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Article ; Online: Symbiotic Beams: Using Non-microscopy Electron Sources to Bring LPTEM's Puzzles into Better Focus.

Gibson, Wyeth / Mulvey, Justin / Patterson, Joe

Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada

2023 Volume 29, Issue Supplement_1, Page(s) 1491–1492

Language	English
Publishing date	2023-08-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1385710-1
ISSN	1435-8115 ; 1431-9276
ISSN (online)	1435-8115
ISSN	1431-9276
DOI	10.1093/micmic/ozad067.766
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Article ; Online: WITHDRAWN: A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients.

Mulvey, J Justin / Magro, Cynthia M / Ma, Lucy X / Nuovo, Gerard J / Baergen, Rebecca N

publication RETRACTED

Annals of diagnostic pathology

2020 Volume 46, Page(s) 151529

Keywords	covid19
Language	English
Publishing date	2020-04-25
Publishing country	United States
Document type	Journal Article ; Retracted Publication
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2020.151529
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Article ; Online: The skin as a critical window in unveiling the pathophysiologic principles of COVID-19.

Magro, Cynthia / Nuovo, Gerard / Mulvey, J Justin / Laurence, Jeffrey / Harp, Joanna / Crowson, A Neil

Clinics in dermatology

2021 Volume 39, Issue 6, Page(s) 934–965

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	COVID-19/immunology ; COVID-19/physiopathology ; COVID-19 Vaccines ; Cytokines ; Humans ; Skin Diseases/immunology ; Skin Diseases/virology ; Spike Glycoprotein, Coronavirus
Chemical Substances	COVID-19 Vaccines ; Cytokines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1064149-x
ISSN	1879-1131 ; 0738-081X
ISSN (online)	1879-1131
ISSN	0738-081X
DOI	10.1016/j.clindermatol.2021.07.001
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Article ; Online: Historical ABO blood group discrepancy: a blessing in disguise to unravel a medical identity theft.

Mulvey, J Justin / Matnani, Rahul / Cushing, Melissa M

Transfusion

2017 Volume 57, Issue 4, Page(s) 1096–1097

Language	English
Publishing date	2017-04
Publishing country	United States
Document type	Letter
ZDB-ID	208417-x
ISSN	1537-2995 ; 0041-1132
ISSN (online)	1537-2995
ISSN	0041-1132
DOI	10.1111/trf.14052
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Article ; Online: Analysis of complement deposition and viral RNA in placentas of COVID-19 patients.

Mulvey, J Justin / Magro, Cynthia M / Ma, Lucy X / Nuovo, Gerard J / Baergen, Rebecca N

Annals of diagnostic pathology

2020 Volume 46, Page(s) 151530

Abstract: COVID-19, the disease caused by the novel Coronavirus, SARS-CoV-2, is increasingly being recognized as a systemic thrombotic and microvascular injury syndrome that may have its roots in complement activation. We had the opportunity to study the placental ...

Abstract	COVID-19, the disease caused by the novel Coronavirus, SARS-CoV-2, is increasingly being recognized as a systemic thrombotic and microvascular injury syndrome that may have its roots in complement activation. We had the opportunity to study the placental pathology of five full-term births to COVID-19 patients. All five exhibited histology indicative of fetal vascular malperfusion characterized by focal avascular villi and thrombi in larger fetal vessels. Vascular complement deposition in the placentas was not abnormal, and staining for viral RNA and viral spike protein was negative. While all cases resulted in healthy, term deliveries, these findings indicate the systemic nature of COVID-19 infection. The finding of vascular thrombosis without complement deposition may reflect the systemic nature of COVID-19's procoagulant effects unrelated to systemic complement activation.
MeSH term(s)	Betacoronavirus/genetics ; COVID-19 ; Coronavirus Infections/complications ; Coronavirus Infections/virology ; Female ; Humans ; Pandemics ; Placenta/virology ; Pneumonia, Viral/complications ; Pneumonia, Viral/virology ; Pregnancy ; RNA, Viral/genetics ; SARS-CoV-2 ; Thrombosis/etiology
Chemical Substances	RNA, Viral
Keywords	covid19
Language	English
Publishing date	2020-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2020.151530
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Article ; Online: Resolution of a steroid-resistant, hypereosinophilic immune diathesis with mepolizumab and concomitant amelioration of a mixed thrombotic microangiopathy.

Mulvey, J Justin / Magro, Cynthia / Chadburn, Amy

Blood cells, molecules & diseases

2017 Volume 69, Page(s) 38–42

Abstract: The anaphylatoxins produced by an unbridled complement cascade in atypical hemolytic uremic syndrome (aHUS) can alter the leukocyte environment in tissues and peripheral blood, causing clinically significant eosinophilia. While the membrane attack ... ...

Abstract	The anaphylatoxins produced by an unbridled complement cascade in atypical hemolytic uremic syndrome (aHUS) can alter the leukocyte environment in tissues and peripheral blood, causing clinically significant eosinophilia. While the membrane attack complex and C5a anaphlatoxin can be suppressed with anti-C5 biologics, the production of C3a is still capable of driving a destructive hypereosinophilic syndrome in spite of anticomplement therapy. The side-effects of glucocorticoids in treating hypereosinophilic syndrome limit their therapeutic index in long-term treatment and this behooves the use of alternative strategies. While use of the anti-IL-5 antibody, mepolizumab, has been reported for treatment of primary hypereosinophilic syndromes off-label, its usage in the setting of complement-driven thrombotic microangiopathy has not been attempted. We report mepolizumab's rapid resolution of a glucocorticoid-resistant hypereosinophilic syndrome that caused multi-organ dysfunction in a patient with a complex immune diathesis. The patient's long standing TTP/aHUS disease activity, shown to have direct correlation with his eosinophil count, improved with anti-IL-5 therapy, suggesting a reciprocal enhancement between the conditions.
MeSH term(s)	Adult ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biomarkers ; Biopsy ; Bone Marrow/pathology ; Disease Susceptibility/immunology ; Drug Resistance ; Eosinophils/immunology ; Eosinophils/pathology ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Male ; Steroids/pharmacology ; Steroids/therapeutic use ; Thrombotic Microangiopathies/diagnosis ; Thrombotic Microangiopathies/drug therapy ; Thrombotic Microangiopathies/immunology ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal, Humanized ; Biomarkers ; Immunoglobulins, Intravenous ; Steroids ; mepolizumab (90Z2UF0E52)
Language	English
Publishing date	2017-05-02
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2017.04.008
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Article ; Online: Analysis of complement deposition and viral RNA in placentas of COVID-19 patients

Mulvey, J. Justin / Magro, Cynthia M. / Ma, Lucy X. / Nuovo, Gerard J. / Baergen, Rebecca N.

Annals of Diagnostic Pathology

2020 Volume 46, Page(s) 151530

Keywords	Pathology and Forensic Medicine ; General Medicine ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2020.151530
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Article ; Online: WITHDRAWN

Mulvey, J. Justin / Magro, Cynthia M. / Ma, Lucy X. / Nuovo, Gerard J. / Baergen, Rebecca N.

Annals of Diagnostic Pathology

A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients

2020 Volume 46, Page(s) 151529

Keywords	Pathology and Forensic Medicine ; General Medicine ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2020.151529
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Article ; Online: Cutaneous, Purpuric Painful Nodules Upon Addition of Ibrutinib to RCVP Therapy in a CLL Patient: A Distinctive Reaction Pattern Reflecting Iatrogenic Th2 to Th1 Milieu Reversal.

Mulvey, Joseph Justin / Nuovo, Gerard J / Magro, Cynthia M

The American Journal of dermatopathology

2016 Volume 38, Issue 7, Page(s) 492–498

Abstract: A 70-year-old white man with stage C chronic lymphocytic leukemia who was being successfully treated with ibrutinib and rituximab developed bilateral, purpuric, painful cutaneous nodules. Biopsies of these nodules did not reveal the usual Th2 milieu of ... ...

Abstract	A 70-year-old white man with stage C chronic lymphocytic leukemia who was being successfully treated with ibrutinib and rituximab developed bilateral, purpuric, painful cutaneous nodules. Biopsies of these nodules did not reveal the usual Th2 milieu of chronic lymphocytic leukemia but instead exhibited a Th1-rich lymphocytic infiltrate with resultant neutrophil and granulomatous inflammation. The eruption resolved with drug cessation emphasizing the potential importance of this drug in treating conditions associated with Th2 dysregulation.
MeSH term(s)	Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; B7-H1 Antigen/analysis ; Biomarkers, Tumor/analysis ; Biopsy ; Drug Administration Schedule ; Drug Eruptions/etiology ; Drug Eruptions/immunology ; Drug Eruptions/pathology ; Humans ; Iatrogenic Disease ; Immunoglobulins, Intravenous/administration & dosage ; Interleukin-10/analysis ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Male ; Neoplasm Staging ; Phenotype ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Pyrazoles/administration & dosage ; Pyrazoles/adverse effects ; Pyrimidines/administration & dosage ; Pyrimidines/adverse effects ; Rituximab/administration & dosage ; Skin/drug effects ; Skin/immunology ; Skin/pathology ; Th1 Cells/drug effects ; Th1 Cells/immunology ; Th2 Cells/drug effects ; Th2 Cells/immunology ; Time Factors ; Treatment Outcome
Chemical Substances	B7-H1 Antigen ; Biomarkers, Tumor ; CD274 protein, human ; IL10 protein, human ; Immunoglobulins, Intravenous ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; Interleukin-10 (130068-27-8) ; ibrutinib (1X70OSD4VX) ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2016-03-30
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	448469-1
ISSN	1533-0311 ; 0193-1091
ISSN (online)	1533-0311
ISSN	0193-1091
DOI	10.1097/DAD.0000000000000441
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Article ; Online: Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage.

Laurence, Jeffrey / Nuovo, Gerard / Racine-Brzostek, Sabrina E / Seshadri, Madhav / Elhadad, Sonia / Crowson, A Neil / Mulvey, J Justin / Harp, Joanna / Ahamed, Jasimuddin / Magro, Cynthia

The American journal of pathology

2022 Volume 192, Issue 9, Page(s) 1282–1294

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Acute Kidney Injury ; Antiviral Agents ; Biopsy ; COVID-19 ; Complement Membrane Attack Complex ; Humans ; Interferon Type I ; Mannose-Binding Protein-Associated Serine Proteases ; Respiratory Distress Syndrome ; Spike Glycoprotein, Coronavirus ; Thrombosis
Chemical Substances	Antiviral Agents ; Complement Membrane Attack Complex ; Interferon Type I ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; MASP2 protein, human (EC 3.4.21.-) ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-)
Language	English
Publishing date	2022-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2022.05.006
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