Rationale for targeting complement in COVID‐19

Polycarpou, Anastasia; Howard, Mark; Farrar, Conrad A.; Greenlaw, Roseanna; Fanelli, Giorgia; Wallis, Russell; Klavinskis, Linda; Sacks, Steven

doi:10.15252/emmm.202012642

Cited by 114 publications

(135 citation statements)

References 132 publications

(160 reference statements)

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“…With the extensive complement activation and widespread endothelial destruction, inhibition of complement pathways may also represent a favorable therapeutic target [ 61 , 62 ]. Compassionate use of the C3 inhibitor AMY-101, as well as the anti-CD5 monoclonal antibody eculizumab have shown anecdotal success [ [63] , [64] , [65] ].…”

Section: Discussionmentioning

confidence: 99%

“…Compassionate use of the C3 inhibitor AMY-101, as well as the anti-CD5 monoclonal antibody eculizumab have shown anecdotal success [ [63] , [64] , [65] ]. Mannan binding lectin has also been proposed as a therapeutic target given its gatekeeping role in complement activity and endothelial damage [ 66 ]. A number of trials are now underway with inhibitors to complement and mannan binding lectin as novel therapeutic targets [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Severe COVID-19: A multifaceted viral vasculopathy syndrome

Magro

Mulvey

Kubiak

et al. 2021

Annals of Diagnostic Pathology

116

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The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Severe COVID-19: A multifaceted viral vasculopathy syndrome

Magro

Mulvey

Kubiak

et al. 2021

Annals of Diagnostic Pathology

116

View full text Add to dashboard Cite

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“…That supposition was first supported by promising data from patients treated with complement inhibitors (116)(117)(118)(119). Polycarpou et al (120) suggested that targeting complement might contribute to reducing COVID-19 systemic complications (multiorgan failure, coagulopathy), mediated by lectin pathway activation. Therefore, inhibition of the complement system at the levels of C3 or C5a/ C5aR is considered a possible therapeutic option (121,122).…”

Section: Possible Associations Of Complement Activation Via the Lectimentioning

confidence: 99%

The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System

Świerzko

Cedzyński

2020

Front. Immunol.

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Lung diseases are among the leading causes of morbidity and mortality. Complement activation may prevent a variety of respiratory infections, but on the other hand, could exacerbate tissue damage or contribute to adverse side effects. In this review, the associations of factors specific for complement activation via the lectin pathway (LP) with infections of the respiratory system, from birth to adulthood, are discussed. The most extensive data concern mannose-binding lectin (MBL) which together with other collectins (collectin-10, collectin-11) and the ficolins (ficolin-1, ficolin-2, ficolin-3) belong to patternrecognition molecules (PRM) specific for the LP. Those PRM form complexes with MBLassociated serine proteases (MASP-1, MASP-2, MASP-3) and related non-enzymatic factors (MAp19, MAp44). Beside diseases affecting humanity for centuries like tuberculosis or neonatal pneumonia, some recently published data concerning COVID-19 are summarized.

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“…A therapeutic anti‐inflammatory strategy against complement has the potential to stem the downstream inflammatory response and capillary leak, and, consequently, lung damage and CARDS, assuming adequate tissue penetration of drug to the site of complement activation [ 95 ]. A number of clinically ready potential therapeutic agents are available.…”

Section: Other Potential Therapiesmentioning

confidence: 99%

Pharmacological management of COVID-19 patients with ARDS (CARDS): A narrative review

Matera

Rogliani

Calzetta

et al. 2020

Respiratory Medicine

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Coronavirus disease 2019 (COVID-19) is highly infectious. It has been highlighted that if not expertly and individually managed with consideration of the vasocentric features, a COVID-19 patient with an acute respiratory distress syndrome (CARDS) may eventually develop multiorgan failure. Unfortunately, there is still no definite drug for CARDS that is capable of reducing either short-term or long-term mortality and no specific treatments for COVID-19 exist right now. In this narrative review, based on a selective literature search in EMBASE, MEDLINE, Scopus, The Cochrane Library, Web of Science, and Google Scholar and ClinicalTrials.gov , we have examined the emerging evidence on the possible treatment of CARDS. Although numerous pharmacologic therapies to improve clinical outcomes in CARDS have been studied also in clinical trials, none have shown efficacy and there is great uncertainty about their effectiveness. There is still no recommendation for the therapeutic use of any specific agent to treat CARDS because no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale trials. However, there exist a number of drugs that may be useful at least in some patients. The real challenge now is to link the right patient to the right treatment.

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Rationale for targeting complement in COVID‐19

Cited by 114 publications

References 132 publications

Severe COVID-19: A multifaceted viral vasculopathy syndrome

Severe COVID-19: A multifaceted viral vasculopathy syndrome

The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System

Pharmacological management of COVID-19 patients with ARDS (CARDS): A narrative review

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