4.4. Possible Reasons for Carboxyhemoglobinemia in COVID-19 Patients
Since the blood COHb concentration reflects the balance between endogenous CO production and CO elimination, carboxyhemoglobinemia in COVID-19 patients could indicate an increased endogenous CO production and/or a decreased CO elimination ability.
Endogenous CO production is mainly due to the inducible heme oxygenase (HO-1) enzyme, which catalyzes the heme moiety of Hb to biliverdin and liberates CO during this process. CO can then react with Hb, leading to the formation of COHb. HO-1 is upregulated in case of oxidative stress and inflammation which leads to increased COHb production [73,74]. Hemolytic anemia facilitates the production process of COHb so that an increased COHb blood level can be seen as a manifestation of hemolytic anemia [75]. Since anemia and hemolysis possibly occur during the course of disease in COVID-19 patients [17,18,22,54], hemolytic anemia may also be responsible for their COHb elevation. Because intracellular NADPH depletion and consecutive oxidative stress with damaged erythrocytes (hemolysis) is typical for G6PD deficiency, it is not surprising that G6PD deficiency in COVID-19 patients seems to be associated with elevated MetHb and COHb levels [20].
A decreased CO elimination occurs when respiration is impaired. As COVID-19 patients are characterized by respiratory impairment, increased COHb levels can be explained by reduced CO elimination and thus a higher probability of COHb formation. Mechanical ventilation may also be relevant since, for example, an increase in the inspired O2 fraction leads to an increase in exhaled CO concentration [76], possibly leading to a reduced COHb production.
Interestingly, while elevated COHb levels seem to be correlated with COVID-19 severity, intensive care mortality from other causes was found to be associated with too low [12,77] and both too low or too high COHb values [11], indicating the existence of an optimal COHb level for optimal physiological functioning [12]. HO-1 upregulation, associated with elevations of COHb, has immunomodulatory and anti-inflammatory effects [78]. Inflammation changes COHb levels in the blood in a complex time-dependent manner as demonstrated by experimental endotoxemia in humans [79], highlighting the non-linear relationship between inflammation, disease severity and COHb levels.