Targeting complement in severe coronavirus disease 2019 to address microthrombosis

Abstract

There is no approved therapy for coronavirus disease 2019 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection], and the number of worldwide deaths on current standard therapy is staggering [1]. Current therapy is aimed at decreasing viral replication, supporting vital functions and addressing the most damaging consequences of the disease such as hyperinflammation (the so-called cytokine storm) and thrombosis. The latter two involve the use of anti-inflammatory therapies and heparin, respectively. We suggest that complement-blocking strategies such as eculizumab should be considered in severe cases not responding well to current therapy, including tocilizumab, in the context of clinical trials. Complement is thought to contribute to microangiopathies associated with infectious diseases [2].Recent histological data from COVID-19 patients are compatible with acute respiratory distress syndrome (ARDS) [3]. Additionally, vascular congestion and inflammatory cell infiltrates were present [4], as well as microvascular thrombi in multiple organs including kidneys in patients who died of COVID-19 and SARS [5,6]. Immunohistochemically, deposits of C5b-9, C4d and mannose-binding lectin-associated serine protease-2 have been found in the microvasculature of lungs and skin in patients with . Furthermore, COVID-19 shares some features with entities that are complement mediated, such as disseminated intravascular coagulation, thrombotic microangiopathy (TMA) and antiphospholipid antibody syndrome. These include increased lactate dehydrogenase (LDH) , platelet disease, hypertransaminasaemia, anaemia and extrapulmonary involvement, such as the

Kidney disease and electrolytes in COVID-19: more than meets the eye

“…AKI may fail to resolve, leading to acute kidney disease and, potentially, to post-COVID-19 CKD, a possibility that requires prospective follow-up. However, thrombotic microangiopathy as well as glomerular injury have also been observed [ 30 ]. Both the genetic background and comorbidities may impact on the severity of COVID-19 and on the type and severity of COVID-19-associated kidney injury.…”

“…Experimental tissue protective therapies undergoing clinical trials include anti-complement strategies (e.g. eculizumab) as well as the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i), which are drugs that may protect the kidneys and heart in both diabetic and non-diabetic environments [ 30 ]. Some images are taken from https://commons.wikimedia.org/wiki/File : Kidney_Nephron_Cells.png; https://commons.wikimedia.org/wiki/File : Pituitary_gland_image.png and https://commons.wikimedia.org/wiki/File : Heart_%26_Lungs.png.…”

“…Additionally, COVID-19 shares features with other microangiopathies such as thrombotic microangiopathy, disseminated intravascular coagulation and anti-phospholipid syndrome, as reviewed by Valga et al [ 30 ]. In fact, some patients develop anti-phospholipid antibodies; there is evidence for endothelial cell injury, complement activation and deposition (of C5-b9, C4d and mannose-binding lectin-associated serin protease) and microthrombi, in addition to predisposition to arterial and venous thrombosis [ 4 , 9 , 31–36 ].…”

“…In fact, some patients develop anti-phospholipid antibodies; there is evidence for endothelial cell injury, complement activation and deposition (of C5-b9, C4d and mannose-binding lectin-associated serin protease) and microthrombi, in addition to predisposition to arterial and venous thrombosis [ 4 , 9 , 31–36 ]. In addition to routine systemic anticoagulation, complement inhibition has been proposed as therapy and clinical trials are ongoing [ 30 , 37 ].…”

Complement and protection from tissue injury in COVID-19

“…Two manuscripts provide insights into the role of complement activation and its potential as a therapeutic target [ 1 , 2 ] in line with an increasing number of calls to target complement in COVID-19 [ 5–9 ]. While complement components are not usually assessed in routine care of COVID-19 patients, as illustrated by a recent detailed report of risk factors for severity of COVID-19 in chronic dialysis patients [ 10 ], Prendecki et al [ 1 ] took advantage of the thrice-weekly venous access in haemodialysis patients to describe a characteristic time course of circulating complement activation products that may help to define the severity and stage of the disease.…”