Influence of complement system genomic variations on the course of COVID-19

Background: The pandemic of SARS-CoV- 2 is a severe worldwide problem increasing morbidity and mortality.1, 2 Severe COVID-19 presents as multiple organ failure caused by systemic inflammation, thrombin generation, and hypofibrinolysis. Diffuse microvascular thrombi and inter-alveolar deposits of complement fragments are observed. The enhanced immunothrombosis is mediated by direct overactivation of complement by virus surface components or damaged cells.3-5 Aims: The study aimed to find whether genetic changes responsible for complement dysregulation known in atypical hemolytic-uremic syndrome (aHUS) can be found in severe COVID-19 patients. Method(s): The study included adult COVID-19 subjects undergoing extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome. Two independent physicians signed informed consent, and the study was approved by a local ethics committee (No. 109/2021) and supported by the University Hospital fund. Next-Generation Sequencing Panel of C3 component, membrane cofactor protein (CD46), complement factor B (CFB), complement factor H (CFH), complement factor H related genes 1-5 (CFHR 1-5), diacylglycerol Kinase Epsilon, thrombomodulin (THBD) and mannose-binding lectin (MBL) genes were performed, with confirmations of positive results by Sanger sequencing. Result(s): Twenty-two patients (13 were male) aged 33 to 65 years were included. No pathogenic gene variants in the C3, CD46, CFB, CFH genes, CFHR 5, CFI, THBD were detected. However, we have shown the presence of modifiers (CFH-H3 haplotype, MCP-GGAAC haplotype, and CFH/CFHR1), which may, together with triggers (infection), increase the severity of the disease (aHUS).6-8 Moreover, we have identified single nucleotide polymorphisms in exon 1 at codon 52 (c.154C>T) and 54 (c.161G>A) of the MBL2 gene promoter associated with low serum levels or dysfunctional MBL and higher incidence of infections. Conclusion(s): We did not detect any complement-related pathogenic gene variants known in aHUS. Thus, It is unlikely that complement dysregulation is the main factor influencing immunothrombosis in a cohort of the most severe COVID-19 patients.

The first 50 COVID-19 positive patients at the Department of Haemato-oncology, Faculty Hospital Ostrava in 2020

Aim: The novel coronavirus (SARS-CoV-2) is a highly contagious disease with a significant mortality rate. Haematological patients are among those most at risk. We evaluate here the disease course, association between comorbidities and COVID-19 severity and seroconversion potential in 50 positive patients at our clinic. Methods: We performed 1,600 diagnostic PCR nasopharyngeal swabs over a period of 8 months. We introduced a set of preventive measures so as to protect our patients and personnel. In 50 COVID-19 positive patients, we closely evaluated the course of the disease, the impact of underlying risk factors and the principal haematological diagnoses. We also evaluated the potential for seroconversion in 15 COVID-19 positive patients. Results: Strict barrier measures, especially in patients undergoing autologous stem cell transplantation, have been shown as being crucial for reducing the spread of disease.We did not record any disease outbreak and registered only one positive case during the peri-transplant period at our facility. The most common comorbidities were arterial hypertension or other cardiovascular disease, type 2 diabetes and renal impairment. Two-thirds of positive patients were on first line treatment. Hypogammaglobulinemia did not prove to be a risk factor for a severe COVID-19 course and we did not observe it to be an obstacle for seroconversion. Conclusion: Preventive measures are significant for reducing the spread of disease, especially in haematology centres. In our single centre experience, we report a mortality of 14%. Although we report a relatively small cohort and much remains yet to be clarified, our results can even now be implemented in daily practice.

COVID-19 associated coagulopathy: Mechanisms and host-directed treatment.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19) and can result in thrombotic complications and/or death. This COVID-19-associated coagulopathy (CAC) exhibits some of the features associated with thrombotic microangiopathy, particularly complement-mediated hemolytic-uremic syndrome. In some cases, due to the anti-phospholipid antibodies, CAC resembles catastrophic anti-phospholipid syndrome. In other patients, it exhibits features of hemophagocytic syndrome. CAC is mainly identified by: increases in fibrinogen, D-dimers, and von Willebrand factor (released from activated endothelial cells), consumption of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), over activated and dysregulated complement, and elevated plasma cytokine levels. CAC manifests as both major cardiovascular and/or cerebrovascular events and dysfunctional microcirculation, which leads to multiple organ damage. It is not clear whether the mainstay of COVID-19 is complement overactivation, cytokine/chemokine activation, or a combination of these activities. Available data have suggested that non-critically ill hospitalized patients should be administered full-dose heparin. In critically ill, full dose heparin treatment is discouraged due to higher mortality rate. In addition to anti-coagulation, four different host-directed therapeutic pathways have recently emerged that influence CAC: (1) Anti-von Willebrand factor monoclonal antibodies; (2) activated complement C5a inhibitors; (3) recombinant ADAMTS13; and (4) Interleukin (IL)-1 and IL-6 antibodies. Moreover, neutralizing monoclonal antibodies against the virus surface protein have been tested. However, the role of antiplatelet treatment remains unclear for patients with COVID-19.