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1.
Viruses ; 13(4)2021 04 08.
Article in English | MEDLINE | ID: covidwho-1178429

ABSTRACT

Vascular changes represent a characteristic feature of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leading to a breakdown of the vascular barrier and subsequent edema formation. The aim of this study was to provide a detailed characterization of the vascular alterations during SARS-CoV-2 infection and to evaluate the impaired vascular integrity. Groups of ten golden Syrian hamsters were infected intranasally with SARS-CoV-2 or phosphate-buffered saline (mock infection). Necropsies were performed at 1, 3, 6, and 14 days post-infection (dpi). Lung samples were investigated using hematoxylin and eosin, alcian blue, immunohistochemistry targeting aquaporin 1, CD3, CD204, CD31, laminin, myeloperoxidase, SARS-CoV-2 nucleoprotein, and transmission electron microscopy. SARS-CoV-2 infected animals showed endothelial hypertrophy, endothelialitis, and vasculitis. Inflammation mainly consisted of macrophages and lower numbers of T-lymphocytes and neutrophils/heterophils infiltrating the vascular walls as well as the perivascular region at 3 and 6 dpi. Affected vessels showed edema formation in association with loss of aquaporin 1 on endothelial cells. In addition, an ultrastructural investigation revealed disruption of the endothelium. Summarized, the presented findings indicate that loss of aquaporin 1 entails the loss of intercellular junctions resulting in paracellular leakage of edema as a key pathogenic mechanism in SARS-CoV-2 triggered pulmonary lesions.


Subject(s)
Aquaporin 1/metabolism , COVID-19/pathology , Endothelial Cells/metabolism , Endothelial Cells/ultrastructure , Inflammation/pathology , Animals , Blood Vessels/ultrastructure , Disease Models, Animal , Immunohistochemistry , Lung/blood supply , Lung/ultrastructure , Lung/virology , Mesocricetus , SARS-CoV-2 , Vasculitis/pathology , Vasculitis/virology
2.
Atherosclerosis ; 322: 39-50, 2021 04.
Article in English | MEDLINE | ID: covidwho-1083495

ABSTRACT

BACKGROUND AND AIMS: The new coronavirus disease (COVID-19) is a systemic disease. Mounting evidence depict signs and symptoms involving multiple organs, most of which supported by pathological data. A plausible link to these manifestations is vascular and endothelial dysfunction/damage. However, much of the current knowledge relies on opinion and incipient evidence. We aim to objectively appraise current evidence on the association between COVID-19 and vascular disease, specifically endotheliitis and vasculitis. METHODS: Two researchers independently entered the search terms COVID-19 OR SARS-CoV-2 AND vasculitis, endotheliitis OR endothelium in the following online platforms: MedRxiv and LitCovid (PubMed). The search period was set from November 1, 2019 to August 28, 2020. Manuscripts with unavailable full texts, not in English, mainly on pre-clinical data, presenting only study designs or not directly related to the topics of this review were excluded. Retrospective and prospective studies, especially longitudinal ones, were given priority to the purpose of this review. Since there was paucity of prospective controlled evidence, case reports/series were also considered. RESULTS: A total of 318 manuscripts were initially found. Sixty-seven (21%) were excluded: 59 (18.5%) met exclusion criteria and 8 (2.5%) were duplicates. One hundred and forty-two manuscripts (44,6%) did not provide original data and were also excluded: 35 (11%) were comments, 108 (33.9%) reviews; 1 (0.3%) position paper. One hundred and seven (33.6%) studies were considered for the present scoping review: 81 (25,5%) case reports/series; 18 (5.7%) prospective; 8 (2.5%) retrospective. Viral inclusions in endothelial cells, mononuclear cell infiltrates in the intima of small vessels and markers of endothelial cell apoptosis were demonstrated. Specificities of COVID-19 may lead to diverse vascular manifestations in different levels of the vascular bed. CONCLUSIONS: Evidence indicates that COVID-19 targets vasculature and endothelium. However, high quality data is still lacking and studies with prospective designs and appropriately matched controls are needed.


Subject(s)
COVID-19/complications , Endothelium, Vascular/pathology , Inflammation/virology , Vasculitis/virology , Endothelial Cells/virology , Humans , Prospective Studies , Retrospective Studies
4.
Br J Dermatol ; 183(4): 729-737, 2020 10.
Article in English | MEDLINE | ID: covidwho-1081133

ABSTRACT

BACKGROUND: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established. OBJECTIVES: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue. METHODS: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one. RESULTS: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. CONCLUSIONS: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.


Subject(s)
Chilblains/virology , Coronavirus Infections/complications , Endothelium, Vascular/pathology , Pneumonia, Viral/complications , Skin Diseases/virology , Vasculitis/virology , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , Biopsy , COVID-19 , Chilblains/pathology , Child , Coronavirus Infections/pathology , Coronavirus Infections/virology , Endothelial Cells/pathology , Endothelial Cells/ultrastructure , Endothelial Cells/virology , Endothelium, Vascular/virology , Humans , Immunohistochemistry , Microscopy, Electron , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Skin/blood supply , Skin/pathology , Skin/virology , Skin Diseases/pathology , Vasculitis/pathology
5.
Br J Haematol ; 193(1): 43-51, 2021 04.
Article in English | MEDLINE | ID: covidwho-1066629
6.
Int J Dermatol ; 60(5): 547-553, 2021 May.
Article in English | MEDLINE | ID: covidwho-1061116

ABSTRACT

INTRODUCTION: Since COVID-19 has become a pandemic, extensive literature has been produced. The commonest symptoms of COVID-19 disease are fever, cough, anosmia, and lymphocytopenia. However, other apparently less common clinical symptoms have been described, including skin lesions. We conducted a systematic review to evaluate skin involvement in COVID-19. METHODS: The authors performed a systematic review of literature, in accordance with the Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA). The search was reiterated until May 06, 2020. RESULTS: Overall, 1593 patients (M/F ratio: 1 : 9) with suspect of COVID-19 were examined. The mean age was 37.8 (range 0-91) years. Among the analyzed patients, 84 (5.3%) were pediatrics (<18 years). Chilblains are very common among skin lesions and represent almost half of all skin lesions reported (46%); in 75% of patients with cutaneous manifestation, the latter presented before other typical clinical manifestation of COVID-19. Vasculitis or thrombosis was identified in almost 70% of patients who suffered from skin manifestations. CONCLUSION: The present study highlights the importance of skin involvement in COVID-19. Limbs should be examined to eventually foresee the onset of further typical symptoms. Chilblains can be considered typical features. Studies with higher scientific evidence are required.


Subject(s)
COVID-19/complications , Skin Diseases/virology , Chilblains/epidemiology , Chilblains/virology , Humans , Pandemics , Skin Diseases/epidemiology , Thrombosis/epidemiology , Thrombosis/virology , Vasculitis/epidemiology , Vasculitis/virology
7.
J Thromb Haemost ; 19(2): 574-581, 2021 02.
Article in English | MEDLINE | ID: covidwho-939789

ABSTRACT

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Immunity, Innate , Influenza, Human/immunology , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , Vasculitis/immunology , COVID-19/diagnosis , COVID-19/virology , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Influenza, Human/diagnosis , Influenza, Human/virology , Lung/pathology , Lung/virology , Neutrophils/virology , Predictive Value of Tests , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Vasculitis/virology
8.
Adv Clin Chem ; 104: 299-340, 2021.
Article in English | MEDLINE | ID: covidwho-893387

ABSTRACT

Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.


Subject(s)
Biomarkers/blood , COVID-19/complications , Cryoglobulinemia/blood , Cryoglobulins/analysis , Hepatitis C/physiopathology , Animals , Autoantibodies/blood , Chemical Precipitation , Cryoglobulinemia/therapy , Cryoglobulins/chemistry , Hepatitis C/blood , Humans , Vasculitis/virology
9.
Inflamm Res ; 69(12): 1181-1189, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-754698

ABSTRACT

BACKGROUND: COVID-19-associated coagulopathy (CAC) characterized by the elevated D-dimer without remarkable changes of other global coagulation markers is associated with various thrombotic complications and disease severity. The purpose of this review is to elucidate the pathophysiology of this unique coagulopathy. METHODS: The authors performed online search of published medical literature through PubMed using the MeSH (Medical Subject Headings) term "COVID-19," "SARS-CoV-2," "coronavirus," "coagulopathy," and "thrombus." Then, selected 51 articles that closely relevant to coagulopathy in COVID-19. RESULTS: The primary targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the pneumocytes, immune cells, and vascular endothelial cells. The alveolar damage and the pulmonary microvascular thrombosis are the major causes of acute lung injury in COVID-19. The endotheliopathy that occurs is due to direct SARS-CoV-2 infection and activation of other pathways that include the immune system and thromboinflammatory responses leading to what is termed CAC. As a result, both microvascular and macrovascular thrombotic events occur in arterial, capillary, venule, and large vein vascular beds to produce multiorgan dysfunction and thrombotic complications. In addition to the endothelial damage, SARS-CoV-2 also can cause vasculitis and presents as a systemic inflammatory vascular disease. Clinical management of COVID-19 includes anticoagulation but novel therapies for endotheliopathy, hypercoagulability, and vasculitis are needed. CONCLUSION: The endotheliopathy due to direct endothelial infection with SARS-COV-2 and the indirect damage caused by inflammation play the predominant role in the development of CAC. The intensive control of thromboinflammation is necessary to improve the outcome of this highly detrimental contagious disease.


Subject(s)
Betacoronavirus , Blood Coagulation Disorders/virology , Coronavirus Infections/complications , Endothelium, Vascular/physiopathology , Pneumonia, Viral/complications , Vasculitis/virology , Blood Coagulation Disorders/drug therapy , COVID-19 , Coronavirus Infections/physiopathology , Endothelial Cells , Fibrin Fibrinogen Degradation Products/analysis , Humans , Lung/blood supply , Microvessels , Pandemics , Pneumonia, Viral/physiopathology , PubMed , Pulmonary Embolism , SARS-CoV-2 , Thrombosis/virology
10.
Am J Case Rep ; 21: e925779, 2020 Aug 13.
Article in English | MEDLINE | ID: covidwho-713485

ABSTRACT

BACKGROUND Coronavirus disease 2019 (COVID-19) infection commonly presents as fever, cough, and shortness of breath in adults. Children are thought to have milder respiratory symptoms and to recover more quickly. We describe a new presentation of COVID-19 infection in children consisting of multisystem inflammation with decreased left ventricular function and evidence of lung disease. CASE REPORT Three children presented with fever, conjunctivitis, dry and cracked lips, rash, and/or cervical lymphadenopathy for at least 5 days. Two of these children required mechanical ventilation, and 1 of the 2 needed extracorporeal membrane oxygenation (ECMO) to support cardiorespiratory function. All of these children had moderate to severe hyponatremia and lymphopenia, which is usually seen in COVID-19. They were treated with intravenous immunoglobulin and high-dose aspirin. All of the children recovered. CONCLUSIONS Early recognition of children with multisystem inflammation is important because they are at increased risk for deterioration. Treatment with intravenous immunoglobulin and aspirin was used because this regimen has been shown to be beneficial in vasculitis of Kawasaki disease. The development of shock due to cardiac involvement may require ECMO.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Systemic Inflammatory Response Syndrome/virology , Antipyretics/therapeutic use , Aspirin/therapeutic use , COVID-19 , Child , Child, Preschool , Conjunctivitis/therapy , Conjunctivitis/virology , Coronavirus Infections/therapy , Exanthema/therapy , Exanthema/virology , Extracorporeal Membrane Oxygenation , Female , Fever/therapy , Fever/virology , Heart Failure/therapy , Heart Failure/virology , Humans , Hyponatremia/therapy , Hyponatremia/virology , Immunoglobulins, Intravenous , Lymphadenopathy/therapy , Lymphadenopathy/virology , Lymphopenia/therapy , Lymphopenia/virology , Male , Pandemics , Pneumonia, Viral/therapy , Respiration, Artificial , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/therapy , Vasculitis/therapy , Vasculitis/virology
11.
J Thromb Thrombolysis ; 50(3): 499-511, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-662425

ABSTRACT

The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.


Subject(s)
Betacoronavirus/pathogenicity , Blood Vessels/virology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Vasculitis/virology , Animals , Betacoronavirus/immunology , Blood Coagulation , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/physiopathology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Prognosis , Risk Factors , SARS-CoV-2 , Vasculitis/diagnosis , Vasculitis/immunology , Vasculitis/physiopathology
14.
Clin Immunol ; 217: 108493, 2020 08.
Article in English | MEDLINE | ID: covidwho-574786

Subject(s)
Antigen-Antibody Complex/biosynthesis , Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Complex Diseases/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Vasculitis/immunology , Antibodies, Viral/biosynthesis , Antigen-Antibody Complex/drug effects , Betacoronavirus/immunology , Blood Vessels/drug effects , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/virology , COVID-19 , Complement C3/antagonists & inhibitors , Complement C3/biosynthesis , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Humans , Immune Complex Diseases/complications , Immune Complex Diseases/drug therapy , Immune Complex Diseases/virology , Immunity, Humoral/drug effects , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/biosynthesis , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Vasculitis/complications , Vasculitis/drug therapy , Vasculitis/virology
15.
Clin Immunol ; 217: 108487, 2020 08.
Article in English | MEDLINE | ID: covidwho-436345

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Immune Complex Diseases/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Th2 Cells/immunology , Vasculitis/immunology , Aged , Antibodies, Viral/biosynthesis , Antigen-Antibody Complex/biosynthesis , Betacoronavirus/immunology , Blood Vessels/immunology , Blood Vessels/pathology , Blood Vessels/virology , COVID-19 , Complement C3/biosynthesis , Coronavirus Infections/complications , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Disease Progression , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Immune Complex Diseases/complications , Immune Complex Diseases/virology , Immunity, Humoral , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Interleukin-6/biosynthesis , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/virology , Th2 Cells/pathology , Th2 Cells/virology , Vasculitis/complications , Vasculitis/virology
19.
Clin Immunol ; 214: 108393, 2020 05.
Article in English | MEDLINE | ID: covidwho-41645

ABSTRACT

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , COVID-19 , Chloroquine/therapeutic use , Cytokines/immunology , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Inflammation/pathology , Interleukin-6/antagonists & inhibitors , Janus Kinases/antagonists & inhibitors , Pandemics , SARS-CoV-2 , Thrombosis/virology , Vasculitis/virology
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