Maculopapular exanthems appear to be the most prevalent of all patterns. In a case series of 375 patients with SARS-CoV-2 infection, 47% presented with maculopapular lesions (17). In smaller case studies, the prevalence varied from 5%–70% (19). The exanthem can occur at any age consisting of small red raised and flat lesions which typically appear on the trunk and spread to the extremities but may appear on the face and neck (Figure 1).

The eruption may or may not be associated with pruritus. The lesions are most notably observed during the mid course of infection when the patient is most symptomatic. A few studies have reported a latent onset up to 27 days after diagnosis (21, 22). Variants of this exanthem have been reported as purpuric-like, erythema-multiforme-like, pityriasis-rosea- like, erythema elevatum diutinum-like and perifollicular patterns (23).

The majority of patients with maculopapular lesions tend to have an uneventful course, but there are reports of SARS-CoV-2 infected pregnant women presenting with only maculopapular eruptions devoid of constitutional symptoms with premature rupture of membranes (24). Rare cases of transplacental transmission of SARS CoV-2 have been reported in maternal infections with maculopapular lesions (25–28). Oropez et al. (25) reported a case of a 34 year old pregnant woman with a diamniotic dichorionic twin pregnancy presenting with mild SARS Co-V-2 infection and a maculopapular eruption in the 3rd trimester. Healthy twins delivered by cesarean section revealed one twin was positive for SARS Co-V-2 IgG antibodies while the other twin was serologically negative. Placental pathology was negative for evidence of SARS-Co-V-2. Maculopapular exanthems have been reported in infants with SARS-CoV-2 infection in association with mild symptomatic disease (17). The primary differential diagnosis includes other viral infections or adverse drug eruptions (Table 1). SARS-CoV-2 antiviral therapy can produce drug reactions appearing identical to viral eruptions making identification of the inciting agent challenging (14).

Polymorphic Eruption of Pregnancy (PEP) (Synonym-PUPP Pruritic Urticarial Papules and Plaques of Pregnancy) and Atopic Eruption of Pregnancy (AEP) may present in pregnant women as maculopapular lesions (29). Erythema toxicum neonatorum (ETN), miliaria, and atopic dermatitis could appear with maculopapular lesions in neonates and infants (30, 31). It is imperative to consider SARS CoV-2 infections in the differential of maculopapular eruptions in pregnant women, neonates and infants for proper intervention to prevent complications and transmission.

Urticarial lesions seen in SARS CoV-2 are generally encountered during the prodromal asymptomatic period of disease and may be the first sign of disease (Table 1). The incidence of urticaria in SARS-CoV-2 infection ranges from 16.7%–19% and has a higher prevalence in females (17, 32, 33). Although several studies have reported SARS CoV-2 associated urticaria primarily in adults, several cases have been documented in children (34). The lesions generally last a week and have been associated with moderate to severe complications in some patients (17). Hive-like, blanching thin plaques which are transient and changeable in shape with severe pruritus typically present on the trunk and spread to the extremities possibly affecting the face and acral areas (Figure 2). Angioedema and urticarial vasculitis may also occur (33).

Urticaria secondary to SARS CoV-2 may be difficult to differentiate from other causes such as medications, food, bacterial, parasitic, other viral infections, allergic reactions and idiopathic urticaria (33, 34). Pathophysiologically, SARS-CoV-2 stimulates mast cell degranulation through either direct viral contact or complement activation and cytokine release. It is theorized serious end organ damage in SARS-CoV-2 infection is due to mast cell activation (13, 35, 36).

With respect to pregnancy, the primary skin disease to differentiate other than drug or infection is PEP (29, 37). PEP tends to occur late in the 3rd trimester or in the post-partum period usually in primigradas and begins within the abdominal striae. Unlike PEP, SARS-CoV-2 associated urticaria tends to resolve around 7 days (17). Newer reports have shown that chronic urticaria can develop particularly in young women after SARS-CoV-2 infection or SARS-CoV-2 vaccines (38, 39). The most common etiologic factors in the differential of urticaria in neonates and infants include infection, food, medications and atopy (40).

SARS-CoV-2 should be considered in the differential diagnosis of urticaria in pregnant women, neonates, and infants without constitutional symptoms due to the possibility of moderate to severe disease complications.

Vesicular eruptions in SARS-CoV-2 were first described as “varicella-like” in April 2020 by Marzano (20). Usually appearing on the trunk, scattered fluid filled blisters may appear localized or diffusely with or without purpura (Figure 3).

The prevalence ranges from 3.7%–15% occurring primarily in adults but has been reported in children (17, 19, 32, 41). SARS-CoV-2 vesicular exanthems are associated with moderate severity of illness and occur when patients are symptomatic in mid course of disease. Cases of early or late onset of vesicular lesions have been reported. The median duration of the eruption is approximately 8–10 days (17, 19, 20, 32). Vesicular eruptions associated with SARS CoV-2 are considered to be specific to the virus and may be useful diagnostically. In a systematic review, Jamshidi reports that vesicular lesions may be associated with neurologic symptoms including headache, dysgeusia, and confusion (42). The pathogenesis of vesicular lesions in SARS-CoV-2 is felt to be related to either a direct cytotoxic effect on dermal vessel endothelium or exaggerated release of cytokines (19, 41).

SARS-CoV-2 infection must be considered in the differential diagnosis of vesicular eruptions in pregnant women, neonates and infants. Causes to be eliminated include viral and bacterial infections, infestations, miliaria, irritant or contact dermatitis, and autoimmune diseases (19, 43, 44) (Table 1). Viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV), measles, and rubella are associated with serious fetal sequelae and must be differentiated (45). HSV and VZV reactivation has been associated with SARS-CoV-2 infection with some patients developing more severe illness (46–48). Flaring of atopic dermatitis can present as vesicular lesions in pregnancy and infancy with secondary staphylococcal or HSV infection requiring immediate therapeutic intervention. Elevated IL-4 levels in pregnancy may be a factor in the exacerbation of atopic dermatitis (49). Common transient conditions in neonates may present with vesicular lesions (ETN, acropustulosis of infancy) or rare conditions such as Hyper IgE syndrome, or histiocytosis (50, 51). Pemphigoid Gestationis, a rare immunobullous disease in pregnancy, usually occurring in the 3rd trimester with periumbilical bullae should be included in the differential diagnosis of SARS-CoV-2 vesicular exanthems (29).

Chilblain-like or “pernio-like” vascular skin lesions of the hands and feet are probably the most recognized of all skin lesions associated with SARS-CoV-2. Multiple reports of non-blanching erythematous or violaceous lesions of the toes associated with SARS-CoV-2 infection help to coin the term “Covid toes” (19, 52) (Figure 4).

Usually seen in asymptomatic or mildly infected young adults and children, SARS-CoV-2 chilblain-like lesions tend to appear late in the course of infection. Numerous studies report the prevalence varies from 14.3%–72% (19). Chilblain and pernio diseases are vascular inflammatory reactive skin disorders to environmental stimuli such as cold exposure or damp humid environments. The hands and feet are primarily affected with a vasoconstrictive response and resultant erythematous, violaceous macules, papules or nodules of the fingers or toes. The most common symptoms are pain and pruritus. SARS-COV-2 associated chilblain-like lesions tend to last 1–2 weeks after the onset of symptoms and resolve without incident (32). Primary chilblain/pernio disease is idiopathic but secondary causes include autoimmune [systemic lupus erythematosus (SLE), antiphospholipid disease, Raynaud's disease] cryoglobulinemia, and hematologic diseases (52). There is controversy whether there is a direct association between SARS-CoV-2 infection and chilblain-like lesions. Colmenero (53) demonstrated the presence of SARS-CoV-2 in endothelial cells of pernio-like lesions by electron microscopy. On the contrary, many patients presenting with chilblain-like skin lesions tested negative with reverse transcription polymerase chain reaction test (RT-PCR), had negative serology, or were not tested at all (54, 55). This may be explained by robust protective levels of IFN-1 in younger patients or the significant variability of current testing. It has been proposed that chilblain-like lesions represent late manifestations of SARS-CoV-2 due to a delayed immunological reaction or an inappropriate type 1 interferon response (56). A literature review by Cappel et al. (56) suggested that the pathogenesis of SARS-CoV-2 chilblain-like lesions involves complex interactions between the virus, angiotension converting enzyme-2 (ACE-2), the renin-angiotension-aldosterone system, sex hormones, and interferon type 1 responses causing endothelial cell dysfunction (56–58).

Histopathology of skin lesions is similar to that found in idiopathic chilblains with epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine lymphocytic inflammation and microthrombi in the vasculature and endothelial cell inflammation (58).

Chilblain-like lesions may be the only sign of SARS CoV-2 in pregnant women, neonates and infants late in the disease course so it is important to properly diagnose this pattern and differentiate from other primary or secondary causes.

Livedo patterns are less common manifestations of SARS CoV-2 ranging from 4%–6% (17, 19, 41). Infected patients presenting with livedo reticularis-like lesions tend to have milder disease and transiently clear over a period of 2 weeks with the average duration approximately 9–10 days (17, 19, 59, 60). The lesions appear as a mottled red-blue-purple net-like discoloration on the trunk, flexor forearm surface, dorsal hands and feet (Figure 5).

A pauci-inflammatory thrombogenic vasculopathy is noted on histopathology with serologic elevated D-Dimer levels (14, 61). It is theorized that the SARS CoV-2 virus directly infects endothelial or smooth muscle vessel cells causing low grade vascular inflammation and vasodilation. This process results in decreased blood flow with deoxygenated hemoglobin but no thromboembolism (60). Livedo reticularis must be differentiated from other causes including either physiologic, secondary, or idiopathic (Table 1).

Livedo racemosa is a more severe variant and is characterized by larger more widespread mottling of the skin that is generally secondary to a pathologic condition. Usually appearing in elderly patients with severe SARS-CoV-2 infection, the lesions can be transient or persistent and appear mid course during active symptoms. In contrast to livedo reticularis, patients presenting with livedo racemosa may develop severe coagulopathy and complications. Galvan Casas et al. (17) reported a mortality rate of 10% in patients presenting with livedo racemosa. Pathologically, vessels are partially occluded which leads to retiform purpura and complete vascular occlusion. Histologically, there is a micro thrombotic vasculopathy with possible dermal arterial thrombosis (62).The vasculopathy is thought to be due to direct viral effects or immune stimulation of the complement cascade with the release of proinflammatory cytokines (IL-6, IL-8, IFN γ, TNF-α) elevated D-Dimer levels, and fibrinogen degradation products which are associated with thrombosis and increased mortality (61, 62). Severity of SARS- CoV-2 illness in pregnant women may be correlated with elevated IFN γ, IL-6, and D Dimer levels (13).

In pregnant women, neonates and infants, livedo patterns can be seen associated with other hypercoagulable diseases including SLE and antiphospholipid antibody syndrome. Interestingly, antiphospholipid antibodies are found in SARS-CoV-2 patients with severe illness, livedo lesions, and severe thrombosis. In a study by Sangle et al. (63), widespread livedo reticularis is thought to be an independent factor of pregnancy complications in patients who have negative antiphospholipid antibodies with or without lupus. Rodriguez et al. (64) reported a case of an infant presenting with livedo racemosa and respiratory failure diagnosed as multisystem inflammatory syndrome (MIS-C). Given the high risk for severe complications of SARS-CoV-2, infected pregnant women, neonates and infants presenting with livedo patterns should closely be monitored and investigated for impending thrombotic events.

Vasculitic or purpuric lesions in SARS CoV-2 infected patients are associated with severe morbidity and mortality (17, 52). Less common than other patterns, various studies report a prevalence of 3%–8% and the lesions occurring during the symptomatic phase of infection(17, 19, 20, 32). The lesions appear as non-blanching hemorrhagic macules, patches, bullae, or palpable purpura on the extremities or acral areas (Figure 6).

Distal acral ischemia may occur leading to necrosis and gangrene of the digits (44). Diffuse spread of vasculitic lesions correlates with severe sequelae (65–67). Elevated D-Dimer and fibrinogen degradation products were found in patients with distal ischemia with some developing disseminated intravascular coagulation (68). Histologically, a true vasculitis is seen with a neutrophilic infiltrate within the small vessel walls, intense lymphocytic perivascular infiltrate, fibrin deposition, and endothelial swelling differentiating this pattern from livedo lesions (43).

Purpuric, petechial, or vasculitic lesions may be present in other viral infections in pregnant women, neonates and infants including hepatitis, human immunodeficiency virus, parvovirus B19 as well as bacterial infections, hematologic, autoimmune and nutritional disorders (45) (Table 1). Adverse drug reactions including antiviral agents are common causes of purpuric vasculitic eruptions in SARS Co-V-2 due to the multitude of therapeutics in severe illness (19). Systemic lupus erythematosus, thrombotic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, and parvo B-19 infections are included in the differential diagnosis of purpuric vasculitic lesions in pregnancy and can lead to serious perinatal and fetal complications (45, 69–71). Although rarely seen in this age group, Ig A vasculitis (Henoch Schonlein Purpura -HSP), Kawasaki's disease, and multisystem inflammatory syndrome should be considered in the differential diagnosis in neonates and infants with purpuric or vasculitic lesions and diagnosed promptly to prevent potential complications (72–74).

Pathogenesis of SARS-CoV2 petechiae/purpura/vasculitis is thought to be due to direct viral damage to endothelial cells causing endotheliitis and endothelial cell injury or a dysregulated inflammatory responses with immune complex deposition and massive cytokine release. Macrophage activation results and leads to the thrombotic lesions and events seen in SARS CoV02 coagulopathy (75).

Recognizing specific skin lesions may be prognostic in disease severity. Vasculitis, livedo racemosa, and distal ischemia are associated with more severe complications while chilblains-like lesions have the highest survival rates. The importance of identifying skin manifestations in SARS-CoV-2 infected pregnant women, neonates, and infants is imperative to allow early intervention and therapeutic management.