Introduction
Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people globally, with many patients requiring hospitalisation and ventilatory support. The pathophysiology of COVID-19 is characterised by microvascular thrombosis and coagulopathy accompanied by diffuse alveolar damage, inflammation, DNA neutrophil extracellular traps (NETS) and hyaline membrane formation [1]. We previously described the scientific rationale for nebulised unfractionated heparin (UFH) to be a potentially effective treatment for COVID-19 because of its broad anti-inflammatory activity combined with its anti-coagulant and anti-viral effects [1].
In early-phase trials in patients with acute lung injury, nebulised UFH reduced microvascular thrombosis and hypercoagulation, improved pulmonary dead space and reduced lung injury, with increased time free of ventilatory support [2-4]. Furthermore, in a pre-pandemic, multicentre, double-blind, randomised controlled study in 256 critically ill ventilated patients, nebulised UFH limited survivors’ lung injury and accelerated their return to home [5]. Nebulised heparin has also been shown to benefit patients with a number of other respiratory conditions including ARDS [6] and COPD [7], importantly without major safety concerns.
We and others have shown that heparin is able to bind the spike protein expressed by the SARs-CoV-2 virus [8, 9] and that UFH in particular reduced the ability of the virus to infect cells in vitro. SARS-CoV-2 Spike protein binding to human epithelial cells requires the engagement of both cell surface heparan sulphate (HS) and angiotensin-converting enzyme 2 (ACE-2), with HS acting as a co-receptor for ACE-2 interaction. UFH has the ability to compete for binding of the SARS-CoV-2 S protein to cell surface HS, and thus reduce infectivity [8]. Additionally, the SARS-CoV-2 Spike S1 protein receptor-binding domain attaches to UFH and undergoes a conformational change that blocks the binding to the AC2 receptor and infectivity of SARS-CoV-2 to Vero E6 cells [9]. This inhibition of SARS-CoV-2 infection of Vero E6 cells by UFH is concentration-dependent, occurs at therapeutically relevant concentrations likely to be achieved following inhalation, and exhibited a significantly stronger anti-viral effect compared to low molecular weight heparins (LMWHs) [8, 9].
These observations suggest that UFH uniquely possesses anti-coagulant, anti-inflammatory, and anti-viral activity [1, 10, 11] of relevance to the treatment of COVID-19. It is now well recognised that the use of systemic heparin provides an overall beneficial effect in the treatment of patients with COVID-19 when administered as part of the standard of care [12]. The rationale for investigating nebulized UFH is that when administered by this route, the drug is retained within the lung and therefore could provide local anti-inflammatory, anticoagulant, and antiviral activity on top of the effect of systemic heparin and other treatments recognised as standard of care; thus, local availability of heparin in the lung following nebulisation may ensure sufficient airway luminal concentrations capable of reducing viral infection, alveolar coagulation and inflammation above that achieved with systemic administration of heparin.
If efficacy is confirmed, the low cost of the drug may make this treatment accessible for low- and middle-income countries.
Here, we report the safety and efficacy of nebulised UFH in a pilot study in patients with COVID-19 admitted to two hospitals in the state of Sao Paulo, Brazil during the regional peak of the pandemic with the delta variant of SARs-CoV-2. This trial also forms part of a larger meta-trial established to investigate the potential benefit of nebulised UFH in hospitalised COVID-19 patients [13]