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1.
J Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
3.
Hamostaseologie ; 41(5): 397-399, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1428942

ABSTRACT

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired clonal haematological disease characterized by complement-mediated haemolysis, bone marrow failure and venous thrombosis. Anticomplement therapy eculizumab improves survival and reduces complications. Severe acute respiratory distress syndrome corona virus 2 (SARS-CoV-2) disease 2019 (COVID-19) is associated with high incidence of both venous and arterial thrombosis in hospitalized patients with pneumonia. Deep venous thrombosis (DVT) as the presenting symptom of COVID-19 is a rare event. We describe a well-controlled PNH patient on eculizumab for more than 5 years who presented with DVT, while on warfarin, as the first sign of COVID-19. To our knowledge, this is the first described case of DVT in a PNH patient with COVID-19.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Hemoglobinuria, Paroxysmal/complications , SARS-CoV-2 , Venous Thrombosis/complications , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , Complement Inactivating Agents/therapeutic use , Hemoglobinuria, Paroxysmal/drug therapy , Humans , Male , Venous Thrombosis/diagnosis , Warfarin/therapeutic use
4.
Muscle Nerve ; 64(2): 212-215, 2021 08.
Article in English | MEDLINE | ID: covidwho-1378943

ABSTRACT

INTRODUCTION/AIMS: Eculizumab has been shown to be efficacious in acetylcholine receptor antibody-positive (AChR+ ) Myasthenia Gravis Foundation of America (MGFA) class II, III, and IV generalized myasthenia gravis (gMG) patients. However, it has not been studied in MGFA class V gMG patients. METHODS: We report three AChR+ , refractory, MGFA class V gMG patients treated with eculizumab. MGFA class, MG-Composite (MGC) score and MG Activities of Daily Living (MG-ADL) score were assessed before and after eculizumab. RESULTS: Two of three gMG patients, refractory to intravenous immunoglobulin, plasmapheresis, prednisone, and (in one case) rituximab, showed a robust response to eculizumab with marked improvement in MGFA, MG-ADL, and MGC measures. The third patient showed a partial response to eculizumab but remained on noninvasive ventilation and gastrostomy intubation. Patients 1 and 2 achieved minimal manifestation status at week 4 and week 6, respectively, and showed continued improvement on MG-ADL and MGC scores through weeks 55 and 43, respectively, with eculizumab. The third patient showed a partial response at week 10, followed by a slight decline in his MG-ADL score, but noted a slow but an incomplete improvement afterward on MG-ADL and MGC scores, possibly due to delayed eculizumab infusion. DISCUSSION: Eculizumab may play a role in the treatment of patients with MGFA class V, refractory gMG. Larger studies are required to provide further evidence.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Complement Inactivating Agents/therapeutic use , Myasthenia Gravis/drug therapy , Ventilators, Mechanical , Activities of Daily Living , Adult , Aged , Female , Humans , Male , Middle Aged , Rituximab/therapeutic use , Ventilators, Mechanical/adverse effects
5.
Adv Biol Regul ; 81: 100822, 2021 08.
Article in English | MEDLINE | ID: covidwho-1364204

ABSTRACT

Severe COVID-19 is characterized by lung and multiorgan inflammation and coagulation in the presence of overactivation of the complement system. Complement is a double edged-sward in SARS-Cov-2 infection. On one hand, it can control the viral infection in milder cases, on the other hand in cases with severe and prolonged infection massive complement activation occurs, which can intensify lung and systemic inflammation and promote a procoagulant and prothrombotic state. Several uncontrolled studies and controlled clinical trials with different complement inhibitors have been performed and others are ongoing. Results are promising in some but negative in others. Further studies are required to elucidate the benefit to risk profile of complement inhibitors in COVID-19 patients at different stages of the disease and to clarify the best targets in the complement cascade.


Subject(s)
COVID-19/blood , COVID-19/drug therapy , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Complement System Proteins/metabolism , SARS-CoV-2/metabolism , Humans , Lung/metabolism , Lung/pathology , Severity of Illness Index
6.
Front Immunol ; 12: 680567, 2021.
Article in English | MEDLINE | ID: covidwho-1304591

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. A clinical series of Kawasaki-like multisystem inflammatory syndrome (MIS), occurring after SARS-CoV-2 infection, have been described in children (MIS-C) and adults (MIS-A), but the pathophysiology remains unknown. Case Presentation: We describe a case of post-COVID-19 MIS-A in a 46-year-old man with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with eculizumab was initiated promptly and led to a dramatic improvement of renal function. Conclusion: Our case suggests that that TMA could play a central role in the pathophysiology of post-COVID-19 MIS-A, making complement blockers an interesting therapeutic option.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/diagnosis , Complement Inactivating Agents/therapeutic use , Kidney/metabolism , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/diagnosis , Thrombotic Microangiopathies/diagnosis , COVID-19/drug therapy , Humans , Kidney/pathology , Male , Middle Aged , Pandemics , Recovery of Function , Systemic Inflammatory Response Syndrome/drug therapy , Thrombotic Microangiopathies/drug therapy
9.
Clin Immunol ; 226: 108716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1152310

ABSTRACT

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Complement Pathway, Alternative/immunology , Lung Injury/immunology , Aged , Aged, 80 and over , COVID-19/complications , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Immunohistochemistry , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung Injury/complications , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged
10.
Int Immunopharmacol ; 95: 107516, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1108363

ABSTRACT

After the advent of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in the late 2019, the resulting severe and pernicious syndrome (COVID-19) immediately was deployed all around the world. To date, despite relentless efforts to control the disease by drug repurposing, there is no approved specific therapy for COVID-19. Given the role of innate and acquired immune components in the control and elimination of viral infections and inflammatory mutilations during SARS-CoV2 pathogenesis, immunotherapeutic strategies appear to be beneficent. Passive immunotherapies such as convalescent plasma, which has received much attention especially in severe cases, as well as suppressing inflammatory cytokines, interferon administration, inhibition of kinases and complement cascade, virus neutralization with key engineered products, cell-based therapies, immunomodulators and anti-inflammatory drugs are among the key immunotherapeutic approaches to deal with COVID-19, which is discussed in this review. Also, details of leading COVID-19 vaccine candidates as the most potent immunotherapy have been provided. However, despite salient improvements, there is still a lack of completely assured vaccines for universal application. Therefore, adopting proper immunotherapies according to the cytokine pattern and involved immune responses, alongside engineered biologics specially ACE2-Fc to curb SARS-CoV2 infection until achieving a tailored vaccine is probably the best strategy to better manage this pandemic. Therefore, gaining knowledge about the mechanism of action, potential targets, as well as the effectiveness of immune-based approaches to confront COVID-19 in the form of a well-ordered review study is highly momentous.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Immunotherapy/methods , COVID-19 Vaccines/therapeutic use , Cell- and Tissue-Based Therapy/methods , Complement Inactivating Agents/therapeutic use , Cytokines/antagonists & inhibitors , Cytokines/therapeutic use , Humans , Immunologic Factors/therapeutic use , Protein Kinase Inhibitors/therapeutic use
11.
Life Sci ; 272: 119245, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1087130

ABSTRACT

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Complement System Proteins/immunology , SARS-CoV-2/immunology , Animals , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Complement Activation/drug effects , Complement C3/immunology , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology
12.
Clin Immunol ; 222: 108634, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064947

ABSTRACT

The world is engulfed by one of the most widespread and significant public health crises in decades as COVID-19 has become among the leading causes of death internationally. The novel SARS-CoV-2 coronavirus which causes COVID-19 has unified the scientific community in search of therapeutic and preventative solutions. The top priorities at the moment are twofold: first, to repurpose already-approved pharmacologic agents or develop novel therapies to reduce the morbidity and mortality associated with the ever-spreading virus. Secondly, the scientific and larger pharmaceutical community have been tasked with the development, testing, and production of a safe and effective vaccine as a longer-term solution to prevent further spread and recurrence throughout the populace. The purpose of this article is to review the most up-to-date published data regarding both the leading pharmacological therapies undergoing clinical trials and vaccine candidates in development to stem the threat of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/drug therapy , COVID-19/prevention & control , SARS-CoV-2 , Adrenal Cortex Hormones/therapeutic use , Complement Inactivating Agents/therapeutic use , Humans
13.
Hum Immunol ; 82(4): 264-269, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1039363

ABSTRACT

The novel Coronavirus SARS-CoV-2 is the viral pathogen responsible for the ongoing global pandemic, COVID-19 (Coronavirus disease 2019). To date, the data recorded indicate 1.62 Mln deaths and 72.8 Mln people infected (WHO situation report Dec 2020). On December 27, the first anti-COVID-19 vaccinations started in Europe. There are no direct antivirals against SARS-CoV-2. Understanding the pathophysiological and inflammatory/immunological processes of SARS-CoV-2 infection is essential to identify new drug therapies. In the most severe COVID-19 cases, an unregulated immunological/inflammatory system results in organ injury that can be fatal to the host in some cases. Pharmacologic approaches to normalize the unregulated inflammatory/immunologic response is an important therapeutic solution. Evidence associates a non-regulation of the "complement system" as one of the causes of generalized inflammation causing multi-organ dysfunction. Serum levels of a complement cascade mediator, factor "C5a", have been found in high concentrations in the blood of COVID-19 patients with severe disease. In this article we discuss the correlation between complement system and COVID-19 infection and pharmacological solutions directed to regulate.


Subject(s)
COVID-19/drug therapy , Complement Activation/drug effects , Complement C3a/antagonists & inhibitors , Complement C5a/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/pathology , COVID-19/physiopathology , Complement Activation/immunology , Complement C3a/immunology , Complement C5a/immunology , Humans , SARS-CoV-2/immunology
15.
Front Immunol ; 11: 599417, 2020.
Article in English | MEDLINE | ID: covidwho-1000095

ABSTRACT

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.


Subject(s)
Complement C5a/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Complement Membrane Attack Complex/antagonists & inhibitors , Kidney Diseases/drug therapy , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Complement Activation/immunology , Complement System Proteins/metabolism , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Humans , Kidney/pathology , Kidney Diseases/immunology , Kidney Diseases/pathology , Lupus Nephritis/drug therapy , Lupus Nephritis/pathology
16.
Eur Rev Med Pharmacol Sci ; 24(23): 12593-12608, 2020 12.
Article in English | MEDLINE | ID: covidwho-995021

ABSTRACT

The coronavirus disease 2019 (COVID-19) is declared as an international emergency in 2020. Its prevalence and fatality rate are rapidly increasing but the medication options are still limited for this perilous disease. The emergent outbreak of COVID-19 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps propagating globally. The present scenario has emphasized the requirement for therapeutic opportunities to relive and overcome this latest pandemic. Despite the fact, the deteriorating developments of COVID-19, there is no drug certified to have considerable effects in the medical treatment for COVID-19 patients. The COVID-19 pandemic requests for the rapid testing of new treatment approaches. Based on the evidence, hydroxychloroquine is the first medicine opted for the treatment of disease. Umifenovir, remdesivir, and fevipiravir are deemed the most hopeful antiviral agent by improving the health of infected patients. The dexamethasone is a first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients. The current review recapitulates the existing evidence of possible therapeutic drugs, peptides, humanized antibodies, convulsant plasma, and vaccination that has revealed potential in fighting COVID-19 infections. Many randomized and controlled clinical trials are taking place to further validate these agent's safety and effectiveness in curing COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Amides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antiparasitic Agents/therapeutic use , COVID-19/prevention & control , Cannabinoids/therapeutic use , Chloroquine/therapeutic use , Complement Inactivating Agents/therapeutic use , Dexamethasone/therapeutic use , Drug Combinations , Enzyme Inhibitors/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/therapeutic use , Interferons/therapeutic use , Ivermectin/therapeutic use , Lopinavir/therapeutic use , Nitro Compounds , Pyrazines/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2 , Teicoplanin/therapeutic use , Tetracyclines/therapeutic use , Thiazoles/therapeutic use
18.
J Nephrol ; 33(6): 1373-1376, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-802152

ABSTRACT

While there are increasing reports of acute kidney injury among hospitalized adults with COVID-19, there is still limited information on renal complications associated with COVID-19 in children. The cause of kidney involvement in COVID-19 is likely multifactorial, and appears to involve a complex process, including complement dysregulation and thrombotic microangiopathy. We present a pediatric case of COVID-19 and renal failure due to thombotic microangiopathy, successfully treated with eculizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/epidemiology , Kidney Failure, Chronic/therapy , Renal Dialysis/methods , SARS-CoV-2 , Adolescent , Comorbidity , Complement Inactivating Agents/therapeutic use , Female , Humans , Kidney Failure, Chronic/epidemiology , Pandemics
20.
Clin Immunol ; 220: 108598, 2020 11.
Article in English | MEDLINE | ID: covidwho-778645

ABSTRACT

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Subject(s)
Betacoronavirus/pathogenicity , Complement C3/antagonists & inhibitors , Complement C5/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Cohort Studies , Complement Activation/drug effects , Complement C3/genetics , Complement C3/immunology , Complement C5/genetics , Complement C5/immunology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Extracellular Traps/drug effects , Female , Gene Expression , Humans , Interleukin-6/metabolism , Male , Middle Aged , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/virology , Pandemics , Peptides, Cyclic/therapeutic use , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Severity of Illness Index
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