Complement levels at admission as a reflection of coronavirus disease 2019 (COVID-19) severity state.

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.

Complement C3 identified as a unique risk factor for disease severity among young COVID-19 patients in Wuhan, China.

Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38-55, range 18-60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

Risk Factors for Mortality of COVID-19 Patient Based on Clinical Course: A Single Center Retrospective Case-Control Study.

Background: Epidemiological factors, clinical characteristics, and risk factors for the mortality of COVID-19 patients have been studied, but the role of complementary systems, possible inflammatory and immune response mechanisms, and detailed clinical courses are uncertain and require further study. Methods: In this single center, retrospective case-control study, we included all COVID-19 inpatients transferred or admitted to Wuhan Tongji Hospital from January 3 to March 30 2020 who had definite clinical outcomes (cured or deceased) with complete laboratory and radiological results. Clinical data were extracted from the electronic medical records, and compared between the cured and deceased patients. ROC curves were used to evaluate the prognostic value of the clinical parameters, and multivariable logistic regression analysis was performed to explore the risk factors for mortality. The correlation between the variables was evaluated by Spearman correlation analysis. Results: 208 patients were included in this study, 182 patients were cured and discharged, 26 patients died from COVID-2019. Most patients had comorbidities, with hypertension as the most common chronic disease (80; 38%). The most common symptoms at onset were fever (149; 72%), cough (137; 66%), and dyspnea (113; 54%). Elevated leucocytes, neutrophils, inflammatory biomarkers (CRP, ferritin, IL6, IL8, procalcitonin), PT, D-dimer, myocardial enzymes, BUN, decreased lymphocyte and subsets (T cells, CD4 T cells, CD8 T cells, NK cells, T cells + B cells + NK cells), and immunological factors (C3, C4) indicated poor outcome. PT, C3, and T cells were confirmed as independent prognostic factors for mortality by logistic regression models. IL6 and CPR were positively correlated with neutrophils, but negatively with lymphocytes and lymphocyte subsets except B cells. IL8 and ferritin were negatively related to T cells and CD4 T cells. Positive associations existed between C3 and T cells, CD4 T cells, and CD8 T cells, whereas there was no significant correlation between C4 and lymphocyte subsets. PT was found positively correlated with IL6, IL8, and CRP. Reverse correlations were explored between C3, C4, and PT, CK-MB, total bilirubin. Conclusions: T cells, C3, and PT were identified as independent prognostic factors for mortality. Decreased C3 and C4, dysregulation of lymphocyte subsets and cytokines may lead to death after SARS-CoV-2 infection.

Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients.

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients were associated with the severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56- CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA, and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless of their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes, and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic intervention.

Decreased complement C3 levels are associated with poor prognosis in patients with COVID-19: A retrospective cohort study.

OBJECTIVES: To describe the humoral immune feature of patients with coronavirus disease 2019 (COVID-19). METHODS: The levels of total immunoglobulins (IgG, IgM, IgA, and IgE), complement (C3, C4) results were retrospectively analyzed in COVID-19 patients. Univariable and multivariable logistic regression were performed to explore the risk factors associated with the in-hospital death. RESULT: A total of 236 patients were enrolled in this study, of which 169 were transferred to another institution or discharged (survival group) and 67 died in hospital (non-survival group). Compared with survivors, the levels of IgA and IgE in non-survivors increased significantly, and level of complement C3 decreased. Non-survivors also showed higher incidence of chest tightness, breath shortness and dyspnoea; higher levels of inflammatory indicators, leukocytes and neutrophils; and low levels of lymphocyte subsets. Multivariable regression showed increasing odds of in-hospital death associated with older age (HR: 1.099; 95%CI: 1.057-1.143; p < 0.0001), d-dimer greater (HR: 1.294; 95%CI: 1.138-1.473; p < 0.0001) and decreased complement C3 level (HR: 0.073; 95%CI: 0.007-0.722; p = 0.025) on admission. Finally, in survival COVID-19 patients whose humoral immunity was re-examined, C3 levels tended to increase, while in non-survivors it decreased. CONCLUSION: Low level of complement C3 may be an alert to the admitted COVID-19 patients with additional management. Inhibition of the complement pathway might be an effective therapeutic to COVID-19 patients.

Contribution of acute-phase reaction proteins to the diagnosis and treatment of 2019 novel coronavirus disease (COVID-19).

The emergence of 2019 novel coronavirus disease (COVID-19) is currently a global concern. In this study, our goal was to explore the changing expression levels of acute-phase reaction proteins (APRPs) in the serum of COVID-19 patients and to elucidate the immunological characteristics of COVID-19. In the study design, we recruited 72 COVID-19 patients, including 22 cases of mild degree, 38 cases of moderate degree and 12 cases of severe degree. We also recruited 20 patients with community-acquired pneumonia (CAP) and 20 normal control subjects as a comparison. Fasting venous blood was taken to detect the content of complement 3 (C3), complement 4 (C4), C-reactive protein (CRP), serum amyloid A (SAA) and prealbumin (PA). When compared the COVID-19 group with the CAP and normal control groups, respectively, the mean value of CRP and SAA in the COVID-19 group (including mild, moderate and severe patients) had increased significantly (P < 0.01), whereas the mean values of C3, C4 and PA decreased (P < 0.01). For the asymptomatic or mild symptomatic patients with COVID-19, the actual aggravation of disease may be more advanced than the clinical appearances. Meanwhile, the statistical analyses indicated that the development of COVID-19 brought about a significant increase in the content of CRP and SAA (P < 0.01), and a decline in the content of C3, C4 and PA (P < 0.01). These findings suggested that the changes in the level of APRPs could be used as indicators to identify the degree and progression of COVID-19, and the significant changes might demonstrate the aggravation of disease. This study provided a new approach to improve the clinical management plan and prognosis of COVID-19.