COVID-19-induced hypoxaemia: Focus on endothelium-red blood cell interaction
Dear Editor,
The mechanism of severe hypoxaemia during early stages of COVID-19 has remained a mystery. Although, early studies suggested viral pneumonitis as the main cause of hypoxemia, recent reports have questioned the existence of a typical acute respiratory distress syndrome (ARDS) as the main pathophysiologic feature of severe hypoxemia during SARS-Cov2 infection 1. The main characteristics of atypical ARDS in COVID-19 are as follows: (a) severe hypoxemia with relatively well-preserved lung mechanics1, (b) increased chance of pulmonary thrombosis2, (c) the presence of severe ventilation/prefusion mismatch. To explain all these features, we should have a closer look at red blood cell (RBC) and endothelium interaction in patients with COVID-19. The dynamic crosstalk between RBCs and endothelium is crucial in maintaining pulmonary perfusion in health and disease. The following evidence may suggest a role of RBC-endothelium interaction during COVID-19:
(1) Angiotensin-Converting Enzyme-2 (ACE2) is abundantly expressed in arterial and venous endothelial cells in the lung 3. This surface protein appears to be the main binding site of SARS-Cov2 as well as the main point of entry to the endothelial cells4. Endothelial cells adapt their phenotype (e.g. procoagulant phenotype) according to the local microenvironment, particularly during viral infection 5.
(2) SARS-Cov2 can also bind and enter RBCs through CD147 (the same point of entry of malaria parasite) 6. A recent in silico study has suggested that the viral protein (i.e. ORF1ab, ORF10, and ORF3a) may bind to haemoglobin beta-chain and release free haem7. Chloroquine, which has recently been considered for clinical management of COVID-19, has an apparent ability to inhibit SARS-Cov2-haemoglobin interaction 7.
(3) Endothelial cells are the main cells involved in haem metabolism using haem oxygenase, a critical enzyme responsible for production of the endogenous gaseous transmitter, carbon monoxide (CO). It is well known that free haem upregulates endothelial haem oxygenase expression8. Increased production of endogenous CO has not yet been investigated in COVID-19 patients. However, at least in theory, exaggerated production of CO may further inhibit haemoglobin saturation and causes vasodilatation in the pulmonary circulation. Local hypoxia-induced vasoconstriction is a physiological compensatory mechanism in the lung to prevent formation of shunt and ventilation/perfusion mismatch. Exaggerated formation of gaseous transmitters such as CO can attenuate this physiological mechanism and may enhance ventilation/perfusion mismatch and thus hypoxaemia.
Investigating the complex interaction between RBC and endothelium may bring together different parts of the jigsaw puzzle on the pathophysiology of COVID-19 (pulmonary thrombosis, pulmonary shunt and severe hypoxaemia). If future investigations show that such interaction is impaired in COVID-19, RBC/endothelium could become a plausible target for therapy in patients with severe hypoxaemia. Thus, the following therapies can be suggested in management of COVID-19-induced hypoxaemia:
(a) Blood transfusion in conjunction with iron chelation: Blood transfusion is not routinely recommended in typical ARDS9. However, the unique pathophysiology of COVID-19 may make it an exceptional respiratory distress syndrome that respond to transfusion. At least in theory, RBC transfusion or therapeutic red cell exchange may increase the pool of RBCs that are able to carry oxygen in patients with COVID-19-induced hypoxemia. Since SARS-Cov2 binds to RBCs, new red cells may also act as a decoy receptor and reduce viral load. To prevent iron overload and exacerbation of tissue injury during blood transfusion, iron chelators (e.g. deferoxamine) may be given in conjunction with blood transfusion. This is similar to the treatments strategy currently used in patients with hemoglobinopathies such as beta thalassemia.
(b) Hyperbaric oxygen therapy: Our knowledge on optimum characteristics of mechanical ventilation is evolving during the pandemic. Some critical care specialists suggest that protocol-driven mechanical ventilation used for standard ARDS could be doing more harm than good in patients with COVID-19 1. If studies show that gaseous transmitters (such as CO and hydrogen sulphide) play an important role in pathophysiology of COVID-19, hyperbaric oxygen therapy might be a good way to support patients with severe symptoms.
(c) Inhibition of haem oxygenase: Another strategy could be considering haem oxygenase as a target for therapy. Understanding the role of endogenous CO in pathophysiology of ventilation/perfusion mismatch in COVID-19 may open new insight into finding novel targets for therapy.
(d) Stimulation of foetal haemoglobin expression: If beta chain of haemoglobin is the main target for SARS-Cov2 related protein inside the RBCs, it is logical to suggest that stimulation of foetal haemoglobin (HbF) expression may help COVID-19 patients who are at risk of severe hypoxemia. Short-chain fatty acids as well as erythropoietin are shown to stimulate HbF expression 10. This can be considered within the context of COVID-19.
Ali R. Mania, Keshvad Hedayatyanfardb, Razieh Mohammad Jafaric, Parsa Mohammadic, Shahram Ejtemaei Mehrc, Ahmad R. Dehpourc
a Division of Medicine, UCL, London, UK (a.r.mani@ucl.ac.uk)