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]