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DOI: 10.1055/a-1581-6899
Microvascular Skin Manifestations Caused by COVID-19
- Abstract
- Introduction
- Pathomechanisms Observed in the Skin
- Clinical Presentations
- Conclusion
- References
Abstract
Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2–mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.
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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.
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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]
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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.
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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]
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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.
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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]
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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]
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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.
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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].
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]
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“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]
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Retiform Lesions
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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]
![](https://www.thieme-connect.de/media/10.1055-s-00034925/202105/thumbnails/10-1055-a-1581-6899-i210025-2.jpg)
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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]
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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]
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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.
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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.
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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]
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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]
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Conclusion
Systemic coagulopathy and vascular injury underlie morbidity due to COVID-19 infection.[10] Vascular skin manifestations in SARS-CoV-2 infection are manifold and may be the first clinical sign of underlying hypercoagulability and inflammation. In some patients, they may even be the only symptom in COVID-19 disease.[58] It is necessary that clinicians are aware of the different pathologies that demand for different therapeutic strategies. Moreover, it is necessary to be aware that pathologies directly observed and diagnosed in the skin are the same that occur in other organs, representing both inflammatory and thrombotic pathomechanisms.[24] By understanding the pathomechanisms in COVID-19 infection, therapies can be more specific in counteracting effects caused by SARS-CoV-2.
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Conflict of Interest
The authors declare that they have no conflict of interest.
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Address for correspondence
Publication History
Received: 31 March 2021
Accepted: 09 August 2021
Article published online:
25 October 2021
© 2021. Thieme. All rights reserved.
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