Legend
Table 1: Modified Ordinal Clinical Scale for COVID-19
Figure 1:
Panel A: Lung injury in coronavirus disease 2019 (COVID-19). Severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to
angiotensin-converting enzyme 2 (ACE-2) primarily on type II alveolar
cells. After endocytosis of the viral complex, surface ACE-2 is
down-regulated, resulting in unopposed angiotensin II accumulation.
SARS-CoV-2 further causes lung injury through activation of residential
macrophages, lymphocyte apoptosis, and neutrophils. The macrophages
produce cytokines and chemokines, resulting in a cytokine storm.
Inflammatory exudate rich in plasma borne coagulation factors enters the
alveolar space, followed by expression of tissue factor by alveolar
epithelial cells and macrophages and the formation of fibrin and the
hyaline membrane. Neutrophils in the alveoli cause formation of NETs,
composed of extracellular DNA, cytotoxic histones and neutrophil
elastase, which cause further lung injury. COVID-19 also induces
microvascular endothelial damage leading to increased permeability,
expression of tissue factor with coagulation activation and thrombus
formation.
Panel B: Proposed effects of inhaled nebulised unfractionated heparin
(UFH) in COVID-19 lung injury. UFH prevents SARS-CoV-2 from binding to
ACE-2 and from entering the alveolar cells. UFH reduces formation of the
hyaline membrane and microvascular thrombosis, counteracts the
hyperinflammation and the formation of NETs, increases NO release with
vasodilation, and also has mucolytic properties.
NETs = neutrophil extracellular traps, SARS-CoV-2 = severe acute
respiratory syndrome coronavirus 2, ACE-2 = angiotensin-converting
enzyme 2, COVID-19 = Coronavirus disease 2019
Appendix: Reporting checklist for a protocol, based on the SPIRIT
guidelines