Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.

Microvascular Skin Manifestations Caused by COVID-19.

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.

Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches.

Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.

Cardiovascular, hematological and neurosensory impact of COVID-19 and variants.

OBJECTIVE: The purpose of this article was to review our clinical experience with COVID-19 patients observed in the Cardiovascular Division of Pompidou Hospital (University of Paris, France) and the Department of Neurology of the Eastern Piedmont University (Novara, Italy), related to the impact on the cardiovascular, hematological, and neurologic systems and sense organs. PATIENTS AND METHODS: We sought to characterize cardiovascular, hematological, and neurosensory manifestations in patients with COVID-19 and variants. Special attention was given to initial signs and symptoms to facilitate early diagnosis and therapy. Indications of ECMO (extracorporeal membrane oxygenation) for cardiorespiratory support were evaluated. RESULTS: Preliminary neurosensorial symptoms, such as anosmia and dysgeusia, are useful for diagnosis, patient isolation, and treatment. Early angiohematological acro-ischemic syndrome includes hand and foot cyanosis, Raynaud digital ischemia phenomenon, skin bullae, and dry gangrene. This was associated with neoangiogenesis, vasculitis, and vessel thrombosis related to immune dysregulation, resulting from "cytokine storm syndrome". The most dangerous complication is disseminated intravascular coagulation, with mortality risks for both children and adults. CONCLUSIONS: COVID-19 is a prothrombotic disease with unique global lethality. A strong inflammatory response to viral infection severely affects cardiovascular and neurological systems, as well as respiratory, immune, and hematological systems. Rapid identification of acro-ischemic syndrome permits the treatment of disseminated intravascular coagulation complications. Early sensorial symptoms, such as gustatory and olfactory loss, are useful for COVID-19 diagnosis. New variants of SARS-CoV-2 are emerging, principally from United Kingdom, South Africa, and Brazil. These variants seem to spread more easily and quickly, which may lead to more cases of COVID.

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. METHODS: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. RESULTS: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. CONCLUSION: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Cryoglobulinemic vasculitis: pathophysiological mechanisms and diagnosis.

PURPOSE OF REVIEW: Cryoglobulins (CG) are immunoglobulins that precipitate in the cold, and dissolve at 37°C. In vivo, in cold exposed tissues and organs, they can induce vasculitis and occlusive vasculopathy after deposition on vascular endothelium under low temperature and high concentration conditions. Clinical manifestations are cutaneous (purpura, ulcers, vasomotor symptoms, and livedo reticularis), rheumatological (arthralgia and arthritis), and peripheral neuropathy (paresthesia and pain in the lower limbs). In profound organs such as the kidneys, CG deposition is less temperature-dependent, favored by local protein and anion concentrations, and can lead to glomerulonephritis. This review will focus on cryoglobulinemic vasculitis and vascular lesion, and their diagnosis. RECENT FINDINGS: The mechanisms of vascular lesions of pathogenic CG in function of CG type and their characteristics are better defined. Optimal conditions for CG detection are critical. The importance of looking for underlying diseases, especially hepatitis C virus status in mixed CG, is reminded. SUMMARY: A decision diagram for CG vasculitis diagnosis based on clinical and biological parameters is proposed.

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

Serum TNF-α Level Is Associated with Disease Severity in Adult Patients with Immunoglobulin A Vasculitis Nephritis.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is a proinflammatory factor involved in the pathogenesis of immunoglobulin A vasculitis (IgAV). The association between serum TNF-α and disease severity in adult patients with IgAV nephritis (IgAV-N) has been inadequately evaluated. METHODS: Serum TNF-α was measured by chemiluminescence immunoassay in 53 renal biopsy-proved IgAV-N patients, 53 healthy controls, and 53 IgA nephropathy (IgAN) patients. The correlations of clinicopathologic parameters of IgAV-N patients with serum TNF-α were analyzed. RESULTS: In this cross-sectional study, the median age of IgAV-N patients was 29 (25-37) years, and 67.9% were female. Serum TNF-α was significantly higher in the IgAV-N group than in the healthy group [7.4 (5.7-9.4) pg/mL vs. 5.9 (5.0, 7.1) pg/mL, P = 0.001], but comparable with sex, age, and estimated glomerular filtration rate (eGFR) grade-matched IgAN patients. Serum creatinine (P = 0.006) and serum cystatin C (P = 0.001) were positively correlated with serum TNF-α level, while albumin (P = 0.014) and eGFR (P = 0.021) were negatively correlated with serum TNF-α level. Multivariate linear regression analysis revealed that eGFR (P = 0.007) was an independent clinical predictor of serum TNF-α. Patients with higher pathological classification grade also had higher serum TNF-α. CONCLUSIONS: Serum TNF-α is associated with renal function and the pathological classification of adult patients with IgAV-N. TNF-α is a potential biomarker for the assessment of IgAV-N severity.

Successful Induction Treatment With Rituximab of Isolated Pauci-Immune Pulmonary Capillaritis Presenting as Diffuse Alveolar Hemorrhage in a Pediatric Patient.

Diffuse alveolar hemorrhage often presents as dyspnea, cough, or hemoptysis, and it is mediated by both immune and nonimmune processes. Isolated pauci-immune capillaritis (IPPC) is a rare diagnosis in which capillaritis, small-vessel vasculitis of the lung, is found on biopsy in the absence of an underlying systemic disorder. Traditionally, IPPC has been treated similarly to anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis with cyclophosphamide and glucocorticoids. However, few cases describing management options are available in the literature, especially among pediatric patients. Our report of successful induction of remission in an adolescent girl suggests that the combination of IV rituximab and pulse methylprednisolone may be a viable option for disease control in pediatric patients with IPPC.

A 47-Year-Old Hispanic Man Who Developed Cutaneous Vasculitic Lesions and Gangrene of the Toes Following Admission to Hospital with COVID-19 Pneumonia.

BACKGROUND Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, in late 2019 and has led to an ongoing pandemic. COVID-19 typically affects the respiratory tract and mucous membranes, leading to pathological involvement of various organ systems. Although patients usually present with fever, cough, and fatigue, less common manifestations have been reported including symptoms arising from thrombosis and thromboembolism. A spectrum of dermatologic changes is becoming recognized in patients with COVID-19 who initially present with respiratory symptoms. The mechanism behind these manifestations remains unclear. This report presents the case of a 47-year-old Hispanic man who developed cutaneous vasculitic lesions and gangrene of the toes following admission to hospital with COVID-19 pneumonia. CASE REPORT COVID-19 has been associated with cardiovascular disease entities including stroke, acute coronary syndrome, venous thromboembolism, and peripheral vascular disease. We present a case in which a 47-year-old Hispanic man arrived at the Emergency Department with COVID-19 and was admitted for respiratory failure. Despite anticoagulation initiated on admission in the presence of an elevated D-dimer, the patient developed gangrene of all his toes, which required bilateral transmetatarsal amputation. CONCLUSIONS This case shows that dermatologic manifestations may develop in patients who initially present with COVID-19 pneumonia. These symptoms may be due to venous thrombosis following SARS-CoV-2 vasculitis, leading to challenging decisions regarding anticoagulation therapy. Randomized controlled trials are needed to evaluate the efficacy of anticoagulation, to choose appropriate anticoagulants and dosing, and to assess bleeding risk.

The utility of PET/CT in large vessel vasculitis.

18F-FDG PET/CT occupies a growing role in the diagnosis of large vessel vasculitis (LVV), illustrating enhanced uptake in the lining of large vessels. A retrospective single center study was conducted of patients who underwent 18F-FDG PET/CT scans between 2009 and 2019 at Sheba Medical Center, Israel. The imaging results were analyzed for evidence of LVV. We reviewed the PET/CT scans of 126 patients and identified 57 studies that either showed evidence of active LVV or that had been performed in patients previously treated for systemic vasculitis. In 6 patients with fevers of unknown origin and elevated inflammatory markers, PET/CT revealed LVV. Six of 13 patients previously treated for systemic vasculitis demonstrated persistent large vessel uptake. LVV was identified in 8 patients with other autoimmune diseases, and in 4 diagnosed with infectious aortitis. In 26 patients who underwent malignancy surveillance, PET/CT revealed more localized large vessel wall inflammation. Our results illustrate that PET/CT may identify large vessel wall inflammation in patients with a suspicion of LVV, and incidentally in patients who undergo malignancy surveillance. PET/CT may also help delineate the presence and extent of vessel inflammation in patients with LVV and in those with other autoimmune diseases.

Scabies complicated by necrotizing lymphocytic vasculitis in an infant.

Scabies is very common among children. It is often a harmless infectious disease, responding well to antiparasitic medication. Nevertheless, severe forms can occur in immunocompromised populations like newborns and infants. We report a unique case of scabies in a three-months-old infant, complicated by generalized cutaneous lymphocytic vasculitis and unilateral acral necroses.

Inhibition of the Lectin Pathway of the Complement System as a Novel Approach in the Management of IgA Vasculitis-Associated Nephritis.

IgA vasculitis can present as a glomerulonephritis histologically indistinguishable from IgA nephropathy (IgAN). In IgAN, the alternative and lectin pathways mediate glomerular injury and contribute to kidney function decline. Narsoplimab is a monoclonal antibody against mannan-binding lectin serine peptidase 2 (MASP-2), a key component of the lectin pathway. It is being evaluated in a phase III trial in IgAN (NCT03608033). Histopathological similarities with IgAN suggest lectin pathway activation also occurs in IgAV-associated nephritis (IgAVN). Here, we report the first ever case of narsoplimab use for the treatment of IgAVN.

COVID-19-associated vasculitis and vasculopathy.

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.

A Patient with Necrotizing Vasculitis Related to Sarcoidosis, which Was Diagnosed via Immunohistochemical Methods Using Propionibacterium acnes-specific Monoclonal Antibodies.

Propionibacterium acnes (P. acnes) is a commensal bacterium indigenous to the skin. Previous reports have suggested that infection with P. acnes causes sarcoidosis, a systemic granulomatous disease. We present the case of a 63-year-old woman who developed subcutaneous nodules. A skin biopsy revealed necrotizing vasculitis and noncaseating granulomas, which are characteristic of sarcoidosis. Immunohistostaining revealed a P. acnes skin infection, which led to the diagnosis of sarcoidosis. Minocycline treatment resolved the infection and improved the patient's symptoms. We herein report a case in which immunohistochemistry was useful in the diagnosis of sarcoidosis.

Mitochondrial Fission Mediates Endothelial Inflammation.

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.