Recurrent meningococcal infections as a sign of inborn error immunity.

Invasive meningococcal diseases (IMD) caused by Neisseria meningitidis are generally rare. They affect mostly selected age categories and risk groups of patients (in terms of age, comorbidities, or applied therapy), and the immune system and its defects may play an important modifying role. Meningococcal infections could be the first and only clinical sign of unrecognised immunodeficiency.

New-Onset Complement-Mediated Thrombotic Microangiopathy during the COVID-19 Pandemic.

Introduction: The coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus is alleged to enable a proinflammatory state that leads to the activation of the coagulation and the complement cascade. In this study, we aimed to establish the impact of the COVID-19 pandemic on patients with new onset of cTMA/aHUS in the Vienna TMA cohort and whether COVID-19 or SARS-CoV-2 vaccinations would pose a greater risk of initial manifestation of cTMA/aHUS.

sMR and PTX3 levels associate with COVID-19 outcome and survival but not with Long COVID.

Biomarkers for monitoring COVID-19 disease course are lacking. Study aim was to identify biomarkers associated with disease severity, survival, long-term outcome, and Long COVID. As excessive macrophages activation is a hallmark of COVID-19 and complement activation is key in this, we selected the following proteins involved in these processes: PTX3, C1q, C1-INH, C1s/C1-INH, and sMR.

Circulating mortalin in blood and activation of the alternative complement pathway as risk indicators in COVID-19 infection.

Background: Mortalin/GRP75 is a ubiquitous mitochondrial chaperone related to the cytosolic heat shock protein 70. It protects cells from various types of damages and from senescence. Our goal was to determine whether COVID-19 patients have circulating mortalin in their blood and to assess its prognostic value in anticipating disease severity.

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years.

Introduction: The complement external quality assurance (EQA) program was first organized in 2010 by a group of researchers working in diagnostic complement laboratories. Starting in 2016, INSTAND e.V.

Complement C7 and clusterin form a complex in circulation.

Introduction: The complement system is part of innate immunity and is comprised of an intricate network of proteins that are vital for host defense and host homeostasis. A distinct mechanism by which complement defends against invading pathogens is through the membrane attack complex (MAC), a lytic structure that forms on target surfaces. The MAC is made up of several complement components, and one indispensable component of the MAC is C7.

Storage of Transfusion Platelet Concentrates Is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor.

Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 °C for seven days and assessed daily for complement and platelet activation markers.

Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.

Background: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission.

Objectives: To investigate whether open ADAMTS-13, represented by a conformation index >0.

MAP-2:CD55 chimeric construct effectively modulates complement activation.

The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement-driven inflammatory pathologies. The enzymatically inactive MAP-2 has been reported to inhibit the lectin pathway by competing with its homologous serine protease MASP-2.

Immunosuppressive Therapy of Antibody-Mediated aHUS and TTP.

The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS with antibodies against complement factor H (CFH-ab) and two with TTP with antibodies against metalloproteinase ADAMTS13.

The Rationale of Complement Blockade of the MCP Haplotype following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review.

We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36-252 months). The median number of relapses before CBT initiation (Eculizumab) was two.

Class switch towards spike protein-specific IgG4 antibodies after SARS-CoV-2 mRNA vaccination depends on prior infection history.

Vaccinations against SARS-CoV-2 reduce the risk of developing serious COVID-19 disease. Monitoring spike-specific IgG subclass levels after vaccinations may provide additional information on SARS-CoV-2 specific humoral immune response. Here, we examined the presence and levels of spike-specific IgG antibody subclasses in health-care coworkers vaccinated with vector- (Sputnik, AstraZeneca) or mRNA-based (Pfizer-BioNTech, Moderna) vaccines against SARS-CoV-2 and in unvaccinated COVID-19 patients.

Pregnancy in Complement-Mediated Thrombotic Microangiopathy: Maternal and Neonatal Outcomes.

Rationale & Objective: Pregnancy, delivery, and neonatal outcomes in women with complement-mediated thrombotic microangiopathy (cTMA) have not been well described. A better understanding of these outcomes is necessary to provide women with competent pregnancy counseling.

Study Design: Cohort study.

Differentiating between activation via the lectin or the classical complement pathway in patients with systemic lupus erythematosus.

Complement activation is a hallmark of systemic lupus erythematosus (SLE) and can proceed through the classical (CP), lectin (LP), or alternative pathway (AP). When managing SLE patients, pathway-specific complement activation is rarely monitored as clinical assays are unavailable. In this study, we aim to differentiate between CP- or LP-mediated complement activation in SLE patients by quantifying pathway-specific protein complexes, namely C1s/C1-inhibitor (C1-INH) (CP-specific activation) and MASP-1/C1-INH (LP-specific activation).

Complement-Mediated Thrombotic Microangiopathy Related to COVID-19 or SARS-CoV-2 Vaccination.

Introduction: Infectious diseases and vaccinations are trigger factors for thrombotic microangiopathy. Consequently, the COVID-19 pandemic could have an effect on disease manifestation or relapse in patients with atypical hemolytic syndrome/complement-mediated thrombotic microangiopathy (aHUS/cTMA).

Methods: We employed the Vienna TMA cohort database to examine the incidence of COVID-19 related and of SARS-CoV-2 vaccination-related relapse of aHUS/cTMA among patients previously diagnosed with aHUS/cTMA during the first 2.

[Reducing the risk of infections in hereditary and acquired complement deficiencies.].

Hereditary complement deficiencies are relatively rare worldwide, they account for about 1-10% of primary immunodeficiencies. Acquired complement deficiencies are more prevalent and with the more frequent use of complement inhibitor therapy, the incidence of patients with iatrogenic complement deficiency is increasing. Alike in the inherited forms, patients have a high risk of severe and life-threatening infections caused by encapsulated bacteria (sepsis, meningitis).

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of genotype subgroups.

Introduction: While complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature.

Introduction: As the global pandemic continues, new complications of COVID-19 in pediatric population have turned up, one of them being hemolytic uremic syndrome (HUS), a complement-mediated thrombotic microangiopathy (CM-TMA) characterized by triad of thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI). With both multisystem inflammatory syndrome in children (MIS-C) and HUS sharing complement dysregulation as one of the key factors, the aim of this case report is to highlight differences between these two conditions and also emphasize the importance of complement blockade as a treatment modality.

Case Report: We describe a 21-month-old toddler who initially presented with fever and confirmed COVID-19.

Distinction of early complement classical and lectin pathway activation quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs.

The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation.

Evidence, detailed characterization and clinical context of complement activation in acute multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C develops with high fever, marked inflammation and shock-like picture several weeks after exposure to, or mild infection with SARS-CoV-2. Deep immune profiling identified activated macrophages, neutrophils, B-plasmablasts and CD8 + T cells as key determinants of pathogenesis together with multiple inflammatory markers.

Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study.

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135).

Atypical hemolytic uremic syndrome triggered by mRNA vaccination against SARS-CoV-2: Case report.

Atypical hemolytic uremic syndrome (aHUS), also called complement-mediated hemolytic uremic syndrome (CM-HUS), is a rare disease caused by dysregulation in the alternative complement activation pathway. It is a life-threatening condition causing ischemia of a number of organs, and it typically causes acute kidney injury. This disorder may be triggered by various factors including viral or bacterial infections, pregnancy, surgery, and injuries.