Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel viral infection with dual pathogenicity that can ultimately affect multiple organ systems. It begins as a flulike infection by the SARS-CoV-2 virus. In a significant minority of patients, as the immune system overcomes the phase of viral replication, the immune response advances to an accelerating inflammatory phase, typically resulting in an organizing pneumonia.¹ A cytokine release syndrome can progress to involve multiple organ systems, including the heart and kidneys, with an associated coagulopathy that has caused thrombotic events in otherwise healthy people.^2–6 Secondary bacterial and fungal infections can occur during the inflammatory phase.¹

The major features of the COVID-19 inflammatory phase are so severe that less attention has been devoted to associated skin problems. One large-scale study noted that 8.8% of patients positive for SARS-CoV-2 presented with cutaneous findings, in which involvement of the trunk or extremities (6.8%) was more common than that of acral surfaces (3.1%).⁷ Occasionally, cutaneous symptoms were the first manifestation of COVID-19 infection (17%), and sometimes the skin rash or lesion was the only symptom (21%).⁷ Notably, another study observed that significantly more patients with rash secondary to COVID-19 required invasive mechanical ventilation (60.9%) than those without rash (30.3%).⁸

Several primary patterns of cutaneous involvement in COVID-19 include eruptions consisting of macules and papules, perniosis/pseudochilblain lesions, vesicular rash, urticarial rash, and livedoid/vaso-occlusive lesions. Of these different morphologies, vesicular eruptions can appear early in the course (15% before other symptoms), and pseudochilblain lesions frequently occur late in the disease course.^9–11 The disease stage associated with each morphology may help guide appropriate treatment. However, it is also true that these different morphologies may exist concurrently, as we have seen in a single patient (Fig. 11.1, Fig. 11.2, Fig. 11.3, Fig. 11.4).

Eruptions Composed of Macules and Papules

Several observational, large-scale studies have identified eruptions composed of macules and papules as the most commonly reported cutaneous morphology associated with SARS-CoV-2, as high a proportion as 47%.⁹ These eruptions presented as a diverse array of clinical patterns, including morbilliform, purpuric, erythema multiforme–like, pityriasis rosea–like, erythema elevatum diutinum–like, and perifollicular.^9,12 The trunk was most frequently involved, followed by the neck, extremities, and buttocks.^12–14 Most patients reported pruritus and less commonly pain or burning.^9,14,15 Several cases of these eruptions co-occurring with other morphologies, including urticaria, pernio, and purpura, were reported.^9,14 Most often, the eruptions occurred at or after the onset of other COVID-19 symptoms, suggesting a viral exanthem during the phase of viral replication.^9,10,14 The average age of patients with this type of rash varied from 35.8 to 55.3 years.^9,15 A single study noted a significant female predominance among patients with morbilliform eruptions (p = 0.008).¹⁶ The mean length of the rash was 8 days (2 to 14 days).¹⁷

Regarding the different clinical morphologies observed, morbilliform eruptions were the most frequent subtype (45.5%). Most commonly, the morbilliform rash was generalized, symmetric, and confluent, starting in the trunk with centrifugal progression, and lasted 7.2 days (±4.3 days). A nonspecific pattern (20%) was recognized as localized or generalized nonconfluent erythematous macules or papules with occasional scaling, which persisted for an average of 11.8 days. Most cases were symptomatic (63.9%), primarily with pruritus. Purpuric eruptions (14.2%) were more common in males (60%), predominantly involved the trunk and upper extremities with a mean duration of 7.4 days (±4.5 days), and most often (44%) presented with pruritus. A significant proportion (88.2%) of the erythema multiforme–like eruptions (9.7%) occurred in females. These were characterized by generalized, symmetric, and confluent erythematous–violaceous macules and papules with occasional targetoid lesions that began on the trunk. Some patients had palmoplantar involvement. The mean duration of erythema multiforme–like eruptions was 9.7 days (±4.9 days). Pruritus and burning occurred in 65% of the cases. Pityriasis rosea–like eruptions (5.7%) primarily manifested as erythematous, brown, scaly, discrete annular plaques on the trunk in a generalized distribution. These lesions persisted for an average duration of 12.1 days (±4.5 days), and similar to other morphologies, symptomatic cases (50%) noted pruritus. Erythema elevatum diutinum–like eruptions (2.3%) were identified as pink to erythematous papules on the dorsum of the hands, which were present for 6 days (±4.1 days). Most cases were symptomatic (75%) with pruritus or burning. Lastly, perifollicular eruptions (2.3%) were defined as erythematous, brownish perifollicular papules mainly localized to the trunk in a symmetric and confluent distribution, lasting on average 4.5 ± 1 days. Unlike other clinical patterns, these lesions were primarily asymptomatic (75%).¹⁸

The most common concurrent SARS-CoV-2 symptoms in patients with an eruption consisting of macules and papules included fever, cough, dyspnea, and asthenia.^9,14 Notably, the morbilliform and erythema multiforme–like subtypes were associated with the highest rate of admission to the hospital secondary to pneumonia (80 and 76.5%, respectively), with 18.8% escalated to intensive care and 11.5% needing noninvasive mechanical ventilation.¹⁸ Of the other morphologies consisting of macules and papules, about 44% required hospital admission due to pneumonia.¹⁸ One study reported a 2% mortality rate in patients with SARS-CoV-2, with associated rash consisting of macules or papules.⁹ The therapies these patients received were not specifically targeted for their rash; instead, the treatments was for the underlying SARS-CoV-2 infection.^17,18 There is limited evidence to suggest that topical steroids are effective.¹⁹

The histological features identified in these eruptions include superficial perivascular dermatitis with lymphocytic infiltrate and dilated middermal and papillary vessels with eosinophils and neutrophils. Involvement of the epidermis includes foci of hydropic changes and parakeratosis, minimal acanthosis, subcorneal pustules, spongiosis, and basal cell vacuolation.¹⁷ Histological samples from six patients showed neither intranuclear viral inclusions nor COVID-19 positivity on in situ hybridization and immunohistochemistry.²⁰ These findings challenged the theory that these maculopapular rashes in SARS-CoV-2 are due to direct viral damage, postulated by other studies.^20,21 Rather, these findings suggest that these cutaneous lesions were immune mediated.

A caveat to the association between SARS-CoV-2 and maculopapular eruptions is that the etiology could be due to drug-induced hypersensitivity reactions in some cases. Certain histological features that are statistically more unique to a drug-mediated rash consisting of macules and papules would include lymphocytic exocytosis and dermal infiltrates of eosinophils, lymphocytes, and histiocytes and may assist in distinguishing an eruption due to SARS-CoV-2 infection from a drug-induced reaction.²²

Perniosis/Pseudochilblains

Pernio- or chilblainlike lesions are another common cutaneous morphology linked to COVID-19 infection; some studies have reported as high a proportion as 46%.²³ These lesions are often referred to as pseudochilblains, given that the clinical appearance of erythematous or violaceous, occasionally ulcerated, papules favoring acral sites is similar but lacks cold exposure as the inciting event. These findings have been commonly referred to as “COVID toes” when involving the feet. Pseudochilblains usually present as erythematous or violaceous papules on acral surfaces, occasionally with vesicles or pustules.¹⁰ The feet are affected in 94% of cases and the hands in 15%. Acrocyanosis and acral desquamation have been observed.^11,24 The majority of the cases (66%) present with pain/burning, while 43% report pruritus.¹¹ This cutaneous reaction is more commonly reported in white patients (89%) versus only 7.3% in Asians, 0.7% for African American, and 2.7% for Hispanic/Latino.¹¹ Differences in how visible inflammation manifests in various skin tones may partly account for the discrepancy in ethnicities affected. The perniolike lesions presented after the onset of COVID-19 symptoms in 35.8 to 54% of cases, and the reported median duration was 14 days (14–23).^10,11

The perniolike rash occurred predominately in younger patients (mean age of 27.2 years) and was associated with a good prognosis (98.7% survival).¹⁰ It was reported by a single study that 75% of these cases did not have other comorbidities, 98% were outpatients, and, of those hospitalized, 0.6% died.¹¹ It must be underscored that several of the patients with these pseudochilblain lesions tested negative for SARS-CoV-2. Only 29% met Centers for Disease Control and Prevention (CDC) passing criteria, a lower proportion than patients who developed morbilliform, vesicular, or urticarial eruptions.¹⁴ Pseudochilblains may be a late-phase symptom occurring after viral clearance, as 55% of patients reported having no other symptoms of SARS-CoV-2.^11,16

Data regarding the histopathology of these perniolike lesions of SARS-CoV-2 are limited. Reported findings include lymphoid/lymphoplasmacytic infiltrate in the dermis with a prevalent perivascular pattern, and superficial and deep dermal lymphocytic infiltrates with mild vacuolar interface dermatitis, as well as occasional basal vacuolization.^11,25 Given that vasculopathy, which is found in classic pernio, was not consistently identified on histology, it has been proposed that the pseudochilblain lesions may instead be inflammatory.¹¹ A study examining the histology of perniosis associated with COVID-19 infection demonstrated a superficial and deep angiocentric lymphocytic infiltrate with minimal vascular damage.²⁶ However, several studies of patients with pseudochilblains have shown neither positive SARS-CoV-2 polymerase chain reaction tests nor positive immunoglobulin M (IgM) or IgG antibodies to SARS-CoV-2.^24,27

There are no dedicated studies examining treatments specifically for perniolike lesions associated with COVID-19 infection. Therapies used in treating classic chilblains, such as avoidance of cold and vasoconstrictive substances and the use of potent topical steroids, calcium channel blockers, or topical nitroglycerin, have been suggested.²⁵ Additionally, given that SARS-CoV-2 appears to induce a prothrombotic state, low-dose aspirin, when appropriately administered considering other comorbidities, may potentially aid in preventing the pseudochilblain lesions.²⁵

Vesicular Eruption

Vesicular eruptions account for approximately 11% of cutaneous lesions secondary to SARS-CoV-2. The most commonly affected sites on the body were the chest, abdomen, upper and lower extremities, and buttocks.^14,27 Most vesicular lesions were symptomatic, as 68 to 72% experienced pruritus and 50% reported pain or burning.^9,14 The median age was 54.3 to 55 years.^9,14 The average duration of rash was 10.4 days.⁹

Studies have shown two major subtypes of vesicular eruptions, namely, a diffuse presentation and a localized presentation. The diffuse presentation, which involved more than one region of the body, was present more frequently (75%) and consisted of 7- to 8-mm papules, vesicles, and pustules, each presenting simultaneously.²⁷ The localized presentation (25%) appeared to favor the chest, upper abdomen, or back and consisted of 3- to 4-mm monomorphic lesions, each in the same stage of evolution.²⁷ Hemorrhagic vesicles were also observed.⁹

The most common noncutaneous symptoms present in association with a vesicular rash were cough, fever, asthenia, and sore throat.^9,14 The majority of these patients were treated through ambulatory care; the few hospitalized in one study did not require supplemental oxygen.¹⁴ Akin to patients with eruptions composed of macules and papules, patients with vesicular forms of rash did not receive therapies specifically targeting the cutaneous component.^9,27 Patients with vesicular eruptions demonstrated an overall survival of 96.1 to 100%.^9,10

A reported 29 to 79.2% of vesicular eruptions occurred after the onset of symptoms from SARS-CoV-2, 12.5 to 56% noted rash at the same time as other symptoms, and approximately 15% experienced cutaneous lesions an average of 14 days before other symptoms.^9,10,14,27

The histology of these vesicular eruptions has been described as intraepidermal vesicles with scattered multinucleated and ballooned keratinocytes with mild acantholysis.²⁷ Evaluation of deeper sections showed epidermal detachment and confluent keratinocyte necrosis in addition to intravesicular fibrinoid material with acute inflammatory infiltrate.²⁸ Other histological findings include basket-weave hyperkeratosis, atrophic epidermis, basal vacuolization with hyperchromatic keratinocytes, and dyskeratotic cells.²⁹