Discussion
In the present study, we determined that the COHb levels of COVID-19 patients treated in our center were low at admission and increased with treatment. In particular, we observed that low COHb level is an important risk factor for the development of MAS and ARDS. In our study, nonsurviving COVID-19 patients had lower COHb levels than surviving patients. COHb levels increased significantly during 5-day follow-up in patients who developed ARDS and MAS compared to patients who did not develop ARDS and MAS. Correlation analysis between COHb levels and parameters associated with mortality in the literature revealed negative correlations between COHb levels and CRP, ferritin, and troponin and positive correlations between COHb levels and lymphocyte and PaO2/FiO2 ratio.
The novel coronavirus detected in Wuhan, China at the end of 2019 was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses because it is closely related to SARS-CoV and MERS-CoV, viruses responsible for past epidemics that caused high morbidity and mortality. Due to the rapid spread of COVID-19, the epidemic in China quickly escalated to a global pandemic, with the number of confirmed COVID-19 cases worldwide approaching 4 million at the time of this writing 10.
Although most patients with COVID-19 present with fever, coughing, and shortness of breath, a smaller proportion of patients may present to emergency departments with confusion, diarrhea, sore throat, chest pain, nausea, and vomiting. Less common presenting symptoms also include loss or attenuation of smell and taste, and palpitations due to myocardial wall involvement as a complication of viral respiratory tract infections. COVID-19 causes high rates of morbidity and mortality, especially in older patients and those with comorbidities such as HT, DM, immunosuppressive therapy, and obesity. MAS-related multiorgan failure and acute respiratory failure are among the primary causes of mortality in COVID-19 3,11.
Lymphopenia is the most common abnormality in laboratory tests, which suggests that leukocytes, especially T-lymphocytes, are affected in COVID-19 patients. Viral particles that spread from the respiratory tract and infect other cells create a cytokine storm. In a cytokine storm, myriad proinflammatory cytokines are released, primarily TNF- alpha, IL-1, IL-2, IL-6, and nitric oxide. These cytokines play an important role in increasing vascular permeability, endothelial damage, and microthrombus formation 12. Progressive increases in CRP, ferritin, D-dimer levels, and if measurable, IL-6 levels in patients’ clinical follow-up have become predictive biomarkers of cytokine storm syndrome and MAS for clinicians. However, while there is no definite cut-off value for these parameters, it indicates that clinical follow-up plays an important role in the use of IL-1 antagonist canakinumab and IL-6 antagonist tocilizumab 3,13.
The level of CO naturally synthesized in the body can be measured using COHb, the product of its high-affinity binding to hemoglobin. In addition to its anti-inflammatory activity, it also plays an important role in vascular remodeling and prevention of tissue damage. Endogenous COHb is generated in the body when heme oxygenase-1 (HOX-1) converts heme to biliverdin. COHb released as a result of HOX-1 activation is eliminated by the respiratory system and can be measured in exhaled breath. HOX-1 has an important role in the reduction of reactive oxygen radicals and induction of enzymes that are cytoprotective for many organ and tissue epithelia, primarily the respiratory tract epithelium14. Low COHb level was found to be associated with high mortality in studies of intensive care patients. In addition, low COHb levels were shown to be correlated with poor prognosis in patients presenting with community-acquired pneumonia, myocardial infarction, stroke, and acute pulmonary thromboembolism 5-8,15. In this study, we observed that COVID-19 patients’ COHb levels were low at admission and progressively increased with treatment. Furthermore, COHb levels were even lower in patients who developed MAS and ARDS, for which early treatment is of great importance. In nonsurviving patients who developed ARDS, COHb levels on day 5 of treatment were higher than in surviving patients who did not develop ARDS. Patients who developed MAS exhibited greater changes in COHb on day 5 of treatment relative to patients who did not. This may be related to the higher admitting respiratory rates observed in patients who developed ARDS and MAS compared to those who did not. This higher respiratory rate may have reduced the COHb elimination rate in patients with ARDS and MAS. The lower PaCO2 values in these patients also indicated impaired ventilation capacity at admission, which further suggests impaired CO excretion. The decrease in CO levels in correlation with oxygen saturation in patients with ARDS due to acute pulmonary embolism demonstrates that CO levels decrease with increased respiratory effort, which supports our findings. In addition, although there has been no previous study on this subject in the literature, a decrease in HOX-1 system activation associated with clinical worsening of COVID-19 may also have reduced COHb production. Improved immune response and decreased respiratory workload with treatment may have resulted in an increase in COHb, which is known to have anti-inflammatory activity. CRP, ferritin, troponin, and PaO2/FiO2ratio have been shown to be closely associated with MAS and mortality, and the correlations observed between these parameters and COHb support previous studies as well as our present findings.
The main limitation of this study was that the number of nonsurviving patients in our sample was too small to establish an association between COHb level and mortality. However, our finding that COHb levels in patients who developed ARDS and MAS were consistent with those of nonsurviving patients suggests that our results can be generalized.
In conclusion, low COHb level at admission in COVID-19 patients may be an easily accessible biomarker that guides early follow-up and treatment planning to avoid ARDS, MAS, and mortality.