Hrev_master Abstract COVID-19 can affect multiple organs, including skin. A wide range of skin manifestations have been reported in literature. Six main phenotypes have been identified: i) urticarial rash, ii) conflu- ent erythematous/maculopapular/morbilliform rash, iii) papulovesicular exanthem, iv) a chilblain-like acral pattern, v) a livedo reticularis/racemosa-like pattern, and vi) a purpuric vas- culitic pattern. The pathogenetic mechanism is still not completely clear, but a role of hyperactive immune response, complement acti- vation and microvascular injury have been postulated. The only correlation between the cutaneous phenotype and the severity of COVID-19 has been observed in the case of chilblain-like acral lesions, that is generally associated with the benign/subclinical course of COVID-19. Herein, we report two cases of SARS-CoV- 2 infection in patients who developed cutaneous manifestations that completely solved with systemic steroids and antihistamines. The first case is a female patient not vaccinated for SARS-CoV-2 with COVID-19 associated pneumonia, while the second case is a vaccinated female patient with only skin manifestations. Case Reports Case 1 is an 87-year-old woman who was hospitalized in our Emergency Department (ED) for COVID-19 pneumonia with acute respiratory failure requiring oxygen therapy via nasal cannu- las. High-resolution chest CT scan showed a diffuse interstitial pat- tern with subpleural bilateral consolidations with an estimated visual score of 25%. She had not been vaccinated for Sars-CoV-2 and her past medical history consisted in hypertension, diabetes mellitus type 2, overweight, and a previous femoral fracture. Therapeutic management included dexamethasone 6 mg iv daily, low molecular weight heparin at prophylaxis dose, remdesivir 200 mg iv the first day and 100 mg daily for the next four days, and subcutaneous insulin to control plasmatic glucose levels. On day 2, she developed red macular slightly itching patches (wheals) on the skin of her abdomen and thighs (Figure 1) that increased in size in the next 2 days and progressively disappeared after a week. The Emergency Care Journal 2022; volume 18:10468 Correspondence: Erika Poggiali, Emergency Department, “Guglielmo da Saliceto” Hospital, Via Giuseppe Taverna 49, Piacenza, Italy. Tel.: +39.0523.303044 E-mail: poggiali.erika@gmail.com Key words: COVID-19; SARS-CoV-2; skin manifestations; coron- avirus; angioedema; urticaria. Contributions: DB, GB, PR and EP drafted the manuscript. DB, GB, PR and EP cared for the patient. EP, AM e AV critically revised the manu- script. All authors approved the final version and stated the integrity of the whole work. Conflicts of interest: The authors declare no conflict of interest. EP is member of the editorial board of Emergency Care Journal. Availability of data and materials: All data underlying the findings are fully available upon reasonable request to Erika Poggiali, poggiali.erika@gmail.com. Ethics approval and consent to participate: As this was a descriptive case report and data was collected without patient identifiers, ethics approval was not required under our hospital’s Institutional Review Board guidelines. Informed consent: The patients provided consent for the access to med- ical records at the time of admission. Received for publication: 18 March 2022. Revision received: 15 April 2022. Accepted for publication: 19 April 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Emergency Care Journal 2022; 18:10468 doi:10.4081/ecj.2022.10468 Publisher's note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organiza- tions, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its man- ufacturer is not guaranteed or endorsed by the publisher. [Emergency Care Journal 2022; 18:10468] [page 9] COVID-19 and cutaneous manifestations: Two cases and a review of the literature Davide Bastoni,1 Giorgia Borio,2 Paola Rienzo,2 Andrea Magnacavallo,1 Andrea Vercelli,1 Erika Poggiali1 1Emergency Department, Guglielmo da Saliceto Hospital, Piacenza; 2Emergency Department, San Raffaele Hospital IRCCS, Milano, Italy Highlights - Skin rash can be an extrapulmonary manifestation of COVID-19. - COVID-19 cutaneous lesions can be classified in six main clinical patterns: i) urticarial rash, ii) confluent erythematous/maculopapular/morbilliform rash, iii) papulovesicular exanthem, iv) a chilblain-like acral pattern, v) a livedo reticularis/racemosa-like pattern, and vi) a purpuric vasculitic pattern. - The pathogenesis is not completely clear, but a role of hyperactive immune response, complement activation and microvascular injury have been postulated. - Therapy is based on topical or systemic corticosteroids with or without antihistamines, or a “wait-and-see” strategy, depending on the clinical pattern. Non -co mmerc ial us e o nly patient was discharged after 10 days of recovery in good clinical condition without oxygen need. Case 2 is a 65-year-old woman with an asymptomatic SARS- CoV-2 infection, who was admitted to our ED for acute onset of facial oedema with pruritus, treated by her general practitioner with dexamethasone 4 mg im and chlorphenamine 10 mg im with partial benefit. She was vaccinated with 3 doses of tozinameran, with no adverse reactions. She denied dyspnea or fever. She had a history of alpha 1 antitrypsin deficiency with chronic obstructive pulmonary disease, rheumatoid arthritis, and hypercholes- terolemia. Her medications included alpha-1 antitrypsin, adali- mumab and vitamin D. She was allergic to pollen with cough and rhinitis. During the observation in the emergency room, she devel- oped urticarial rash of the trunks and lower limbs with itch and facial angioedema in absence of respiratory symptoms (Figure 2). Chest CT scan excluded interstitial pneumoniae, confirming panacinar emphysema and bronchiectasis. Blood analysis was nor- mal, including procalcitonin, C-reactive protein and erythrocyte rate sedimentation. IL-6 resulted increased (28.21 pg/mL, normal value < 6.4). She was treated with systemic corticosteroids (methylprednisolone 40 mg bid) and antihistamines (chlor- phenamine 10 mg daily) with progressive improvement of the cutaneous lesions, which completely solved after 7 days. She did not develop respiratory failure during the recovery, and she was completely asymptomatic at discharge with a negative RT-PCR nasopharyngeal swab. Discussion Since the first case of COVID-19 in December 2020, clinicians have learned that the most common clinical manifestations of this disease are flu-like symptoms, such as cough, fever and fatigue, and respiratory symptoms ranging from exertional dyspnea to acute respiratory distress syndrome. With the worldwide spread of the SARS-CoV-2, new symptoms are emerging, and an increasing number of reports are documenting extrapulmonary manifestations of COVID-19, including dermatological signs. It is well-known that most viruses can cause skin manifestations acting as foreign particles in the skin1,2 through an inflammatory process,3 and COVID-19 associated skin rashes can be a manifestation of viremia,4 as firstly reported by Recalcati et al. in a case series of 18 COVID-19 patients.5 Since 2020 an increasing number of reports regarding COVID-19 associated cutaneous manifestations has been published,5-10 but the real incidence of the COVID-19 associ- ated cutaneous manifestations has yet to be estimated due to their heterogeneous spectrum of presentation. A difficulty in determin- ing the actual prevalence has been mostly linked to the fact that in some countries only patients with pneumoniae or requiring hospi- talization are screened. In a binational Chinese-Italian cohort of 678 hospitalized adults with laboratory confirmed disease, the prevalence was 7.8%, but cutaneous lesions are likely to have been underestimated for many other reasons, including the paucity of dermatology consultations.11 Moreover, cutaneous lesions may be neglected as their duration can be very short and local symptoms can be minimal or absent. The first large clinical study of 375 Mini Review Figure 2. Urticarial rash (A) of the trunk (B) and lower limbs (C). Figure 1. Urticarial rash involving the abdomen (A) and the thighs (B). [page 10] [Emergency Care Journal 2022; 18:10468] Non -co mmerc ial us e o nly patients with COVID-19 associated skin manifestations has been published in 2020 by Galvan Casas et al.12 The authors recognized five clinical patterns of presentation, as follows: i) acral areas of erythema with vesicles or pustules (pseudo-chilblains) (19%), ii) other vesicular eruptions (9%), iii) urticarial lesions (19%), iv) maculopapular eruptions (47%), and v) livedo or necrosis (6%). Vesicular eruptions were found to appear early in the course of the disease (before other symptoms in 15% of cases), chilblain-like lesions frequently appear late over the disease course, whereas the remaining patterns tend to develop during the illness phase. Chilblain-like lesions also tend to have a longer duration as com- pared to the other forms. A gradient of severity of COVID-19 could be observed ranging from less severe disease in acral lesions to most severe in the case of livedo.12 Subsequently, Marzano et al. identified 6 main phenotypes on the basis of the available literature and direct clinical experience, including: i) urticarial rash, ii) con- fluent erythematous/maculopapular/morbilliform rash, iii) papulovesicular exanthem, iv) a chilblain-like acral pattern, v) a livedo reticularis/racemosa-like pattern, and vi) a purpuric vas- culitic pattern.13 In addition, case series of a miscellany of other cutaneous presentations that cannot be included in this classifica- tion, such as erythema multiforme like,14 pityriasis rosea like,15 and Grover disease like manifestations16 have been published. Considering the pathophysiological mechanisms, these six patterns can be assigned to two broader categories: i) inflammatory/exan- thematous eruptions, including urticarial rash, confluent erythema- tous/maculopapular/morbilliform rash and papulovesicular exan- them, and ii) vasculopathic/vasculitic lesions, including chilblain- like acral pattern, livedo reticularis/racemosa-like pattern and pur- puric “vasculitic” pattern. The most frequent cutaneous pheno- types are confluent erythematous/maculopapular/morbilliform rash and a chilblain-like acral pattern, whereas the least frequent is a livedo reticularis-like/racemosa-like pattern. Mucous membrane lesions have very rarely been reported in COVID-19 patients. The median latency between the onset of the cutaneous manifestations and systemic symptoms is 14 days, varying from 4 days in the case of papulovesicular exanthem to 24.5 days in the case of a livedo reticularis-like/racemosa-like pattern, and the median duration of the cutaneous manifestations is 12 days, ranging from 8 days in the case of urticarial rash to 22 days in the case of a chilblain-like acral pattern. Only chilblain-like acral phenotype is significantly associ- ated with the benign/subclinical course of COVID-19. Chilblain- like acral phenotype is also associated with a younger age, whereas the livedo-like/vasculitic and maculopapular phenotypes are asso- ciated with an older age.13 Here we report the main characteristics for each phenotype (Table 1). Inflammatory/exanthematous eruptions Urticarial rash and angioedema Estimated incidence of urticarial eruptions associated with COVID-19 varies from 16.7% to 19% of total skin manifesta- tions.5,12 Familial clusters have been reported.17 The rash tends to appear simultaneously with systemic symptoms, involving pre- dominantly the trunk and limbs, and relatively sparing the acral sites.18 Itch is generally, as reported in the case 1. The rash lasts approximately 1 week, and it is associated with medium high severity of COVID-19.12 Angioedema can accompany the urticari- al rash, as reported in the case 2 and by Najafzadeh et al.19 Histopathological studies are poor.20 Amatore et al. documented the presence of lichenoid and vacuolar interface dermatitis, associ- ated with mild spongiosis, dyskeratotic basal keratinocytes and Mini Review Table 1. The six main COVID-19 related cutaneous manifestations. Type Clinical features Body involvement Therapy Inflammatory/ Urticarial rash Itching urticarial rash Trunk and limbs Low-dose systemic corticosteroids + Exanthematous lasting 1 week +/- angioedema non-sedating antihistamines eruptions Confluent erythematous / Symmetrical itchy maculopapular Trunk and limbs with Topical steroids. maculopapular / eruption after COVID-19 centrifugal progression Parenteral route for severe morbilliform rash systemic symptoms’ onset. and widespread cases Evolution in morbilliform rash. Papulovesicular exanthem “Varicella-like”: i) widespread pattern: small papules, i) Widespread; Wait and see vesicles, and pustules of different sizes; ii) Mid chest, upper ii) localized pattern: monomorphic abdominal region or the back papulovescicular lesions Vasculopathic/ Chilblain-like acral pattern Erythematous-violaceous patches or Feet and hands, rarely Wait and see Vasculitic lesions plaques + pain/burning sensation auricular region + pruritus Livedo reticularis / i) Livedo reticularis: tight, Not specific Wait and see racemosa-like pattern symmetrical, lace-like, dusky patches forming complete rings surrounding a pale center. ii) Livedo racemosa: larger, irregular, and asymmetrical rings. Possible microthrombotic vasculopathy and severe coagulopathy. Purpuric vasculitic pattern Purpuric lesions with possible evolution Acral distribution or Topical corticosteroids in haemorrhagic blisters and intertriginous regions for mild cases. necrotic-ulcerative lesions Systemic corticosteroids for ulcerative lesions and widespread presentation [Emergency Care Journal 2022; 18:10468] [page 11] Non -co mmerc ial us e o nly superficial perivascular lymphocytic infiltrate.21 Rodriguez- Jiménez et al. found a vacuolar interface dermatitis with occasion- al necrotic keratinocytes compatible with an erythema multiforme- like pattern in a 60-year-old woman with persistent urticarial erup- tion and interstitial pneumonia who was not under any medication.22 Low-dose systemic corticosteroids combined with non-sedat- ing antihistamines have been suggested as therapeutic option,23 based on the hypothesis of hyperactivity of the immune system in COVID-19 patients. Confluent erythematous/maculopapular/morbilliform rash The clinical picture of this group may range from erythema- tous confluent rashes to maculopapular eruptions and morbilliform exanthems, similar to non-specific rashes observed in common viral infections. The most commonly reported skin manifestations are maculopapular eruptions,12 which appear generalized, symmet- rical, itchy, and predominantly localized on the trunk and limbs with centrifugal progression,24 more frequently after COVID-19 systemic symptoms’ onset.25 Erythematous lesions can progress to a purpuric evolution25 or coexist with purpuric lesions.26 Maculopapular eruptions can change in a morbilliform pattern.27 Histopathological studies were possible only in a few patients. Gianotti at al. described a vascular damage in all the 3 cases inves- tigated,28 while Reymundo et al. documented a mild superficial perivascular lymphocytic infiltrate.29 The main differential diagnoses are drug-induced cutaneous reactions and viral exanthems. The therapeutic management consists in corticosteroids according to the severity of the rash: topical steroids can be used successfully in most cases, reserving the parenteral route to severe and widespread cases.27 Papulovesicular exanthem COVID-19-associated papulovesicular exanthem was firstly described as “varicella-like” in an Italian multicentre case series of 22 patients.30 As reported by Marzano et al.20 this exanthem is a rare, but specific COVID-19 skin manifestation, that resembles that observed in true varicella, but with a different pattern, as fol- lows: a frequent trunk involvement, usually scattered distribution, and mild/absent pruritus. Lesions generally appear 3 days after systemic symptoms and disappear after 8 days without leaving scarring, and they are associated with intermediate COVID-19 severity.20 This rash is more common in adult patients,30 but also children can be affected.31 Two different presentation patterns have been reported: i) a more common widespread polymorphic pattern consisting of small papules, vesicles, and pustules of different sizes, and ii) a localized pattern, less frequent and consisting of monomorphic lesions, usually involving the mid chest/upper abdominal region or the back.32 The prevalence is extremely vari- able. Indeed, in a cohort of 375 patients with COVID-19-associat- ed cutaneous manifestations patients with papulovesicular exan- them were 34 (9%),12 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 respective- ly by Askin et al.,33 Recalcati,5 and De Giorgi et al.11 Histopathological studies showed epidermal necrosis with acantholysis, dyskeratosis and signs of endotheliitis in the dermal vessels.20,34,35 Immunohistochemical analysis has demonstrated the presence of SARS-CoV-2 in the endothelial cells of damaged skin.32 In all the published studies PCR assays failed to detect the presence of SARS-CoV-2 inside the vesicles. However, as reported by Magro et al. a small viral load can result in false negative results, and PCR assays in skin samples are not standardized.32 The differential diagnosis with infections caused by the Herpes viridae family can be difficult and in some cases Herpes Zoster can complicate the course of COVID-19.36 The current opinion is to consider herpes viruses as a mere superinfection in patients with dysfunctional immune response associated with COVID-19.37 Given the self-limiting course, a “wait-and-see” strategy is the most recommend therapeutic option. Vasculopathic/vasculitic lesions Chilblain-like acral pattern Chilblain-like acral lesions associated with COVID-19 are peculiar cutaneous manifestations, more common in Caucasians,38,39 that appear as erythematous-violaceous patches or plaques predominantly involving the feet and hands,40,41 and rarely other acral sites, such as the auricular region.42 The lesions fre- quently appear late over the disease course and tend to have a longer duration. In a large Italian study by Marzano et al. the chilblain-like acral phenotype was significantly associated with less severe COVID-19.13 The acral eruption is frequently charac- terized by erythematous-violaceous papules and macules, with possible bullous evolution, or digital swelling. Pain/burning sensa- tion, as well as pruritus, are commonly reported symptoms. Dermoscopy revealed the presence of an indicative pattern repre- sented by a red background area with purpuric globules.43 Young patients confined at home, in the absence of cold exposure, comor- bidities or other potential triggers, and without systemic symptoms seem to be mostly affected.12,44 The pathogenesis is not completely clear. Different hypotheses have been proposed, including increased interferon release induced by COVID-19 and consequent cytokine-mediated inflam- matory response, and virus-induced endothelial damage with oblit- erative microangiopathy and coagulation abnormalities.45 Data on the relationship between the SARS-CoV-2 infection and these clin- ical manifestations are controversial. In most cases laboratory con- firmation of the infection was not performed or gave negative results. Colmenero et al. demonstrated the presence of SARS CoV- 2 in endothelial cells of skin biopsies of 7 children with chilblain- like acral lesions by immunohistochemistry and electron microscopy, suggesting that virus-induced vascular damage and secondary ischemia could explain the pathophysiology of these lesions.46 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. In the absence of significant therapeutic options and given the tendency of these cutaneous lesions to spontaneously heal, a “wait and see” strategy is recommended. Livedo reticularis/racemosa-like pattern Livedo appears as a reticulate pattern of slow blood flow, with consequent desaturation of blood and bluish cutaneous discol- oration. It can be classified in 2 types, as follows: i) livedo reticu- laris, which develops as tight, symmetrical, lace-like, dusky patch- es forming complete rings surrounding a pale center, and ii) livedo racemosa, characterized by larger, irregular, and asymmetrical rings.47 In a large cases series of 716 patients by Freeman et al. livedo reticularis-like lesions and livedo racemosa-like lesions accounted for 3.5% and 0.6% of all cutaneous manifestations, respective- ly.18 Therefore, livedo reticularis and racemosa-like lesions have been suggested to occur in elderly patients with severe systemic symptoms and were pronounced and/or persistent.12 The basis of Mini Review [page 12] [Emergency Care Journal 2022; 18:10468] Non -co mmerc ial us e o nly the pathogenetic mechanisms is an occlusive/microthrombotic vas- culopathic aetiology13 with a mechanism not completely under- stood, but probably due to several mechanisms including neuro- genic, microthrombotic and immune-complex mediated processes.48 The histopathology of these lesions has been described by Magro et al. who documented the presence of thrombotic microvascular damage in the lung and/or skin of five critical COVID-19 patients.49 The authors demonstrated that in 3 patients with severe COVID-19, purpuric/livenoid skin lesions were char- acterized by a pauci-inflammatory microthrombotic vasculopa- thy, associated with a minimal interferon response, that cause an increased viral replication with the release of viral proteins, that localize into the endothelium inducing widespread complement activation. The same authors suggested that severe COVID-19 may induce a catastrophic generalized microvascular injury syn- drome mediated by intense activation of the alternative and lectin complement pathways and an associated procoagulant state. Therefore, Chinese authors reported the development of severe acro-ischemia in a few intensive care unit patients in Wuhan, man- ifesting as finger/toe cyanosis, skin blisters and dry gangrene, resulting from a hypercoagulable status or confirmed disseminated intravascular coagulation.50 In general, livedo reticularis-like lesions are frequently mild, transient, and not associated with thromboembolic complica- tions.51,52 On the contrary, livedo racemosa-like lesions and reti- form purpura have often been described in patients with severe coagulopathy.53,54 In absence of a targeted therapy, a “wait-and-see” approach is suggested with the recommendation to always assess and monitor platelet count, coagulation times, and fibrin degradation products. Purpuric “vasculitic” pattern The purpuric “vasculitic” pattern is the expression of a “true” vasculitic process due to the direct damage of the endothelial cells by the virus, or dysregulated host inflammatory responses induced by COVID-19. It is very rare, more frequent in elderly patients with severe COVID-19 and always associated with high- mortality.12 The first case has been reported in March 2020 by Joob and Wiwanitkit, who described a petechial rash misdiagnosed as dengue in a COVID-19 patient.8 In a case series Freeman et al. reported 1.8% and 1.6% of patients with purpura and dengue-like eruption, respectively.18 Purpuric lesions can be generalized or localized in the intertriginous regions or arranged in an acral dis- tribution.55-57 Del Giudice et al. described a case of an 83-year-old man affected by obesity and distal arteriopathy, who developed a catastrophic acute bilateral lower limbs and foot necrosis associat- ed with COVID -19 as a likely consequence of a malignant syner- gy of the vasculitis and severe coagulopathy.58 When performed, histopathology showed leukocytoclastic vas- culitis,55 severe neutrophilic infiltrate within the small vessel walls, intense lymphocytic perivascular infiltrates, presence of fibrin and endothelial swelling.57,59 Topical corticosteroids have been successfully used for treat- ing mild cases of purpuric lesions.56 Patients with necrotic-ulcera- tive lesions and widespread presentation can be treated with sys- temic corticosteroids. Other unclassifiable COVID-19 skin lesions Rare COVID-19-related cutaneous manifestations, that cannot be pigeonholed in the classification proposed by Marzano et al.,13 include the erythema multiforme-like eruption,60 pityriasis rosea- like rash,15 multi-system inflammatory syndrome in children,61 anagen effluvium,62 and a pseudo herpetic variant of Grover dis- ease.16 Pityriasis rosea like and erythema multiforme like patterns are the most frequently reported skin manifestations falling outside the classification, but it is still debated whether the former is directly mediated by SARS-CoV-2 or caused by COVID-19-relat- ed immune system dysfunction leading to human herpes virus 6/7 reactivation5, and whether the latter is triggered by SARS-CoV-2 or other viruses. Conclusions Cutaneous manifestations in COVID-19 patients are still an emerging issue as documented by the current literature. It is evi- dent that the spectrum of COVID-19-associated skin manifesta- tions is still incomplete, and it is expected that new skin lesions will be described. Dermatologists play a central role in the diagno- sis and the treatment strategy. The presence of cutaneous findings can lead to suspect COVID-19 and identify potentially contagious cases with indolent course. The role of COVID-19-associated skin manifestations as prognostic markers needs to be further investi- gated. When possible, histological analysis and detection of SARS-CoV-2 in the content of the skin lesions should be per- formed both to clarify the pathophysiological process at the basis of COVID-19 associated cutaneous manifestations, and to design a tailored therapy for each patient. References 1. Molina-Ruiz AM, Santonja C, Rütten A, et al. Immunohistochemistry in the diagnosis of cutaneous viral infections--part I. Cutaneous viral infections by herpesviruses and papillomaviruses. Am J Dermatopathol 2015;37:1-14. 2. 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