Development of a Skin-Directed Scoring System for Stevens-Johnson Syndrome and Epidermal Necrolysis: A Delphi Consensus Exercise.

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings: In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance: This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

A dermatologic assessment of 101 mpox (monkeypox) cases from 13 countries during the 2022 outbreak: Skin lesion morphology, clinical course, and scarring.

BACKGROUND: In the 2022 mpox (monkeypox) outbreak, 79,000 global cases have been reported. Yet, limited dermatologic data have been published regarding lesion morphology and progression. OBJECTIVE: The objective of this study was to characterize skin lesion morphology, symptomatology, and outcomes of mpox infection over time. METHODS: The American Academy of Dermatology/International League of Dermatological Societies Dermatology COVID-19, Mpox, and Emerging Infections Registry captured deidentified patient cases of mpox entered by health care professionals. RESULTS: From August 4 to November 13, 2022, 101 cases from 13 countries were entered, primarily by dermatologists (92%). Thirty-nine percent had fewer than 5 lesions. In 54% of cases, skin lesions were the first sign of infection. In the first 1-5 days of infection, papules (36%), vesicles (17%), and pustules (20%) predominated. By days 6-10, pustules (36%) were most common, followed by erosions/ulcers (27%) and crusts/scabs (24%). Crusts/scabs were the predominant morphology after day 11. Ten cases of morbilliform rash were reported. Scarring occurred in 13% of the cases. LIMITATIONS: Registry-reported data cannot address incidence. There is a potential reporting bias from the predilection to report cases with greater clinical severity. DISCUSSION: These findings highlight differences in skin findings compared to historical outbreaks, notably the presence of skin lesions prior to systemic symptoms and low overall lesion counts. Scarring emerged as a major possible sequela.

Azathioprine hypersensitivity syndrome manifesting as subcutaneous Sweet syndrome and acute pancreatitis.

Azathioprine (AZA) is a commonly used immunosuppressive therapy that has been implicated in a number of cutaneous and systemic inflammatory reactions. Initiation of AZA has been associated with a hypersensitivity syndrome manifesting as acute pancreatitis and Sweet syndrome. Subcutaneous Sweet syndrome is a rare variant of Sweet syndrome where the dominant localization of inflammation is within the subcutaneous fat; it is commonly associated with underlying myeloproliferative disease. However, it has not been reported in the literature as a cutaneous manifestation of AZA hypersensitivity syndrome. We present a unique case of acute pancreatitis and biopsy-proven subcutaneous Sweet syndrome following the initiation of AZA with resolution upon discontinuation.

Mammalian Target of Rapamycin Pathway Assessment in Antiphospholipid Antibody-Positive Patients with Livedo.

OBJECTIVE: In antiphospholipid antibody (aPL) nephropathy, activation of the mammalian target of rapamycin (mTOR) contributes to endothelial cell proliferation, a key finding of aPL microvascular disease. Here, we examined mTOR activation in the skin of aPL-positive patients with livedo. METHODS: Three patient groups with livedo were studied: (1) persistently aPL-positive with systemic lupus erythematosus (SLE); (2) persistently aPL-positive without SLE; and (3) aPL-negative SLE (control). After collecting aPL-related medical history, two 5-mm skin biopsies of livedo were performed on each patient: (1) peripheral (erythematous-violaceous lesion); and (2) central (nonviolaceous area). We stained specimens for phosphorylated protein kinase B (p-AKT) and phosphorylated S6 ribosomal protein (p-S6RP) as mTOR activity markers, CD31 to identify endothelial cells, and Ki-67 to show cellular proliferation. We counted cells in the epidermis and compared mTOR-positive cell counts between peripheral and central samples, and between patient groups, using Freidman test and Wilcoxon signed-rank test. RESULTS: Ten patients with livedo reticularis were enrolled: 4 aPL-positive without SLE (antiphospholipid syndrome [APS] classification met, n = 3), 4 aPL-positive SLE (APS classification met, n = 3), and 2 aPL-negative SLE (control). In all aPL-positive patients, epidermal p-AKT and p-S6RP staining were significantly increased in both peripheral and central skin samples when compared to aPL-negative SLE controls; both were more pronounced in the lower basal layers of epidermis. CONCLUSION: Our study demonstrates increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE, with more prominent activity in the lower basal layers of the epidermis. These findings may serve as a basis for further investigating the mTOR pathway in aPL-positive patients.

Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage.

Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I-driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I-based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre-COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.

The skin as a critical window in unveiling the pathophysiologic principles of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is a single-stranded RNA virus whose sequence is known. COVID-19 is associated with a heterogeneous clinical phenotype ranging from asymptomatic to fatal disease. It appears that access to nasopharyngeal respiratory epithelia expressing angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV-2, is followed by viral replication in the pulmonary alveolar septal capillary bed. We have demonstrated in earlier studies that incomplete viral particles, termed pseudovirions, dock to deep subcutaneous and other vascular beds, potentially contributing to the prothrombotic state and systemic complement activation that characterizes severe and critical COVID-19. A variety of skin eruptions have been described in the setting of SARS-CoV-2 infection and more recently, after COVID-19 vaccination. The vaccines deliver a laboratory-synthesized mRNA that encodes a protein that is identical to the spike glycoprotein of SARS-CoV-2, allowing the production of immunogenic spike glycoprotein that will then elicit T cell and B cell adaptive immune responses. In this contribution, we review an array of cutaneous manifestations of COVID-19 that provide an opportunity to study critical pathophysiologic mechanisms that underlie all clinical facets of COVID-19, ranging from asymptomatic/mild to severe and critical COVID-19. We classify cutaneous COVID-19 according to underlying pathophysiologic principles. In this regard we propose three main pathways: (1) complement mediated thrombotic vascular injury syndromes deploying the alternative and mannan binding lectin pathways and resulting in the elaboration of cytokines like interleukin 6 from endothelium in the setting of severe and critical COVID-19 and (2) the robust T cell and type I interferon-driven inflammatory and (3) humoral-driven immune complex mediated vasculitic cutaneous reactions observed with mild and moderate COVID-19. Presented are novel data on cutaneous vaccine reactions that manifest a clinical and morphologic parallel with similar eruptions observed in patients with mild and moderate COVID-19 and in some cases represent systemic eczematoid hypersensitivity reactions to a putative vaccine-based antigen versus unmasking subclinical hypersensitivity due to immune enhancing effects of the vaccine. Finally, we demonstrate for the first time the localization of human synthesized spike glycoprotein after the COVID-19 vaccine to the cutaneous and subcutaneous vasculature confirming the ability of SARS-CoV-2 spike glycoprotein to bind endothelium in the absence of intact virus.

Cutaneous Manifestations of COVID-19 in the Inpatient Setting.

Cutaneous findings have increasingly been reported in patients with coronavirus disease 2019 (COVID-19). This review discusses associated skin findings in patients with COVID-19 in the inpatient setting, ranging from vasculopathy-related lesions associated with high hospitalization rate and poor prognosis to inflammatory vesicular and urticarial eruptions that are rarely associated with prolonged hospitalization. We also discuss other reported COVID-19 cutaneous manifestations such as Sweet's syndrome, purpuric eruptions, and Multisystem Inflammatory Syndrome in Children. Although the relationship between dermatologic changes and COVID-19 disease progression is not fully elucidated, familiarity with cutaneous manifestations is valuable for physicians caring for patients hospitalized with COVID-19 and may help improve disease recognition and care.

Cutaneous Manifestations of COVID-19: Characteristics, Pathogenesis, and the Role of Dermatology in the Pandemic.

Cutaneous manifestations of COVID-19-SARS-CoV-2-are common and varied. Morbilliform, vesicular, and urticarial eruptions may be nonspecific initial features of the disease. Chilblainlike lesions on the fingers or toes typically occur as part of a resolution phase, signifying a milder course, whereas livedoid lesions and retiform purpura are associated with coaguloapthy and more severe disease. Additionally, a severe Kawasaki-like multisystem inflammatory syndrome rarely is seen in children. This diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologic responses to SARS-CoV-2 and may inform disease pathophysiology.

Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease.

BACKGROUND: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data. METHODS: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic. RESULTS: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone. LIMITATIONS: Selection bias and single-center nature. CONCLUSIONS: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions.

Docked severe acute respiratory syndrome coronavirus 2 proteins within the cutaneous and subcutaneous microvasculature and their role in the pathogenesis of severe coronavirus disease 2019.

The purpose of this study was to examine the deltoid skin biopsy in twenty-three patients with coronavirus disease 2019 (COVID-19), most severely ill, for vascular complement deposition and correlate this with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA and protein localization and ACE2 expression. Deltoid skin microvascular complement screening has been applied to patients with various systemic complement-mediated microvascular syndromes, best exemplified by atypical hemolytic uremic syndrome. In 21 of 23 cases, substantial microvascular deposition of complement components was identified. The two patients without significant complement deposition included one patient with moderate disease and a severely ill patient who although on a ventilator for a day was discharged after 3 days. The dominant microvascular complement immunoreactant identified was the terminal membranolytic attack complex C5b-9. Microvascular complement deposition strongly colocalized in situ with the SARS-CoV-2 viral proteins including spike glycoproteins in the endothelial cells as well as the viral receptor ACE2 in lesional and nonlesional skin; viral RNA was not evident. Microvascular SARS-CoV-2 viral protein, complement, and ACE2 expression was most conspicuous in the subcutaneous fat. Although the samples from severely ill patients with COVID-19 were from grossly normal skin, light microscopically focal microvascular abnormalities were evident that included endothelial cell denudement, basement membrane zone reduplication, and small thrombi. It is concluded that complement activation is common in grossly normal skin, especially in the subcutaneous fat which may provide a link between severe disease and obesity, in people with severe COVID-19, and the strong colocalization with the ACE2 receptor and viral capsid proteins without viral RNA suggests that circulating viral proteins (ie, pseudovirions) may dock onto the endothelial of these microvessels and induce complement activation.

Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19.

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.

The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations. OBJECTIVE: To characterize the diversity of cutaneous manifestations of COVID-19 and facilitate understanding of the underlying pathophysiology. METHODS: Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies. RESULTS: The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients. LIMITATIONS: We cannot estimate incidence or prevalence. Confirmation bias is possible. CONCLUSIONS: This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were nonspecific, whereas others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology.

Navigating immunosuppression in a pandemic: A guide for the dermatologist from the COVID Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists.

Dermatologists treating immune-mediated skin disease must now contend with the uncertainties associated with immunosuppressive use in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Although the risk of infection with many commonly used immunosuppressive agents remains low, direct data evaluating the safety of such agents in coronavirus disease 2019 (COVID-19) are scarce. This article reviews and offers guidance based on currently available safety data and the most recent COVID-19 outcome data in patients with immune-mediated dermatologic disease. The interdisciplinary panel of experts emphasizes a stepwise, shared decision-making approach in the management of immunosuppressive therapy. The goal of this article is to help providers minimize the risk of disease flares while simultaneously minimizing the risk of iatrogenic harm during an evolving pandemic.

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.