scholarly journals Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

2021 ◽  
Author(s):  
Lina Ma ◽  
Sanjaya K. Sahu ◽  
Marlene Cano ◽  
Vasanthan Kuppuswamy ◽  
Jamal Bajwa ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Distinctive Feature ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Multiorgan Failure ◽  
Invasive Mechanical Ventilation ◽  
Tertiary Care ◽  
Endothelial Injury ◽  
Pathway Activation ◽  
Tertiary Care Centers

ABSTRACTComplement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.SUMMMARYComplement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.

scholarly journals Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

2021 ◽  
Vol 6 (59) ◽  
pp. eabh2259
Author(s):  
Lina Ma ◽  
Sanjaya K. Sahu ◽  
Marlene Cano ◽  
Vasanthan Kuppuswamy ◽  
Jamal Bajwa ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Distinctive Feature ◽  
Complement Activation ◽  
Invasive Mechanical Ventilation ◽  
Tertiary Care ◽  
Endothelial Injury ◽  
School Of Medicine ◽  
Tertiary Care Centers ◽  
Angiopoietin 2 ◽  
Von Willebrand

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

scholarly journals Time-Dependent Activation of Complement system during Storage of Platelet Product

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4287-4287
Author(s):  
Jian Chen ◽  
Shangbin Yang ◽  
Spero R Cataland ◽  
Haifeng M Wu
Keyword(s):  
Complement System ◽  
Complement Activation ◽  
Research Funding ◽  
Storage Time ◽  
Adverse Reactions ◽  
Alternative Pathway ◽  
Pathway Activation ◽  
The Complement System ◽  
Transfusion Reactions

Abstract Platelet transfusion is known for carrying a high incidence of clinically significant transfusion reactions such as febrile nonhemolytic transfusion reaction. The mechanism responsible for these transfusion-associated adverse events, however, is poorly understood. In this study, we hypothesize that prolonged in vitro storage activates the complement system in the platelet product that in turn causes a high frequency of transfusion reactions. Fresh platelet units obtained from three blood donors were stored on a temperature controlled platelet rotator between 22-24 C°. An aliquot of platelet product was obtained using sterile techniques from each unit on day 2 through day 7. The platelet product from each collection was then immediately centrifuged to obtain platelet poor plasma for the study of complement activation levels. For all study samples, C4d levels were assayed to evaluate the activation of the classical pathway, factor Bb levels were measured to determine the status of the complement alternative pathway, C3a levels were used to examine common pathway activation, and C5a and C5b-9 were assayed for determination of the terminal pathway activation of the complement system. The reference range for each complement factor was determined using citrated plasma from 40 healthy donors. As shown in table 1, both C4d and C3a demonstrated time-dependent increases relevant to storage time. On day 7, C4d and C3a levels were five-fold higher than their baseline levels measured on day 2. In contrast, factor Bb levels remained stable and within the normal range throughout the study. Over a storage span of seven days, the terminal complement factors C5a and C5b-9 were also significantly increased, although not as dramatically as C4d and C3a. Figure 1 illustrates a progressive increase of C3 activation in all three study donors over the time of storage (2-7 days). This report, for the first time, provides strong evidence that substantial complement activation occurs in the platelet products under standard storage conditions. A longer storage time of platelet product in vitro is accompanied by a remarkable elevation of complement activation biomarkers. By examining the pattern of complement profiles in the stored platelets, we further demonstrated that the activation of the classic pathway, rather than alternative pathway, appears to be the driving event that leads up to a level of over-reactivity of the complement system. Given the fact that complement hyperactivation is known to disrupt host homeostasis and cause disease, the adverse reactions seen in platelet recipients is likely related to the infusion of C3a and C5a which are known to be potent inflammatory cytokines. The observations from this study therefore provide a new perspective in understanding the pathophysiology responsible for adverse reactions from platelet transfusions. Further studies will be required to fully evaluate the clinical impact of complement activation in transfused platelet products. Figure 1 Figure 1. Disclosures Cataland: Alexion Corporation: Honoraria, Research Funding, Speakers Bureau. Wu:Alexion Corporation: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Anti-Factor B Antibodies and Acute Postinfectious GN in Children

2020 ◽  
Vol 31 (4) ◽  
pp. 829-840 ◽  
Author(s):  
Sophie Chauvet ◽  
Romain Berthaud ◽  
Magali Devriese ◽  
Morgane Mignotet ◽  
Paula Vieira Martins ◽  
...  
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Functional Characterization ◽  
C3 Glomerulopathy ◽  
Contributing Factors ◽  
Factor B ◽  
Pathway Activation ◽  
Nephritic Syndrome ◽  
French Registry

BackgroundThe pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis.MethodsThis retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia.ResultsAll children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity in vitro, confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity.ConclusionsThese findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.

scholarly journals Complement Factor D protects mice from ethanol-induced inflammation and liver injury

2018 ◽  
Vol 315 (1) ◽  
pp. G66-G79 ◽  
Author(s):  
Rebecca L. McCullough ◽  
Megan R. McMullen ◽  
Megan M. Sheehan ◽  
Kyle L. Poulsen ◽  
Sanjoy Roychowdhury ◽  
...  
Keyword(s):  
Liver Injury ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Chronic Ethanol ◽  
Apoptotic Cells ◽  
Complement Factor ◽  
Complement Protein ◽  
Short Term ◽  
Pathway Activation

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa−/−, lacking classical pathway activation), complement protein 4-deficient ( C4−/−, lacking classical and lectin pathway activation), complement factor D-deficient ( FD−/−, lacking alternative pathway activation), and C1qa/FD−/− (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa−/−, C4−/−, or C1qa/FD−/− mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD−/− mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD−/− mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD−/− mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.

scholarly journals Urine complement activation fragments are increased in patients with kidney injury after cardiac surgery

2019 ◽  
Vol 317 (3) ◽  
pp. F650-F657 ◽  
Author(s):  
Jennifer Laskowski ◽  
Heather Thiessen Philbrook ◽  
Chirag R. Parikh ◽  
Joshua M. Thurman
Keyword(s):  
Acute Kidney Injury ◽  
Cardiac Surgery ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Urine Biomarkers ◽  
Pathway Activation ◽  
Alternative Pathway Of Complement ◽  
Subsequent Rise

Experiments in mouse models have shown that the complement cascade is activated within the kidney after ischemia-reperfusion and that complement activation contributes to tubular injury in this setting. Less is known, however, about complement activation in human kidneys after ischemia or whether complement activation in the tubulointerstitium can be detected by measurement of complement fragments in the urine. We hypothesized that urine biomarkers of complement activation would rapidly increase in patients who develop ischemic acute kidney injury, signaling complement activation within the kidney. We confirmed that the alternative pathway of complement is activated in the kidneys of mice after ischemia-reperfusion, and we found that levels of factor B fragments (generated during alternative pathway activation) rapidly increase in the urine. We next performed a case-control study in which we measured complement fragments in human urine samples from patients undergoing cardiac surgery using ELISAs. The level of Ba increased after cardiac surgery and was significantly higher in patients who developed acute kidney injury. The increase in Ba also correlated with magnitude of the subsequent rise in serum creatinine and with the need for hemodialysis during the hospitalization. These findings demonstrate that the alternative pathway of complement is activated in patients who develop acute kidney injury after cardiac surgery and that increases in the level of urine Ba may be a predictive and functional biomarker of severe kidney injury.

Inhaled Nitric Oxide Treatment for Stabilization and Emergency Medical Transport of Critically Ill Newborns and Infants

PEDIATRICS ◽  
1995 ◽  
Vol 95 (5) ◽  
pp. 773-776
Author(s):  
John P. Kinsella ◽  
Jeffrey M. Schmidt ◽  
Jeff Griebel ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Respiratory Failure ◽  
Critically Ill ◽  
Tertiary Care ◽  
Inhaled Nitric Oxide ◽  
Hypoxemic Respiratory Failure ◽  
Emergency Medical ◽  
Medical Transport ◽  
Tertiary Care Centers ◽  
Inhaled No

Stabilization and transport of critically ill newborns and infants is a vital component of regionalized care. With the advent and proliferation of new therapies for the management of severe hypoxemic respiratory failure, emergency medical transport to tertiary care centers increasingly requires novel transport innovations. Inhaled nitric oxide (NO) therapy has been used in the management of severe persistent pulmonary hypertension of newborns (PPHN) and of hypoxemic respiratory failure in older pediatric patients.1-5 We report the use of inhaled NO therapy during transport in six patients with critical hypoxemia. This report describes a practical approach to stabilization and transport of critically ill newborns and infants using inhaled NO.

scholarly journals Thrombomodulin is Associated with Increased Mortality and Organ Failure in Mechanically Ventilated Children with Acute Respiratory Failure: A Prospective Observational Study.

2021 ◽  
Author(s):  
Ana C Monteiro ◽  
Heidi Flori ◽  
Mary K Dahmer ◽  
Myung Shin Sim ◽  
Michael W. Quasney ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Observational Study ◽  
Vascular Injury ◽  
Prospective Observational Study ◽  
Cox Regression ◽  
Multiorgan Failure ◽  
Invasive Mechanical Ventilation ◽  
Oxygenation Index ◽  
Mixed Effect ◽  
Soluble Thrombomodulin

Abstract BACKGROUNDAcute respiratory failure (ARF) can progress to acute respiratory distress syndrome (ARDS) and death. Biomarkers such as soluble thrombomodulin (sTM), implicated in pulmonary vascular injury, may allow for risk stratification and prognostic enrichment in ARF.METHODSThis was a prospective observational study of 432 patients aged 2 weeks - 17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-hour intervals within 5 days after intubation. sTM was assayed by ELISA. Hazard ratio (HR) for 90-day mortality was determined by cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses.RESULTSsTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n=432, adjusted HR= 1.003, p=0.02) and worse OI in the first 5 days after intubation (n=252, Estimate = 0.02, p<0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate=0.003, p<0.0001; and slope, Estimate=0.01, p=0.0009, n= 386). CONCLUSIONSPlasma sTM are associated with mortality, severity of ARDS extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in pathogenesis of ARF and provide potential application for targeted therapies. TRIAL REGISTRATIONNCT00814099

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