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\begin{document}

\title{Is endogenous carboxyhemoglobin level a useful biomarker of clinical
course and prognosis in COVID-19 patients?}



\author[1]{Buğra  Kerget}%
\author[2]{Ferhan Kerget}%
\author[2]{Abdullah Osman  Koçak}%
\author[2]{İlker Akbaş}%
\author[2]{Ömer Araz}%
\author[2]{Elif Yilmazel Ucar}%
\author[3]{Metin Akgun}%
\affil[1]{Ataturk Universitesi}%
\affil[2]{Affiliation not available}%
\affil[3]{School of Medicine, Ataturk University}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: SARS-CoV-2 has caused nearly 4 million confirmed cases of
COVID-19 worldwide in the approximately 4 months since it emerged in
Wuhan, China in December 2019. Comorbidities increase morbidity and
mortality in COVID-19, and many laboratory parameters have been
associated with mortality. The aim of the present study was to identify
the relationship between endogenous carboxyhemoglobin (COHb) level and
the clinical course and prognosis of COVID-19. Methods: The study
included 48 non-smokers or ex-smokers aged 18 years or older who
presented to the emergency department, were diagnosed with COVID-19 by
real-time PCR analysis of nasopharyngeal swab sample, and were treated
in the pulmonary diseases ward of the Atat\selectlanguage{ngerman}ürk University hospital after
between March 24, 2020 and April 15, 2020. The patients' laboratory
parameters and demographic data were analyzed retrospectively. Results:
Prothrombin time and C-reactive protein (CRP), troponin-I, and D-dimer
levels decreased in COVID-19 patients during follow-up (p=0.024,
p=0.001, p=0.001, p=0.001), while PaO2/FiO2 ratio and COHb increased
(p=0.002, p=0.001). COHb level at admission was significantly lower in
patients who developed macrophage activation syndrome (MAS), acute
respiratory distress syndrome (ARDS), and those who died compared to the
other patients (p=0.002, p=0.001). COHb level on day 5 of treatment was
significantly higher in patients with ARDS and patients who died
(p=0.001, p=0.001).Significant correlations were detected between COHb
level and CRP (r=-0.425, p=0.001), ferritin (r=-0.395, p=0.001) and
PaO2/FiO2 ratio (r=0.431, p=0.001). Conclusions: COHb level may be an
easily accessible biomarker that guides early follow-up and treatment
planning to avoid ARDS, MAS, and mortality in COVID-19.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Is endogenous carboxyhemoglobin level a useful biomarker of
clinical course and prognosis in COVID-19 patients?}

\textbf{Short title:} Carboxyhemoglobin level in COVID-19 patients

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget\textsuperscript{1*}, Ferhan Kerget\textsuperscript{2},
Abdullah Osman Ko\selectlanguage{ngerman}çak\textsuperscript{3}, \selectlanguage{polish}İ\selectlanguage{english}lker Akba\selectlanguage{polish}ş\selectlanguage{english}\textsuperscript{4},
\selectlanguage{ngerman}Ömer Araz\textsuperscript{1}, Elif Y\selectlanguage{polish}ı\selectlanguage{english}lmazel U\selectlanguage{ngerman}çar\textsuperscript{1},
Metin Akgu\selectlanguage{english}n\textsuperscript{1}

\textsuperscript{1} Department of Pulmonary Diseases, Ataturk University
School of Medicine, 25240,

Yakutiye, Erzurum, Turkey

\textsuperscript{2} Depertmant of Infection Diseases and Clinical
Microbiology, Health Sciences University

Erzurum Regional Education and Research Hospital, Erzurum, Turkey

\textsuperscript{3} Department of Emergency Medicine, Ataturk University
School of Medicine, 25240,

Yakutiye, Erzurum, Turkey

\textsuperscript{4} Department of Emergency Medicine, Bing\selectlanguage{ngerman}öl State
Hospital, 12400, Bingöl, Turkey

*Corresponding Author:

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget,MD

Yakutiye Medical Research Center

Chest Disease Department

25240, Yakutiye

Erzurum, TURKEY

\textbf{Conflict of interest statement}

The authors received no financial support for the research and/or
authorship of this article.The authors declare that they have no
conflict of interest to the publication of this article.

\textbf{Is endogenous carboxyhemoglobin level a useful biomarker of
clinical course and prognosis in COVID-19 patients?}

\textbf{Abstract}

\textbf{Objective:} SARS-CoV-2 has caused nearly 4 million confirmed
cases of COVID-19 worldwide in the approximately 4 months since it
emerged in Wuhan, China in December 2019. Comorbidities increase
morbidity and mortality in COVID-19, and many laboratory parameters have
been associated with mortality. The aim of the present study was to
identify the relationship between endogenous carboxyhemoglobin (COHb)
level and the clinical course and prognosis of COVID-19.

\textbf{Methods:} The study included 48 non-smokers or ex-smokers aged
18 years or older who presented to the emergency department, were
diagnosed with COVID-19 by real-time PCR analysis of nasopharyngeal swab
sample, and were treated in the pulmonary diseases ward of the Atat\selectlanguage{ngerman}ürk
University hospital after between March 24, 2020 and April 15, 2020. The
patients' laboratory parameters and demographic data were analyzed
retrospectively.

\textbf{Results} : Prothrombin time and C-reactive protein (CRP),
troponin-I, and D-dimer levels decreased in COVID-19 patients during
follow-up (p=0.024, p=0.001, p=0.001, p=0.001), while
PaO\textsubscript{2}/FiO\textsubscript{2} ratio and COHb increased
(p=0.002, p=0.001). COHb level at admission was significantly lower in
patients who developed macrophage activation syndrome (MAS), acute
respiratory distress syndrome (ARDS), and those who died compared to the
other patients (p=0.002, p=0.001). COHb level on day 5 of treatment was
significantly higher in patients with ARDS and patients who died
(p=0.001, p=0.001).Significant correlations were detected between COHb
level and CRP (r=-0.425, p=0.001), ferritin (r=-0.395, p=0.001) and
PaO2/FiO2 ratio (r=0.431, p=0.001).

\textbf{Conclusions:} COHb level may be an easily accessible biomarker
that guides early follow-up and treatment planning to avoid ARDS, MAS,
and mortality in COVID-19.

\textbf{Keywords:} COVID-19, endogenous carboxyhemoglobin, acute
respiratory distress

\textbf{What's already known about this topic?}

Carbon monoxide (CO) is naturally synthesized in the body and plays an
important role in the regulation of physiological functions such as
vasodilation, angiogenesis, vascular remodeling, protection against
tissue damage, and modulation of the inflammatory response.
Approximately 85\% of CO is produced by heme oxygenase and is excreted
from the body through the respiratory system. In critical diseases such
as acute respiratory failure, chronic obstructive pulmonary disease,
acute pulmonary embolism, and acute myocardial infarction, low initial
endogenous carboxyhemoglobin (COHb) level has been associated with high
mortality and poor prognosis . The leading causes of morbidity and
mortality in COVID-19 are acute respiratory failure, microthombi, and
cardiac involvement.

\textbf{What does this article add?}

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.

\textbf{Introduction}

After appearing in Wuhan, China in December 2019, coronavirus disease
(COVID-19) spread rapidly around the world, with over 3 million
confirmed cases by the end of April 2020. In the majority of infected
patients, COVID-19 is either asymptomatic or presents with mild symptoms
such as loss of taste and smell, sore throat, fatigue, and joint pain.
However, it can have a much more severe course in older people, patients
with hypertension (HT), and conditions that can impair immunity such as
diabetes mellitus (DM), HIV, long-term immunosuppressive therapy, and
pregnancy \textsuperscript{1}.

While many comorbidities have been associated with COVID-19 mortality,
there are also laboratory diagnostic tests associated with early poor
prognosis. Of these, the most frequently used parameters are D-dimer,
ferritin, leukopenia, fibrinogen, prothrombin time, and IL-6 level.
These parameters alone are not effective in directing treatment, but
evaluation of correlation with clinical condition revealed a
relationship with macrophage activation syndrome (MAS), which is among
the most important causes of mortality. This led to the investigation of
parameters that can be associated with mortality in this emerging
disease \textsuperscript{2,3}.

Carbon monoxide (CO) is naturally synthesized in the body and plays an
important role in the regulation of physiological functions such as
vasodilation, angiogenesis, vascular remodeling, protection against
tissue damage, and modulation of the inflammatory response.
Approximately 85\% of CO is produced by heme oxygenase and is excreted
from the body through the respiratory system \textsuperscript{4,5}. In
critical diseases such as acute respiratory failure, chronic obstructive
pulmonary disease, acute pulmonary embolism, and acute myocardial
infarction, low initial endogenous carboxyhemoglobin (COHb) level has
been associated with high mortality and poor prognosis . The leading
causes of morbidity and mortality in COVID-19 are acute respiratory
failure, microthombi, and cardiac involvement \textsuperscript{5-8}.

COVID-19 is a new disease that does not have specific laboratory
findings as in other known diseases, and as such is the focus of intense
research. The aim of the present study was to determine the value of
COHb levels measured at admission and follow-up in the prediction of
clinical course and prognosis in COVID-19 patients who develop MAS and
acute respiratory failure.

\textbf{Methods}

\emph{Study population}

This retrospective study included never-smokers or ex-smokers aged 18
and over who presented to the Atatürk University Emergency Service with
complaints of recent-onset fever, cough, shortness of breath,
listlessness, and/or sudden attenuation of taste and smell, and who had
returned from travel abroad or had contact with suspected COVID-19
patient within the last 14 days.

As specified in the guidelines, COVID-19 patients with respiratory
symptoms underwent posterior--anterior chest radiography, and if any
suspicious lesions were detected, a more detailed evaluation was
performed using high-resolution chest computed
tomography\textsuperscript{9}. Nasopharyngeal swab samples were obtained
from the patients and COVID-19 diagnosis was established using real-time
PCR analysis. A total of 48 patients treated in our pulmonary diseases
ward between March 24, 2020 (admission date of the first
COVID-19-positive patient to our center) and April 15, 2020 were
included in our study. Local ethics committee approval was obtained to
use patients' records for our retrospective research study.

\emph{Laboratory analysis}

Analyses of hematological parameters, biochemical parameters including
liver and kidney function tests, coagulation parameters, ferritin,
D-dimer, troponin-I, C-reactive protein (CRP), procalcitonin, and
arterial blood gas parameters were performed upon admission and repeated
daily.

\emph{Definitions and Treatment}

Fever was defined as an axillary temperature of 37.3°C or higher.
Positive endotracheal aspirate or lower respiratory tract sputum culture
with signs and symptoms of bacteremia or pneumonia was considered
secondary bacterial infection. Treatment of patients diagnosed as having
ventilator-associated or hospital-acquired pneumonia was planned based
on available guidelines. Diagnosis and grading of acute respiratory
distress syndrome (ARDS) was done according to Berlin 2015 diagnostic
criteria. If the patients' daily cardiac-specific troponin level was
above normal, echocardiography was performed to evaluate for the
development of new cardiac pathologies. Coagulopathy was defined as a
prothrombin time more than 3 seconds higher than normal and partial
thromboplastin time 5 seconds higher than normal. Treatment strategies
were implemented according to the Turkish Ministry of Health COVID-19
Adult Diagnosis and Treatment guidelines based on the patients' disease
severity. Patients were monitored for MAS in the presence of signs such
as persistent fever, persistently high or increasing CRP and ferritin
levels, elevated D-dimer levels, lymphopenia/thrombocytopenia,
deterioration in liver function tests, hypofibrinogenemia, and
increasing triglyceride levels despite treatment. Patients with
successive increases in daily measurements of these parameters which
could not be explained by secondary bacterial infections were
administered 400 mg of tocilizumab for MAS if they had no
contraindications. In patients who showed appropriate clinical and
laboratory response after 24 hours, treatment was not continued.
However, if an appropriate clinical and laboratory response was not
observed, treatment was repeated at the same dosage.

\textbf{Statistical analysis}

Statistical analyses were performed using IBM SPSS Statistics for
Windows version 22.0 (IBM Corp., Armonk, NY). Between-group comparisons
were performed using Pearson's chi-square test for parametric data and
Mann--Whitney U test for non-normally distributed numerical data. The
groups' demographic data and laboratory parameters were compared using
independent-samples t test. Wilcoxon analysis was performed to compare
repeated measures for laboratory parameters within groups. Pearson
correlation analysis was used to evaluate correlation between COHb and
CRP, ferritin, D-dimer level, lymphocyte count, and the ratio of
arterial oxygen partial pressure to fractional inspired oxygen
(PaO\textsubscript{2}/FiO\textsubscript{2}). A p-value \textless{} 0.05
was considered statistically significant.

\textbf{Results}

The mean age of the 48 patients included in the study was 57.6±17.6
years. Twenty-two of the patients were women (mean age 55.8±18.3 years)
and 26 were men (mean age 59.1±17.3 years). Twenty-eight of the patients
had HT, 12 had DM, 4 had asthma, and 1 had epilepsy. Body mass index
(BMI) was \textgreater{} 30 kg/m\textsuperscript{2} in 15 of the
patients. Of 26 patients who developed ARDS, 20 had HT, 8 had DM, 1 had
epilepsy, and 6 had BMI \textgreater{} 30 kg/m\textsuperscript{2}. Of
the patients who developed MAS, 10 had HT, 4 had DM, and 1 had epilepsy.

In the physical examination performed at hospital admission, mean
respiratory rate (breaths/minute) was 21.4 ± 12.3 among patients who
later developed MAS, 24.6 ± 13.4 among patients who developed ARDS, and
15.4 ± 4.8 in patients without ARDS and MAS. Comparison of patients with
and without ARDS and MAS showed that respiratory rate was statistically
significantly higher in the ARDS and MAS groups (p=0.001, p=0.001). On
day 5 of treatment, the mean respiratory rate was 18.4 ± 4.5 in the MAS
group, 20.1 ± 5.6 in the ARDS group, and 14.4 ± 3.6 in the group of
patients without MAS or ARDS.

A comparative analysis of the patients' laboratory parameters at
hospital admission and on day 5 of treatment is shown in Table 1. When
patients with and without MAS were compared in terms of their COHb
levels at admission and on day 5 of treatment, it was found that
patients who developed MAS had lower COHb level at admission (p=0.002).
Comparison of the changes in COHb levels over the course of 5 days
showed a statistically significant increase in patients who developed
MAS (Figure 1) (p=0.001). When patients with and without ARDS were
compared in terms of COHb levels at admission, it was found that COHb
level was significantly lower at admission but higher on day 5 (p=0.001,
p=0.001). As in the patients who developed MAS, COHb levels increased
further over the course of 5 days in patients who developed ARDS (Figure
1) (p=0.001). Changes in other laboratory parameters in patients who
developed MAS and ARDS are shown in Tables 2 and 3. Comparison of COHb
levels between deceased (n=4) and surviving patients (n=44) showed that
in deceased patients, COHb levels were significantly lower at admission
and higher on day 5 of treatment (p=0.04, p=0.001).

In the correlation analysis between COHb level and laboratory parameters
and demographic data, moderate negative correlations were detected
between COHb level and CRP (r=-0.425, p=0.001), ferritin (r=-0.395,
p=0.001) (Figure 2), and age (r=-0.314, p=0.001). Moderate positive
correlations were detected between COHb and lymphocyte count (r=0.43,
p=0.001) (Figure 2) and
PaO\textsubscript{2}/FiO\textsubscript{2}(r=0.431, p=0.001). There was
also a weak negative correlation between COHb and troponin-I level
(r=-0.287, p=0.05).

In correlation analysis between COHb level on day 5 of treatment and
laboratory parameters, a moderate positive correlation was detected
between COHb level and CRP (r=0.55, p=0.001), prothrombin time (r=0.387,
p=0.001), and creatinine (p=0.408, p=0.001), but no significant
difference was detected in other parameters at time of admission.

\textbf{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
PaO\textsubscript{2}/FiO\textsubscript{2} 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 \textsuperscript{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 \textsuperscript{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 \textsuperscript{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 \textsuperscript{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
epithelium\textsuperscript{14}. 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
\textsuperscript{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 PaCO\textsubscript{2} 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
PaO\textsubscript{2}/FiO\textsubscript{2}ratio 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.

\textbf{References}

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9. AKÇAY M\selectlanguage{polish}Ş, \selectlanguage{ngerman}Özlü T, Yilmaz A. Radiological approaches to COVID-19
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13. Zhang C, Wu Z, Li J-W, Zhao H, Wang G-Q. The cytokine release
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antagonist Tocilizumab may be the key to reduce the
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14. Ryter SW, Kim HP, Nakahira K, Zuckerbraun BS, Morse D, Choi AM.
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\textbf{Figure legends}

\textbf{Figure 1.} Comparison of COHb levels at admission and on day 5
of treatment in COVID-19 patients who did and did not develop macrophage
activation syndrome (MAS) and acute respiratory distress syndrome (ARDS)

\textbf{Figure 2.} Correlation analysis of COHb level with CRP and
PaO\textsubscript{2}/FiO\textsubscript{2} levels in COVID-19 patients

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