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 2.5 years of the COVID-19 pandemic. We calculated incidence rates, including respective confidence intervals (CIs) and used Cox proportional hazard models for comparison of aHUS/cTMA episodes following infection or vaccination. Results: Among 27 patients with aHUS/cTMA, 13 infections triggered 3 (23%) TMA episodes, whereas 70 vaccinations triggered 1 TMA episode (1%; odds ratio 0.04; 95% CI 0.003-0.37, P = 0.01). In total, the incidence of TMA after COVID-19 or SARS-CoV-2 vaccination was 6 cases per 100 patient years (95% CI 0.017-0.164) (4.5/100 patient years for COVID-19 and 1.5/100 patient years for SARS-CoV-2 vaccination). The mean follow-up time was 2.31 ± 0.26 years (total amount: 22,118 days; 62.5 years) to either the end of the follow-up or TMA relapse (outcome). Between 2012 and 2022 we did not find a significant increase in the incidence of aHUS/cTMA. Conclusion: COVID-19 is associated with a higher risk for aHUS/cTMA recurrence when compared to SARS-CoV-2 vaccination. Overall, the incidence of aHUS/cTMA after COVID-19 infection or SARS-CoV-2 vaccination is low and comparable to that described in the literature.

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 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. Methods: We therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome. Results: We show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID. Conclusion: In conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted.

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. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement. Conclusion Although reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.

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. His condition quickly deteriorated and he developed oliguria, accompanied with diarrhea, vomiting and oral intake intolerance. HUS was suspected, supported with compelling laboratory findings, including decreased platelets count and C3 levels, elevated LDH, urea, serum creatinine and sC5b-9 and presence of schistocytes in peripheral blood, negative fecal Shiga toxin and normal ADAMTS13 metalloprotease activity. The patient was given C5 complement blocker Ravulizumab and started to display rapid improvement. Conclusion: Although reports of HUS in the setting of COVID-19 continue to pour in, the questions of exact mechanism and similarities to MIS-C remain. Our case for the first time accentuates the use of complement blockade as a valuable treatment option in this scenario. We sincerely believe that reporting on HUS as a complication of COVID-19 in children will give rise to improved diagnosis and treatment, as well as better understanding of both of these intricating diseases.

The diagnostic value of rapid anti IgM and IgG detecting tests in the identification of patients with SARS CoV-2 virus infection / [A specifikus IgM- és IgG-antitesteket detektáló gyorstesztek értéke a SARS CoV-2 vírusfertozés kimutatásában (A COVID-19-pandémia orvosszakmai kérdései)]

Introduction: At the end of March, 2020, rapid tests detecting the presence of antiviral IgM and IgG antibodies against SARS-CoV-2 virus were introduced in Hungary for the identification of SARS-CoV-2 infection (COVID-19 disease). Aim: We evaluated two rapid tests (Anhui and Clungene) in comparison with those of real-time PCR tests considered as the gold standard in the detection of infection. Method: Between 16, March and 14, April, 2020, we performed rapid IgM and IgG detecting tests without PCR; PCR without rapid tests; and PCR WITH rapid tests in 4140, 3210 and 1654 patients, respectively. (Out of these 1654 patients, Anhui and Clungene tests were used for testing in 625 and 1029 patients, respectively.) Patients were considered as positive in PCR and rapid tests when PCR positivity and IgM or IgG positivity occurred at any time, respectively. (Note: Clungene test is also marketed as 'Lungene'.) Results: The prevalence of PCR positivity in 4864 patients tested with PCR was 6.3%. The sensitivity and specificity of Anhui and Clungene tests were 33.3% and 72.85%, and 35.48% and 85.02%, respectively. At 6% PCR positivity, the positive and negative predictive values of Anhui and Clungene were 7.28%, 94.48%, 13.13%, and 95.38%, respectively. Conclusion: The low positive predictive values indicate that Anhui and Clungene rapid tests detecting the presence of anti-IgM and anti-IgG against SARS-CoV-2 virus infection are not suitable for screening SARS-CoV-2 vírus infection in the general population. These results strongly support that Anhui and Clungene rapid tests detecting IgM and IgG antibodies against SARS-CoV-2 virus should not be used in the differential diagnosis of infection. Orv Hetil. 2020; 161(20): 807-812.

Distinction of early complement classical and lectin pathway activation via 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. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p<0.0001). The newly developed assays measure C1-INH complex levels in an accurate way. C1s/C1-INH and MASP-1/C1-INH complexes are suitable markers to assess early classical and lectin pathway activation. An initial reference range was set and first studies showed that these markers have added value for investigating and unraveling complement activation in human disease.

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. The disease rapidly responds to intravenous immunoglobulin (IVIG) treatment with clear changes of immune features. Here we present the results of a comprehensive analysis of the complement system in the context of MIS-C activity and describe characteristic changes during IVIG treatment. We show that activation markers of the classical, alternative and terminal pathways are highly elevated, that the activation is largely independent of anti-SARS-CoV-2 humoral immune response, but is strongly associated with markers of macrophage activation. Decrease of complement activation is closely associated with rapid improvement of MIS-C after IVIG treatment.

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. In about 60% of cases, the genetic origin of the disease can be identified—commonly mutations affecting complementary factor H and MCP protein. Eculizumab, a monoclonal antibody to the C5 component of the complement, represents the current effective treatment.We describe a case of a young woman with a previous history of polyvalent allergies, who developed atypical hemolytic uremic syndrome after vaccination with mRNA vaccine against SARS-CoV-2. The disease manifested by scleral bleeding, acute renal insufficiency, anemia, and thrombocytopenia. The patient was treated with plasma exchanges without sufficient effect;remission occurred only after starting treatment with eculizumab. Genetic examination showed that the patient is a carrier of multiple inherited risk factors (a rare pathogenic variant in CFH, MCPggaac haplotype of the CD46 gene, and the risk haplotype CFH H3). The patient is currently in hematological remission with persistent mild renal insufficiency, continuing treatment with eculizumab/ravulizumab. By this case report, we meant to point out the need for careful monitoring of people after vaccination, as it may trigger immune-mediated diseases, especially in those with predisposing factors.

Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study.

Background: Dysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients. Materials and Methods: In this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression. Results: A total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54-75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6-234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state. Conclusion: Consumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.

Decreased circulating dipeptidyl peptidase-4 enzyme activity is prognostic for severe outcomes in COVID-19 inpatients.

Aim: To investigate the serum circulating DPP4 activity in patients with COVID-19 disease. Materials & methods: Serum samples from 102 hospitalized COVID-19 patients and 43 post-COVID-19 plasma donors and 39 SARS-CoV-2 naive controls and their medical data were used. Circulating DPP4 activities according to different COVID-19 disease peak severity (WHO) groups at sampling and at peak were assessed. Results: A significant decrease (p < 0.0001) in serum DPP4 activity was found in study groups of higher disease severity. When the circulating DPP4 activity was assessed as a prognostic marker, the logistic regression (p = 0.0023) indicated that the enzyme activity is a predictor of mortality (median 9.5 days before death) with receiver operating characteristic area under the curves of 73.33% (p[area = 0.5] < 0.0001) as single predictor and 83.45% (p[area = 0.5] < 0.0001) in combination with age among hospitalized patients with COVID-19. Conclusion: Decreased circulating DPP4 activity is associated with severe COVID-19 disease and is a strong prognostic biomarker of mortality.

Case Report: A Case of COVID Vaccine-Induced Thrombotic Thrombocytopenia Manifested as Pulmonary Embolism and Hemorrhagia. A First Reported Case From Slovakia.

COVID-19 vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenoviral vector (ChAdOx1 nCoV-19) vaccine administration. It is presented as thrombocytopenia and thrombotic manifestations in various sites, especially in cerebral veins. Pulmonary emboli have been reported rarely. We present a case of a young male patient who developed severe thrombocytopenia and pulmonary embolism 12 days after the first dose of the vaccine. Severe thrombocytopenia, skin hematomas, and segmental pulmonary emboli were detected. Anti-platelet factor 4 (aPF-4) antibody was highly positive supporting the diagnosis of VITT. Prompt treatment with fondaparinux, intravenous immunoglobulin, and prednisone led to a marked improvement of clinical condition and thrombocytes count. We report the first known case of VITT in Slovakia.

Associations between the von Willebrand Factor-ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality.

BACKGROUND: Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated. OBJECTIVES: We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19. METHODS: Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records. RESULTS: VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio-indicating complement overactivation and consumption-was a strong independent predictor of in-hospital mortality. CONCLUSION: Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.

COVID-19: a trigger for severe thrombotic microangiopathy in a patient with complement gene variant.

The evidence regarding thrombotic microangiopathy (TMA) related to Coronavirus Infectious Disease 2019 (COVID-19) in patients with complement gene mutations as a cause of acute kidney injury (AKI) are limited. We presented the case of a 23-year-old male patient admitted with an asymptomatic form of COVID-19, but with uncontrolled hypertension and AKI. Kidney biopsy showed severe lesions of TMA. In evolution patient had persistent microangiopathic hemolytic anemia, decreased level of haptoglobin and increased LDH level. Decreased complement C3 level and the presence of schistocytes were found for the first time after biopsy. Kidney function progressively decreased and the patient remained hemodialysis dependent. Complement work-up showed a heterozygous variant with unknown significance in complement factor I (CFI) c.-13G>A, affecting the 5' UTR region of the gene. In addition, the patient was found to be heterozygous for the complement factor H (CFH) H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q and E936D polymorphisms) reported as a risk factor of atypical hemolytic uremic syndrome. This case of AKI associated with severe TMA and secondary hemolytic uremic syndrome highlights the importance of genetic risk modifiers in the alternative pathway dysregulation of the complement in the setting of COVID-19, even in asymptomatic forms.

Comparison of virus neutralization activity and results of 10 different anti-SARS-CoV-2 serological tests in COVID-19 recovered plasma donors.

Serological testing is a tool to predict protection against later infection. This potential heavily relies on antibody levels showing acceptable agreement with gold standard virus neutralization tests. The aim of our study was to investigate diagnostic value of the available serological tests in terms of predicting virus neutralizing activity of serum samples drawn 5-7 weeks after onset of symptoms from 101 donors with a history of COVID-19. Immune responses against Receptor Binding Domain (RBD), Spike1 and 2 proteins and Nucleocapsid antigens were measured by various ELISA tests. Neutralizing antibody activity in serum samples was assessed by a cell-based virus neutralization test. Spearman correlation coefficients between serological and neutralization results ranged from 0.41 to 0.91 indicating moderate to strong correlation between ELISA test results and virus neutralization. The sensitivity and specificity of ELISA tests in the prediction of neutralization were 35-100% and 35-90% respectively. No clear cut off levels can be established that would reliably indicate neutralization activity. For some tests, however, a value below which the sample is not expected to neutralize can be established. Our data suggests that several of the ELISA kits tested may be suitable for epidemiological surveys 1-2 months after the infection, estimating whether a person may have recently exposed to the virus. Sensitivities considerably superseding specificity at the cut-off values proposed by the manufacturers suggest greater potential in the identification of insufficient antibody responses than in confirming protection. Nevertheless, the former might be important in assessing response to vaccination and characterizing therapeutic plasma preparations.

Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection.

Objectives: Uncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19. Methods: In this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records. Results: Increased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55-8.45, 95% CI) and 6.1 (2.1-17.8), respectively]. Conclusion: Increased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.