Pictures of dermatology problems: The request could not be satisfied

31.08.197512.10.2021 by alexxlab

Содержание

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives – FullText – Dermatology 2021, Vol. 237, No. 1

Abstract

Background: Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months. Summary: The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.

Introduction

In December 2019, a novel zoonotic RNA virus named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) was isolated in patients with pneumonia in Wuhan, China. Since then, the disease caused by this virus, called “coronavirus disease-19” (COVID-19), has spread throughout the world at a staggering speed becoming a pandemic emergency [1]. Although COVID-19 is best known for causing fever and respiratory symptoms, it has been reported to be associated also with different extrapulmonary manifestations, including dermatological signs [2]. Whilst the COVID-19-associated cutaneous manifestations have been increasingly reported, their exact incidence has yet to be estimated, their pathophysiological mechanisms are largely unknown, and the role, direct or indirect, of SARS-CoV-2 in their pathogenesis is still debated. Furthermore, evidence is accumulating that skin manifestations associated with COVID-19 are extremely polymorphic [3]. In this regard, our group proposed the following six main clinical patterns of COVID-19-associated cutaneous manifestations in a recently published review article: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern (shown in Fig. 1) [2]. Other authors have attempted to bring clarity in this field, suggesting possible classifications of COVID-19-associated cutaneous manifestations [4-6]. Finally, distinguishing nosological entities “truly” associated with COVID-19 from cutaneous drug reactions or exanthems due to viruses other than SARS-CoV-2 remains a frequent open problem.

Fig. 1.

Clinical features of COVID-19-associated cutaneous manifestations.

Herein, we have striven to provide a comprehensive overview of the cutaneous manifestations associated with COVID-19 subdivided according to the classification by Marzano et al. [2], focusing on clinical features, histopathological features, hypothesized pathophysiological mechanisms and therapeutic management.

Urticarial Rash

Clinical Features and Association with COVID-19 Severity

It is well known that urticaria and angioedema can be triggered by viral and bacterial agents, such as cytomegalovirus, herpesvirus, and Epstein-Barr virus and mycoplasma. However, establishing a cause-effect relationship may be difficult in single cases [7, 8]. Urticarial eruptions associated with COVID-19 have been first reported by Recalcati [9] in his cohort of hospitalized patients, accounting for 16.7% of total skin manifestations. Urticaria-like eruptions have been subsequently described in other cohort studies. Galván Casas et al. [4] stated that urticarial rash occurred in 19% of their cohort, tended to appear simultaneously with systemic symptoms, lasted approximately 1 week and was associated with medium-high severity of COVID-19. Moreover, itch was almost always present [4]. Freeman et al. [10] found a similar prevalence of urticaria (16%) in their series of 716 cases, in which urticarial lesions predominantly involved the trunk and limbs, relatively sparing the acral sites. As shown in Table 1, urticaria-like signs accounted for 11.9% of cutaneous manifestations seen in an Italian multicentric cohort study on 159 patients [unpubl. data]. Urticarial lesions associated with fever were reported to be early or even prodromal signs of COVID-19, in the absence of respiratory symptoms, in 3 patients [11-13]. Therefore, the authors of the reports suggested that isolation is needed for patients developing such skin symptoms if COVID-19 infection is suspected in order to prevent possible SARS-CoV-2 transmission [11-13]. COVID-19-related urticaria occurred also in a familial cluster, involving 2 patients belonging to a Mexican family of 5 people, all infected by SARS-CoV-2 and suffering also from anosmia, ageusia, chills and dizziness [14]. Angioedema may accompany COVID-19-related urticaria, as evidenced by the case published in June 2020 of an elderly man presenting with urticaria, angioedema, general malaise, fatigue, fever and pharyngodynia [15]. Urticarial vasculitis has also been described in association with COVID-19 in 2 patients [16].

Table 1.

Prevalence of different clinical patterns in the main studies on COVID-19-associated cutaneous manifestations

Histopathological Findings

Histopathological studies of urticarial rashes are scant. In a 60-year-old woman with persistent urticarial eruption and interstitial pneumonia who was not under any medication, Rodriguez-Jiménez et al. [17] found on histopathology slight vacuolar interface dermatitis with occasional necrotic keratinocytes curiously compatible with an erythema multiforme-like pattern. Amatore et al. [18] documented also the presence of lichenoid and vacuolar interface dermatitis, associated with mild spongiosis, dyskeratotic basal keratinocytes and superficial perivascular lymphocytic infiltrate, in a biopsy of urticarial eruption associated with COVID-19 (Fig. 2).

Fig. 2.

Histopathological features of the main cutaneous patterns associated with COVID-19. a Urticarial rash. b Confluent erythematous maculopapular/morbilliform rash. c Chilblain-like acral lesions. d Purpuric “vasculitic” pattern.

Therapeutic Options

Shanshal [19] suggested low-dose systemic corticosteroids as a therapeutic option for COVID-19-associated urticarial rash. Indeed, the author hypothesized that low-dose systemic corticosteroids, combined with nonsedating antihistamines, can help in managing the hyperactivity of the immune system in COVID-19, not only to control urticaria, but also to improve possibly the survival rate in COVID-19.

Confluent Erythematous/Maculopapular/Morbilliform Rash

Clinical Features and Association with COVID-19 Severity

Maculopapular eruptions accounted for 47% of all cutaneous manifestations in the cohort of Galván Casas et al. [4], for 44% of the skin manifestations included in the study by Freeman et al. [10], who further subdivided this group of cutaneous lesions into macular erythema (13%), morbilliform exanthems (22%) and papulosquamous lesions (9%), and for 30. 2% of the cutaneous manifestations included in the unpublished Italian multicentric study shown in Table 1. The prevalence of erythematous rash was higher in other studies, like that published by De Giorgi et al. [20] in May 2020, in which erythematous rashes accounted for 70% of total skin manifestations. In the series by Freeman et al. [10], macular erythema, morbilliform exanthems and papulosquamous lesions were predominantly localized on the trunk and limbs, being associated with pruritus in most cases. In the same series, these lesions occurred more frequently after COVID-19 systemic symptoms’ onset [21]. The clinical picture of the eruptions belonging to this group may range from erythematous confluent rashes to maculopapular eruptions and morbilliform exanthems. Erythematous lesions may show a purpuric evolution [21] or coexist from the beginning with purpuric lesions [22]. Erythematous papules may also be arranged in a morbilliform pattern [23]. In a subanalysis of the COVID-Piel Study [4] on maculopapular eruptions including also purpuric, erythema multiforme-like, pityriasis rosea-like, erythema elevatum diutinum-like and perifollicular eruptions, morbilliform exanthems were the most frequent maculopapular pattern (n = 80/176, 45. 5%) [24]. This study showed that in most cases lesions were generalized, symmetrical and started on the trunk with centrifugal progression. In the same subanalysis, hospital admission due to pneumonia was very frequent (80%) in patients with a morbilliform pattern [24]. In this group, the main differential diagnoses are represented by exanthems due to viruses other than SARS-CoV-2 and drug-induced cutaneous reactions.

Histopathological Findings

Histopathology of erythematous eruptions was described by Gianotti et al. [25], who found vascular damage in all the 3 cases examined. A clinicopathological characterization of late-onset maculopapular eruptions related to COVID-19 was provided also by Reymundo et al. [26], who observed a mild superficial perivascular lymphocytic infiltrate on the histology of 4 patients. In contrast, Herrero-Moyano et al. [27] observed dense neutrophilic infiltrates in 8 patients with late maculopapular eruptions. The authors of the former study postulated that this discrepancy could be attributable to the history of new drug assumptions in the series of Herrero-Moyano et al. [26] (Fig. 2).

Therapeutic Options

The management of confluent erythematous/maculopapular/morbilliform rash varies according to the severity of the clinical picture. Topical corticosteroids can be sufficient in most cases [23], systemic corticosteroids deserving to be administered just in more severe and widespread presentations.

Papulovesicular Exanthem

Clinical Features and Association with COVID-19 Severity

COVID-19-associated papulovesicular exanthem was first extensively reported in a multicenter Italian case series of 22 patients published in April 2020 [28]. In this article, it was originally described as “varicella-like” due to resemblance of its elementary lesions to those of varicella. However, the authors themselves underlined that the main clinical features of COVID-19-associated papulovesicular exanthem, namely trunk involvement, scattered distribution and mild/absent pruritus, differentiated it from “true” varicella. In this study, skin lesions appeared on average 3 days after systemic symptoms’ onset and healed after 8 days, without scarring sequelae [28]. The exact prevalence of papulovesicular exanthems is variable. Indeed, in a cohort of 375 patients with COVID-19-associated cutaneous manifestations [4], patients with papulovesicular exanthem were 34 (9%), while they were 3 out of 52 (5.8%), 1 out of 18 (5.5%) and 2 out of 53 (4%) in the cohorts published by Askin et al. [29], Recalcati [9] and De Giorgi et al. [20], respectively. In the Italian multicentric study shown in Table 1, papulovesicular rash accounted for 18.2% of skin manifestations. Furthermore, even if papulovesicular exanthem tends to involve more frequently the adult population, with a median age of 60 years in the study by Marzano et al. [28], also children may be affected [30]. Galván Casas et al. [4] reported that vesicular lesions generally involved middle-aged patients, before systemic symptoms’ onset in 15% of cases, and were associated with intermediate COVID-19 severity. Fernandez-Nieto et al. [31] conducted a prospective study on 24 patients diagnosed with COVID-19-associated vesicular rash. In this cohort, the median age (40.5 years) was lower than that reported by Marzano et al. [28], and COVID-19 severity was mostly mild or intermediate, with only 1 patient requiring intensive unit care support. In our cohort of 22 patients, a patient was hospitalized in the intensive care unit and 3 patients died [28]. Vesicular rash, which was generally pruritic, appeared after COVID-19 diagnosis in most patients (n = 19; 79.2%), with a median latency time of 14 days [31]. Two different morphological patterns were found: a widespread polymorphic pattern, more common and consisting of small papules, vesicles and pustules of different sizes, and a localized pattern, less frequent and consisting of monomorphic lesions, usually involving the mid chest/upper abdominal region or the back [31].

Histopathological Findings

Mahé et al. [32] reported on 3 patients with typical COVID-19-associated papulovesicular rash, in which the histological pattern of skin lesions showed prominent acantholysis and dyskeratosis associated with the presence of an unilocular intraepidermal vesicle in a suprabasal location. Based on these histopathological findings, the authors refused the term “varicella-like rash” and proposed a term which was more suitable in their view: “COVID-19-associated acantholytic rash.” Histopathological findings of another case of papulovesicular eruption revealed extensive epidermal necrosis with acantholysis and swelling of keratinocytes, ballooning degeneration of keratinocytes and signs of endotheliitis in the dermal vessels [33]. Acantholysis and ballooned keratinocytes were found also by Fernandez-Nieto et al. [31] in 2 patients.

The differential diagnosis with infections caused by members of the Herpesviridae family has been much debated. Tammaro et al. [34] described the onset of numerous, isolated vesicles on the back 8 days after COVID-19 diagnosis in a Barcelonan woman and reported on 2 patients from Rome presenting with isolated, mildly pruritic erythematous-vesicular lesions on their trunk, speculating that these manifestations might be due to viruses belonging to the Herpesviridae family. On the other hand, classic herpes zoster has been reported to complicate the course of COVID-19 [35].

The controversy regarding the role of herpesvirus in the etiology of papulovesicular exanthems fuelled an intense scientific debate. Indeed, some authors raised the question whether papulovesicular exanthem associated with COVID-19 could be diagnosed without ruling out varicella zoster virus and herpes simplex virus with Tzanck smear or polymerase chain reaction (PCR) for the Herpesviridae family in the vesicle fluid or on the skin [36, 37]. In our opinion, even if seeking DNA of Herpesviridae family members is ideally advisable, clinical diagnosis may be reliable in most cases, and the role of herpes viruses as mere superinfection in patients with dysfunctional immune response associated with COVID-19 needs to be considered [38]. To our knowledge, SARS-CoV-2 has not been hitherto isolated by means of reverse transcriptase PCR in the vesicle fluid of papulovesicular rash [33, 31].

Therapeutic Options

No standardized treatments for COVID-19-related papulovesicular exanthem are available, also given that it is self-healing within a short time frame. Thus, a “wait-and-see” strategy may be recommended.

Chilblain-Like Acral Pattern

Clinical Features and Association with COVID-19 Severity

COVID-19-related chilblain-like acral lesions have been first described in a 13-year-old boy by Italian authors in early March [39]. Since then, several “outbreaks” of chilblain-like acral lesions chiefly involving young adults and children from different countries worldwide have been posted on social media and published in the scientific literature [40-46]. Caucasians seem to be significantly more affected than other ethnic groups [47, 48]. Chilblain-like acral lesions were the second most frequent cutaneous manifestation (n = 46/159; 28.9%) in the multicenter Italian study shown in Table 1. Different pathogenetic hypotheses, including increased interferon release induced by COVID-19 and consequent cytokine-mediated inflammatory response, have been suggested [49]. Furthermore, virus-induced endothelial damage as well as an obliterative microangiopathy and coagulation abnormalities could be mechanisms involved in the pathogenesis of these lesions [50]. Chilblain-like acral lesions associated with COVID-19 were depicted as erythematous-violaceous patches or plaques predominantly involving the feet and, to a lesser extent, hands [40, 51]. Rare cases of chilblain-like lesions involving other acral sites, such as the auricular region, were also reported [52]. The occurrence of blistering lesions varied according to the case series analyzed; Piccolo et al. [51], indeed, reported the presence of blistering lesions in 23 out of 54 patients, while other authors did not describe bullous lesions in their series [40, 47]. Dermoscopy of these lesions revealed the presence of an indicative pattern represented by a red background area with purpuric globules [53]. Pain/burning sensation as well as pruritus were commonly reported symptoms, even if a small proportion of patients presented with asymptomatic lesions [40, 44, 47]. Unlike other COVID-19-related cutaneous findings, chilblain-like acral lesions tended to mostly involve patients without systemic symptoms.

The frequent occurrence of chilblain-like lesions in the absence of cold exposure and the involvement of patients without evident COVID-19-related symptoms raised the question whether these manifestations were actually associated with SARS-CoV-2 infection.

Histopathological and Pathophysiological Findings

Chilblain-like lesions share many histopathological features with idiopathic and autoimmunity-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic inflammation. Vascular changes such as endotheliitis and microthrombi may be found [40, 45, 54, 55] (Fig. 2).

Data on the real association between chilblain-like acral lesions and COVID-19 are controversial.

The first case series failed to perform SARS-CoV-2 testing in all patients, also due to logistic problems and economic restrictions, and diagnosed COVID-19 only in a minority of patients with chilblain-like acral lesions [40, 44, 47]. Subsequently, some authors systematically sought SARS-CoV-2 with serology and/or nasopharyngeal swab in patients with chilblain-like acral lesions. In their cohort of 38 children with pseudo-chilblain, Caselli et al. [56] showed no evidence of SARS-CoV-2 infection by PCR or serology. Chilblain-like acral lesions appeared not to be directly associated with COVID-19 also in the case series by Herman et al. [57]. These authors failed to detect SARS-CoV-2 in nasopharyngeal swabs and skin biopsies and demonstrated no specific anti-SARS-CoV-2 immunoglobulin IgM or IgG antibodies in blood samples. Therefore, they concluded that lifestyle changes associated with lockdown measures might be a possible explanation for these lesions [57]. Similar results were obtained also by other authors [58-63] weakening the hypothesis of a direct etiological link between SARS-CoV-2 and chilblain-like acral lesions.

Opposite conclusions have been drawn by Colmenero et al. [64], who demonstrated by immunohistochemistry and electron microscopy the presence of SARS-CoV-2 in endothelial cells of skin biopsies of 7 children with chilblain-like acral lesions, suggesting that virus-induced vascular damage and secondary ischemia could explain the pathophysiology of these lesions.

In the absence of definitive data on chilblain-like acral lesions’ pathogenesis, the occurrence of such lesions should prompt self-isolation and confirmatory testing for SARS-CoV-2 infection [65].

Therapeutic Options

In the absence of significant therapeutic options for chilblain-like acral lesions associated with COVID-19 and given their tendency to spontaneously heal, a “wait-and-see” strategy may be suggested.

Livedo Reticularis/Racemosa-Like Pattern

Clinical Features and Association with COVID-19 Severity

Livedo describes a reticulate pattern of slow blood flow, with consequent desaturation of blood and bluish cutaneous discoloration. It has been divided into: (i) livedo reticularis, which develops as tight, symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center, generally associated with cold-induced cutaneous vasoconstriction or vascular flow disturbances such as seen in polycythemia and (ii) livedo racemosa, characterized by larger, irregular and asymmetrical rings than seen in livedo reticularis, more frequently associated with focal impairment of blood flow, as it can be seen in Sneddon’s syndrome [66].

In our classification, the livedo reticularis/racemosa-like pattern has been distinguished by the purpuric “vasculitic” pattern because the former likely recognizes a occlusive/microthrombotic vasculopathic etiology, while the latter can be more likely considered the expression of a “true” vasculitic process [2]. Instead, the classification by Galván Casas et al. [4] merged these two patterns into the category “livedo/necrosis”.

In a French study on vascular lesions associated with COVID-19, livedo was observed in 1 out of 7 patients [43]. In the large cases series of 716 patients by Freeman et al. [10], livedo reticularis-like lesions, retiform purpura and livedo racemosa-like lesions accounted for 3.5, 2.6 and 0.6% of all cutaneous manifestations, respectively. In the multicentric Italian study, livedo reticularis/racemosa-like lesions accounted for 2.5% of cutaneous manifestations (Table 1).

The pathogenic mechanisms at the basis of small blood vessel occlusion are yet unknown, even if neurogenic, microthrombotic or immune complex-mediated etiologies have been postulated [67].

Livedo reticularis-like lesions are frequently mild, transient and not associated with thromboembolic complications [68, 69]. On the contrary, livedo racemosa-like lesions and retiform purpura have often been described in patients with severe coagulopathy [60-72].

Histopathological and Pathophysiological Findings

The histopathology of livedoid lesions associated with COVID-19 has been described by Magro et al. [73], who observed in 3 patients pauci-inflammatory microthrombotic vasculopathy. The same group demonstrated that in the thrombotic retiform purpura of patients with severe COVID-19, the vascular thrombosis in the skin and internal organs is associated with a minimal interferon response permitting increased viral replication with release of viral proteins that localize to the endothelium inducing widespread complement activation [74], which is frequent in COVID-19 patients and probably involved in the pathophysiology of its clinical complications [75].

Therapeutic Options

In view of the absence of significant therapeutic options for livedo reticularis/racemosa-like lesions associated with COVID-19, a “wait-and-see” strategy may be suggested.

Purpuric “Vasculitic” Pattern

Clinical Features and Association with COVID-19 Severity

The first COVID-19-associated cutaneous manifestation with purpuric features was reported by Joob et al. [76], who described a petechial rash misdiagnosed as dengue in a COVID-19 patient. Purpuric lesions have been suggested to occur more frequently in elderly patients with severe COVID-19, likely representing the cutaneous manifestations associated with the highest rate of COVID-19-related mortality [4]. This hypothesis is corroborated by the unfavorable prognosis observed in several cases reported in the literature [77, 78].

The purpuric pattern reflects the presence of vasculitic changes probably due to the direct damage of endothelial cells by the virus or dysregulated host inflammatory responses induced by COVID-19.

These lesions are likely to be very rare, representing 8.2% of skin manifestations included in the Italian multicentric study shown in Table 1. In their case series of 7 patients with vascular skin lesions related to COVID-19, Bouaziz et al. [43] reported 2 patients with purpuric lesions with (n = 1) and without (n = 1) necrosis. In the series by Freeman et al. [10], 12/716 (1.8%) and 11/716 (1.6%) cases of patients with palpable purpura and dengue-like eruption, respectively, have been reported. Galván Casas et al. [4] reported 21 patients with “livedo/necrosis,” most of whom presenting cutaneous signs in concomitance with systemic symptoms’ onset.

Purpuric lesions may be generalized [79], localized in the intertriginous regions [80] or arranged in an acral distribution [81]. Vasculitic lesions may evolve into hemorrhagic blisters [77]. In most severe cases, extensive acute necrosis and association with severe coagulopathy may be seen [78]. Dermoscopy of purpuric lesions revealed the presence of papules with incomplete violaceous rim and a central yellow globule [82].

Histopathological Findings

When performed, histopathology of skin lesions showed leukocytoclastic vasculitis [77, 79], severe neutrophilic infiltrate within the small vessel walls and in their proximity [77], intense lymphocytic perivascular infiltrates [81], presence of fibrin [79, 81] and endothelial swelling [82] (Fig. 2).

Therapeutic Options

Topical corticosteroids have been successfully used for treating mild cases of purpuric lesions [80]. Cases with necrotic-ulcerative lesions and widespread presentation may be treated with systemic corticosteroids.

Other COVID-19-Associated Cutaneous Manifestations

Other peculiar rare COVID-19-related cutaneous manifestations that cannot be pigeonholed in the classification proposed by our group [2] include, among others, the erythema multiforme-like eruption [83], pityriasis rosea-like rash [84], multi-system inflammatory syndrome in children [85], anagen effluvium [86] and a pseudoherpetic variant of Grover disease [87]. However, the spectrum of possible COVID-19-associated skin manifestations is likely to be still incomplete, and it is expected that new entities associated with this infection will be described.

Conclusion

COVID-19-associated cutaneous manifestations have been increasingly reported in the last few months, garnering attention both from the international scientific community and from the media. A few months after the outbreak of the pandemic, many narrative and systematic reviews concerning the dermatological manifestations of COVID-19 have been published [2, 3, 6, 88-91]. A summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations has been provided in Table 2.

Table 2.

Summary of clinical features, histopathological findings, severity of COVID-19 systemic symptoms and therapeutic options of COVID-19-related skin manifestations

Albeit several hypotheses on pathophysiological mechanisms at the basis of these skin findings are present in the literature [50, 92, 93], none of them is substantiated by strong evidence, and this field needs to be largely elucidated. Moreover, cutaneous eruptions due to viruses other than SARS-CoV-2 [35, 37] or drugs prescribed for the management of this infection [94, 95] always need to be ruled out.

Experimental pathophysiological studies and clinical data derived from large case series are still needed for shedding light onto this novel, underexplored and fascinating topic.

Key Message

Although COVID-19-associated cutaneous manifestations have been increasingly reported, their pathophysiological mechanisms need to be extensively explored. The conditions may be distinguished in six clinical phenotypes, each showing different histopathological patterns.

Acknowledgment

We would like to thank Dr. Cosimo Misciali, Dr. Paolo Sena and Prof. Pietro Quaglino for kindly providing us with histopathological pictures.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This paper did not receive any funding.

Author Contributions

Giovanni Genovese wrote the paper with the contribution of Chiara Moltrasio. Angelo Valerio Marzano and Emilio Berti supervised the work and revised the paper for critical revision of important intellectual content.

References

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb;395(10223):497–506.

Marzano AV, Cassano N, Genovese G, Moltrasio C, Vena GA. Cutaneous manifestations in patients with COVID-19: a preliminary review of an emerging issue. Br J Dermatol. 2020 Sep;183(3):431–42.

Matar S, Oulès B, Sohier P, Chosidow O, Beylot-Barry M, Dupin N, et al. Cutaneous manifestations in SARS-CoV-2 infection (COVID-19): a French experience and a systematic review of the literature. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16775.

Galván Casas C, Català A, Carretero Hernández G, Rodríguez-Jiménez P, Fernández-Nieto D, Rodríguez-Villa Lario A, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020 Jul;183(1):71–7.

Potekaev NN, Zhukova OV, Protsenko DN, Demina OM, Khlystova EA, Bogin V. Clinical characteristics of dermatologic manifestations of COVID-19 infection: case series of 15 patients, review of literature, and proposed etiological classification. Int J Dermatol. 2020 Aug;59(8):1000–9.

Gisondi P, PIaserico S, Bordin C, Alaibac M, Girolomoni G, Naldi L. Cutaneous manifestations of SARS-CoV-2 infection: a clinical update [online ahead of print]. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16774.

Imbalzano E, Casciaro M, Quartuccio S, Minciullo PL, Cascio A, Calapai G, et al. Association between urticaria and virus infections: A systematic review. Allergy Asthma Proc. 2016 Jan-Feb;37(1):18–22.

Yong SB, Yeh WC, Wu HJ, Chen HH, Huang JY, Chang TM, et al. Impact of mycoplasma pneumonia infection on urticaria: A nationwide, population-based retrospective cohort study in Taiwan. PLoS One. 2019 Dec;14(12):e0226759.

Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020 May;34(5):e212–3.

Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Desai SR, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020 Oct;83(4):1118–29.

van Damme C, Berlingin E, Saussez S, Accaputo O. Acute urticaria with pyrexia as the first manifestations of a COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Jul;34(7):e300–1.

Quintana-Castanedo L, Feito-Rodríguez M, Valero-López I, Chiloeches-Fernández C, Sendagorta-Cudós E, Herranz-Pinto P. Urticarial exanthem as early diagnostic clue for COVID-19 infection. JAAD Case Rep. 2020 Apr;6(6):498–9.

Hassan K. Urticaria and angioedema as a prodromal cutaneous manifestation of SARS-CoV-2 (COVID-19) infection. BMJ Case Rep. 2020 Jul;13(7):e236981.

Cepeda-Valdes R, Carrion-Alvarez D, Trejo-Castro A, Hernandez-Torre M, Salas-Alanis J. Cutaneous manifestations in COVID-19: familial cluster of urticarial rash. Clin Exp Dermatol. 2020 May;45(7):895–6.

Najafzadeh M, Shahzad F, Ghaderi N, Ansari K, Jacob B, Wright A. Urticaria (angioedema) and COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e568–70.

de Perosanz-Lobo D, Fernandez-Nieto D, Burgos-Blasco P, Selda-Enriquez G, Carretero I, Moreno C, et al. Urticarial vasculitis in COVID-19 infection: a vasculopathy-related symptom? J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e566–8.

Rodríguez-Jiménez P, Chicharro P, De Argila D, Muñoz-Hernández P, Llamas-Velasco M. Urticaria-like lesions in COVID-19 patients are not really urticaria – a case with clinicopathological correlation. J Eur Acad Dermatol Venereol. 2020 May;34(9): https://doi.org/10.1111/jdv.16618.

Amatore F, Macagno N, Mailhe M, Demarez B, Gaudy-Marqueste C, Grob JJ, et al. SARS-CoV-2 infection presenting as a febrile rash. J Eur Acad Dermatol Venereol. 2020 Jul;34(7):e304–6.

Shanshal M. Low-dose systemic steroids, an emerging therapeutic option for COVID-19-related urticaria. J Dermatolog Treat. 2020 Jul;16:1–2. DOI: 10.1080/09546634.2020.1795062.

De Giorgi V, Recalcati S, Jia Z, Chong W, Ding R, Deng Y, et al. Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy. J Am Acad Dermatol. 2020 Aug;83(2):674–5.

Rivera-Oyola R, Koschitzky M, Printy R, Liu S, Stanger R, Golant AK, et al. Dermatologic findings in 2 patients with COVID-19. JAAD Case Rep. 2020 Apr;6(6):537–9.

Jimenez-Cauhe J, Ortega-Quijano D, Prieto-Barrios M, Moreno-Arrones OM, Fernandez-Nieto D. Reply to “COVID-19 can present with a rash and be mistaken for dengue”: petechial rash in a patient with COVID-19 infection. J Am Acad Dermatol. 2020 Aug;83(2):e141–2.

Najarian DJ. Morbilliform exanthem associated with COVID-19. JAAD Case Rep. 2020 Apr;6(6):493–4.

Català A, Galván-Casas C, Carretero-Hernández G, Rodríguez-Jiménez P, Fernández-Nieto D, Rodríguez-Villa A, et al. Maculopapular eruptions associated to COVID-19: A subanalysis of the COVID-Piel study [Online ahead of print]. Dermatol Ther (Heidelb). 2020 Aug;e14170.

Gianotti R, Veraldi S, Recalcati S, Cusini M, Ghislanzoni M, Boggio F, et al. Cutaneous Clinico-Pathological Findings in three COVID-19-Positive Patients Observed in the Metropolitan Area of Milan, Italy. Acta Derm Venereol. 2020 Apr;100(8):adv00124–2.

Reymundo A, Fernáldez-Bernáldez A, Reolid A, Butrón B, Fernández-Rico P, Muñoz-Hernández P, et al. Clinical and histological characterization of late appearance maculopapular eruptions in association with the coronavirus disease 2019. A case series of seven patients. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16707.

Herrero-Moyano M, Capusan TM, Andreu-Barasoain M, Alcántara-González J, Ruano-Del Salado M, Sánchez-Largo Uceda ME, et al. A clinicopathological study of eight patients with COVID-19 pneumonia and a late-onset exanthema. J Eur Acad Dermatol Venereol. 2020 May;34(9): https://doi.org/10.1111/jdv.16631.

Marzano AV, Genovese G, Fabbrocini G, Pigatto P, Monfrecola G, Piraccini BM, et al. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol. 2020 Jul;83(1):280–5.

Askin O, Altunkalem RN, Altinisik DD, Uzuncakmak TK, Tursen U, Kutlubay Z. Cutaneous manifestations in hospitalized patients diagnosed as COVID-19. Dermatol Ther (Heidelb). 2020 Jun;24:e13896.

Genovese G, Colonna C, Marzano AV. Varicella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue? Pediatr Dermatol. 2020 May;37(3):435–6.

Fernandez-Nieto D, Ortega-Quijano D, Jimenez-Cauhe J, Burgos-Blasco P, de Perosanz-Lobo D, Suarez-Valle A, et al. Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital. Clin Exp Dermatol. 2020 May;45(7):872–5.

Mahé A, Birckel E, Merklen C, Lefèbvre P, Hannedouche C, Jost M, et al. Histology of skin lesions establishes that the vesicular rash associated with COVID-19 is not ‘varicella-like’. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e559–61.

Trellu LT, Kaya G, Alberto C, Calame A, McKee T, Calmy A. Clinicopathologic Aspects of a Papulovesicular Eruption in a Patient With COVID-19. JAMA Dermatol. 2020 Aug;156(8):922–4.

Tammaro A, Adebanjo GA, Parisella FR, Pezzuto A, Rello J. Cutaneous manifestations in COVID-19: the experiences of Barcelona and Rome. J Eur Acad Dermatol Venereol. 2020 Jul;34(7):e306–7.

Elsaie ML, Nada HA. Herpes zoster (shingles) complicating the course of COVID-19 infection. J Dermatolog Treat. DOI: 10.1080/09546634.2020.1782823. Epub 2020 Oct 12.

Lim SY, Tey HL. Response to ‘Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases’: vesicular eruption in COVID-19 – to exclude varicella. Br J Dermatol. 2020 Oct;183(4):790–1.

Llamas-Velasco M, Rodríguez-Jiménez P, Chicharro P, De Argila D, Muñoz-Hernández P, Daudén E. Reply to “Varicella-like exanthem as a specific COVID-19-associated skin manifestation: Multicenter case series of 22 patients”: To consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out. J Am Acad Dermatol. 2020 Sep;83(3):e253–4.

Marzano AV, Genovese G. Response to: “Reply to ‘Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients’: To consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out.” J Am Acad Dermatol. 2020 Sep; 83(3):e255–e256.

Mazzotta F, Troccoli T. Acute acro-ischemia in the child at the time of COVID-19. Eur J Pediatr Dermatol. 2020;30(2):71–4.

Colonna C, Genovese G, Monzani NA, Picca M, Boggio F, Gianotti R, et al. Outbreak of chilblain-like acral lesions in children in the metropolitan area of Milan, Italy, during the COVID-19 pandemic. J Am Acad Dermatol. 2020 Sep;83(3):965–9.

Alramthan A, Aldaraji W. Two cases of COVID-19 presenting with a clinical picture resembling chilblains: first report from the Middle East. Clin Exp Dermatol. 2020 Aug;45(6):746–8.

Fernandez-Nieto D, Jimenez-Cauhe J, Suarez-Valle A, Moreno-Arrones OM, Saceda-Corralo D, Arana-Raja A, et al. Characterization of acute acral skin lesions in nonhospitalized patients: A case series of 132 patients during the COVID-19 outbreak. J Am Acad Dermatol. 2020 Jul;83(1):e61–3.

Bouaziz JD, Duong TA, Jachiet M, Velter C, Lestang P, Cassius C, et al. Vascular skin symptoms in COVID-19: a French observational study. J Eur Acad Dermatol Venereol. 2020 Apr;34(9): https://doi.org/10.1111/jdv.16544.

de Masson A, Bouaziz JD, Sulimovic L, Cassius C, Jachiet M, Ionescu MA, et al.; SNDV (French National Union of Dermatologists-Venereologists). Chilblains is a common cutaneous finding during the COVID-19 pandemic: A retrospective nationwide study from France. J Am Acad Dermatol. 2020 Aug;83(2):667–70.

Cordoro KM, Reynolds SD, Wattier R, McCalmont TH. Clustered cases of acral perniosis: clinical features, histopathology, and relationship to COVID-19. Pediatr Dermatol. 2020 May;37(3):419–23.

Fernandez-Nieto D, Ortega-Quijano D, Suarez-Valle A, Burgos-Blasco P, Jimenez-Cauhe J, Fernandez-Guarino M. Comment on: “To consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out. Characterization of herpetic lesions in hospitalized COVID-19 patients”. J Am Acad Dermatol. 2020 Sep;83(3):e257–9.

Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Takeshita J, et al.; American Academy of Dermatology Ad Hoc Task Force on COVID-19. Pernio-like skin lesions associated with COVID-19: A case series of 318 patients from 8 countries. J Am Acad Dermatol. 2020 Aug;83(2):486–92.

Deutsch A, Blasiak R, Keyes A, Wu J, Marmon S, Asrani F, et al. Covid toes: phenomenon or epiphenomenon? J Am Acad Dermatol. 2020;83(5):e347–e348.

Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, et al. Overly exuberant innate immune response to SARS-CoV-2 infection. SSRN Electronic J. 2020; DOI: 10.2139/ssrn.3551623.

Kaya G, Kaya A, Saurat JH. Clinical and Histopathological Features and Potential Pathological Mechanisms of Skin Lesions in COVID-19: review of the Literature. Dermatopathology (Basel). 2020 Jun;7(1):3–16.

Piccolo V, Neri I, Filippeschi C, Oranges T, Argenziano G, Battarra VC, et al. Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients. J Eur Acad Dermatol Venereol. 2020 Jul;34(7):e291–3.

Proietti I, Tolino E, Bernardini N, Mambrin A, Balduzzi V, Marchesiello A, et al. Auricle perniosis as a manifestation of Covid-19 infection. Dermatol Ther (Heidelb). 2020 Jul;e14089.

Navarro L, Andina D, Noguera-Morel L, Hernández-Martín A, Colmenero I, Torrelo A. Dermoscopy features of COVID-19-related chilblains in children and adolescents. J Eur Acad Dermatol Venereol. 2020 Jul;jdv.16800.

Kanitakis J, Lesort C, Danset M, Jullien D. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): Histologic, immunofluorescence, and immunohistochemical study of 17 cases. J Am Acad Dermatol. 2020 Sep;83(3):870–5.

Locatelli AG, Robustelli Test E, Vezzoli P, Carugno A, Moggio E, Consonni L, et al. Histologic features of long-lasting chilblain-like lesions in a paediatric COVID-19 patient. J Eur Acad Dermatol Venereol. 2020 Aug;34(8):e365–8.

Caselli D, Chironna M, Loconsole D, Nigri L, Mazzotta F, Bonamonte D, et al. No evidence of SARS-CoV-2 infection by polymerase chain reaction or serology in children with pseudo-chilblain [Online ahead of print]. Br J Dermatol. 2020 Oct;183(4):784–5.

Herman A, Peeters C, Verroken A, Tromme I, Tennstedt D, Marot L, et al. Evaluation of Chilblains as a Manifestation of the COVID-19 Pandemic. JAMA Dermatol. 2020 Sep;156(9):998–1003.

Docampo-Simón A, Sánchez-Pujol MJ, Juan-Carpena G, Palazón-Cabanes JC, Vergara-De Caso E, Berbegal L, et al. Are chilblain-like acral skin lesions really indicative of COVID-19? A prospective study and literature review. J Eur Acad Dermatol Venereol. 2020 May;34(9): https://doi.org/10.1111/jdv.16665.

Denina M, Pellegrino F, Morotti F, Coppo P, Bonsignori IM, Garazzino S, et al. All that glisters is not COVID: low prevalence of seroconversion against SARS-CoV-2 in a pediatric cohort of patients with chilblain-like lesions. J Am Acad Dermatol. 2020 Dec;83(6):1751–53.

Ko CJ, Harigopal M, Damsky W, Gehlhausen JR, Bosenberg M, Patrignelli R, et al. Perniosis during the COVID-19 pandemic: negative anti-SARS-CoV-2 immunohistochemistry in six patients and comparison to perniosis before the emergence of SARS-CoV-2 [Online ahead of print]. J Cutan Pathol. 2020 Aug;47(11):997–1002.

Le Cleach L, Dousset L, Assier H, Fourati S, Barbarot S, Boulard C, et al.; French Society of Dermatology. Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol. 2020 Nov;183(5):866–74.

Lesort C, Kanitakis J, Villani A, Ducroux E, Bouschon P, Fattouh K, et al. COVID-19 and outbreak of chilblains: are they related? J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16779.

Roca-Ginés J, Torres-Navarro I, Sánchez-Arráez J, Abril-Pérez C, Sabalza-Baztán O, Pardo-Granell S, et al. Assessment of Acute Acral Lesions in a Case Series of Children and Adolescents During the COVID-19 Pandemic. JAMA Dermatol. 2020 Sep;156(9):992–7.

Colmenero I, Santonja C, Alonso-Riaño M, Noguera-Morel L, Hernández-Martín A, Andina D, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. 2020 Oct;183(4):729–37.

Ladha MA, Luca N, Constantinescu C, Naert K, Ramien ML. Approach to chilblains during the COVID-19 pandemic. J Cutan Med Surg. 2020 Sep/Oct;24(5):504–17.

Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D. Rook’s textbook of dermatology. 9th ed, rev. Hoboken: Wiley‐Blackwell; 2016.

Khalil S, Hinds BR, Manalo IF, Vargas IM, Mallela S, Jacobs R. Livedo reticularis as a presenting sign of severe acute respiratory syndrome coronavirus 2 infection. JAAD Case Rep. 2020 Sep;6(9):871–4.

Manalo IF, Smith MK, Cheeley J, Jacobs R. A dermatologic manifestation of COVID-19: transient livedo reticularis. J Am Acad Dermatol. 2020 Aug;83(2):700.

Verheyden M, Grosber M, Gutermuth J, Velkeniers B. Relapsing symmetric livedo reticularis in a patient with COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16773.

Chibane S, Gibeau G, Poulin F, Tessier P, Goulet M, Carrier M, et al. Hyperacute multi-organ thromboembolic storm in COVID-19: a case report. J Thromb Thrombolysis. 2020 Jun;6:1–4.

Droesch C, Do MH, DeSancho M, Lee EJ, Magro C, Harp J. Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19. JAMA Dermatol. 2020 Sep;156(9):1–3.

Bosch-Amate X, Giavedoni P, Podlipnik S, Andreu-Febrer C, Sanz-Beltran J, Garcia-Herrera A, et al. Retiform purpura as a dermatological sign of coronavirus disease 2019 (COVID-19) coagulopathy. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e548–9.

Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020 Jun;220:1–13.

Magro C, Mulvey JJ, Laurence J, Sanders S, Crowson N, Grossman M, et al. The differing pathophysiologies that underlie COVID-19 associated perniosis and thrombotic retiform purpura: a case series. Br J Dermatol. 2020 Jul;bjd.19415.

Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation in patients with COVID-19: A novel therapeutic target. J Allergy Clin Immunol. 2020 Jul;146(1):215–7.

Joob B, Wiwanitkit V. COVID-19 can present with a rash and be mistaken for dengue. J Am Acad Dermatol. 2020 May;82(5):e177.

Negrini S, Guadagno A, Greco M, Parodi A, Burlando M. An unusual case of bullous haemorrhagic vasculitis in a COVID-19 patient. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16760.

Del Giudice P, Boudoumi D, Le Guen B, Reverte M, Gutnecht J, Lacour JP, et al. Catastrophic acute bilateral lower limbs necrosis associated with COVID-19 as a likely consequence of both vasculitis and coagulopathy. J Eur Acad Dermatol Venereol. 2020 Jun;jdv.16763.

Caputo V, Schroeder J, Rongioletti F. A generalized purpuric eruption with histopathologic features of leucocytoclastic vasculitis in a patient severely ill with COVID-19. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e579–81.

Karaca Z, Yayli S, Çalışkan O. A unilateral purpuric rash in a patient with COVID-19 infection. Dermatol Ther (Heidelb). 2020 Jul;33(4):e13798.

García-Gil MF, Monte Serrano J, García García M, Barra Borao V, Matovelle Ochoa C, Ramirez-Lluch M, et al. Acral purpuric lesions associated with coagulation disorders during the COVID-19 pandemic. Int J Dermatol. 2020 Sep;59(9):1151–2.

Larrondo J, Cabrera R, Gosch M, Larrondo F, Aylwin M, Castro A. Papular-purpuric exanthem in a COVID-19 patient: clinical and dermoscopic description. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e570–2.

Jimenez-Cauhe J, Ortega-Quijano D, Carretero-Barrio I, Suarez-Valle A, Saceda-Corralo D, Moreno-Garcia Del Real C, et al. Erythema multiforme-like eruption in patients with COVID-19 infection: clinical and histological findings. Clin Exp Dermatol. 2020 May;45(7):892–5.

Ehsani AH, Nasimi M, Bigdelo Z. Pityriasis rosea as a cutaneous manifestation of COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 May;34(9): https://doi.org/10.1111/jdv.16579.

Gupta A, Gill A, Sharma M, Garg M. Multi-System Inflammatory Syndrome in a Child Mimicking Kawasaki Disease. J Trop Pediatr. 2020 Aug;fmaa060.

Shanshal M. COVID-19 related anagen effluvium. J Dermatolog Treat. 2020 Jul;16:1–2. DOI: 10.1080/09546634.2020.1792400.

Llamas-Velasco M, Chicharro P, Rodríguez-Jiménez P, Martos-Cabrera L, De Argila D, Fernández-Figueras M, et al. Comment on ‘Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital’. Pseudoherpetic Grover disease seems to occur in patients with COVID-19 infection. Clin Exp Dermatol. 2020 May;45(7):896–8.

Almutairi A, Alfaleh M, Alasheikh M. Dermatological Manifestations in Patients With SARS-CoV-2: A Systematic Review. Cureus. 2020 Jul;12(7):e9446.

Seirafianpour F, Sodagar S, Pour Mohammad A, Panahi P, Mozafarpoor S, Almasi S, et al. Cutaneous manifestations and considerations in COVID-19 pandemic: A systematic review. Dermatol Ther (Heidelb). 2020 Jul;e13986.

Zhao Q, Fang X, Pang Z, Zhang B, Liu H, Zhang F. COVID-19 and cutaneous manifestations: a systematic review. J Eur Acad Dermatol Venereol. DOI: 10.1111/jdv.16778. Epub 2020 Jun 28.

Wang Y, Fang R, Zhang H, Tang K, Sun Q. Contributions of dermatologists to COVID-19 research: A brief systematic review. Dermatol Ther (Heidelb). 2020 Jul;33(4):e13713.

Criado PR, Abdalla BM, de Assis IC, van Blarcum de Graaff Mello C, Caputo GC, Vieira IC. Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms. Inflamm Res. 2020 Aug;69(8):745–56.

Novak N, Peng W, Naegeli MC, Galván C, Kolm-Djamei I, Brüggen C, et al. SARS-CoV-2, COVID-19, skin and immunology – What do we know so far? Allergy. 2020 Jul;all.14498.

Herman A, Matthews M, Mairlot M, Nobile L, Fameree L, Jacquet LM, et al. Drug reaction with eosinophilia and systemic symptoms syndrome in a patient with COVID-19. J Eur Acad Dermatol Venereol. 2020 Jul;jdv.16838.

Delaleu J, Deniau B, Battistella M, de Masson A, Bensaid B, Jachiet M, et al. Acute generalized exanthematous pustulosis induced by hydroxychloroquine prescribed for COVID-19. J Allergy Clin Immunol Pract. 2020 Sep;8(8):2777–9.

Author Contacts

Angelo Valerio Marzano

Dermatology Unit

Università degli Studi di Milano

Via Pace 9, IT–20122 Milan (Italy)

[email protected]

Article / Publication Details

First-Page Preview

Received: September 01, 2020
Accepted: November 10, 2020
Published online: November 24, 2020

Issue release date: January 2021

Number of Print Pages: 12

Number of Figures: 2

Number of Tables: 2

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Lack of darker skin in textbooks, journals harms patients of color

When dermatologist Jenna Lester learned that rashes on skin and toes were a symptom of Covid-19, she started searching the medical literature for images of what the rashes looked like on Black skin so she’d recognize it in her Black patients. She couldn’t find a single picture.

“I was frustrated because we know Covid-19 is disproportionately impacting communities of color,” said Lester, an assistant professor of dermatology at the University of California, San Francisco who recently published her analysis. “I felt like I was seeing a disparity being built right before my eyes.”

The dearth of images in the Covid-19 literature is just the newest example of the glaring lack of representation of Black and brown skin that has persisted in dermatology research journals and textbooks for decades. The issue is coming under closer scrutiny now as dermatologists, like many physicians, grapple more openly with systemic racism and the health disparities it is causing in their field.

“Black Lives Matter is forcing a lot of people to look inward and say, ‘Where are our shortcomings?’” said Nada Elbuluk, an associate professor of clinical dermatology at the University of Southern California and the founder of a diversity and inclusion program in her department. “Dermatology is no different.”

The discrimination in her specialty extends beyond images and gaps in training, to restrictive insurance coverage for skin conditions that affect people with heavily pigmented skin, and to the many dermatologists who don’t accept patients with Medicaid.

It may be no surprise that a field that focuses on skin is now reckoning with skin color. In dermatology, where images are critical for diagnoses, the lack of images of darker skin poses a roadblock to proper treatment and medical education. Skin conditions that involve redness or pinkness in light skin can be subtler or harder to see in dark skin, and physicians who haven’t been adequately trained with such images are prone to misdiagnose people of color. “We absolutely need a diversity of images,” said Elbuluk.

An analysis of textbooks by Jules Lipoff, an assistant professor of clinical dermatology at the University of Pennsylvania, showed the percentage of images of dark skin ranged from 4% to 18%. “We are not teaching (and possibly not learning) skin of color,” Lester wrote in a separate analysis she conducted. Many worry the field’s shift toward using artificial intelligence to aid diagnosis of disease will further deepen the divide, because the machine learning algorithms are trained with datasets consisting primarily of fair-skinned images.

Dermatologist Jenna Lester treats Geoffry Blair Hutto at the UCSF skin of color clinic. Courtesy Barbara Ries, UCSF

It gets worse. While many textbooks depict the vast majority of skin diseases using light skin, there is one notable exception: Black skin is more often used to depict sexually transmitted diseases, a glaring example of stereotyping that is all the more painful given the U.S. government’s complicity in the notorious Tuskegee experiments that left syphilis untreated for decades in a group of poor, Black men.

Lipoff’s analysis, published this year, showed many dermatology textbooks had zero images of dark skin with acne, psoriasis, or dermatitis. When it came to syphilis, however, many books relied heavily on images of dark skin. Lester’s analysis found that while 28% of images of infectious diseases used images of darker skin, the number of depictions of dark skin was twice as high for infections that were sexually transmitted.

“In the textbooks I used in medical school, every penis was a Black penis showing an STD. We’ve got to stop that,” said Susan Taylor, a pioneer in the push for better dermatologic care for patients with dark skin and the Sandra Lazarus professor of dermatology at the Perelman School of Medicine at the University of Pennsylvania.

Considered a trailblazer in the field of dermatology, Taylor established the nation’s first “Skin of Color” dermatology clinic at Mount Sinai in New York in the late 1990s. In 2004, she founded the Skin of Color Society to help educate fellow dermatologists about how to treat patients of color, push for research and clinical trials to include people with darker skin, and mentor and encourage medical students of color to enter dermatology, where only 3% of practitioners are Black and 4% are Hispanic. “These are really abysmal numbers,” Taylor said. “That’s got to change.”

Taylor is also the lead author of the textbook Dermatology for Skin of Color, a guide considered invaluable by many dermatologists. But even those who rely on the book say it’s frustrating that a separate book on dark skin is still required — when as a nation we are just a few decades away from a majority of residents having skin of color.

“This is the white patient treated as the default and the Black patient as the asterisk,” said Lipoff. “You can’t make skin of color a lecture that students get once a year. It can’t be ‘otherized’ or put in a separate textbook.”

Taylor agrees. “Nothing would make me happier than to not have to publish another edition of that book,” she said.

Dermatologists say the lack of images is one reason why many conditions, including Lyme disease, spider bites, and cancers can go misdiagnosed or underdiagnosed in darker skinned patients, sometimes with dangerous results. The five-year melanoma survival rate for Black patients is just 70% compared with 94% for white patients.

The mother of a mixed-race 13-year-old from Connecticut said she was told by her child’s pediatrician when she was 8 that the white patches on her skin were pityriasis alba, a skin rash that’s usually not considered a serious condition. She was given a lotion, but the skin patches never went away. “I kept going online and looking at things but I couldn’t see anyone with issues that looked like hers,” said the mother, who didn’t want her name used to protect the girl’s privacy. “And the doctor was casual about it.”

Partly because of insurance issues, and partly because the mother thought there was nothing to worry about, it took five years before her daughter’s white patches were properly diagnosed: She had T-cell lymphoma, a cancer. While she will require maintenance light therapy for life, her overall prognosis is good. But her case highlights the difficult and sometimes frightening challenge many patients of color face to get a proper dermatologic diagnosis.

“Black Lives Matter is forcing a lot of people to look inward and say, ‘Where are our shortcomings?’ Dermatology is no different.”

Nada Elbuluk, associate professor of clinical dermatology at USC

When Ellen Buchanan Weiss noticed patches on the dark brown skin of her toddler son, she wondered if it was eczema, or something more serious. “I Googled it and noticed immediately the pictures were all of white skin,” she said. “I Googled other conditions and it was the same. No matter what I searched, there were almost no images of dark skin.”

The patches did turn out to be eczema and were easily treated. Still, the disparity bothered her for months. About a year ago, Weiss, a stay-at-home mom in Raleigh, N.C., decided to create an Instagram account called “Brown Skin Matters.” She posted images of skin conditions in darker skin next to images of the same condition in white skin and asked followers to send in more photos. The account exploded almost immediately.

“I’ve had tons of medical schools, physicians, nurses, and pharmacists all contact me saying this was useful,” she said. “I never thought this was going to become a diagnostic tool.”

Instagram is not exactly the best platform for making medical diagnoses, so Weiss is now working with medical experts to help create a more rigorous and searchable web-based tool for diagnosis of skin diseases in darker skin. It still floors Weiss that she, a person with no medical background, is at the center of it. “It’s curious to me, and troubling, that this is 2020 and this gap is still here,” she said. “Some large medical institution should have been taking care of this, not me.”

The issue of textbooks failing to adequately represent skin of color is not a new one. Yet Lipoff’s study compared today’s textbooks with those of 15 years ago and found little has changed. Jean Bolognia, a professor of dermatology at the Yale School of Medicine, has spent more than two decades editing the widely used textbook, Dermatology; she said providing a wide spectrum of skin tones is critical and something she’s worked hard to include, though she acknowledged there’s more work to do.

“I’m not saying it’s perfect, but we’ve been working really hard for over 15 years to show the whole spectrum,” said Bolognia, who is now working on the fifth edition of the textbook. “I feel you can always do better and I realize I don’t have enough images of Asian skin, so that is something I’m addressing.”

Bolognia said she tries to include photos of the same condition in darkly pigmented and lightly pigmented skin, cropped exactly the same way and side-by-side for comparison so readers can see how the same condition can appear significantly different on darker skin. She also includes many more images of dark skin of conditions, like cutaneous lupus or scarring folliculitis, that are more likely to affect Black people.

Comparison of atopic dermatitis in infants with darkly pigmented versus lightly pigmented skin, from the widely used textbook, Dermatology. Courtesy Bolognia JL, Schaffer JV, and Cerroni L, eds. Dermatology. 4th ed. Elsevier

Bolognia said she is extremely sensitive about not stigmatizing people of color by using only images of darkly pigmented skin to illustrate sexually transmitted diseases or drug users. “I noticed this as a student, the images of STDs were nearly all of patients with darkly pigmented skin, but the people I saw with syphilis were often fair-skinned,” she said. “I wondered about the possibility that pictures were being taken of individuals who were less likely to say no.”

The field’s other widely used textbook is Andrews’ Diseases of the Skin. That book’s lead author, William James, is a longtime champion of diversity in dermatology, according to his colleagues at Penn, who include Taylor and Lipoff. James said representing a variety of skin tones was an important issue, but said authors were challenged by limits placed on the number of photos by textbook publishers and because findings of redness or pinkness can be hard to see in images of darker skin. “Deciding if an entity is represented at all, or more than once, is always difficult,” he said in an email.

James said his textbook includes more photos of Black skin than white skin in conditions that are more common in Black patients, and noted that eight of 14 photos of syphilis are in lighter skin.

Agrowing number of dermatologists are following Taylor’s lead and opening skin of color clinics that provide care for darker-skinned patients. Lester opened one at UCSF last year. Elbuluk has worked at or founded three skin of color clinics throughout her training and early career, including at Penn, NYU Medical School, and, in 2018, at USC, where she hopes to also spur much-needed clinical research on darker skin. “It’s surprising to me when large cities don’t have these,” Elbuluk said.

There are many reasons why people of color, particularly those who do not have private health insurance, lack access to dermatologists. Lipoff, who has examined the issue, said many dermatologists do not take Medicaid. Racial bias that discourages the treatment of Black patients, he said, is literally built into the physician reimbursement system. Many conditions that affect darker skin are often not covered by insurance because they are considered cosmetic.

Meanwhile, the highest revenue procedures, Lipoff said, include those for the diagnosis and treatment of skin cancer, which is more likely to occur in white patients. This difference in how procedures are valued and reimbursed, he said, is a perfect example of structural racism that drives practices to directly and indirectly focus on white patients and marginalize Black patients. “If Black patients earned practices three times the revenue,” he said, “the disparity would disappear overnight.”

“It’s curious to me, and troubling, that this is 2020 and this gap is still here. Some large medical institution should have been taking care of this, not me.”

Ellen Buchanan Weiss, Raleigh resident who created the “Brown Skin Matters” Instagram account

Until it does, physicians who run skin of color clinics are hoping to address the lack of care, and poor care, Black and brown patients have received. The clinics are a welcome addition to people like Dar Bray, a 45-year-old behavioral therapist and darker-skinned Black man from Los Angeles.

Bray had dealt for years with deep and persistent scars caused by acne, trying bleaching creams and expensive cosmetic products, all with no success. “I went to so many doctors who didn’t know what to do with my skin. All the pictures they had on their wall were fair-skinned people,” Bray said. “It didn’t feel like racism, it felt like just plain ignorance.”

Seeing Elbuluk, he said, was immediately different. Bray is now undergoing chemical peels to remove scarring and using simple (and inexpensive) cleansers and moisturizers, and says he sees a huge improvement in his skin. He’s also wearing sunscreen, something no physician had ever told him was necessary; like many, he had believed the myth “Black don’t crack.” “When I went to the beach, I never wore sunscreen,” he said. “Now I have years of sun damage.”

Mistrust of white physicians led Gregory Hines, a 63-year-old longshoreman who lives in Oakland, to go years without seeing a doctor about growths under his arm, on his back, and on his neck, even as they puffed up and became, in his words “kind of weird and ugly.”

“I experience it a lot, going to doctors — especially white, male doctors — they assume they know more than you. They assume they already know what your problem is the minute you walk through the door,” he said.

When he heard UCSF’s Skin of Color clinic had opened, he was willing to give it a try. “When Dr. Lester walked in, I said, ‘Whoa, this is great,’” he said. “I wanted a Black doctor who understands Black skin.”

Lester ended up removing the masses, one of which was nearly as large as a golf ball, and sent them for tests to see if they were cancerous. Fortunately, they were not.

Lester is the only Black dermatologist in San Francisco. She’s hoping that will change after her current crop of residents decides where they will establish their practices. Her Black patients, she said, are often shocked when she walks in the door.

“I’ve had patients ask if they can take a picture with me to show their grandkids,” she said. “They want to talk all about me and how I got here, and I have to say, ‘No, this time is for you.’”

Wrestling and Skin Conditions – What Is THAT?

All of these skin diseases MAY NOT BE COVERED FOR COMPETITION!

Report anything suspicious to your athletic trainer or physician ASAP so you can stay competitive!

The sport of wrestling requires close skin-to-skin contact amongst opponents. This close contact means there is a high possibility of catching or spreading a variety of skin conditions amongst competitors. Various different common skin conditions are outlined below, so that you can be aware, identify and get treatment for as soon as possible, so that you can stay on the mat and not on the sidelines.

Herpetic Lesions

Herpetic Lesions (aka herpes simplex, herpes zoster, herpes gladiatorium, cold sore/fever blister) are a viral infection transmitted by direct contact and may appear ANYWHERE ON THE BODY.

Signs and Symptoms:

Lesion: Numerous clustered vesicles (blisters) filled with clear fluid on a reddened background. The vesicles continue to develop for 7-10 days and eventually become dry, crusted lesions. Recurrent outbreaks are sometimes preceded by irritability, headache, and tingling, burning and/or itching of the skin at the site of recurrence
Other symptoms may mimic a mild viral illness with fever, joint aches and pains, sore throat, swollen lymph nodes near the affected area and inflammation of the eyes