Introduction
In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) emerged in China and has since spread globally. Nearly 20% of patients with coronavirus disease 2019 (COVID-19) experience hypoxaemia, which is the primary reason for hospitalisation.[1] A significant proportion of patients admitted to hospital for COVID-19 develop acute respiratory failure, with 12-24% requiring intubation for invasive mechanical ventilation.[2-6]
The pathophysiology of COVID-19 associated lung injury is summarised in Figure 1A and is characterised by diffuse alveolar damage, hyperinflammation, coagulopathy, DNA neutrophil extracellular traps (NETS), hyaline membranes and microvascular thrombosis. The scientific rationale and current pre-clinical and clinical evidence for the use of nebulised unfractionated heparin (UFH) as a treatment for COVID-19 has been outlined previously.[7, 8] Nebulised UFH has anti-viral, anti-inflammatory, anticoagulant, and mucolytic effects. The SARS-CoV-2 Spike S1 protein receptor binding domain attaches to UFH and undergoes conformational change that prevents it from binding to the Angiotensin Converting Enzyme 2 (ACE-2) receptor.[9, 10] It was recently demonstrated that spike protein binding to human epithelial cells requires engagement of both cell surface heparan sulphate (HS) and ACE-2, with HS acting as a co-receptor for ACE-2 interaction, and UFH blocked the binding and infectivity of SARS-CoV-2 to human bronchial epithelial cells.[11] The inhibition of SARS-CoV-2 infection of Vero E6 cells by an UFH preparation was found to be concentration dependent, occurred at therapeutically relevant concentrations and is significantly stronger compared to low molecular weight heparins (LMWHs).[12] The anti-inflammatory effects of inhaled UFH are thought to reduce pulmonary hyperinflammation and the generation of DNA NETs, both of which contribute to COVID-19 lung injury. The anticoagulant actions of nebulised UFH limit fibrin deposition, hyaline membrane formation and microvascular thrombosis, which are also important features of COVID-19. The effects of nebulised UFH in COVID-19 are summarised in Figure 1B.
Animal studies of nebulised UFH in different acute lung injury models have consistently shown a positive effect on pulmonary coagulation, inflammation and oxygenation.[7] Small human studies indicate that nebulised UFH limits pulmonary fibrin deposition, attenuates progression of acute lung injury and hastens recovery.[7] Early-phase trials in patients with acute lung injury and related conditions found that nebulised UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis, improved lung injury and increased time free of ventilatory support.[13-17] A multi-centre randomised double-blind placebo-controlled trial of nebulised heparin in 256 patients with or at risk of developing ARDS demonstrated reduced progression of lung injury, fewer cases of ARDS and accelerated recovery with more survivors at home by day 60.[18]
We hypothesise that treatment with inhaled nebulised UFH of hospitalised patients with COVID-19 limits progression to acute respiratory failure requiring intubation, reduces the risk of death, reduces the risk of clinical worsening, and improves oxygenation. The collective goal of the proposed meta-trial is to reach a conclusion about the efficacy of inhaled UFH in COVID-19 as quickly as possible by pooling information from multiple clinical trials not originally configured as a network.[19]