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\begin{document}

\title{Comparison And Correlation of Serum Parameters And Cytokines Among
Vaccinated And Unvaccinated COVID-19 Patients In Iraq}



\author[1]{Hayder ALadilee}%
\author[1]{Massoumeh Ebtekar}%
\author[2]{Haethem Qassim}%
\affil[1]{Tarbiat Modares University}%
\affil[2]{Wasit University}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
This study aimed to establish an association between induced cytokines
and COVID-19 disease severity and moderate to help in prognosis and
clinical care in both vaccinated and non-vaccinated patients, Immune
parameters for COVID-19 patients with or without previous vaccination
are evaluated.%
\end{abstract}%



\sloppy


\textbf{Comparison and correlation of serum parameters and cytokines
among vaccinated and unvaccinated COVID-19 patients in Iraq}

\textbf{Hayder Ali Aladilee\textsuperscript{1} , Massoumeh
Ebtekar\textsuperscript{1}*, Haethem Qassim \textsuperscript{2}}

\textbf{1 Department of Immunology, Faculty of Medical Sciences, Tarbiat
Modares University, Tehran, Iran}

\textbf{2 Department of Medical Microbiology, Wasit University, Faculty
of Medicine, Wasit, Iraq.}

\textbf{*} corresponding author \textbf{email: ebtekarm@modares.ac.ir ,
Phone Number: 82883891}

Abstract

Objective

This study aimed to establish an association between induced cytokines
and COVID-19 disease severity and moderate to help in prognosis and
clinical care in both vaccinated and non-vaccinated patients, Immune
parameters for COVID-19 patients with or without previous vaccination
are evaluated.

Methods

40 COVID-19+ patients (20 vaccinated with Pfizer-Biotech COvid-19
vaccine and 20 unvaccinated) were studied during and after infection. 12
healthy and vaccinated controls (6 in each group) were also enrolled in
this study. This study has been performed in Iraq to evaluate and find
correlation of metabolic and immune parameters in vaccinated and
unvaccinated patients as compared to healthy controls. In this work we
evaluated CRP, lymphocyte counts, cholesterol levels, IgM and IgG
detection and IL6, IL10 and IL17 levels during and after COVID-19
infection.

Results

In this work, 80 -90\% of vaccinated~and unvaccinated COVID-19 patients
had above normal CRP levels. Cholesterol levels were above normal in
65\% of unvaccinated patients. ~Differences between cytokine levels
during and after the infection were significant.(P\textless{}0.001)
~\textbar{}Also a positive correlation between cholesterol and all
cytokines studied was observed.(P\textless{}0.001 ) ~~A significant
increase in ~IL-6 levels have been observed in patients as compared to
healthy controls while the difference between vaccinated and
unvaccinated patients is also significant (P\textless{}0.001). ~As for
IL-10, the increase in patients as compared to healthy controls is
significant P=0.00. For IL-17, our studies show that the increase in
patients is significant P=0.00~while there is no significant difference
in IL-17 levels between vaccinated and unvaccinated patients
P\textgreater{}0.001 or healthy controls (P\textgreater{}0.001). ~A
positive correlation between IL6 and CRP levels as well as IL10 and CRP
levels is also observed in our work (P\textless{}.0.001). ~~~A
significant relationship was observed between IgM and all parameters
including: CRP (P=0.00) Cholesterol (P=.008) and IL17 (P=0.00), IL6
(P=0.0) and IL10 (P=0.0). ~~A significant relationship was observed
between IgG and all parameters CRP (P=0.00) and IL17 (P=0.00), IL6 with
P=0.0 and IL10 with P=0.0, as well as cholesterol, except for lymphocyte
counts.

Conclusion This study has been performed for the first time in Iraq and
will serve as an important standard for future basic and clinical
research in this field. It shows a meaningful relationship between
cholesterol levels, IgM/ IgG detection, CRP levels, and IL-6, IL-10, and
IL-17. Further studies on the long-term consequences of COVID on life
quality parameters are also underway.

\textbf{Introduction}

Coronaviruses are a large family of viruses discovered in 1960 that can
cause the common cold. Coronavirus disease 2019 (COVID-19), induced by
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was
first reported in December 2019, and the number of affected countries
grew rapidly, prompting the World Health Organization to disclose it as
a pandemic in 2020. Almost all of the COVID-19 patient populations are
clinically silent or have mild to severe respiratory illness. However,
death cases involving sub and systemic manifestations such as sepsis,
septic shock, and multiple organ dysfunction syndromes (MODS) have been
reported. (1)

The pandemic had caused more than 629 million cases and 6.58 million
confirmed deaths as of October 27, 2022, helping to make it one of the
toughest in history. (2)

From 3 January 2020 to 5:43 pm CEST on 28 October 2022, there were
2,461,107 known cases of COVID-19 in Iraq, with 25,358 fatalities,
according to WHO data. A total of more 19,394,050 vaccine doses has been
delivered as of Oct 22, 2022. (3)

The cytokine storm is critical in the pathophysiology of severe COVID-19
patients. (4)

Cytokine storms can also be caused by a variety of viral and especially
non-disorders, and they can cause serious damage to several organs. (5)

The apparent long term effects of COVID-19 on aggravating heart damage,
inflammation, and plaque activity have led to the hypothesis that
cholesterol metabolism may be involved and that medicines lowering all
of these unfavorable outcomes might be helpful tools for COVID-19
therapy. In this context, the pleiotropic benefits of statins
(beneficial effects beyond cholesterol-lowering) include
anti-inflammatory, immunomodulatory, and antithrombotic qualities, all
of which are observable before lipid-lowering is visible. (6)

Studies have shown that CRP levels are important inflammatory markers
which need to be studied in this disease. The findings might be
extremely useful in designing treatments for specific patients and
following up on them. (7)

Lymphocyte counts have been used for differential diagnosis in COVID-19
patients and are an important indicator. A recent meta-analysis shows
that those with lymphopenia have a 3-fold higher risk of developing
severe COVID-19. Lymphopenia is a prominent feature of COVID-19 and
lymphocyte counts may be a useful, easily available biomarker in
predicting the severity and clinical outcomes. (8)

Immunoglobulins IgM and IgG have an important role in confronting viral
diseases and are important markers for diagnosis Additionally, IgG,
IgM-specific antibodies targeting SARS-CoV-2 can also be found in the
majority of patients. Clarifying these immune-pathological variations
might indicate potential targets for immunotherapy and is important for
specialists in selecting the appropriate therapeutic care. (9)

However, despite numerous clinical studies and meta-analyses, any
reliable prognostic method that can predict patient progression to
severe disease based on cytokine levels at admission remains imprecise.
Studies have shown that higher inflammation and specific cytokine
profiles contribute to disease severity. Multivariate comparisons showed
that TNF-, IL-2, IL-6, IL-10, IL17, and CRP were statistically
different, while IFN and IL-4 were not. (10)

The COVID-19 pandemic's global scope makes the need for a vaccine more
urgent than ever, in contrast to SARS and MERS, which often resolve on
their own after a local epidemic. Numerous diverse methods of vaccine
development have been adopted as a result of this pressing necessity.
First of all, because of their capacity to be generated using just
sequence information, novel vaccination platforms, such as nucleic acid
vaccines and viral vector vaccines, are quickly rising to the top of the
COVID-19 vaccine development field. (11) Mortality rates of COVID-19
have diminished in vaccinated individuals and societies with higher
vaccination rates have demonstrated lower mortality. Vaccination has
been shown in several studies to reduce morbidity and death. According
to an Italian study, the risk of SARS-CoV-2 infection, hospitalization,
and mortality gradually reduce after the initial two weeks. (12)

Although many clinical studies have been performed during the COVID-19
pandemic, however due to the continuing spread of the disease in many
countries and the diverse manifestations and mortality rates it is
necessary to elucidate the immune pathways involved for better diagnosis
and therapy and long term follow up.

In this work we studied the relationship between CRP and cholesterol
levels, lymphocyte counts and detection of IgM and IgG with IL6, IL10
and IL17 levels and compared them in vaccinated and unvaccinated healthy
and COVID-19+ patients in Iraq.

\textbf{Material and Methods}

\textbf{Study design}

This study was performed in the Wasit Province of Iraq Al-Zahra Teaching
Hospital, between March -- June 2022. 40 COVID-19+ patients (20
vaccinated with Pfizer-BioNTech COVID-19 vaccine and 20 unvaccinated)
were studied during and after COVID-19 infection and 12 healthy and
vaccinated controls (6 in each group) were also enrolled in this study.
30 were male and 22 were female participants in this study. Blood
samples were collected over two time periods i.e.: during infection and
2-3 weeks after the onset of the disease. All individuals in this study
provided an informed consent for enrollment.

Immunological, biochemical and serological and hematological tests were
performed for all groups.

The inclusion criteria for the participants in the study were being
adults (between 20-70 years old) hospitalized for at least seven days
from the onset of COVID-19 symptoms, which is when usually the
inflammatory phase begins, with a diagnosis of pneumonia due to COVID-19
based on clinical-radiological criteria and a laboratory PCR which
confirmed SARS-CoV-2 infection diagnosis, oxygen saturation \textless{}
94\% and 25(OH) D serum levels \textless{} 30 ng/ml. Vaccinated
participants had received two doses of Pfizer BioNTech COVID-19 vaccine
three to four months prior to the study.

Participants were excluded if they were lactating, pregnant women, were
participating in other clinical trials with drugs with potential
antiviral action for COVID-19, or diseases such as cancer, autoimmune
disease, thalassemia and allergy.

\textbf{Methods}

Measurement of CRP was done by the instrument for AFIAS-6 tests to show
CRP concentration in sample. Measurement of cholesterol was performed by
the instrument for semi- auto biochemistry (Mindray). Lymphocytes were
measured by Auto Hematology Analyzer BC-30 Mindray instrument. Detection
of SarsCoV2 specific IgG and IgM was performed using the BIOZEK COVID-19
IgG/IgM Rapid Test Cassette (Whole Blood/ Serum/Plasma). Cytokines
IL-10, IL-6, Il-17 were measured by competitive ELISA technique using
ELISA kit (KPGene Company).

\textbf{Statistical analysis}

The~statistics SPSS 25.0 software was utilized for analysis, the data
was also entered into Graphpad Prism7. The mean SD of standard normal
measured values was used for variance analysis. Statistical significance
was indicated by the correlation between paired data analysis and
p-value [?]0.05.

\textbf{Results}

In this study, 12 people from the healthy group tested negative and 40
patients tested positive for COVID-IgM. Also, 14 people (12 healthy
participants and 2 patients) tested negative and 38 patients tested
positive for COVID - IgG.

The lymphocyte count of 8 participants (15.4\%) was low, 20 people
(38.5\%) were normal, and 24 people (46.2\%) were high. Out of these, 10
people from non-vaccinated patients and 14 vaccinated patients had high
lymphocyte levels, and lymphocyte counts in the healthy control group
were all normal.

In this work, 80\% of vaccinated and 90\% of unvaccinated COVID-19
patients had above normal CRP levels. CRP levels in all healthy
participants were normal.

Cholesterol levels were above normal in 65\% of unvaccinated patients
while in vaccinated patients only 15\% had cholesterol levels above
normal. Cholesterol levels in all healthy participants were normal.

Based on our statistical analysis, there was no significant relationship
between gender and other parameters studied in this work, however there
was a significant relationship between age and CRP (P=0.007) and IL17
(P=0.03) and close to significant relationship for IL6. The residence
location of participants had no meaningful correlation with any of the
parameters studied.

According to statistical analysis, there was a significant relationship
between IgM and all parameters including: CRP (P=0.00) Cholesterol
(P=.008) and IL17 (P=0.00), IL6 (P=0.0) and IL10 ( P=0.0). Likewise, the
correlation between IgM and the number of lymphocytes is close to being
significant. According results and statistical analysis, there was a
significant relationship between IgG and all parameters CRP (P=0.00) and
IL17 (P=0.00), IL6 with P=0.0 and IL10 with P=0.0, as well as
cholesterol, except for lymphocyte counts.

\textbf{Figure 1. Cytokine levels for all groups during (D) and after
(A) infection. As shown there is a statistically significant difference
(P\textless{}0.05) between all groups.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Cholesterol} & \textbf{Cholesterol} & &\tabularnewline
& \textbf{Mean} & \textbf{Std. error} & \textbf{p-value}\tabularnewline
\textbf{IL6 A} & \textbf{133.4} & \textbf{14.91} &
\textbf{\textless{}0.0001}\tabularnewline
\textbf{IL10 A} & \textbf{127.9} & \textbf{14.91} &
\textbf{\textless{}0.0001}\tabularnewline
\textbf{IL17 A} & \textbf{107.9} & \textbf{14.91} &
\textbf{\textless{}0.0001}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1. Correlation between cholesterol and cytokine levels
after infection. As indicated a positive correlation between cholesterol
and all cytokines studied was observed.}

Comparison of cytokine levels among study groups showed that in most
groups significant differences have been observed.

As figure2 indicates a significant increase in l IL-6 levels have been
observed in patients as compared to healthy controls while the
difference between vaccinated and unvaccinated patients is also
significant P\textless{}0.001.

\textbf{Figure 2. Comparison between four groups for interleukin-6 after
infection.}

As for IL-10, the increase in patients as compared to healthy controls
is significant P=0.00 while there is no significant difference in IL-10
levels between vaccinated and unvaccinated groups. P\textgreater{}0.001

\textbf{Figure 3. Comparison between four groups for interleukin-10
after infection.}

For IL-17, our studies show that the increase in patients as compared to
healthy controls is significant P=0.00 while there is no significant
difference in IL-17 levels between vaccinated and unvaccinated patients
P\textgreater{}0.001 or healthy controls P\textgreater{}0.001.

\textbf{Figure 4. Comparison between four groups for interleukin-17
after infection.}

CRP measurements have shown that while differences among patient and
healthy patients are significant P\textless{} 0.001. A comparison of
levels between vaccinated and unvaccinated patients also show
significant differences P\textless{}0.001.

\textbf{Figure 5. Comparison between four groups for CRP after
infection. Patients have significantly higher CRP levels in both
vaccinated and unvaccinated groups as compared to healthy controls.
P\textless{}0.001}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 6. Correlation trend line between CRP and IL6 after the
infection This graph shows a positive correlation between IL-6 and CRP
in COVID-19 patients after the infection. (P\textless{}0.001)}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

\textbf{Figure 7. Correlation trend line between CRP and IL10 after the
infection. This graph shows a positive correlation between IL-10 and CRP
in COVID-19 patients after the infection. (P\textless{}0.001)}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{Figure 8. Correlation trend line between CRP and Cholesterol
after the infection. This graph shows a positive correlation between
Cholesterol and CRP in COVID-19 patients after the infection.
(P\textless{}0.001)}

\textbf{Discussion}

The world observed the SARS outbreak in 2002 and 2003, as well as the
MERS spread in 2011, both of which were caused by coronaviruses. Another
coronavirus that causes respiratory disease was found in Wuhan, China,
near the end of 2019, and was formally designated COVID-19. (13) This
infection has advanced to other regions of China and other countries
since late 2019, and its transmission rate, fatality rate, and clinical
manifestations have all been determined. However, it will take several
months, if not years, to completely understand all of the disease's
qualities and characteristics, including its genesis, symptoms, and the
patient's immunological response to this infection. The production of
high levels of cytokines such as IL-1, IL-2, IL-4, IL-6, IL-10, IL-17 ,
TNF- alpha and IFN-gamma in infected patients, is involved in the
underlying pathophysiology of the present COVID-19 pandemic,(13,14)
while specific immunoglobulins IgG and IgM (15), cholesterol levels (16)
CRP (17) and lymphocyte counts (18) are implicated in the diagnosis and
progression of the disease.

In our study there was a significant relationship between lymphocyte
count and all parameters including lymphocyte counts, CRP (P=0.02), IL10
(P=0.0), and cholesterol levels in all groups. (19)This is in accordance
with other studies that have indicated that lymphocyte counts are an
important indicator of COVID-19 and disease progression. (19)

In our study lymphocyte counts in unvaccinated patients 50\% had higher
lymphocyte counts while in vaccinated patients only 70\% had lymphocyte
counts higher than normal. Lymphocyte counts in all control groups were
normal. In our study since the lymphocyte count measurement was made 2-3
weeks after infection only 15.4\% of the patients had lower than normal
counts. Many clinical studies indicated a decrease in lymphocyte counts
which was became a standard diagnosis parameter for COVID. These studies
show that severe disease is specifically identified by an increased
neutrophil count is among the key results which is combined with a lower
lymphocyte count (therefore the neutrophil to lymphocyte ratio has
increased significantly). (20)

In unvaccinated patients 65\% had higher cholesterol levels, while in
vaccinated patients only 15\% had cholesterol levels higher than normal.
Cholesterol levels in all control groups were normal. Our results show
that 65\% of unvaccinated patients in this study have higher cholesterol
levels which might be a reason for the higher susceptibility of this
group and the correlation between the studied cytokines and cholesterol
levels is significant (Table1) which indicates a meaningful relationship
in COVID-19 patients and warrants further investigation. (20)

In the unvaccinated patient group 90\% had CRP levels significantly
higher than normal (P\textless{}0.05) while in the vaccinated patients
group 80\% had higher than normal CRP levels. (Figure 5) CRP levels in
all control groups were normal. Our results show that higher CRP levels
are a reliable indicator for COVID-19 diagnosis in most cases and this
result is in accordance with other studies. (21)

In our study 100\% of unvaccinated patients and 90\% of vaccinated
patients had significantly higher than normal IL6 levels after the
infection. (Figure 2) IL6 in all control groups were normal. Our
findings correlated with many other clinical studies that indicated that
IL6 is a major inflammatory factor in COVID-19 and plays a key role in
the events leading to a cytokine storm. (22) High levels of IL-6, a
pro-inflammatory cytokine, are known to inhibit NK cell function and
have also been linked to an impaired lytic activity. Disease progression
symptoms such as elevated body temperature, elevations in inflammatory
indicators such as CRP and serum ferritin, and advanced chest computed
tomography imaging were related to higher IL-6 levels that decreased
during recovery in COVID-19 patients. This link between IL-6 and
pulmonary diseases has previously been established in individuals with
radiation-induced pneumonia or severe alveolitis. (23) In our work, also
the levels of IL6 after infection (first day of positive PCR) was higher
than after recovery. (Figure 2)

In our work, 95\% of unvaccinated patients and 100\% of the vaccinated
patients had statistically significant higher than normal levels of IL10
after the infection as compared to healthy controls. IL10 levels in all
control groups were within the normal range. (Figure 3 ) These results
indicate that an increase in IL-10 during COVID-19 is a hallmark of both
vaccinated and unvaccinated patients. IL-10, on the other hand, is an
anti-inflammatory cytokine that has been observed to be increased in
individuals with severe COVID-19. T-cell stress was also observed to be
associated with IL-6, IL-10, and TNF-levels in COVID-19 patients. IL-10
is a key molecule with the main role of suppressing the inflammatory
process. IL-10 has also been associated with T-cell immune activation
and non-responsiveness in anti-tumor cell responses, in addition to
viral infection. Studies show that an antibody against IL-10 or its
receptor or genetic ablation of IL-10 resulted in the eradication of
viral or bacterial pathogen attacks. Thus, higher IL-10 levels in severe
COVID-19 patients were first attributed to a negative feedback
mechanism, including its anti-inflammatory actions. (23)

In our study 95\% of unvaccinated patients and 90\% of vaccinated
patients had significantly higher IL17 after the infection. IL17 in all
control groups were normal. (Figure 4) IL-17 specifically boosts
proinflammatory, but not antiviral gene expression in human cells
infected with respiratory viruses by stimulating non immune cells
(fibroblasts and epithelial cells) to produce increased amounts of
proinflammatory cytokines and chemokines in response to viral infections
that attract other immune cell types (for example, neutrophils) which
can lead to increased morbidity while simultaneously remaining
inefficient in inhibiting the spread of the pathogen. Th17 cells appear
to play a major role in COVID-19 disease, not only by stimulating the
cytokine pathway, but also by promoting Th2 responses, blocking Th1
differentiation, and inhibiting regulatory T cells. (24)

Also correlation studies in our work show significant correlation
between CRP, IL-6, IL-10 and IL-17 (Figure 6,7) indicating that common
signaling pathways may be involved between inflammatory factors and
these cytokines as other work have indicated.(25)

In conclusion, it may be inferred that while research on the COVID-19
pandemic at the global level is ongoing our clinical studies have
displayed a meaningful relationship between cholesterol levels, IgM/ IgG
detection, CRP levels and IL-6, IL-10 and IL-17 pointing to the
importance of these immune and metabolic factors for diagnosis and
therapy for COVID-19 patients. Further studies on the long term
consequences of COVID on life quality parameters are also underway and
will shed light on the ambiguous dimensions of the Long COVID phenomena.
This study has been performed for the first time in Iraq , Wasit
province and will serve as an important standard for future basic and
clinical research in this field.

\textbf{Declaration of Competing Interest}

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.

\textbf{Acknowledgement}

We thank all participants in this study for their invaluable
contribution

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\end{enumerate}

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