologic features of infectious
exanthema induced by viremia or dissemination of infectious agents
through the blood are shown in Table 2 and Fig. 6A.

\emph{1.2 Virus induced vesicular eruptions}

Virus induced vesicular eruptions are quite common for herpes simplex
virus or varicella zoster virus induced skin lesions in which the
vesicles are caused by intraepidermal blister and epithelial necrosis.
Either reticular degeneration of the epidermis or ballooning of
keratinocytes might cause intraepidermal vesicle formation (\textbf{53,
54} ) (Table 2). Another example for virus induced vesicular eruptions
are caused by Coxsackie A16 virus, an enterovirus, which is responsible
for Hand-foot-and mouth diseases. Intraepidermal vesicles with reticular
degeneration and ballooned cells are characteristic features. Papillary
edema and mild perivascular infiltrates might be detectable as well. In
all of those virus induced skin eruptions, viral antigens are detectable
in various cutaneous structures using different methods such as antibody
staining, electron-microscopy or others (\textbf{53, 54} ).

Whether vesicular eruptions observed in part of the COVID-19 patients
are caused by SARS-CoV-2, needs to be evaluated in further studies.

Some reports of erythemato-violaceous papules and patches with a
pseudo-vesicle in the center, resembling erythema-multiforme and an
enanthem of the oral cavity in some of those patients during or after
improvement of COVID-19 symptoms exist (\textbf{55-58} ). If those
lesions are related to SARS-CoV-2 infection or drugs applied in this
context or both remains to be elucidated in further studies.

\emph{1.3 Virus induced urticarial rashes}

Urticaria and acute urticarial rashes go along with up to 50\% of all
cases with infections of the upper respiratory tract (\textbf{59} ) and
are most often mediated by complement activation and serum sickness
induced by viral antigens or secondary mechanisms, due to the
interaction of the immune system with viral antigens. This could be also
the case in part of the SARS-CoV-2 positive patients with urticarial
eruptions (Fig. 7).

\emph{1.4 Virus induced vasculitis}

Infectious diseases are the cause of over 20\% of cutaneous vasculitis
(\textbf{60} ). Most of them have a self-limiting course, but the
involvement of other organs is possible.

Vasculitis can affect small, medium and large vessels (Fig. 8).
Mechanisms might be type III or immune complex-mediated reactions to
viral antigens or part of viral antigens. In this context, large immune
complexes might precipitate and accumulate within vessels, a process
leading to vascular injury (Fig. 8A) (\textbf{61} ). Histologic features
of vasculitis are an inflammatory infiltrate in wall of dermal or
subcutaneous vessels (which can be neutrophilic, lymphocytic or
granulomatous), red blood cell extravasation, variable fibrinoid
necrosis of vessel walls, and nuclear debris. Further on, deposits of
immunoglobulin, complement or fibrin in the vessel wall are detectable
by direct immunofluorescence staining (\textbf{62} ). Polyarthritis
nodosa related to Hepatitis B infection is one example for a vasculitis
directly induced by a viral antigen (\textbf{63} ). Interestingly,
specific virus genotypes of Hepatitis B and C Virus have been
identified, which are associated with particular forms of vasculitis,
which explains in part why only a subgroup of virus-infected patients
develops such cutaneous vascular reactions in some viral diseases
(\textbf{60} ).

Cell-mediated hypersensitivity, in which exposure to viral antigens
induce recruitment of lymphocytes, which release proinflammatory
cytokines and further attract macrophages and more lymphocytes leading
to tissue damage of the vessels, has also been described as a pathway in
some infectious vasculitis types (Fig. 8B).

Furthermore, abnormal immune regulation including different expression
of adhesion molecules and cytokines in vascular endothelium by different
virus-related processes as well as direct endothelial cell invasion of
the virus (Fig. 8C) or direct stimulation of the immune system by
infectious agents might take place (\textbf{62} ).

Whether and which kind of virus induced mechanisms of infectious
vasculitis play a major role in SARS-CoV-2 vascular lesions is unclear,
but immune complex mediated mechanisms are likely to be of relevance.

Furthermore, since ACE2 expression has been described for endothelial
cells (\textbf{63, 64} ), it is quite speculative but still conceivable
at this time point - but even possible - that the virus directly
interacts with endothelial cells leading to tissue damage and the
resulting skin lesions.

In children an association of COVID-19 with Kawasaki-like disease with
mucocutaneous involvement, polymorphic rash, erythema of the palms and
soles, firm induration of the hands or feet, or both besides other
symptoms of Kawasakis disease has been postulated (\textbf{65).}Kawasaki
disease is classified a systemic vasculitis of medium size vessels (Fig.
8) and pathogens including different virus types have been suspected as
one causative factor in a rather multifactorial pathogenesis. Further
studies are needed to demonstrate a correlation of Kawasaki disease with
SARS-CoV-2 in larger patient groups and time courses.

\emph{2. Previous skin diseases}

Skin manifestations, such as urticaria, psoriasis, autoimmune diseases,
or others, might result from the SARS-CoV-2 related reactivation or
aggravation of pre-existing skin diseases.

\emph{Chilblain}

Idiopathic chilblain or also called acro-ischemic lesions, presenting as
violaceous, infiltrated painful and sometimes even pruritic plaques on
erythematous skin with predilection on the back of the toes or feet has
been described to occur in a special group of SARS-CoV-2 positive,
suspected patients as well as asymptomatic or non-infected patients
(Fig. 4F) (\textbf{66, 67} ). Histologic features of these lesions were
typical for a lymphocytic vasculitis, with a superficial and deeper
lymphocytic infiltration around vessels and close to eccrine glands, a
papillary edema, vacuolar degeneration of the basal layer as well as
lymphocytic exocytosis to the epidermis. Red cell extravasation as well
as focal thrombosis in papillary dermal capillaries as well as vessels
of the reticular dermis were described in some reports as well
(\textbf{49, 68} ). The pathologic pathways behind these lesions are
still unknown and remain to be elucidated. If it is related to
SARS-Cov-2 infection remains to be demonstrated.

\emph{3. Cutaneous drug reactions}

Cutaneous drug reactions are classified into immediate and nonimmediate
drug hypersensitivity reactions. The latter have been subclassified into
5 groups based on the type of immune mechanisms in the foreground (Table
3). Part of the skin and vascular lesions are most likely related to
drug hypersensitivity reactions.

\emph{3.1 Drug induced urticarial rashes}

Urticaria and urticarial rashes belong at least in part to cutaneous
type I (IgE-mediated) drug- hypersensitivity reactions (Table 3)(Fig.
7). Other mechanisms involved are direct mast cell activation, immune
complex formation/precipitation (Fig. 7) and activation of complement
during serum sickness or interaction with metabolic pathways of drugs
such as arachidonic acid metabolism (\textbf{69} ). Urticaria or
urticarial rashes in SARS-CoV-2 patients could be drug induced, induced
by drugs, viral RNA or a mixture of both. Infection-associated
re-activation or exacerbation of pre-existing urticaria might be
possible as well.

\emph{3.2 Drug induced maculopapular exanthema}

In general, about 7\% of hospitalized patients develop drug
hypersensitivity reactions of variable severity, and exanthema occurs in
2-3\% of these cases (\textbf{70, 71} ).

Both, drugs and metabolites of drugs might elicit exanthematous
drug-hypersensitivity reactions (Table 4).

Some skin lesions observed in COVID-19 patients might result from
cutaneous type IV (T-cell mediated) drug hypersensitivity reactions.
Typical immunologic characteristics of maculopapular eruptions are
summarized in Figure 5B (type IVb) and 5C (type IVc) and histologic
features are summarized in Table 5 and shown in Figure 6B. The most
common histologic feature of drug-induced maculopapular exanthema is a
perivascular dermal lymphohistiocytic infiltrate with or without
infiltration of eosinophilic granulocytes. The epidermis can be normal
or exhibit interface changes with vacuolar degeneration of the basal
layer, apoptotic keratinocytes and exocytosis of lymphocytes can be
present. Additional features can be edema in the upper dermis,
extravasation of red blood cells and dilatation of blood vessels. It is
often impossible to histologically distinguish viral and drug induced
exanthema. Lichenoid -- and less frequently- spongiotic or psoriasiform
pattern of reactions may be related to maculopapular drug reactions.
Sometimes even systemic eosinophilia and elevated CRP levels might occur
(\textbf{72} ). Typical immunologic characteristics of maculopapular
eruptions are summarized in Figure 5B (type IVb) and 5C (type IVc) and
histologic features are summarized in Table 5 and shown on Figure 6B.

\emph{3.3 Severe cutaneous adverse drug reaction}

There are COVID-19 positive cases with DRESS (drug reaction with
eosinophilia and systemic symptoms) described (unpublished reports),
which is a severe cutaneous drug reaction with non-specific histologic
findings (Figure 9A and B). The diagnosis is based on a combination of
clinical symptoms and laboratory parameters including frequently
occurring hepatic abnormalities, eosinophilia and exanthema with facial
swelling and lymphadenopathy (\textbf{73} ). The culprit drug should be
stopped immediately upon identification. In some cases, eosinophilia
could hardly be controlled with corticosteroids, which led to the
successful use of agents interfering with the IL-5 axis (unpublished
reports).

\emph{4. Drug induced vasculitis}

Drug hypersensitivity reactions with changes of the vasculature or
vascular pathways such as vasculitis, livedo racemosa or purpura
represent a proportion of 10-20\% of cutaneous reactions to drugs and
can occur relatively late (7-14 days) during or even after drug
exposure, but the time of onset to the related drug varies and depending
on the causative drug (\textbf{74} ).

Numerous drugs can induce vasculitis, which manifests primarily as
cutaneous vasculitis, mediated as III hypersensitivity reactions (Table
3), i.e. immune complex deposits with antigen excess in arteries,
arterioles, venules or capillaries (Fig. 8). It is of notice that some
drugs might also induce antibody production (\textbf{62} ).

Drug-induced vasculitis includes leukocytoclastic or hypersensitivity
vasculitis, necrotizing vasculitis, Panarteritis-nodosa like vasculitis
and others (\textbf{62} ).

Histologic features of vasculitis are an inflammatory infiltrate in the
wall of dermal or subcutaneous vessels (which can be neutrophilic,
lymphocytic or granulomatous), red blood cell extravasation, variable
fribrinoid necrosis of vessel walls and nuclear debris (\textbf{74} ).

The number of drugs, which have been reported to be applied to COVID-19
patients all over the world is high and ranges from specific antiviral
drugs, antiphlogistics, antibiotics, anti-coagulants, immunosuppressive
as well as immunoregulatory drugs. All of these drugs are approved and
tested for other infectious diseases or entities so that not much
experience about putative side effects in COVID-19 patients exists and
knowledge gained about skin lesions induced by drugs applied during
other diseases can only be used and transferred to speculate on this
issue.

Summing up, COVID-19 skin manifestations, could be caused for each one
or a mixture of the components mentioned above i.e. reaction to the
infection, drug hypersensitivity reaction, pre-existing immune state of
the skin/immune system, combined with an impaired general health
condition and other co-factors such as age of the individual. Therefore,
it is important to discuss also putative additional trigger factors
related primarily to the susceptibility to infection with SARS-CoV-2 and
the risk to undergo severe courses of COVID-19 as an indirect factor
predisposing subsets of patients to skin and vascular lesions.

\textbf{Conclusion}

Recent observation of involvement of the skin and the vasculature in
subgroups of SARS-CoV-2 infected patients illustrates the need for a
precise stratification and differential diagnostic evaluation of those
patients in order to gain more insight into mechanisms of this novel
virus. So far, pathophysiologic mechanisms behind the skin lesions
occurring in the context of COVID-19 are speculative, could be related
to the virus, drugs and other co-factors. Knowledge from other viral
infections and drug induced lesions of the skin and vascular system
might be transferred and observations on SARS-CoV-2 patients
systematically evaluated to rapidly increase our knowledge on this
issue. For mild cases of COVID-19, skin lesions can be a diagnostic
hint; for severe cases, due to multiorganic involvement and
interdisciplinary approach is of outmost importance.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Upper respiratory airways} & \textbf{Lower respiratory
airways}\tabularnewline
\midrule
\endhead
229E & SARS-CoV\tabularnewline
NL63 & SARS-CoV-2\tabularnewline
OC43 & MERS-CoV\tabularnewline
HKU1 &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1:} Human coronaviruses

SARS: severe respiratory syndrome coronavirus; MERS: Middle East
respiratory syndrome coronavirus

\textbf{Table 2:} Histologic characteristics of infectious exanthemas
(adapted from 51)\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Location} & \textbf{Histology} & \textbf{Skin
lesion}\tabularnewline
\midrule
\endhead
Capillary endothelium dermis & Damage of vessels, endothelial swelling,
perivascular edema, hemorrhage & Macules, papules,
petechiae\tabularnewline
Dermis & Edema, cellular infiltrate, hemorrhage, visualization of
organism by electron microscopy & Papules, urticaria, purpura,
vesicles\tabularnewline
Epidermis & Cytopathic effects of the virus, i.e., inclusion,
ballooning, vacuolar degeneration, necrosis & Papules, vesicles,
ulcer\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} : Immunological classification of (cutaneous) drug
reactions (modified from 75).\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
I\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Specific IgE\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Anaphylaxis\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IgG or IgM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hemolytic anemia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IgG or IgM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Serum sickness\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type IVa\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Th1 (IFN-\selectlanguage{greek}γ\selectlanguage{english})\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Monocyte activation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eczema\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type IVb\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Th2 (IL-4/IL-5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eosinophilic inflammation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maculopapular exanthema, Drug Rush with Eosinophilia and systemic
symptoms (DRESS)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Type IVc\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CTL Perforin/ Granzyme B\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CD4/CD8 mediated killing of cells\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Maculopapular exanthema Toxic epidermal necrolysis\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type IVd\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
T cells (IL-8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Neutrophil activation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Acute generalized exanthematic pustulosis (AGEP)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type IVe\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Th2 cells\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CD4/CD8 cell activation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Common} & \textbf{Less common} & \textbf{Severe cutaneous drug
reactions}\tabularnewline
\midrule
\endhead
Maculo-papular exanthems & Lichenoid eruptions & DRESS\tabularnewline
Urticaria & Pityiriasis rosea-like eruptions & AGEP\tabularnewline
& Purpura &\tabularnewline
& Vasculitis &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4:} Common and less common cutaneous (drug) eruptions
(modified from 76), which have also been described in COVID-19 patients.

Dress=Drug Rash and Eosinophilia and Systemic Sympotms; AGEP= Acute
generalized exanthematic pustulosis

\textbf{Table 5:} Features of drug-induced exanthema (modified from 72)

Lymphocytic exocytosis

Perivascular lymphohistiocytic infiltrate with or without eosinophils

Interface changes (vacuolar degeneration of basal layer, apoptotic
keratinocytes, exocytosis of lymphocytes), lichenoid-, spongiotic- or
psoriasiform changes

Papillary dermal edema

Extravasation of red blood cells

Elevated serum CRP and eosinophilia

\textbf{Figure legends:}

Figure 1: Structure of SARS-CoV-2 Virus with its typical capsid and the
spikes, ``corona''.

ssRNA=single stranded RNA; ACE2=Angiotensin receptor 2;
TMPRSS2=transmembrane protease serine subtype 2.

Figure 2: Symptoms of COVID-19.

Figure 3: Cascade of events in lung epithelium during SARS-CoV-2
infection. SARS-CoV-2 infects lung epithelial cells via ACE2 and TMPRSS2
receptor, the host cells undergo apoptosis in consequence of virus
replication and release and the undergoing cell releases
damage-associated molecular patterns, which induce the production of
pro-inflammatory mediators by epithel and endothel cells in the
neighbourhood. Inflammatory cells such as monocytes, macrophages, and T
cells are recruited from the blood to the lung epithel, increase the
production of inflammatory mediates and further infiltration of the lung
by inflammatory cells, leading to damage of the lung structure and a
``cytokine storm'', which reaches the vasculature and other organs.

ssRNA=single stranded RNA; ACE2=Angiotensin receptor 2;
TMPRSS2=transmembrane protease serine subtype 2; Mo=monocyte, T=T
lymphocyte, M=macrophage.

Figure 4 A: Typical skin lesions (vesicular eruptions occurring early
during COVID-19 (A), with symptoms of COVID-19, i.e. maculopapular
exanthema (B), urticarial rash (C), vasculitis (D) and later during
COVID-19 disease Chilblain eruptions (E).

Figure 5: Immunologic features in the skin of virus-induced
maculopapular exanthema (A) with virus antibody activation and
interaction with immune cells in the blood, recruitment of activated
cells to the skin, extravasation of erythrocytes through the blood
vessels,, cytokine production and keratinocyte apoptosis and related
changes to the dermis and epidermis and drug-induced maculopapular rush
type IVb (B) and IVc (C) derived by activated T cells, extravasation of
erythrocytes, perivascular infiltrates and perforin and granzyme B and
Th1 cytokines as well as different chemokines and recruitment of T cells
and eosinophils to the dermis and respective changes to the dermis and
epidermis; DC=dendritic cell; B=B cell; Mo=monocyte, Eo=Eosinophil.

Figure 6: Histologic features of skin biopsies taken from two SARS-CoV-2
positive patients with maculo-papular eruptions.

A: Skin sections showing epidermis with mild hyperkeratosis,
keratinocytes with frosted glass nuclei, with intranulcular and
occasionally multinucleate inclusions,

reminiscent of cytopathic damage. Dermis without edema, perivascular
inflammatory infiltrate extending focally to the basal layer, causing
slight vacuolate damage and

pigmentary incontinence. No eosnophils are observed

B: Histology (H\&E stain) showing an inconspicous epdermis and a very
subtle perivascular lymphohistiocytic infiltrate in the upper dermis
with admixture of few eosinophilic granulocytes.

Figure 7: IgE-, direct- and antigen-immuncomplex-mediated mast cell
activation in urticaria.

Figure 8: Vasculitis of small, medium and large vessels, with formation
of antigen-immune-complexes, which accumulate within the vessels and
damage of the endothel, which leads to extravasation of cells and
neutrophil recruitment.

Figure 9 A: 58-year old male patient diagnosed with COVID-19 and DRESS
syndrome.

B: Histology (H\&E stain) showing interface changes (vacuolar
degeneration of the basal layer, apoptotic keratinocytes, exocytosis of
lymphocytes) as well as spongiotic changes with hyperparakeratosis.
Perivascular lymphohistiocytic infiltrate with admixture of few
eosinophilic granulocytes. Mild extravasation of erythrocytes.

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