key: cord-0847396-t50bg7pq
authors: Lavery, Michael Joseph; Bouvier, Charles Alexis; Thompson, Ben
title: Cutaneous manifestations of COVID-19 in children (and adults): A virus that does not discriminate
date: 2020-11-01
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2020.10.020
sha: 93c86d6d9295e8781af739c829da812cc46dddea
doc_id: 847396
cord_uid: t50bg7pq

COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a beta coronavirus with a characteristic S-glycoprotein ‘spike’ on the cell surface.(1) Initial reports did not include cutaneous manifestations as a feature of COVID-19; however, there is a growing repertoire of reports demonstrating an array of dermatologic manifestations on the skin in children and adults. Dermatologic afflictions have been summarized into different categories several times, with the most recent analysis identifying six clinical patterns: urticaria, maculopapular-morbilliform eruption, papulovesicular exanthem, chilblain-like acral pattern, livedo reticularis-livedo racemose pattern, and purpuric ‘vasculitic’ pattern.(2) In children, the dermatologic features appear to occur before or concomitantly with other COVID-19 manifestations. Dermatologists play a key role in diagnosing patients with COVID-19 who may present for the first time unwittingly exhibiting early signs of COVID-19. We have reviewed the current evidence on the dermatologic impact of COVID-19 in both the adult and pediatric population.

manifestations. Dermatologists play a key role in diagnosing patients with COVID-19 who may present for the first time unwittingly exhibiting early signs of COVID-19. We have reviewed the current evidence on the dermatologic impact of COVID-19 in both the adult and pediatric population.

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus, a beta-coronavirus of the coronaviridae family, is considered to have originated from bats at a food market in Wuhan, China; however, its main transmission since has been human to human. 3, 4 Transmission is via respiratory droplets (and possibly aerosols), although there is recent evidence of fecal-oral transmission in children. 5, 6 SARS-CoV-2 enters cells by attaching to angiotensin-converting enzyme-2 (ACE-2) receptors. 4, 7, 8 This receptor is found on numerous mucosal sites, 9, 10 including the endothelium of dermal blood vessels and epithelial cells in eccrine glands, which may account for the cutaneous manifestations of COVID-19. 11, 12 Current evidence suggests that children are less likely to succumb to infection, accounting for 1-8% of all COVID-19 cases. 9, 13, 14 There is, however, an increased morbidity in infants and young children, when compared to older children, as well as in children with a complex medical background. 13 While neonatal cases have been reported, there is no sign of breast milk transmission, 4 but there are reports of possible vertical transmission. 13 There is also an increased risk amongst children of the Black, Asian, and Minority Ethnic (BAME) community in the United Kingdom of both COVID-19 and the multisystem inflammatory syndrome. [15] [16] [17] The latter has been called the pediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS), 18 or multisystem inflammatory syndrome in children (MIS-C). 9

Initial reports did not include cutaneous manifestations as a feature of COVID-19. 19 Subsequent publications revealed that an eruption was present, albeit in very small numbers. A retrospective review of over 1000 patients throughout China revealed that two patients had developed an eruption (0.18%). 20 A growing body of evidence has since emerged showing an array of cutaneous afflictions in adults. (Table 1) In Thailand, a patient presenting with a petechial eruption and thrombocytopenia was mistakenly diagnosed as having dengue fever, with a subsequent viral swab detecting SARS-CoV-2. 21 A later report revealed a purpuric eruption in the axillae and flank bilaterally in a patient with a positive polymerase chain reaction (PCR) to SARS-CoV-2. While the patient had been given hydroxychloroquine and lopinavir/ritonavir, a viral exanthem was felt more likely, given the rarity of drug eruptions to these medications. 22 The first report to demonstrate cutaneous manifestations on a larger scale was in a cohort of patients in the Lombardy region of northern Italy. Skin afflictions were noted in 20% of inpatients and described as an erythematous eruption, urticaria or chickenpox-like vesicles, all predominantly affecting the trunk. 23 The Spanish Academy of Dermatology and Venereology published a review of 375 patients with suspected or confirmed SARS-CoV-2 who developed cutaneous eruptions. These cutaneous manifestations were divided into five presenting categories: pseudo-chilblain, other vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis. Further analysis noted 'other vesicular eruptions' as an early cutaneous sign and 'pseudo-chilblains' as a late sign although the latter was associated with decreased disease severity. Livedo or necrosis was associated with increased disease severity. 24 Recently, nail changes have been identified in patients with COVID-19 manifesting as a convex half-moon shaped erythematous band at the distal margin of the lunula and coined 'the red half-moon nail sign.' 25, 26 In the United Kingdom (UK), researchers analyzed data from users of the COVID Symptom Study application and noted 8.8% of 336,847 users, with a positive SARS-CoV-2 viral swab, reported a skin eruption. Similar results were noted in patients with no viral swab but one or more UK government listed COVID-19 findings. (8.2%) 27 A subsequent online survey, by the same researchers, of 11,546 SARS-CoV2 positive participants who reported having an eruption, revealed that 17% had a skin eruption as the first clinical feature, with 21% of respondents who had such an eruption were without other symptoms. The cutaneous signs were divided into three main categories: papular (erythemato-papular or erythemato-vesicular), urticaria and acral lesions (chilblains). 27 Some authors have speculated that the pseudo-chilblains may be attributable to novel lifestyle changes due to COVID-19, such as decreased activity or walking barefoot in an unheated environment. 28, 29 Despite these ideas, the constellation of papers reporting cutaneous manifestations of COVID-19 has led to calls of a skin eruption to be included in the list of clinical features suspicious of COVID-19 infection. 27

For reasons currently unknown, SARS-CoV-2 does not have as big an impact on children when compared to adults. This appears counter-intuitive, given the increased prevalence of other viral diseases in this patient population. Children with COVID-19 present in a similar fashion to adults, with pyrexia and cough the most common presenting features. 30 Gastrointestinal symptoms and pharyngeal erythema may also be present. Cutaneous manifestations are similar to what is witnessed with other viral exanthems including macular, papular and vesicular eruptions.

A varicella-like eruption has been reported in an 8-year old girl who presented to the clinic with a papulovesicular eruption on the trunk sparing other sites, along with a 6-day history of a cough. PCR testing was positive. Inflammatory markers were normal with only a mild thrombocytopenia noted on a routine blood panel. 31 Acral lesions have also been described in children.

In the UK, a teenage boy with a positive PCR swab, presented with a skin eruption accompanied by headache and myalgia with no cough or dyspnea.

While the parents reported a subjective fever, vital signs were normal. On examination there were tender plantar papules, macules and petechiae on the legs and an annular patch developing a few days later. Papules were also noted in the axillae. 32 An erythema multiforme-like eruption has also been reported in a 12-month old infant in Iran who presented with targetoid lesions on the trunk and extremities, along with acral erythema and pyrexia. SARS-CoV-2 PCR was positive. Subsequent clinical deterioration led to admission to the intensive care unit and improvement five days later. 33 A case series from Spain has revealed four pediatric patients (11-17 years old) presenting with an erythema multiforme-like eruption on the arms, legs, and ears, along with evidence of chilblain. Mild respiratory or gastrointestinal symptoms were also reported with one patient otherwise asymptomatic. All 

Another reported manifestation of COVID-19 in children is the development of the pediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS), also termed multisystem inflammatory syndrome in children (MIS-C). This syndrome has similarities to Kawasaki disease. Kawasaki Disease (KD), first described by Tomisaku Kawasaki (1925 Kawasaki ( -2020 in 1967, 36 is an acute vasculitis with a global incidence ranging between 8-67 cases per 100,000. 37 KD commonly affects children under 5-years-old with a 1.5:1 male to female ratio. 38 The underlying pathophysiology is complex but postulated to be secondary to an overactive innate and adaptive immune system in genetically predisposed individuals. 9, 16 The diagnosis of KD requires the presence of fever for ≥5 days, and ≥4 'other features' ( Table 2 ). The diagnosis of KD may also be confirmed with only 3 'other features' when there is evidence of cardiac involvement (e.g. coronary aneurysm, myo/pericarditis, pericardial effusion). 39 Dermatologic features are common in KD and represent the majority of these 'other features.

Manifestations include acral erythema, edema and desquamation, along with oral mucosal pathology that includes a 'strawberry tongue'. A diffuse polymorphic eruption may be noted including macules, papules, micro pustules and an erythema-multiforme like eruption, distributed on the trunk, groin and perineal sites. 40 A pustular eruption in febrile children can be mistaken for other pathologies, such as acute generalized exanthematous pustulosis or pustular psoriasis. 41 The eruption appears early in the illness and may last days to weeks. Nail changes, reported in patients with COVID-19, include transverse erythematous bands and Beau's lines. 42 In addition, transverse red bands have been reported in KD occurring on the mid-distal portion of the nail plate during the active inflammatory phase of the disease. 42 While the pathogenesis of these red lines is unclear, nail bed hyperemia or localized vasculitis has been hypothesized. It is plausible that the transverse erythronychia at the mid-distal nail plate may be observed in children presenting with KD in the context of COVID-19. The pathophysiologic process may be similar to the observed half-moon sign, and it is plausible that these two nail findings could occur in tandem.

While the features of MIS-C are similar to those observed in KD, the two conditions are considered two distinct entities, with less than 25% of patients with MIS-C fulfilling the diagnostic criteria for KD. 43 Although cutaneous manifestations are an important diagnostic criteria for KD, just over half of patients report an eruption as part of their clinical presentation in MIS-C. 43 Multi-organ involvement can occur in pediatric patients with COVID-19 ( Table   3 ). The pulmonary system is the most commonly affected organ in COVID-19.

Children may suffer from pneumonia, which can progress to acute respiratory distress syndrome (ARDS). 7 Other organ systems involved include cardiac, renal, hematologic, neurologic, ophthalmologic, and the gastrointestinal tract. case definition includes all of the above organ involvements. 45 Despite these disparities, the WHO, CDC, and RCPCH case definition for MIS-C all include children with features suggestive of Kawasaki Disease, with which it bears similarities.

Patients presenting with symptoms of COVID-19 undergo investigation with a routine blood panel along with a nasopharyngeal and oropharyngeal swab for PCR testing to SARS-CoV-2. Serum antibody testing to SARS-CoV-2 immunoglobulin G (IgG) is performed several weeks after symptom presentation. False negatives have been reported due to low-test sensitivity, and novel investigational methods have been sought. 46 This was exemplified in an 81-year-old woman in Switzerland who presented with fever and an acral eruption, along with a generalized macular and vasculitic-like eruption. While COVID-19 was clinically suspected, the SARS-CoV-2 PCR swab was negative. A skin biopsy was performed revealing a lichenoid interface dermatitis along with a scant perivascular lymphohistiocytic infiltrate. PCR testing of the skin tissue detected SARS-CoV-2, albeit at low levels. A serology antibody test, performed six weeks later, was negative. 47 The histopathologic, immunohistochemical, (IHC) and electron microscopic analysis have been performed in a cohort of seven pediatric patients presenting with features of chilblain and COVID-19 symptoms and having negative SARS-CoV-2 PCR nasopharyngeal and oropharyngeal swabs. 48 

The COVID-19 pandemic has placed unprecedented burdens on the economy and healthcare services. It has also had a detrimental effect increasing morbidity and mortality through systemic organ involvement. While the cutaneous manifestations were not initially reported, a dearth of data has shown that the largest organ in the body may yield clues for the diagnosis as 

World Health Organization. Naming the Coronavirus Disease (COVID-19) and the virus that causes it

-2019)-andthe-virus-that-causes-it

Cutaneous manifestations in patients with COVID-19: A preliminary review of an emerging issue

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Characterisation of COVID-19 pandemic in paediatric age group: A systematic review and meta-analysis

Infectious SARS-CoV-2 in feces of patient with severe COVID-19

Pathogenesis of COVID-19 from the perspective of the damage-response framework

COVID-19 -clinical management of children admitted to hospital with suspected COVID-19. Royal College of Paediatrics and Child Health Web site

Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children

COVID-19 and multisystem inflammatory syndrome in children and adolescents

Pathophysiology of COVID-19: Why children fare better than adults?

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Exploring the pathogenesis of severe acute respiratory syndrome (SARS): The tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensisn-converting enzyme 2 (ACE2)

An evidence summary of paediatric COVID-19 literature. Don't Forget the Bubbles

COVID-19 and Kawasaki Disease: Novel virus and novel case

Hyperinflammatory shock in children during COVID-19 pandemic

SARS-CoV-2-Related inflammatory multisystem syndrome in children: Different or shared etiology and pathophysiology as Kawasaki Disease?

Autoimmune and inflammatory diseases following COVID-19

Guidance -paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS). Royal College of Paediatrics and Child Health Web site

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study

Clinical characteristics of coronavirus disease 2019 in China

COVID-19 can present with a rash and be mistaken for dengue

Reply to "COVID-19 can present with a rash and be mistaken for dengue": Petechial rash in a patient with COVID-19 infection

Cutaneous manifestations in COVID-19: A first perspective

Classification of the cutaneous manifestations of COVID-19: A rapid prospective nationwide consensus study in Spain with 375 cases

The red half-moon nail sign: A novel manifestation of coronavirus infection

COVID-19 and nail manifestation: Be on the lookout for the red half-moon nail sign

Diagnostic value of skin manifestation of SARS-CoV-2 infection. medRxiv

Evaluation of chilblains as a manifestation of the COVID-19 pandemic

Assessment of acute acral lesions in a case series of children and adolescents during the COVID-19 pandemic

SARS-CoV-2 infection in children

Varicella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?

Rash as a presenting complaint in a child with COVID-19

Fever with rash is one of the first presentations of COVID-19 in children: A case report

Erythema multiforme-like lesions in children and COVID-19

Urticarial eruption in COVID-19 infection

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children

Echocardiography in pediatric and congenital heart disease: From fetus to adult

Diagnosis, treatment, and long-term management of Kawasaki Disease: A scientific statement for health professionals from the American Heart Association

Pustular eruption in Kawasaki Disease

Nail-bed lines in Kawasaki Disease

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. World Health Organization Web site

Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19)

Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid

SARS-CoV-2 PCR testing of skin for COVID-19 diagnostics: A case report

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases

COVID-19 pandemic and the skin: what should dermatologists know?

Table 1: Cutaneous manifestations of coronavirus disease 2019 in both the adult and pediatric population