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2.
Hamostaseologie ; 41(5): 387-396, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483190

ABSTRACT

Hypercoagulability and vascular injury, which characterize morbidity in COVID-19 disease, are frequently observed in the skin. Several pathomechanisms, such as inflammation caused by angiotensin-converting enzyme 2-mediated uptake into endothelial cells or SARS-CoV-2-initiated host immune responses, contribute to microthrombus formation and the appearance of vascular skin lesions. Besides pathophysiologic mechanisms observed in the skin, this review describes the clinical appearance of cutaneous vascular lesions and their association with COVID-19 disease, including acro-ischemia, reticular lesions, and cutaneous small vessel vasculitis. Clinicians need to be aware that skin manifestations may be the only symptom in SARS-CoV-2 infection, and that inflammatory and thrombotic SARS-CoV-2-driven processes observed in multiple organs and tissues appear identically in the skin as well.


Subject(s)
COVID-19/complications , SARS-CoV-2 , Skin/blood supply , Angiotensin-Converting Enzyme 2/physiology , Antibodies, Antiphospholipid/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19/pathology , COVID-19/physiopathology , Complement Activation , Cytokines/metabolism , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Microvessels/immunology , Microvessels/pathology , Microvessels/physiopathology , Pandemics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Skin/immunology , Vasculitis/etiology , Vasculitis/pathology , Vasculitis/physiopathology , Virus Internalization
3.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Article in English | MEDLINE | ID: covidwho-1475573

ABSTRACT

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. DNA vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. Here, we report an ultra-low-cost (<1 USD), handheld (<50 g) electroporation system utilizing a microneedle electrode array ("ePatch") for DNA vaccination against SARS-CoV-2. The low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin's epidermis. Antibody responses against SARS-CoV-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the DNA vaccine. Vaccination was well tolerated with mild, transient effects on the skin. This ePatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible DNA vaccination to combat COVID-19, as well as other epidemics.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , Electroporation/instrumentation , SARS-CoV-2 , Vaccines, DNA/administration & dosage , Animals , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Costs and Cost Analysis , Electroporation/economics , Electroporation/methods , Equipment Design , Female , Genes, Reporter , Humans , Mice , Mice, Inbred BALB C , Microelectrodes , Needles , Pandemics/prevention & control , Proof of Concept Study , Rats , Rats, Wistar , Skin/immunology , Skin/metabolism , Transfection , Vaccination/economics , Vaccination/instrumentation , Vaccination/methods , Vaccines, DNA/genetics , Vaccines, DNA/immunology
7.
Am J Dermatopathol ; 43(2): 144-145, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-1263715

ABSTRACT

ABSTRACT: The varying cutaneous and pathological manifestations of coronavirus 2 (SARS-CoV-2 or COVID-19) may have prognostic implications. Acral ischemic findings present with a hypercoagulable state in critically ill COVID-19 patients. Pathologically confirmed varicella-like exanthem and perniosis COVID-19 cases have correlated with paucisymptomatic and asymptomatic patients in previous reports. We present the second case of biopsy-proven COVID-19 infection-induced chilblains (pernio) in a paucisymptomatic patient with a brisk perieccrine lymphocytic response. Based on an antecedent pathological study, we know coronavirus particles have been seen in the eccrine gland associated with a brisk peri-inflammatory response. The prominent perieccrine inflammation is helpful in the diagnosis of COVID-19 infections. Currently, nonischemic pathological findings correlate with a good prognosis based on the paucisymptomatic or asymptomatic nature of their disease courses. Patients presenting with suspected COVID-19 infection-induced chilblains who are paucisymptomatic or asymptomatic should be isolated and immediately tested with polymerase chain reaction (PCR) testing (as there is a delay in diagnosis based on the poor sensitivity of the current rapid test). We continue to stress the importance of early diagnosis and quarantining to prevent spread to the older and immunocompromised patients.


Subject(s)
COVID-19/virology , Chilblains/virology , SARS-CoV-2/pathogenicity , Skin/virology , Biopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/immunology , COVID-19 Testing , Chilblains/diagnosis , Chilblains/immunology , Early Diagnosis , Female , Host-Pathogen Interactions , Humans , Middle Aged , Skin/immunology , Skin/pathology
8.
Front Immunol ; 12: 672808, 2021.
Article in English | MEDLINE | ID: covidwho-1236674

ABSTRACT

The anti-inflammatory role of extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers is of increasing interest with regard to the search for alternatives to synthetic corticosteroids in the therapy of inflammatory disorders. Despite being very effective in many situations the use of synthetic corticosteroids is often controversial, as exemplified in the treatment of influenza patients and only recently in the current COVID-19 pandemic. Exploring the regulatory capacity of locally produced GCs in balancing immune responses in barrier tissues and in pathogenic disorders that lead to symptoms in multiple organs, could provide new perspectives for drug development. Intestine, skin and lung represent the first contact zones between potentially harmful pathogens or substances and the body, and are therefore important sites of immunoregulatory mechanisms. Here, we review the role of locally produced GCs in the regulation of type 2 immune responses, like asthma, atopic dermatitis and ulcerative colitis, as well as type 1 and type 3 infectious, inflammatory and autoimmune diseases, like influenza infection, psoriasis and Crohn's disease. In particular, we focus on the role of locally produced GCs in the interorgan communication, referred to as gut-skin axis, gut-lung axis or lung-skin axis, all of which are interconnected in the pathogenic crosstalk atopic march.


Subject(s)
Glucocorticoids/immunology , Intestinal Mucosa/immunology , Lung/immunology , Skin/immunology , Anti-Inflammatory Agents , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Epithelium/immunology , Glucocorticoids/biosynthesis , Humans , Inflammation , Intestinal Mucosa/pathology , Lung/pathology , Skin/pathology
9.
JAMA Dermatol ; 157(6): 716-720, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1224947

ABSTRACT

Importance: In response to the coronavirus disease 2019 (COVID-19) pandemic, 2 mRNA vaccines (Pfizer-BioNTech and Moderna) received emergency use authorization from the US Food and Drug Administration in December 2020. Some patients in the US have developed delayed localized cutaneous vaccine reactions that have been dubbed "COVID arm." Objective: To describe the course of localized cutaneous injection-site reactions to the Moderna COVID-19 vaccine, subsequent reactions to the second vaccine dose, and to characterize the findings of histopathologic examination of the reaction. Design, Setting, and Participants: This retrospective case series study was performed at Yale New Haven Hospital, a tertiary medical center in New Haven, Connecticut, with 16 patients referred with localized cutaneous injection-site reactions from January 20 through February 12, 2021. Main Outcomes and Measures: We collected each patient's demographic information, a brief relevant medical history, clinical course, and treatment (if any); and considered the findings of a histopathologic examination of 1 skin biopsy specimen. Results: Of 16 patients (median [range] age, 38 [25-89] years; 13 [81%] women), 14 patients self-identified as White and 2 as Asian. The delayed localized cutaneous reactions developed in a median (range) of 7 (2-12) days after receiving the Moderna COVID-19 vaccine. These reactions occurred at or near the injection site and were described as pruritic, painful, and edematous pink plaques. None of the participants had received the Pfizer-BioNTech vaccine. Results of a skin biopsy specimen demonstrated a mild predominantly perivascular mixed infiltrate with lymphocytes and eosinophils, consistent with a dermal hypersensitivity reaction. Of participants who had a reaction to first vaccine dose (15 of 16 patients), most (11 patients) developed a similar localized injection-site reaction to the second vaccine dose; most (10 patients) also developed the second reaction sooner as compared with the first-dose reaction. Conclusions and Relevance: Clinical and histopathologic findings of this case series study indicate that the localized injection-site reactions to the Moderna COVID-19 vaccine are a delayed hypersensitivity reaction. These reactions may occur sooner after the second dose, but they are self-limited and not associated with serious vaccine adverse effects. In contrast to immediate hypersensitivity reactions (eg, anaphylaxis, urticaria), these delayed reactions (dubbed "COVID arm") are not a contraindication to subsequent vaccination.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Drug Eruptions/epidemiology , Injection Site Reaction/epidemiology , Adult , Aged , Aged, 80 and over , Connecticut/epidemiology , Drug Eruptions/diagnosis , Drug Eruptions/drug therapy , Drug Eruptions/immunology , Female , Histamine Antagonists/therapeutic use , Humans , Injection Site Reaction/diagnosis , Injection Site Reaction/drug therapy , Injection Site Reaction/immunology , Male , Middle Aged , Retrospective Studies , Skin/immunology , Skin/pathology
10.
Adv Drug Deliv Rev ; 171: 164-186, 2021 04.
Article in English | MEDLINE | ID: covidwho-1062195

ABSTRACT

The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions. Microarray patches (MAPs) are an attractive intracutaneous biocargo delivery system that enables safe, reproducible, and controlled administration of vaccine components (antigens, with or without adjuvants) to defined skin microenvironments. This review describes the structure of the SARS-CoV-2 virus and relevant antigenic targets for vaccination, summarizes key concepts of skin immunobiology in the context of prophylactic immunization, and presents an overview of MAP-mediated cutaneous vaccine delivery. Concluding remarks on MAP-based skin immunization are provided to contribute to the rational development of safe and effective MAP-delivered vaccines against emerging infectious diseases, including COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Drug Development/trends , SARS-CoV-2/immunology , Skin/immunology , Transdermal Patch/trends , Administration, Cutaneous , COVID-19/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/metabolism , Drug Development/methods , Humans , Immunity, Innate/drug effects , Immunity, Innate/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Skin/drug effects , Skin/metabolism
12.
Am J Dermatopathol ; 43(5): 342-348, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1010666

ABSTRACT

ABSTRACT: The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading throughout the world. The study describes 12 patients with SARS-CoV-2 pneumonia, who developed an acute erythematous rash with nonfollicular pinhead-sized pustules, without mucosal involvement. The clinical differential diagnosis was viral rash, acute generalized exanthematous pustulosis (AGEP), or multiform erythema. computed tomography with a diagnosis of interstitial pneumonia and a respiratory tract sample positive for SARS-CoV-2 in a reverse transcriptase polymerase chain reaction assay. Patients had signs of respiratory distress and were treated with hydroxychloroquine, darunavir, ritonavir, heparin, ceftriaxone, and azithromycin. Punch biopsies showed subcorneal pustules typical of AGEP. Dermal microvascular injury and thrombosis as described in skin damage by SARS-CoV-2 infection was not observed. The direct immunofluorescence for IgG, IgA, IgM, and C3 was negative in 8 patients investigated. A polymerase chain reaction for RNA SARS-CoV-2 performed on frozen skin was negative in 5 of 6 patients. Most of our patients were treated with systemic corticosteroids. After some days (4-10), the diffuse erythema and pustules had improved. AGEP is classified as a severe cutaneous adverse reaction, provoked by drugs and acute infections. Characteristically, removal of the offending agent leads to spontaneous resolution typically in less than 15 days. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. Cutaneous adverse reactions to drugs are common and are major health problems worldwide causing considerable costs for health care systems. We suggest that in the patients with AGEP during SARS-CoV-2 pneumonia, viral infection is a risk factor for developing drug reaction.


Subject(s)
Acute Generalized Exanthematous Pustulosis/etiology , Antiviral Agents/adverse effects , COVID-19/drug therapy , Skin/drug effects , Acute Generalized Exanthematous Pustulosis/drug therapy , Acute Generalized Exanthematous Pustulosis/immunology , Acute Generalized Exanthematous Pustulosis/virology , Adrenal Cortex Hormones/therapeutic use , Aged , Aged, 80 and over , Biopsy , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , COVID-19 Nucleic Acid Testing , Diagnosis, Differential , Female , Host-Pathogen Interactions , Humans , Male , Middle Aged , Predictive Value of Tests , Risk Factors , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Skin/immunology , Skin/pathology , Skin/virology , Treatment Outcome
15.
Lab Invest ; 101(3): 274-279, 2021 03.
Article in English | MEDLINE | ID: covidwho-968368

ABSTRACT

Disorders involving injury to tissue stem cells that ensure normal tissue homeostasis and repair have potential to show unusually devastating clinical consequences. Acute graft-versus-host disease (aGVHD) is one condition where relatively few cytotoxic immune cells target skin stem cells to produce significant morbidity and mortality. By analogy, SARS-CoV-2 is a vector that initially homes to pulmonary stem cells that preferentially express the ACE2 receptor, thus potentially incurring similarly robust pathological consequences. In older individuals, stem cell number and/or function become depleted due to pathways independent of disease-related injury to these subpopulations. Accordingly, pathologic targeting of stem cells in conditions like aGVHD and COVID-19 infection where these cells are already deficient due to the aging process may have dire consequences in elderly individuals. A hypothesis is herein advanced that, as with aGVHD, lung stem cell targeting is a potential co-factor in explaining age-related severity of COVID-19 infection.


Subject(s)
COVID-19/etiology , Graft vs Host Disease/etiology , SARS-CoV-2 , Age Factors , Aging/immunology , Aging/pathology , COVID-19/immunology , COVID-19/pathology , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Humans , Lung/immunology , Lung/pathology , Models, Biological , Risk Factors , SARS-CoV-2/pathogenicity , Skin/immunology , Skin/pathology , Stem Cells/immunology , Stem Cells/pathology
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