Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19

Valenti, Luca; Griffini, Samantha; Lamorte, Giuseppe; Grovetti, Elena; Renteria, Sara Colonia Uceda; Malvestiti, Francesco; Scudeller, Luigia; Bandera, Alessandra; Peyvandi, Flora; Prati, Daniele; Meroni, Pier Luigi; Cugno, Massimo

doi:10.1016/j.jaut.2021.102595

Cited by 49 publications

(49 citation statements)

References 31 publications

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“…In thrombotic microangiopathies, often a genetic predisposition, in combination with an inciting factor for endothelial damage, triggers a feed-forward loop which contributes to thrombosis and ongoing tissue injury (14). To that accord, a genetic predisposition toward complement activation has been reported in COVID-19 (17,19). Vis-à-vis markers of complement activation, C5a, generated from complement activation, is a potent chemoattractant for myeloid cells such as neutrophils and monocytes/macrophages (40).…”

Section: Discussionmentioning

confidence: 99%

“…2F). Increase in components of the alternative pathway are associated with worse outcomes in COVID- 19 We also investigated specific components of the complement cascade that may facilitate complement activation in COVID-19. In the WUSM cohort, the ratio of iC3b: C3 levels, which indicates complement activation resulting in cleavage of C3 (and is suggestive of but is not exclusively restricted to alternative pathway activation), was higher in patients needing ICU admission (Table 2, Fig.…”

Section: Markers Of Complement Activation Are Higher In Covid-19 Compared To Non-covid-19 Respiratory Failurementioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Markers Of Complement Activation Are Higher In Covid-19 Compared To Non-covid-19 Respiratory Failurementioning

confidence: 99%

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

et al. 2021

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“…In thrombotic microangiopathies, often a genetic predisposition, in combination with an inciting factor for endothelial damage, triggers a feed-forward loop which contributes to thrombosis and ongoing tissue injury (Java et al ., 2020). A genetic predisposition towards complement activation has been reported in COVID-19 (Ramlall et al ., 2020; Valenti et al ., 2021). Additionally, infiltrating neutrophils can express prothrombotic proteins such as tissue factor (TF), both via direct expression and via neutrophil extracellular traps, driving platelet-mediated NET-driven thrombogenicity (Skendros et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The complement system, one of the first lines of the host defense and a key player in the innate immune response, has been implicated in the pathogenesis of severe COVID-19 (Holter et al ., 2020; Java et al ., 2020; Skendros et al ., 2020). Features of disease such as hypercoagulability and tissue necrosis, as well as genetic factors have increased the suspicion that the complement system contributes to severe illness (Java et al ., 2020; Perico et al ., 2020; Ramlall et al ., 2020; Valenti et al ., 2021). The system can be activated by three arms – the classical, lectin or the alternative pathway (Kulkarni et al ., 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Sahu

Cano

et al. 2021

Preprint

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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. 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.

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“…Here, precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis and treatment of many diseases, based on data from multiomics technologies, data statistics and modeling (14)(15)(16)(17)(18)(19)(20)(21). Genome-wide-association studies (GWAS) of COVID-19 are rather at the beginning but are highly promising to reveal critical illness cases (22,23). For data gathering, diagnostics and prediction models machine and deep learning techniques and applications of artificial intelligence are of utmost importance but also need to be critically reviewed (24)(25)(26)(27)(28)(29).…”

Section: From Molecular To Organismal Systems Medicinementioning

confidence: 99%

The Quest for System-Theoretical Medicine in the COVID-19 Era

et al. 2021

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Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and the limits of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum.

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Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19

Cited by 49 publications

References 31 publications

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

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

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

The Quest for System-Theoretical Medicine in the COVID-19 Era

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