Table 4.

Skin Manifestations Observed in our Study Patients and Their Presupposed Pathogenic Mechanisms

Presupposed Mechanism	Dermatological Features	Other Infectious Diseases and/or Inflammatory Diseases With Similar Mucocutaneous Features	Pathophysiological Hypotheses
Vascular leak	Macular exanthema	Dengue: Endothelial swellings of small blood vessels, perivascular edema, and infiltration with mononuclear cells consistent with vascular leak (histology) [21]	“Inflammatory phase” of COVID-19 (7th to 12th days of symptom onset): Due to a “cytokine storm” involving in particular IL-2, IL-6, IL-1, IL-10, and TNFα [22]. Among them, IL-2 and TNFα are thought to be involved in the pathogenesis of the vascular leak syndrome [23, 24].
		Clarkson disease: Capillary leak syndrome [25]
		Angio-edema	None of our patients took converting enzyme inhibitor drugs or angiotensin II receptor blockers.
		EBV: Drug-induced eruption [19]	Synergy between SARS-CoV-2 and drugs, as observed with EBV infection and beta-lactam rash [19].
	Face oedema	Clarkson disease: Capillary leak syndrome [25]	“Inflammatory phase” of COVID-19 pneumonia, leading to “cytokine storm” and vascular leak process (IL-2 and TNFα).
		Angio-edema	No drug and no urticarial lesion associated with face edema in our study.
	Urticarial rashes	- Viral hepatitis - Parvovirus B19 - HHV-6 - Zika virus - Dengue	Mast cells directly infected by viruses [11, 12], leading to MC degranulation, endothelial activation (IL2 and TNFα), and vascular leak process.
		Acute hypersensitivity, type 1	No drug given in the 6 hours before the eruption.
		Urticarial vasculitis	No vasculitis on histological section. Resolution of urticaria within 24 h.
Vasculopathy	Livedo reticularis	Intracellular bacteria: Coxiella burnetti + Anti-phospholipid Antibodies	Hypothesis 1: Increased thromboembolic events have been described in COVID-19 [26]. Antiphospholipid antibodies and associated thromboembolic events have been described in COVID-19 [27].
			Hypothesis 2: Vasculitis or local vasculopathy [28].
		Disseminated intravascular coagulation	In our study, none of our patients had DIC at the time of skin evaluation.
	Purpura	- Parvovirus B19 - Dengue	Pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d co-localized with SARS-CoV-2 spike glycoprotein [29].
T-cell lymphocytes	Oral lichenoid reaction	- HCV - HPV-16	Lymphopenia, with absolute number of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in blood of COVID-19 patients and low expression of IFN-gamma by CD4+ T cells, probably linked to a redistribution of Tc1 CD8+ T-cell lymphocytes in the organs [15]. Keratinocytes infected by SARS-CoV-2 could be the target of Tc1 CD8+ T-cell lymphocytes.
	Oral erosion	HSV-1	Viral reactivation: Related to the decrease of CD4+ and CD8+ T-cell activity against HSV-1 antigen.
Direct excretion of SARS-CoV-2	Conjonctivitis		SARS-CoV-2 was isolated from the conjunctival swabs of 12 patients with ocular manifestations among 38 COVID-19 patients [16].

Abbreviations: COVID-19, coronavirus disease 2019; DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; HCV, hepatitis C virus; HHV, human herpesvirus; HPV, human papillomavirus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; MC, mast cells; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor.