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.