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]