Complement Activation in the Disease Course of Coronavirus Disease 2019 and Its Effects on Clinical Outcomes

Nooijer, Aline H. de; Grondman, Inge; Janssen, Nico; Netea, Mihai G.; Willems, Loek; Veerdonk, Frank L. van de; Giamarellos‐Bourboulis, Evangelos J.; Toonen, Erik J. M.; Joosten, Leo A. B.; Jaeger, Martin; Dijkstra, Helga; Lemmers, Heidi; Emst, Liesbeth van; Schraa, Kiki; Jacobs, C.J.M.G.; Hijmans, Anneke; Jansen, Trees; Weren, Fieke; Fransman, Liz; Gerretsen, Jelle; Maat, Josephine van de; Nijman, Gerine; Moorlag, Simone J.C.F.M.; Taks, Esther; Debisarun, Priya A.; Kouijzer, Ilse J.E.; Wertheim, Heiman; Hopman, Joost; Rahamat‐Langendoen, Janette; Bleeker‐Rovers, Chantal P.; Oever, Jaap ten; Crevel, Reinout van; Hoogerwerf, Jacobien J.; Mast, Quirijn de; Hoeven, Hans van der; Pickkers, Peter; Kox, Matthijs; Frenzel, Tim; Schouten, Jeroen; Hemelaar, Pleun; Beunders, Remi; Velde, Sjef van der; Kooistra, Emma J.; Waalders, Nicole J. B.; Claassen, Wout; Heesakkers, Hidde; Schaik, Tirsa van; Eng, Hetty van der; Rovers, Noortje; Klop-Riehl, Margreet

doi:10.1093/infdis/jiaa646

Cited by 96 publications

(108 citation statements)

References 41 publications

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“…The demonstration of complement C3 overactivation and consumption, and its strong association with COVID-19 severity and outcome, is intriguing and confirms recent observations. First, the RCI-COVID-19 group demonstrated activation of complement with elevated C3a, sC5b-9, and C3c levels in severe COVID-19 ( 27 ). High levels of complement activation markers were associated with mortality and thromboembolic complications, however, prediction of mortality was not formally evaluated in survival models.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with various infections may benefit from laboratory evaluation of the complex system, which can show the presence of complement deficiency, activation state, or consumption of the whole system, or its dedicated pathways (24,25). Two recent studies have shown a clear association between respiratory failure, COVID-19 outcome, and systemic complement activation (26,27) in COVID-19 patients. Furthermore, a large-scale multi-omic analysis of COVID-19 severity mapped several molecular features including the complement system, and identified strong associations between complement activation and severe COVID-19 phenotype (28).…”

Section: Introductionmentioning

confidence: 99%

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

Sinkovits

Mező

Réti³

et al. 2021

Front. Immunol.

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ObjectivesUncontrolled 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.MethodsIn 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.ResultsIncreased 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].ConclusionIncreased 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sinkovits

Mező

Réti³

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

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“…In COVID-19, these activated pathways converge, resulting in production of complement anaphylatoxins C3a and C5a, which are known to increase immune cell recruitment, exacerbate endothelial damage by promoting release of reactive oxygen species, and exert deleterious pro-thrombotic effects [ 152 , 162 , 163 ]. Evidence for C3a/C5a production can be found in multiple clinical studies [ 158 , 163 , 164 ], one of which identified elevated plasma levels of C3a and C5a in 39 COVID-19 patients receiving maintenance hemodialysis [ 157 ]. Furthermore, treatment of COVID-19 patients with an anti-C5a antibody decreased systemic inflammation and increased lung oxygenation [ 160 ].…”

Section: Consequences Of Endothelium Dysfunction In Covid-19mentioning

confidence: 99%

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Bernard

Limonta

Mahal

et al. 2020

Viruses

137

121

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The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.

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“…In addition, the plasma levels of C3a and MAC were higher in ICU when compared to non-ICU patients. However, similar plasma C3c levels were observed in both groups of COVID-19 patients [ 44 ]. In a similar way, Holter et al [ 45 ] observed a systemic activation of the Complement System in COVID-19 patients with increased levels of C4d, C3bBbP, C3bc, C5a, and sC5b-9.…”

Section: The Controversial Role Of the Complement System During Coronmentioning

confidence: 68%

A double edged-sword - The Complement System during SARS-CoV-2 infection

et al. 2021

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In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.

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Complement Activation in the Disease Course of Coronavirus Disease 2019 and Its Effects on Clinical Outcomes

Cited by 96 publications

References 41 publications

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

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

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

A double edged-sword - The Complement System during SARS-CoV-2 infection

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