The majority of ICU hospitalized COVID-19 patients not only experienced ARDS, but also vascular inflammation, thrombosis, and ultimately multi-organ damage. The triggering factors are likely multiple. Among them, excess of free heme is a potential offending agent as it has been shown to exacerbate and contribute to the pathogenesis of numerous inflammatory diseases . Therefore, it may be postulated that accumulated free heme and Hb could be involved in the mechanisms mediating pulmonary permeability and inflammation in COVID-19 patients . Protective mechanisms against free heme include HO-effector molecules biliverdin/bilirubin, CO and ferritin.
Our data clearly show a different profile of arterial CO-Hb levels among non-survivors of COVID-19 infection in the ICU. In the group of survivors, arterial CO-Hb also significantly increased from baseline at 30 days. Maximal arterial CO-Hb levels were in correlation with disease severity as expressed by SOFA score. But no values of arterial CO-Hb were predictive of mortality; however, the cohort was very small. The number of smokers was surprisingly limited in the present study and there was no difference at baseline in arterial CO-Hb levels among smokers and non-smokers. Therefore, it was assumed that exogenous CO did not play a significant role. It is also documented that CO-Hb may vary following hemorrhage or hemolysis but these conditions were not encountered in our patients.
The main source of endogenous CO results from the metabolism of heme by heme oxygenase. There is a direct relationship between the arterial CO-Hb and the endogenous production of CO either in healthy volunteers or in clinical studies [4–6]. Changes in ventilator variables may also affect arterial CO-Hb concentration . Several factors may affect the elimination of the endogenously produced CO: CO lung diffusing capacity, alveolar ventilation, lung capillary oxygen pressure, carboxyhemoglobin concentration, endogenous CO production and CO catabolism. The increase of the inspired fraction of oxygen will logically result in a transient increase in CO lung elimination as a result of a competition of CO and O2 for the same binding sites.
In the present study, changes in inspired oxygen fraction or ventilator settings occurred in almost all of the patients, particularly at the acute initial stage. As arterial CO-Hb was a mean of 4 to 8 daily values for each patient, we can estimate that these changes would have a minimal impact on CO lung excretion. On the other hand, arterial CO-Hb represents a balance between endogenous CO production and CO elimination. It remains difficult to establish if the increase in arterial CO-Hb has to be ascribed to an increase of CO production or to an impaired CO elimination through the alveolo-capillary membrane. There was no correlation between arterial CO-Hb and PCO2, and a strict parallelism between CO and CO2 pulmonary elimination is not expected.
Previous investigations have shown that carboxyhemoglobin levels may be elevated in trauma and surgical patients [8–9], and in patients with inflammatory lung disease [10, 11] and critical illness [4, 12, 13]. We failed to demonstrate a correlation between arterial CO-Hb and serum CRP. The kinetics of both factors appear different, as high CRP levels are likely present at the early phase during the so-called “cytokine storm”, while increase of arterial CO-Hb is slower as reflecting heme catabolism and impairment of the alveolo-capillary membrane.
The heme-catabolizing enzyme heme oxygenase (HO)-1 is highly inducible in oxidative stress. Patients with acute respiratory distress syndrome are reported to have an increased expression of (HO)-1 . Arterial carboxyhemoglobin level was measured in a cohort of 1267 ICU patients mainly admitted after cardiovascular surgery. Both low minimum and high maximum levels of arterial carboxyhemoglobin were associated with increased intensive care mortality . Arterial carboxyhemoglobin levels also correlated with biomarkers of the inflammatory response. These data suggested that the failure to up-regulate the activity of the HO system in the presence of a pro-inflammatory stress may be associated with a worse prognosis, while excessive (HO)-1 induction may also affect negatively the outcome. In patients from a medical ICU, survivors had slightly higher minimal and marginally higher average CO-Hb levels when compared to non-survivors .
Carbon monoxide signaling could have lung protective effects by modulating autophagy, mitochondrial biogenesis, apoptosis, and cellular proliferation .
The administration of exogenous CO has been proposed as therapeutic intervention in various conditions including acute lung injury [18–20]. Contrasting results have been published as some in vivo studies suggested that the endogenous production of CO or its exogenous administration was protective, while other studies were negative . In a human model of sepsis-related ARDS, inhalation of low doses of CO was associated with an increase in arterial CO-Hb ranging from 3.48 to 4.9%. No serious adverse events occurred in the CO-treated group, while circulating mitochondrial DNA levels were reduced .
Carbon monoxide can confer anti-inflammatory protection in rodent models of ventilator-induced lung injury (VILI). This modulation could be partly due to an increased expression of caveolin-1 .
Among the drugs recently proposed to treat COVID-19 infection, dexamethasone seems able to reduce hemolysis and induce HO-1 in macrophages in other conditions . Induction of HO-1 can also been achieved by a large variety of agents, including aspirin, statins, probucol, valsartan, niacin, resveratrol, and curcumin.