Introduction
In the past 20 years, coronavirus-related severe respiratory infections with high
morbidity and mortality affected millions of people. SARS-CoV (severe acute respiratory
syndrome coronavirus) in 2002/2003 and MERS-CoV (Middle East respiratory syndrome
coronavirus) in 2012 caused two major disease outbreaks.[1] In 2019, the new SARS-CoV-2 spread in a pandemic outbreak resulting in 125,781,957
infected and 2,759,432 deceased individuals by March 2021.[2] SARS-CoV-2 is a member of the beta-subfamily of coronaviruses (Coronaviridae) and is an enveloped, single-stranded RNA virus covered with spike proteins.[1]
[3]
Since November 2019, more than 120 million cases of SARS-CoV-2 infection worldwide
have been reported. About 20 to 25% of patients with confirmed SARS-CoV-2 infection
show cutaneous symptoms connected to microcirculation impairment or microvascular
damage.[4]
[5] Several mechanisms have been suggested in patients infected with SARS-CoV-2. The
different pathomechanisms merge together into common pathways, the results of which
can be directly observed on the skin.
The focus of this review is to summarize the effects of SARS-CoV-2 on cutaneous microvasculature
and to describe clinical vascular pathologies seen in dermatologic patients with COVID-19
disease.
Pathomechanisms Observed in the Skin
Inflammation of Vessel Walls: Endothelial Damage Due to Viral Entry into Cells via
ACE2
Several studies have shown that SARS-CoV-2 is able to enter host cells. The virus
expresses a class I fusion protein on its envelope, known as the spike protein.[6] The spike protein possesses a receptor-binding region to angiotensin-converting
enzyme 2 (ACE2) receptor that is expressed on the cells' surface.[7]
[8]
[9] Physiologically, ACE2 is part of the counterregulatory axis of the renin–angiotensin
system (RAS) converting angiotensin II into a protective peptide, angiotensin 1-7
(Ang 1-7). Ang 1-7 binds to the Mas-receptor and antagonizes effects of angiotensin
II. Thus, angiotensin 1-7 causes vasodilatation, reduces oxidative stress, and counteracts
the proinflammatory, prothrombotic, and profibrotic activity of angiotensin II.[10]
[11]
In the skin, ACE2 is found in the basal cell layer of the epidermis, the endothelium
of dermal arterioles and venules, in eccrine gland epithelial cells, and in subcutaneous
fat tissue.[12]
[13]
[14] Binding to ACE2 and priming by cofactor TMPRSS2 (transmembrane protease serine subtype
2) facilitates entry into the cell, followed by membrane fusion, internalization of
the virus, and eventually cell death.[6]
[15]
[16]
[17]
[18] Binding of SARS-CoV-2 to ACE2 subsequently leads to downregulation of ACE2 and reduces
the protective effects of Ang 1-7, which changes the balance in the RAS toward oxidative
stress, inflammation, and vasoconstriction.[18]
[19]
[20] Furthermore, extensive production of inflammatory cytokines, adhesion molecules,
and chemokines, in the context of SARS-COV-2-driven cytokine storm, imposes local
inflammatory cell infiltration, vascular leakage, and indirect endothelial inflammation
on the one side.[21] On the other side, endothelial inflammation caused directly by virus uptake into
the cell and the following immune response (e.g., complement deposition) furthers
apoptosis, endothelial injury, and thrombus formation ([Fig. 1]).[8]
[10]
[22]
Fig. 1 Endotheliitis (arrow) in dermal vessels in a patient with COVID-19 (semi-thin sections
of glutaraldehyde-fixed human skin biopsies, toluidine blue staining).
Of note, Magro et al[24] distinguished between the virus itself that is found in lung tissue in high copies
and virus particles, called “pseudovirions,” that contain viral capsid proteins, but
no RNA, and that circulate systemically to organs other than the lung, such as skin,
brain, and liver, causing endothelial injury and production of cytokines.
Microthrombus Formation Due to High Cytokine Levels
Cytokines are a large group of secreted proteins important for cellular communication
and guidance of the direction of the host immune responses. During inflammation, they
are produced by immune cells (e.g., lymphocytes and macrophages) as well as by endothelial
cells, stromal cells, and fibroblasts.[25]
[26]
[27] In severe COVID-19 infection, high levels of proinflammatory and prothrombotic cytokines
are observed, in particular, interleukin-1β, -6, -8, and tumor necrosis factor-α.
Positive feedback mechanisms in combination with insufficient clearance of chemokines
can result in a cytokine storm, a serious complication in SARS-CoV-2 infection with
progressive thromboinflammatory response and hypercoagulability.[8]
[17]
[18]
[28]
[29]
[30]
Especially type I interferons (IFN) play an important role in SARS-CoV-2 infection.[31] In the early phase of inflammation, type I IFNs limit viral dissemination.[31] However, prolonged and uncontrolled type I IFN signal results in abrogated immune
response, ongoing inflammation, and poor clinical outcome.[32]
[33]
[34] The pathophysiology of microangiopathy and thrombotic complications related to SARS-CoV-2
infection is not yet completely understood. Currently, both direct endothelial cell
involvement and recruitment of innate and adaptive immune cells are focus of extensive
research.[35] Especially of interest is the immune-mediated, type I IFN-driven endothelial dysfunction,
resulting in endothelial cell apoptosis observed most commonly in the lung, and also
in the skin.[21]
[22]
Activation of the Complement System
The complement system is part of the innate immune system and involves more than 40
plasma proteins and proteases with major role in clearing damaged cells and eliminating
pathogens from the organism.[36] Upon activation, an amplifying cascade of proteolytic cleavage results in proinflammatory
reactions and phagocytosis of pathogens. Moreover, in the course of activation, the
membrane attack complex formed by the proteins C5b, C6, C7, C8, and C9 causes disruption
of the cell membrane with subsequent lysis and cell death.[37]
[38] Both C5b-9 and C4d deposits have been shown in thrombotic microangiopathy earlier.[39] In COVID-19 pathology, several studies have described activation of the alternative
and lectin complement pathway in the presence of SARS-CoV-2 envelope protein leading
to microthrombotic vascular injury with deposition of C5b-9 and C4d in both lesional
and normal-appearing skin.[10]
[12] Moreover, Magro et al[10] demonstrated codeposition of the SARS-CoV-2 spike protein and the complement component
C4d in dermal microvasculature.
Elevation of Antiphospholipid Antibodies
Antiphospholipid antibodies are autoantibodies directed against proteins that bind
to phospholipids and are associated with arterial and venous thrombosis.[40] Zuo et al[41] found that in 52% of patients hospitalized with COVID-19, several types of antiphospholipid
antibodies were transiently elevated. Occurrence of antiphospholipid antibodies has
been described by several authors and is assumed to contribute to microvascular pathology
in COVID-19 infection, possibly aggravating thromboinflammatory events arising in
severe disease.[40]
[42]
[43]
[44]
COVID-19-Associated Coagulability
Hypercoagulability due to COVID-19 infection is characterized by elevated fibrinogen
and D-dimer levels in connection with prolongation of prothrombin time (PT).[45]
[46] Also, minor differences in platelet count are observed in up to 41% of patients
infected with SARS-CoV-2.[47] Usually, these changes are mild, but several studies indicated that COVID-19 coagulopathy
is related to the severity of the disease and elevated D-dimer levels have been shown
to positively correlate with mortality in COVID-19-affected individuals.[48]
[49]
[50]
Hypercoagulability is a pathomechanism observed in viral infections in general and
associated with clearance of pathogens from the organism.[38]
[50] It is currently assumed that SARS-CoV-2 is not directly procoagulant; more likely,
hypercoagulability in COVID-19 infection is triggered by increased cytokine release
and endothelial damage as described earlier.[51] As a difference to disseminated intravasal coagulation (DIC), CAC is not associated
with a clinical bleeding tendency and thrombocytopenia is mild.[46]
[50]
[51]
Type III Hypersensitivity
Bacterial or viral pathogens, such as hepatitis or influenza virus, as well as medical
drugs are common triggers of cutaneous small vessel vasculitis.[52] Antigen–antibody immune complex aggregates are deposited in the vessel walls of
postcapillary venules in the dermis with subsequent activation of the complement system
causing inflammation with edema, purpura, and necrosis.[53]
[54] Camprodon Gómez et al[53] confirmed the presence of viral SARS-CoV-2 RNA in the vessel endothelium in biopsies
taken from the skin of patients presenting with vasculitis.
Clinical Presentations
Endotheliitis caused by SARS-CoV-2 and microthrombosis in the dermal vasculature lead
to different skin lesions. Clinical appearance of these skin lesions can give an indication
of the underlying pathology. Vascular skin lesions that can be observed in patients
in association with COVID-19 infection are listed in [Table 1].
Table 1
Overview of microvascular changes in the skin caused by SARS-CoV-2
|
Etiology
|
Pathomechanism
|
Prevalence in cutaneous findings (%)
|
Clinical appearance
|
Histological findings
|
Typical age
|
Appearance
|
Severeness
|
References
|
|
Acro-ischemic lesions
|
|
Pernio-like lesions (chilblain-like lesions, “Covid toe,” acral erythema, acral purpura,
pseudopernio)
|
Direct viral-induced endothelial damage, endotheliitis
|
Lymphocytic vasculitis followed by strong innate type I interferon response
|
19–63
|
Mainly toes (85.7%), violaceous or bluish maculae, with formation of bullae
|
Dermal lymphocytic infiltrate perivascular and perieccrine with a prevalence of cytotoxic
CD8+ lymphocytes, vacuolar degeneration of the basal epidermal layer
|
Adolescents and younger adults, mean age 44 y
|
Late
|
Mild to moderate, 25.4% asymptomatic
|
[23]
[61]
[58]
[63]
[62]
[56]
[59]
[60]
[92]
|
|
“True” acral ischemia (dry gangrene, acute limb ischemia, acral necrosis)
|
Arterial or venous occlusion
|
Likely a combination of arterial vasculitis and coagulopathy compromising perfusion
to acres
|
1.20
|
Ischemia of fingers, toes, nose with livid erythema, dry gangrene
|
|
Older, mean age 70 y
|
Late
|
Critically ill
|
[56]
[73]
[75]
[76]
[77]
|
|
Reticular lesions
|
|
Livedo reticularis
|
Vasomotoric
|
Inflammatory effect of SARS-CoV-2 on endothelial cells or smooth muscle cells that
express ACE 2
|
2.3–4
|
Transient regular purple or bluish net-like pattern with complete rings and a pale
center
|
Chronic inflammatory component. C4c complement deposition in the EBM and the endothelium
of vessels
|
|
|
Mild to moderate
|
[23]
[59]
[62]
[74]
[89]
|
|
Livedo racemosa
|
Cutaneous microthrombosis
|
Partial occlusion of cutaneous blood vessels
|
Not known due to different denomination
|
Persistent livid-violaceous, irregular and discontinuous broken rings
|
Noninflammatory to pauci-inflammatory thrombi, complement including C5b-9 in skin
biopsies
|
Older, mean 78 y
|
Late
|
More often in critically ill
|
[56]
[61]
[62]
[70]
|
|
Retiform purpura
|
Cutaneous microthrombosis
|
Full occlusion of cutaneous blood vessels by complement activation
|
7.1–8.2
|
Central necrotic area with variable surrounding erythema
|
Pauci-inflammatory vascular thrombosis with endothelial cell injury, prominent deposits
of C5b-9 in the microvasculature
|
older, mean 78 y
|
Late
|
Severe and critically ill
|
[56]
[62]
[70]
[87]
[95]
|
|
Cutaneous small vessel vasculitis
|
|
Small vessel vasculitis (non-IgA)
|
Type III hypersensitivity reaction (IgG, IgM)
|
Antigen–antibody complexes that target the vascular endothelium of the skin with immune
complex deposition in postcapillary venules
|
1.8
|
Symmetrical palpable purpura, mostly in the lower legs, may be accompanied by systemic
symptoms
|
Endothelial swelling, neutrophilic vessel wall infiltration with nuclear debris in
vessel walls/scant leukocytoclasia, fibrin deposition in small- and medium-size dermal
vessels with extravasation of erythrocytes. Microthrombi occluding dermal capillaries
|
|
Late onset (latent period 1–4 wk)
|
Mainly mild disease
|
[53]
[92]
[99]
|
|
IgA vasculitis (Schonlein–Henoch purpura)
|
Type III hypersensitivity reaction (IgA)
|
Immune complex deposits containing IgA in skin and organs
|
Reported casuistically
|
Palpable purpura symmetrically over all extremities, gluteal region, lower abdomen;
accompanied by systemic symptoms; focal IgA nephropathy
|
Perivascular and vessel wall infiltration by neutrophils and lymphocytes, leukocytoclasia,
and C3 and IgA deposits in dermal capillaries
|
|
Late, after latent period
|
|
[101]
[102]
[103]
[104]
|
|
Urticarial vasculitis
|
Type III hypersensitivity reaction (IgM, IgG)
|
Immune complex deposition and complement system activation
|
Reported casuistically
|
Urticarial lesions similar to wheals, but lasting more than 24 h, may be accompanied
by periorbital and acral edema
|
Dermal edema and evidence of leukocytoclastic vasculitis; sparse infiltrates, nuclear
debris, or fibrin deposits
|
|
Latent period > 4 wk
|
|
[105]
[106]
|
|
Kawasaki-like disease (Kawa-COVID-19)
|
Probably postinfectious syndrome
|
Vasculitis of small- and medium-size arteries
|
Rare; more frequent occurrence since March 2020
|
Fever, conjunctivitis, abdominal pain, myocardial involvement; macular-papular exanthema,
mainly on the trunk, necrotizing vasculitis; coronary arteries often involved
|
Leukocytoclastic vasculitis with necrosis of the epidermis and most of the dermis
with extravasation of erythrocytes and fibrin thrombi in the capillaries, infiltration
of neutrophils with nuclear debris in vessel walls, and C3 and IgA deposition in a
vascular pattern
|
Mainly children, but also reported in adults
|
Latent period of several weeks
|
|
[30]
[54]
[92]
[109]
[110]
[113]
|
Acral Ischemia
The term “acral ischemia” summarizes a heterogeneous group of lesions on the digits
and toes caused by acute vasomotoric or thrombotic interruption of the blood flow
and subsequent ischemia.[55] Acral ischemia has been described in 1.2% of COVID-19 patients with a higher prevalence
(23%) in critically ill patients.[56]
The clinical patterns reported in acro-ischemia include Raynaud's phenomenon, pernio-like
lesions, reticular lesions including livedoid lesions and retiform purpura, as well
as true acral ischemia with dry gangrene.[56]
Acral Purpura (Pernio-Like Lesions)
Acral purpura describes a chilblain-like acral pattern of erythematous or violaceous
skin lesions.[57] Due to inconsistent designations in various reports concerning SARS-CoV-2, it may
be assumed that the terms “chilblain-like lesions,” “acral perniosis,” “acral erythema,”
and the colloquial “COVID toe” are used synonymously and refer to the same disease
entity.
Patients commonly affected are adolescents and younger adults with no relevant medical
history, which show mild to moderate symptoms of COVID-19 infection, and also in asymptomatic
patients; in about 25%, chilblain-like lesions present the only symptom of COVID-19
infection.[58]
[59]
[60]
[61] Lesions typically appear late in the course of disease (mean after 12.7 days), possibly
indicating a delayed-type immunological reaction to the virus.[58]
[62] Although the pathology of chilblain-like lesions is still unknown, histological
changes suggest a lymphocytic vasculitis in the vessels of the dermis.[63]
[64]
Symptoms reported include pruritic (30–39%) or tender (22–32%) violaceous macules
and dusky, purpuric plaques, predominantly (85.7%) appearing on the distal part of
the toes and in 7% affecting both toes and fingers.[62]
[65]
[66] In more severe cases, digits appear edematous, sometimes presenting with superficial
blistering and hemorrhagic crust without apparent ischemia or necrosis.[67] Moreover, history of cold exposure is usually lacking, as reported by Mawhirt et
al.[23]
Interestingly, SARS-CoV-2 polymerase chain reaction (PCR) test is frequently negative
in nasopharyngeal and oropharyngeal swabs in patients with chilblain-like lesions.[68] In turn, SARS-CoV-2 spike protein was detected in biopsies of pernio-like lesions
in vascular endothelial cells of the upper dermis and also in epithelial cells of
eccrine glands.[68]
[69]
[70]
It has been suggested that the mild course of the disease can be explained by a strong
type I interferon reaction to the SARS-CoV-2 virus, an antiviral host response more
often found in young, healthy patients that leads to accelerated virus elimination
and abortive infection at an early stage.[61]
[63]
[70]
[71]
[72] Older patients, in contrast, may have weaker or delayed type I interferon response
that leads to subsequent cytokine release and increased morbidity and mortality.[63]
“True” Acral Ischemia
While in some studies, the term “acral ischemia” is used to describe pernio-like lesions,
true acral ischemia is caused by complete interruption of blood flow causing ischemia
with subsequent dry gangrene, which may result in loss of that limb. Several cases
of acute limb ischemia have been reported in critically ill patients diagnosed with
COVID-19,[56]
[73]
[74]
[75]
[76] the extent of limb ischemia depending on the size of occluded vessel. Although the
pathophysiology remains unclear, it has been assumed that a number of different factors,
alone or in combination, may contribute to severe limb ischemia. Arterial and venous
thromboembolism due to COVID-19-related coagulopathy with elevated D-dimer levels,
possibly aggravated by the application of inotropic drugs used in critically ill patients,
has been suggested in the pathogenesis of these lesions.[43]
[73]
[77]
[78] Besides that, in several reports, venous gangrene following extensive venous thrombosis
has been described.[79]
[80]
[81] In some of the patients, concurrently elevated antiphospholipid antibodies have
been detected, possibly contributing to thrombus formation.[43]
[75]
[79] Therapeutic attempts with low-molecular-weight heparin have not always been successful
in preventing complete limb ischemia.[56]
Balestri et al[82] reported a case of acral necrosis and dry gangrene 20 days after being tested negative
again after COVID-19 infection, confirming the hypothesis formulated by Piccolo et
al[66] about a delayed-type immune reaction caused by the virus. Moreover, they speculated
that acral necrosis might be caused by the same delayed pathomechanism as are chilblain-like
lesions, but with a weaker type I interferon response in elderly people, that may
progress to “true” acral ischemia with dry gangrene.[70]
[82]
Retiform Lesions
Livedo Reticularis
Livedoid lesions have been described in a number of dermatological conditions earlier.[83] Several studies report an incidence of livedoid lesions in 2.8 to 6.9% in COVID-19
patients with cutaneous manifestations.[59]
[62]
[84]
[85]
[86] In some publications, the terms “livedo reticularis” and “livedo racemosa” are used
synonymously. Nonetheless, it is necessary to differentiate these two entities due
to their different pathophysiology.
Livedo Reticularis
Livedo reticularis, also called cutis marmorata, results from constriction of cutaneous
central arterioles and slowed arteriolar blood flow with subsequent dilatation of
venules in the skin and desaturation of the blood,[87]
[88] thus forming a regular purple or bluish net-like pattern with complete rings and
a pale center ([Fig. 2]).[87]
[89] It may be transient or persistent and may physiologically be found in children and
young to middle-age women[90] as a result of vasoconstriction of cutaneous vessels (e.g., cold-induced).[87] In COVID-19, the transient livedo pattern has been associated with mild to moderate
disease, and may be unilateral or symmetrical often leaving out the trunk.[87]
[91] Coagulation parameters are usually normal which supports the theory of endotheliitis
caused by direct viral uptake into endothelial cells and vascular smooth muscle cells
leading to vasoconstriction.[22]
[91]
[92]
Fig. 2 Clinical image of livedo reticularis. Representative photograph of the lower extremities
in a 49-year-old female patient. Livedo reticularis occurred 3 days after the patient
developed respiratory symptoms. (Courtesy of Wolfram Hoetzenecker and Isabella Pospischil,
Department of Dermatology, Kepler University Hospital, Johannes Kepler University,
Linz, Austria).
Livedo Racemosa
Livedo racemosa, in contrast, is always pathologic, and more commonly associated with
impairment of the blood flow.[87]
[88] With occlusion of cutaneous arterioles and venules, it forms persistent livid-violaceous,
irregular, and discontinuous broken rings, which are seen in a number of systemic
vascular disorders such as livedoid vasculopathy or antiphospholipid syndrome.[87] In COVID-19, it is related to more severe disease and understood as a cutaneous
manifestation of the procoagulant state.[4]
[56] Unlike transient livedo reticularis, which is connected to mild to moderate disease
and good clinical outcome, fixed livedo racemosa is more often found in older patients
with more severe disease, unfavorable outcome, and high mortality up to 10%.[10]
[61]
[62] Biopsy samples have revealed occlusive fibrin thrombi and significant microvascular
deposition of complement (C4c, C4d, C5b-9) in the dermis.[93]
[94] While in livedo reticularis, therapeutic options may include a wait-and-see strategy,
in livedo racemosa, application of low-molecular-weight heparin in preventive dosing
has been recommended.[87]
[91]
Retiform Purpura
The term “retiform purpura” refers to stellate, violaceous lesions of the skin caused
by a complete interruption of dermal and subcutaneous vessel blood flow.[55]
[88] Purpuric lesions are more frequently found in elderly and critically ill patients,
associated with the highest mortality rate in cutaneous lesions.[62]
[70] Indeed, in contrast to the earlier-mentioned pernio-like lesions, patients with
thrombotic retiform purpura show impaired interferon response to the virus.[70] Subsequently, extensive amounts of SARS-CoV-2 envelope and spike proteins were detected
in the endothelium in thrombosed and normal-appearing dermal vasculature.[70]
Clinical morphology of retiform purpura is painful purpuric, reticular patches with
hemorrhagic bullae and crusts that transform into a necrotic area with variable surrounding
erythema.[95] It may be accompanied by nonblanching hemorrhage (purpura). The distribution of
the lesions varies depending on the pathology and may be localized in acral or intertriginous
areas or generalized.[87]
[94]
The pathology of retiform purpura reflects microvascular deposition of complement
components C3d, C4d, C5b-9, and MASP-2 with consecutive vessel wall damage.[70] This may be aggravated by microvascular occlusion phenomena (e.g., antiphospholipid
antibody syndrome or thrombotic thrombocytopenic purpura as well as disseminated intravascular
coagulation),[88] conditions that have been recognized in COVID-19 infection.[96]
[97]
Vasculitis
Small Vessel Vasculitis
Cutaneous small vessel vasculitis is a type III hypersensitivity reaction of small
vessels in the dermis. It can be idiopathic or caused by an excessive immune system
response to pathogens or drugs, in malignancy or autoimmune disease.[53]
[54] Deposition of IgM or IgG immunocomplex aggregates along postcapillary venule walls
leads to the activation of the complement cascade causing inflammation with leakage.[52] Clinical symptoms typically occur after a latent period of 1 to 4 weeks.[52]
[98] The cardinal symptom is palpable purpura mainly concerning dependent areas of the
body, notably the lower legs, but may also affect thighs, arms, and abdomen.[99]
[100]
[101] In cases with high levels of inflammation, bullae and necrosis may develop in the
purpuric skin lesions.[99] Skin symptoms may be accompanied by fever, fatigue, or arthralgia.[52] Small vessel vasculitis has been described as a cutaneous manifestation in COVID-19.[53]
[99]
[100] PCR of skin biopsies has been positive for SARS-CoV-2 virus as reported by previous
studies,[53]
[99]
[100] confirming the presence of SARS-CoV-2 RNA in vascular endothelium, which may be
indicative of a causal relation in vasculitis.
IgA Vasculitis (Schonlein–Henoch Purpura)
Immunoglobulin A (IgA) vasculitis, a subtype of small vessel vasculitis that primarily
affects children,[101] is likewise due to type III hypersensitivity. Complexes of IgA and complement component
C3 are deposited in arterioles, venules, and capillaries in the skin and connective
tissues, and also in other organs like the gastrointestinal tract and kidneys.[102]
[103] Upper respiratory tract infection is commonly preceding the symptoms of vasculitis,
which include palpable purpura, arthralgia, and abdominal pain.[104] In COVID-19, only a few cases of IgA vasculitis have been described affecting both
children and adults.[100]
[101]
[103]
[104] Allez et al[104] reported the case of a patient with IgA vasculitis COVID-19 serology was positive
for IgA only.
Urticarial Vasculitis
Urticarial vasculitis, another subtype of small vessel vasculitis, presents clinically
like acute urticaria with or without angioedema, but then shows a different course
of the disease. While in allergic urticaria, lesions are typically volatile and transient,
in urticarial vasculitis, the wheals typically persist stationary more than 24 hours.
Histologically, changes are discreet with scanty focal, neutrophilic infiltrate, fibrin
deposits, or nuclear debris and may show erythrocyte extravasation.[105] Urticarial vasculitis has been reported casuistically in COVID-19.[105]
[106]
Kawasaki-Like Disease
Kawasaki-like disease is caused by inflammatory vascular disease of small- and medium-size
arteries of unknown cause.[107] It is assumed that it can be triggered by pathogens, likely on the basis of genetic
susceptibility.[108] Kaya et al[30] reported the presence of leukocytoclastic vasculitis in biopsies of patients with
Kawasaki-like disease. Skin lesions, however, are unspecific and may present as maculopapular
or polymorphic exanthema accompanied by mucocutaneous symptoms as well as palmar and
plantar erythema.[109]
[110] Although there are a few reports about Kawasaki-like disease in adults,[111]
[112] it mainly occurs in children.[113] Therefore, Kawasaki-like disease in COVID-19 infection has been termed “multisystem
inflammatory syndrome in children” (MIS-C(. or alternatively “pediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2 infection” (PIMS-TS).[110] Diagnostic criteria include prolonged fever and multisystem organ involvement of
more than two organ systems including cardiac, renal, neurological, hematological,
respiratory, cutaneous, and gastrointestinal manifestations in combination with positive
SARS-CoV-2 antigen test, PCR or serology, or COVID-19 exposure in the past 4 weeks.[114] Verdoni et al[110] reported an increase in monthly incidence of Kawasaki's syndrome in spring 2020
that is 30 times higher than in the 5 years before. Though only few children were
tested positive in SARS-CoV-2 PCR, seroconversion was observed in almost all cases,
suggesting an association with COVID-19 infection. It has been proposed that Kawasaki-like
disease caused by SARS-CoV-2 occurs due to STING pathway activation after binding
to ACE2, which, after a latent period, would cause an excessive immune response.[115]
