SARS-CoV-2 detection by digital polymerase chain reaction and immunohistochemistry in skin biopsies from 52 patients with different COVID-19-associated cutaneous phenotypes.

BACKGROUND: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases. OBJECTIVE: To demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes. METHODS: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA. RESULTS: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry. CONCLUSIONS: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load and immune response.

Intramuscular Polydeoxyribonucleotides in Fibrotic and Atrophic Localized Scleroderma: An Explorative Prospective Cohort Study.

Effective options in the quiescent, scantily inflammatory phase of localized scleroderma (morphea) are lacking. A cohort study in patients with histologically confirmed fibroatrophic morphea explored the therapeutic value of the anti-dystrophic A2A adenosine agonist polydeoxyribonucleotide (PDRN, one daily 5.625 mg/3 mL ampoule for 90 days with a three-month follow-up). Primary efficacy endpoints: Localized Scleroderma Cutaneous Assessment Tool mLoSSI and mLoSDI subscores for disease activity and damage in eighteen areas; Physicians Global Assessment for Activity (PGA-A) and Damage (PGA-D) VAS scores; skin echography. Secondary efficacy endpoints: mLoSSI, mLoSDI, PGA-A, PGA-D, and morphea areas (photographs) over time; Dermatology Life Quality Index (DLQI); skin biopsy scores and induration over time. Twenty-five patients enrolled; 20 completed the follow-up period. Highly significant improvements at the end of the 3-month treatment period: mLoSSI-73.7%, mLoSDI-43.9%, PGA-A-60.4%, PGA-D-40.3%, with further improvements at follow-up visit for all disease activity and damage indexes. Overall, the outcomes suggest that a daily PDRN ampoule intramuscularly for 90 days reduces disease activity and damage rapidly and significantly in quiescent, modestly inflammatory morphea with few currently therapeutic options. The COVID-19 pandemic and lockdowns caused difficulties in enrollment, and some patients were lost to follow-up. Due to low final enrollment, the study outcomes may have only an exploratory value, yet they appear impressive. The anti-dystrophic potential of the PDRN A2A adenosine agonist deserves further in-depth exploration.

The clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations in three tertiary referral centers of northern Italy.

Adverse cutaneous reactions after COVID-19 vaccinations have increased, highlighting not only how SARS-CoV-2 infection but also COVID-19 vaccines may induce adverse cutaneous manifestations. We evaluated the clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations, observed consecutively within three large tertiary centers of the Metropolitan City of Milan (Lombardy), comparing our results with the currently available literature. We retrospectively reviewed medical records and skin biopsies of patients diagnosed with mucocutaneous adverse events after COVID-19 vaccinations and followed at three Italian tertiary referral centers in the Metropolitan City of Milan. One hundred twelve patients (77 women and 35 men (112 total); median age, 60 years) have been included in the present study; a cutaneous biopsy was performed in 41 cases (36%). The trunk and arms were the most involved anatomic areas. Autoimmune reactions after COVID-19 vaccinations, urticaria, morbilliform eruptions, and eczematous dermatitis have been the most commonly diagnosed disorders. Compared to the currently available literature, we performed many more histologic examinations, allowing us to make more precise diagnoses. Most of the cutaneous reactions were self-healing and/or responded to topical and systemic steroids and systemic antihistamines, thus not discouraging the general population from carrying out vaccinations, which currently have a good safety profile.

Bullous Pemphigoid Associated With COVID-19 Vaccines: An Italian Multicentre Study.

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.

Paraviral cutaneous manifestations associated to SARS-CoV-2 Omicron variant.

BACKGROUND: The spreading of the SARS-CoV-2 Omicron variant is probably due to its increased transmissibility and ability to escape from neutralising antibodies. Cutaneous manifestations have been reported after infection with the Omicron strain, consisting mainly of generalised urticarial eruption and prickly heat rash, also known as miliaria, that can persist for several days. Here the impact of Omicron SARS-CoV-2 on skin was investigated. METHODS: The case series of 10 patients with SARS-CoV-2 Omicron variant-related cutaneous manifestations were described; moreover, skin derived cells were challenged in vitro with SARS-CoV-2 Omicron variant. RESULTS: The main clinical cutaneous features observed were urticarial lesions lasting more than 24 h, mainly involving the trunk and sometimes extending to the extremities, and miliaria presenting with clusters of small sweat-filled vesicles, sometimes surrounded by slight erythema. HaCaT keratinocytes, BJ fibroblast cell lines and outer root sheath (ORS) keratinocytes were not susceptible to SARS-CoV-2 Omicron variant infection; they also did not present any evident cytopathic effect or modification of cells viability. CONCLUSION: Our findings suggests that, despite the high number of nucleotide mutations in the spike protein of SARS-CoV-2 Omicron variant, responsible to the higher transmissibility of this virus, and the increased reports of cutaneous manifestation in COVID-19 affected patients, the virus is not able to directly infect and damage the keratinocytes and fibroblasts, thus suggesting an indirect virus-induced activation of the immune system as the major pathogenetic driver.

Cutaneous vasculitis and vasculopathy in the era of COVID-19 pandemic.

Cutaneous vasculitides encompass a heterogeneous group of clinicopathological entities, which may occur as single-organ vasculitis of the skin or present as skin-limited variant of systemic vasculitis (i.e., skin-limited ANCA-associated vasculitis), and are triggered by various factors, including infections, drugs and vaccines. The COVID-19 pandemic has challenged us with a variety of both disease- and vaccine-associated skin manifestations, including vasculitis. Among the latter, cutaneous small-vessel vasculitis, previously known as leukocytoclastic vasculitis, seems to be the most reported in either scenario, i.e., natural infection and vaccination. Vasculopathy without true vasculitic changes on histology develops in but a minority of cases, mostly severe/critical COVID-19 patients, and appears to be the result of endothelial injury due to pauci-immune thromboembolic mechanisms. Herein, we provide an overview of the available literature on COVID-19-associated and anti-SARS-CoV-2-vaccine-associated cutaneous vasculitis. Although evidence is mostly limited to isolated reports, with a proportion of cases lacking histopathological confirmation, ample overlap with pre-pandemic forms is shown.

Urticarial vasculitis: Clinical and laboratory findings with a particular emphasis on differential diagnosis.

Urticarial vasculitis (UV) is a rare cutaneous vasculitis of small vessels characterized by recurrent episodes of wheal-like lesions that tend to last more than 24 hours, healing with a residual ecchymotic postinflammatory hyperpigmentation. The histopathologic pattern of UV is that of leukocytoclastic vasculitis, consisting of fibrinoid necrosis of dermal vessels' walls and neutrophil-rich perivascular inflammatory infiltrates. Although its etiopahogenesis remains still undefined, UV is now regarded as an immune complex-driven disease with activation of the complement cascade, leading to exaggerated production of anaphylatoxins that are responsible for neutrophil recruitment and activation. This condition can be categorized into 2 main entities according to serum complement levels: normocomplementemic UV and hypocomplementemic UV, the latter being associated with circulating anti-C1q autoantibodies and possible extracutaneous manifestations. Systemic multiorgan involvement may be seen particularly in syndromic hypocomplementemic UV, also known as McDuffie syndrome. This review summarizes the clinicopathological and laboratory features as well as the underlying pathophysiological mechanisms of UV. A focus on its main differential diagnoses is provided, that is, chronic spontaneous urticaria, bullous pemphigoid, IgA (Henoch-Schönlein purpura) and IgM/IgG immune complex vasculitis, lupus erythematous tumidus, Wells syndrome, erythema multiforme, cutaneous mastocytosis, cryopyrin-associated periodic syndromes, and coronavirus disease 2019-associated and anti-severe acute respiratory syndrome coronavirus 2-vaccine-associated urticarial eruptions.

Bullous Pemphigoid Associated With COVID-19 Vaccines: An Italian Multicentre Study

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA;in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.

Multisystem Inflammatory Syndrome in Children Associated with COVID-19: A Review with an Emphasis on Mucocutaneous and Kawasaki Disease-Like Findings.

BACKGROUND: COronaVIrus Disease 2019 (COVID-19) affects children with less severe symptoms than adults. However, severe COVID-19 paediatric cases are increasingly reported, including patients with Kawasaki disease (KD) or a multisystem inflammatory syndrome (MIS-C) that can present with features resembling KD. SUMMARY: MIS-C is an emerging severe paediatric syndrome associated with COVID-19 that can show overlapping features of KD, KD shock syndrome, and toxic shock syndrome. MIS-C might be an inflammatory disease distinct from KD resulting from an exaggerated immune response. A high prevalence of mucocutaneous manifestations - in addition to gastrointestinal and cardiovascular involvements - was found in MIS-C. The most frequent mucocutaneous findings were conjunctivitis and rash, often described as macular and/or papular or polymorphous. In this article, we present a brief overview of MIS-C with an emphasis on mucocutaneous findings and the relationship with KD.

The clinical spectrum of COVID-19-associated cutaneous manifestations: An Italian multicenter study of 200 adult patients.

BACKGROUND: COVID-19 is associated with a wide range of skin manifestations. OBJECTIVE: To describe the clinical characteristics of COVID-19-associated skin manifestations and explore the relationships among the 6 main cutaneous phenotypes and systemic findings. METHODS: Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical, and histopathologic data of 200 patients with COVID-19-associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. RESULTS: A chilblain-like acral pattern was significantly associated with a younger age (P < .0001) and, after adjusting for age, significantly associated with less severe COVID-19 (P = .0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (P < .0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype was significantly associated with more severe COVID-19 (P = .015), and this significance disappeared after adjustment for age. LIMITATIONS: Laboratory confirmation of COVID-19 was not possible in all cases. CONCLUSIONS: After adjustment for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19-related skin manifestations, although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/pauci-symptomatic COVID-19.

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.

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.