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\begin{document}

\title{The association between procalcitonin, venous blood gas parameters, and
clinical prognosis in patients with Crimean--Congo Hemorrhagic Fever}



\author[1]{Ferhan Kerget}%
\author[2]{Buğra  Kerget}%
\author[3]{Sibel İba Yılmaz}%
\affil[1]{Affiliation not available}%
\affil[2]{Ataturk Universitesi}%
\affil[3]{Erzurum Bolge Egitim ve Arastirma Hastanesi}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: Crimean--Congo hemorrhagic fever (CCHF) is a zoonotic
infection characterized by fever and hemorrhage that is endemic to
northeastern Turkey. This study aimed to examine the association between
procalcitonin and venous blood gas parameters and clinical course and
prognosis in patients with CCHF. Methods: A total of 96 CCHF patients
who were followed up in the infectious diseases department between March
and September 2020 were included in the study. The patients' routine
laboratory tests, serum procalcitonin, and results of venous blood gas
analysis were analyzed retrospectively. Results: There were
statistically significantly differences in serum platelet, aspartate
transaminase, alanine transaminase, creatinine kinase, lactate
dehydrogenase, potassium, C-reactive protein, sedimentation, D-dimer,
activated partial thromboplastin time, ferritin, procalcitonin and
lactate levels, and platelet/lymphocyte ratio among the patients with
mild, moderate and severe disease (p=0.017 for potassium and p=0.001 for
rest of others). In receiver operating characteristic (ROC) curve
analysis of serum lactate for the differentiation of patients with
severe disease and those with mild/moderate disease, the area under the
curve was 0.802 and a cut-off value of 1.9 mmol/L had 77.8\% sensitivity
and 76.9\% specificity. For serum procalcitonin, the area under the ROC
curve was 0.892 and a cut-off value of 0.61 ng/ml had 83.3\% sensitivity
and 89.7\% specificity. Conclusion: Serum procalcitonin and lactate
levels may be useful and easily obtained parameters to guide the
evaluation of clinical severity and follow-up in patients with CCHF.%
\end{abstract}%



\sloppy


\textbf{Abstract}

\textbf{Objective:} Crimean--Congo hemorrhagic fever (CCHF) is a
zoonotic infection characterized by fever and hemorrhage that is endemic
to northeastern Turkey. This study aimed to examine the association
between procalcitonin and venous blood gas parameters and clinical
course and prognosis in patients with CCHF.

\textbf{Methods:} A total of 96 CCHF patients who were followed up in
the infectious diseases department between March and September 2020 were
included in the study. The patients' routine laboratory tests, serum
procalcitonin, and results of venous blood gas analysis were analyzed
retrospectively.

\textbf{Results:} There were statistically significantly differences in
serum platelet, aspartate transaminase, alanine transaminase, creatinine
kinase, lactate dehydrogenase, potassium, C-reactive protein,
sedimentation, D-dimer, activated partial thromboplastin time, ferritin,
procalcitonin and lactate levels, and platelet/lymphocyte ratio among
the patients with mild, moderate and severe disease (p=0.017 for
potassium and p=0.001 for rest of others). In receiver operating
characteristic (ROC) curve analysis of serum lactate for the
differentiation of patients with severe disease and those with
mild/moderate disease, the area under the curve was 0.802 and a cut-off
value of 1.9 mmol/L had 77.8\% sensitivity and 76.9\% specificity. For
serum procalcitonin, the area under the ROC curve was 0.892 and a
cut-off value of 0.61 ng/ml had 83.3\% sensitivity and 89.7\%
specificity.

\textbf{Conclusion:} Serum procalcitonin and lactate levels may be
useful and easily obtained parameters to guide the evaluation of
clinical severity and follow-up in patients with CCHF.

\textbf{Keywords:} Blood gas, Crimean--Congo hemorrhagic fever,
procalcitonin

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

Blood gas analysis is important for evaluating prognosis in SIRS and
MOF. Studies have shown that low pH, high lactate, and low
carboxyhemoglobin levels in venous blood gas analysis are important
markers of clinical course and prognosis. In particular, lactate level
is a serum marker frequently used in clinical practice. High serum
lactate is an indicator of tissue hypoperfusion. Lactate is produced by
many tissues of the human body and at high levels in muscle tissue.
Under normal circumstances, lactate is rapidly eliminated by the liver
and partly by the kidneys. Procalcitonin level is believed to increase
mostly in bacterial infections and sepsis as part of the systemic
inflammatory response against infection. It is generally not expected to
increase in response to viral infections. However, it has been suggested
that a major increase in cytokine levels may lead to procalcitonin
elevation.

\textbf{What does this article add?}

serum procalcitonin and lactate levels may be important parameters for
the early evaluation of clinical course and prognosis in patients with
CCHF. Large scale studies evaluating the association between these two
parameters and clinical course and mortality may provide more guidance
in the course of the clinical follow-up.

\textbf{Introduction}

Crimean--Congo hemorrhagic fever (CCHF) is an endemic disease in the
Northern Anatolia Region of Turkey that is characterized by fever and
hemorrhage and can have a severe and potentially life-threatening
course\textsuperscript{1}. The CCHF virus is generally transmitted to
humans through tick bites or contact with infected ticks or the bodily
fluids of infected animals. The main targets of CCHF are mononuclear
phagocytes, endothelial cells, and hepatocytes \textsuperscript{2}.
Signs and symptoms occur as a result of the effect of the virus on
target organs. Sudden-onset fever, headache, malaise, anorexia,
widespread body pain, and nausea are the most common
symptoms\textsuperscript{3}.

The pathogenesis of CCHF is not fully understood, though macrophage
activation and hemophagocytosis are known to be the basis of the
pathological process. After entering the body, the virus proliferates in
local lymph nodes and tissues, then spreads via the lymph and monocytes
to other parts of the body, especially the spleen, liver, lymph ganglia,
lungs, adrenal glands, and endothelium \textsuperscript{4}. Secondary
infection of parenchymal cells occurs by macrophage migration.
Macrophage and endothelial cell activation induces inflammatory and
vasoactive processes, resulting in systemic inflammatory response
syndrome (SIRS) \textsuperscript{5}. Coagulation system activation and
extensive fibrin accumulation in the vascular beds lead to disseminated
intravascular coagulation (DIC) and multiple organ failure
(MOF)\textsuperscript{2}.

Blood gas analysis is important for evaluating prognosis in SIRS and
MOF. Studies have shown that low pH, high lactate, and low
carboxyhemoglobin levels in venous blood gas analysis are important
markers of clinical course and prognosis \textsuperscript{6}. In
particular, lactate level is a serum marker frequently used in clinical
practice. High serum lactate is an indicator of tissue hypoperfusion.
Lactate is produced by many tissues of the human body and at high levels
in muscle tissue. Under normal circumstances, lactate is rapidly
eliminated by the liver and partly by the kidneys \textsuperscript{7}.

Procalcitonin level is believed to increase mostly in bacterial
infections and sepsis as part of the systemic inflammatory response
against infection. It is generally not expected to increase in response
to viral infections. However, it has been suggested that a major
increase in cytokine levels may lead to procalcitonin
elevation\textsuperscript{8}.

The aim of our study was to evaluate the relationship between
procalcitonin level and venous blood gas parameters and the clinical
course and prognosis of CCHF.

\textbf{Materials and Methods}

\emph{Study design}

This retrospective study included patients who were under follow-up for
CCHF between March 2020 and September 2020. The study was designed and
conducted in accordance with the ethical guidelines set forth in the
Declaration of Helsinki. The study protocol was approved by the local
ethics committee (BEAH KAEK 2020/20-189) and informed written consent
was obtained from all patients included in the study.

\emph{Sample size and study population}

We calculated minimum sample size as 84 patients with an effect size of
0.4, type 1 error of 0.05, and a power of 0.90 for ANOVA testing of
three groups using GPower 3.1 software.

A total of 96 patients (53 men, 38 women) aged 18 years and older who
were followed up for CCHF in the Erzurum Regional Training and Research
Hospital Department of Infectious Diseases were included in the study.
Patients who developed bacterial superinfection confirmed by blood,
sputum, and urine cultures during CCHF follow-up and patients who were
pregnant, had known malignancies, had liver or kidney failure, used
anti-inflammatory drugs in the last month, or were followed up for acute
coronary syndrome in the last 2 months were excluded.

\emph{Study groups}

The patients were classified as having mild, moderate, or severe disease
according to the criteria defined by Swanepoel et al. and the modified
criteria recommended by Erg\selectlanguage{ngerman}önül et al. \textsuperscript{9,10}, as well
as clinical indicators of poor prognosis. Accordingly, there were 37
patients in the mild group, 40 patients in the moderate group, and 19
patients in the severe group. Blood, urine, and sputum cultures were
performed for all patients whose procalcitonin level exceeded the upper
laboratory limit.

\emph{CCHF diagnosis}

Two blood samples of at least 2 mL each were collected from every
patient with suspected CCHF upon hospital admission. After 30 minutes of
coagulation, the samples were centrifuged at 2000 rpm for 5 min and the
serum was transferred to separate tubes. One serum sample from each
patient was transported under appropriate conditions to the Erzurum
Regional Public Health Laboratory, our regional reference center, for
serologic and virologic tests. CCHF was diagnosed based on specific
anti-IgM antibody detected by immunofluorescence assay (IFA) and/or
polymerase chain reaction (PCR) positivity.

\emph{Measurement of biochemical markers}

All the serum samples were obtained within the first 2 days of the onset
of their symptoms. Further, the patients' biochemical and hematological
parameters were tested on admission, in the laboratory of the our
hospital. Procalcitonin levels were tested with commercial ELISA kits
(Elecsys BRAHMS PCT, Roche, Mannheim, Germany), according to the
manufacturer's recommendations.

\textbf{Statistical analysis}

Data analysis was performed in IBM SPSS Statistics for Windows version
22.0 (IBM Corp., Armonk, NY) and Medcalc version 16 (MedCalc Software
bvba, Ostend, Belgium). Shapiro-Wilk test and Kolmogorov-Smirnov test
were used to evaluate the normality of the distribution of numeric data.
The descriptive statistics were presented as frequency with percentage
for categorical variables, median with interquartile range (IQR) for
non-normally distributed numeric data, and mean with standard deviation
(SD) for normally distributed data. The laboratory findings were
compared among the study groups using Independent-Samples Kruskal-Wallis
Test for non-normally distributed numeric data, and One-way ANOVA Test
for normally distributed numeric data. Post-hoc pairwise comparisons
were done using Dunn's Post-hoc test with Bonferroni correction for
non-normally distributed data. We calculated the difference in median
for determining the effect size in post-hoc pairwise comparison of
laboratory findings among the study groups. Spearman correlation
analysis was used to evaluate the relationships between serum
procalcitonin, lactate, aspartate transaminase (AST) and alanine
transaminase (ALT) levels. Receiver operating characteristic (ROC) curve
analysis was used to estimate the severe disease using serum
procalcitonin and lactate levels. Youden index was used to find the best
cut-off values of these parameters. The AUCs, sensitivity and
specificity with 95\% confidence intervals were calculated. A p-value
less than 0.05 was considered statistically significant.

\textbf{Results}

Of the 96 CCHF patients in our study, 58 (60.4\%) were men and 38
(39.6\%) were women. The median age of the study population was 50 years
with an IQR of 35.3-61.0 years. The clinical symptoms are shown in Table
1. The most common symptoms were malaise, fever, and myalgia/arthralgia,
respectively.

The patients' laboratory findings are shown in Tables 2. There were
statistically significantly differences in serum platelet, aspartate
transaminase (AST), alanine transaminase (ALT), creatinine kinase (CK),
lactate dehydrogenase (LDH), potassium, C-reactive protein (CRP),
sedimentation, D-dimer, activated partial thromboplastin time (aPTT),
ferritin, procalcitonin and lactate levels, and platelet/lymphocyte
ratio (PLR) among the patients with mild, moderate and severe disease
(p=0.017 for potassium and p=0.001 for rest of others).

Post-hoc pairwise comparison of laboratory findings according to the
disease severity is shown in Table 3. PLR was significantly lower in
patients with severe and moderate disease compared to those with mild
disease (p\textless{}0.001 and p\textless{}0.001, respectively). Serum
CRP level was statistically significantly higher in patients with severe
disease compared to those with moderate disease and with mild disease
(p=0.049 and p\textless{}0.001, respectively), and also there was
statistically significant difference in serum CRP level among the
patients with moderate disease and with mild disease (p=0.024). Serum
D-dimer level was statistically significantly higher in patients with
severe disease compared to those with mild disease (p=0.002). Ferritin
level was significantly higher in patients with severe disease compared
to those with moderate disease and those with mild disease
(p\textless{}0.001 and p\textless{}0.001, respectively). Serum
procalcitonin level was statistically significantly higher in patients
with severe disease compared to those with moderate disease and with
mild disease (p=0.001 and p\textless{}0.001, respectively), and also
there was statistically significant difference in serum procalcitonin
level among the patients with moderate disease and with mild disease
(p=0.005). Serum lactate level was statistically significantly higher in
patients with severe disease compared to those with moderate disease and
with mild disease (p=0.004 and p\textless{}0.001, respectively).

For serum procalcitonin and lactate levels in differentiating severe and
moderate/mild disease, the areas under ROC curves (AUCs) were 0.892 and
0.802, and the best cut-off points were \textgreater{}0.61 and
\textgreater{}1.9, respectively. According to these cut-off values, the
sensitivity and specificity of procalcitonin were 83.3\% and 89.7\%, and
the sensitivity and specificity of lactate were 77.8\% and 76.9\%,
respectively (Table 4 and Figure 1).

There were statistically significantly medium positive correlations
between serum procalcitonin level and serum AST (R=0.584,
p\textless{}0.001), ALT (R=0.497, p\textless{}0.001) and lactate
(R=0.441, p\textless{}0.001) levels. Serum lactate level was also
positively correlated with serum AST (R=0.459, p\textless{}0.001) and
ALT (r=0.446, p\textless{}0.001) levels (Table 5 and Figure 2).

\textbf{Discussion}

In our study, we found that procalcitonin and lactate levels were higher
in patients with severe CCHF when compared to patients with mild and
moderate CCHF. In the differentiation of severely ill patients from
mild/moderately ill patients, a lactate cut-off value of 1.9 mmol/L had
77.8\% sensitivity and 76.9\% specificity, whereas a procalcitonin
cut-off value of 0.61 ng/mol had 83.3\% sensitivity and 89.7\%
specificity. Both procalcitonin and lactate levels were positively
correlated with AST and ALT, which are frequently used parameters in
CCHF follow-up.

As in all viral hemorrhagic fevers, the basis of CCHF pathogenesis is
viral infection of various cell types, primarily endothelial cells,
mononuclear cells, and hepatocytes, followed by proliferation and
systematic spread \textsuperscript{11}. Increased endothelial
permeability and consequent endothelial damage is the main pathogenetic
process leading to death. This endothelial damage has been attributed to
two main mechanisms. The first is a direct viral effect on the
endothelial cells, and the second is damage caused indirectly by the
cytokines secreted from infected tissues \textsuperscript{9,12,13}.

The most important of these cytokines are tumor necrosis factor alpha,
interleukin (IL)-1, and IL-6, which are synthesized by type 1 helper T
cells and are involved in monocyte activation. The activation of
monocytes by cytokines impairs platelet activation and degranulation and
leads to an abnormal coagulation cascade in CCHF. Monocyte activation is
considered one of the main causes of hemophagocytic lymphohistiocytosis,
which leads to cytopenia and liver dysfunction in CCHF. Serum AST, ALT,
LDH, and creatine kinase (CK) are liver function indicators that are
frequently used parameters in clinical follow-up and have been
associated with poor prognosis \textsuperscript{14-16}.

Serum lactate level is another parameter frequently used in the clinical
practice, and although it may increase secondary to tissue
hypoperfusion, elevation may also occur due to causes unrelated to
hypoperfusion \textsuperscript{17}. Lactate, which can be synthesized in
many of the body's tissues, is eliminated primarily by the liver and to
a lesser extent by the kidneys. A substantial proportion of studies
evaluating the relationship between lactate level and clinical course
and prognosis have observed that hypoperfusion increases lactate level
due to sepsis and septic shock \textsuperscript{18}. Our literature
search yielded no studies in which lactate level was associated with the
clinical course of CCHF. In the present study, serum lactate level was
found to increase in correlation with clinical severity in CCHF
patients. This may be attributed to the inadequate elimination of
lactate by the liver in CCHF, as liver dysfunction due to hemophagocytic
lymphohistiocytosis plays an important role in the clinical course of
this condition. Moreover, the increased cytokine levels seen in CCHF due
to the indirect effect of the virus might have led to muscle dysfunction
and higher levels of creatine kinase as well as lactate. This is
corroborated by the fact that muscle and joint pain are among the most
common presenting symptoms.

High serum procalcitonin level is often observed in bacterial infections
rather than viral infections. However, it has been found that increased
cytokine levels also increase amount of procalcitonin synthesized by
thyroid C cells in viral infections, independent of bacterial
superinfections \textsuperscript{8,19}. Procalcitonin level was reported
to be higher in patients with fatal CCHF and correlated with CRP level,
which is frequently used in routine practice \textsuperscript{20}. None
of the patients in our study died after clinical follow-up, and in line
with previous studies, we also found that procalcitonin levels were
higher in severely ill patients. This level also correlated with liver
function markers and serum lactate level. The lack of growth in blood,
urine, and sputum cultures performed after the increase in procalcitonin
levels suggest that this was due to high cytokine level.

The main limitation of our study was the inability to detect an
association between lactate and procalcitonin levels and mortality. This
was primarily due to the fact that during the study period, our hospital
was designated as a COVID-19 pandemic hospital during the pandemic, and
as a result there was a sharp decline in the number of patients we
followed due to CCHF in our hospital.

\textbf{Conclusion}

In conclusion, serum procalcitonin and lactate levels may be important
parameters for the early evaluation of clinical course and prognosis in
patients with CCHF. Large scale studies evaluating the association
between these two parameters and clinical course and mortality may
provide more guidance in the course of the clinical follow-up.

Authors' Contribution

FK and BK contributed equally to the working concept and design. The
critical revision of the article was made by S\selectlanguage{polish}İ\selectlanguage{english}Y and BK. All authors
have made significant contributions to the analysis and interpretation
of the data. FK wrote the first draft of the manuscript, and all authors
read and approved the last article.

\textbf{Conflict of interest}

The authors declare no conflict of interest or financial support related
to this study.

\textbf{Ethical Statement}

The study protocol was approved by the Erzurum City Hospital local
ethics committee (BEAH KAEK 2020/20-189) and informed written consent
was obtained from all patients included in the study.

\textbf{Acknowledgment}

None to declare

\textbf{Financial Support}

None to declare

\textbf{References}

1. Karti SS, Odabasi Z, Korten V, et al. Crimean-Congo hemorrhagic fever
in Turkey. \emph{Emerging infectious diseases.} 2004;10(8):1379.

2. Leblebicioglu H, Ozaras R, Fletcher TE, Beeching NJ. Crimean-Congo
haemorrhagic fever in travellers: A systematic review. \emph{Travel
medicine and infectious disease.} 2016;14(2):73-80.

3. Nasirian H. Crimean-Congo hemorrhagic fever (CCHF) seroprevalence: A
systematic review and meta-analysis. \emph{Acta
tropica.}2019;196:102-120.

4. Ak\selectlanguage{polish}ı\selectlanguage{english}nc\selectlanguage{polish}ı \selectlanguage{english}E, Bodur H, Leblebicioglu H. Pathogenesis of Crimean-Congo
hemorrhagic fever. \emph{Vector-Borne and Zoonotic
Diseases.}2013;13(7):429-437.

5. Demirtas E, Bakir M, Buyuktuna SA, et al. Comparison of the
Predictive Performance of qSOFA, APACHE2 and SGS for evaluation of the
disease prognosis of CCHF patients at the Emergency
Department.\emph{Japanese Journal of Infectious Diseases.} 2020:JJID.
2019.2507.

6. Mazza BF, Machado FR, Mazza DD, Hassmann V. Evaluation of blood
transfusion effects on mixed venous oxygen saturation and lactate levels
in patients with SIRS/sepsis. \emph{Clinics.} 2005;60(4):311-316.

7. Goyal M, Pines JM, Drumheller BC, Gaieski DF. Point-of-care testing
at triage decreases time to lactate level in septic patients. \emph{The
Journal of emergency medicine.} 2010;38(5):578-581.

8. Foushee JA, Hope NH, Grace EE. Applying biomarkers to clinical
practice: a guide for utilizing procalcitonin assays. \emph{Journal of
antimicrobial chemotherapy.} 2012;67(11):2560-2569.

9. Swanepoel R, Gill D, Shepherd A, Leman P, Mynhardt J, Harvey S. The
clinical pathology of Crimean-Congo hemorrhagic fever. \emph{Reviews of
infectious diseases.} 1989;11(Supplement\_4):S794-S800.

10. Erg\selectlanguage{ngerman}önül Ö, \selectlanguage{polish}Ş\selectlanguage{english}eref C, Eren \selectlanguage{polish}Ş, \selectlanguage{english}et al. Cytokine response in
Crimean-Congo hemorrhagic fever virus infection. \emph{Journal of
medical virology.} 2017;89(10):1707-1713.

11. Kilinc C, G\selectlanguage{ngerman}ückan R, Capraz M, et al. Examination of the specific
clinical symptoms and laboratory findings of Crimean-Congo hemorrhagic
fever. \emph{Journal of vector borne diseases.} 2016;53(2):162.

12. Burt FJ, Swanepoel R, Shieh W-J, Smith JF. Immunohistochemical and
in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in
human tissues and implications for CCHF pathogenesis. \emph{Archives of
pathology \& laboratory medicine.} 1997;121(8):839.

13. Kerget F, Özkurt Z, Öztürk N, Yilmaz S. The relationship with
clinical course and prognosis of serum endothelin-1, angiopoietin-2, and
tie-2 levels in Crimean-Congo hemorrhagic fever. \emph{Turkish journal
of medical sciences.} 2019;49(4):1192-1197.

14. Ergonul O, Tuncbilek S, Baykam N, Celikbas A, Dokuzoguz B.
Evaluation of serum levels of IL-6, IL-10, and TNF-alpha in patients
with Crimean-Congo hemorrhagic fever. \emph{J Infect Dis.}

15. Ergönül Ö. Crimean-Congo haemorrhagic fever. \emph{The Lancet
infectious diseases.} 2006;6(4):203-214.

16. Kerget F, Demirdö\selectlanguage{polish}ğ\selectlanguage{english}en \selectlanguage{polish}Ş\selectlanguage{english}O, Kerget B. Case Report: A Rare Case of
Crimean--Congo Hemorrhagic Fever Associated with
Epididymo-Orchitis.\emph{The American Journal of Tropical Medicine and
Hygiene.}2021:tpmd201143.

17. Luft D, Deichsel G, Schmulling R-M, Stein W, Eggstein M. Definition
of clinically relevant lactic acidosis in patients with internal
diseases. \emph{American journal of clinical
pathology.}1983;80(4):484-489.

18. Kruse O, Grunnet N, Barfod C. Blood lactate as a predictor for
in-hospital mortality in patients admitted acutely to hospital: a
systematic review. \emph{Scandinavian journal of trauma, resuscitation
and emergency medicine.} 2011;19(1):1-12.

19. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum
procalcitonin and C-reactive protein levels as markers of bacterial
infection: a systematic review and meta-analysis. \emph{Clinical
infectious diseases.} 2004;39(2):206-217.

20. Gul S, Ozturk DB, Kisa U, Kacmaz B, Yesilyurt M. Procalcitonin
levels and their predictive effect on mortality in Crimean-Congo
Hemorrhagic Fever Patients. \emph{Japanese journal of infectious
diseases.} 2015:JJID. 2014.2485.

\textbf{Figure legends}

\textbf{Figure 1.} Receiver operating characteristic curve of serum
lactate and procalcitonin levels in differentiating the severe and
mild/moderate disease

\textbf{Figure 2.} Scatter-plot matrix of serum procalcitonin, aspartate
transaminase, alanine transaminase, and lactate levels

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