Sudan Journal of Medical Sciences
Volume 18, Issue no. 2, DOI 10.18502/sjms.v18i2.13603
Production and Hosting by Knowledge E

Research Article

Serum Cytokine Levels As Critical Parameters
in Early Diagnosis of Disease Progression in
COVID-19: A Pilot Study
Walaa Mohammedsaeed1, Ziab Zakey Alahmadey2, and Nikhat Manzoor3

1Clinical Biochemistry, Department of Medical Laboratory Technology, Faculty of Applied Medical
Sciences, Taibah University, Madinah, Saudi Arabia
2Laboratory Department, Ohud Hospital Madinah, Saudi Arabia
3Medical Mycology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, India

ORCID:
Walaa Mohammedsaeed: https://orcid.org/0000-0002-6696-5441

Abstract
Background: The severity of Coronavirus disease 2019 (COVID-19) has been proposed
to be associated with cytokine dysregulation. A significant number of patients become
serious and need intensive care in hospitals.
Methods: The concentrations of cytokines interleukin (IL-6, IL-10) and tumor necrosis
factor (TNF) were estimated using enzyme-linked immunosorbent assay (ELISA) in
serum samples of 60 adult patients infected with SARS-CoV-2 along with 50 healthy
controls of the same age. The mean age of the subjects was 50-52 years and included
an equal number of males and females. The patients were further grouped as severe
(38 patients) and non-severe cases (22 patients).
Results: The mean serum cytokine levels were significantly higher in the COVID-19
patients than in the healthy controls. IL-6 was excessively elevated in comparison to
IL-10 and TNF. Comparative analysis of severe versus non-severe cases revealed only
slight alterations in the cytokine levels: IL-6 being the most elevated in severe cases.
The concentration of the liver enzyme ALT was higher than AST in both severe and
non-severe cases. The mean concentration of serum electrolytes (Na, K, and Ca) did
not vary much between the patients and healthy controls.
Conclusion: There was a significant positive correlation between the levels of
cytokines serum biomarkers in COVID-19 patients. It may be suggested that early
detection of cytokines, especially IL-6 and serum biomarkers can help predict disease
prognosis and severity in COVID-19 patients.

Keywords: COVID-19, Cytokines, disease severity, diagnosis, liver function, kidney
function

How to cite this article: Walaa Mohammedsaeed, Ziab Zakey Alahmadey, and Nikhat Manzoor (2023) “Serum Cytokine Levels As Critical Parameters
in Early Diagnosis of Disease Progression in COVID-19: A Pilot Study ,” Sudan Journal of Medical Sciences, vol. 18, Issue no. 2, pages 190–202.
DOI 10.18502/sjms.v18i2.13603

Page 190

Corresponding Author: Walaa

Mohammedsaeed; email:

wmohammed-

saeed@taibahu.edu.sa

Received 15 January 2023

Accepted 12 March 2023

Published 30 June 2023

Production and Hosting by

Knowledge E

Walaa Mohammedsaeed

et al. This article is distributed

under the terms of the

Creative Commons

Attribution License, which

permits unrestricted use and

redistribution provided that

the original author and

source are credited.

Editor-in-Chief:

Prof. Nazik Elmalaika Obaid

Seid Ahmed Husain, MD,

M.Sc, MHPE, PhD.

http://www.knowledgee.com
https://creativecommons.org/licenses/by/4.0/
https://creativecommons.org/licenses/by/4.0/


Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

1. Introduction

The SARS-CoV-2 infection (COVID-19) has been wreaking havoc since its outbreak in
December 2019. More than 660 million infections and 6.7 million deaths have been
reported to date. The virus has not only spread worldwide but has also mutated several
times [1]. The disease has pneumonia-like symptoms affecting the lungs with varying
degrees of severity. From the infected lungs, it may spread to other parts of the
body, sometimes leading to multiple organ failure [2]. Acute lung injury in COVID-19
patients may be triggered by the release of inflammatory molecules, activated immune
cells, overproduction of cytokines, and the presence of adhesins [3]. The damage
caused to the lungs and other body organs has been linked to the abnormally strong
proinflammatory host immune response. Described as the ‘cytokine storm syndrome,’ it
plays an important role in the pathophysiology of COVID-19. The clinical symptoms vary
among individuals from asymptomatic and non-specific to more serious, where patients
need hospitalization [4]. The severity of COVID-19 disease depends on several factors
imparting poor prognoses, such as high viral load, old age, and comorbidities (cancer,
coronary heart disease, diabetes, and hypertension) [5, 6]. The disease pathogenesis
is not clearly understood and comprises several intricate and complex physiological
processes. Cytokines are released by immune cells to regulate inflammatory responses
during tissue damage and infections. It has been shown that some proinflammatory
cytokines, namely, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta
(TGF-β), interferon gamma (IFN- γ), interleukins (IL-1, IL-8, and IL-6), play a crucial role in
several pathological conditions [7, 8]. The involvement of TNF-α is an intermediary in
the pathogenesis of certain viral infections like influenza [9]. Some other cytokines,
like IL-4 and IL-10, help reduce inflammation [10]. The role of cytokines in disease
pathogenesis is still unclear, but reports suggest that their excessive outburst may
be responsible for disease progression and sometimes death of the patient [11, 12]. The
serum cytokine levels must be regulated, but whether anti-cytokine therapy has any
benefit needs further evaluation [13]. The liver, heart, and kidneys are vital organs of
the human body that perform some critical functions. Detection of specific biomarkers
and their appropriate concentrations in the blood helps investigate these organs’ health
status [14]. A strong connection has been observed between the severity of COVID-19
and chronic liver diseases accompanied by inflammation and dysregulation of immune
responses. Patients suffering from underlying conditions carry a greater risk of adverse
consequences after contracting COVID-19. Moreover, when infected, healthy individuals
exhibit abnormal liver function, directly implicating the virus in damaging the liver and

DOI 10.18502/sjms.v18i2.13603 Page 191



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

metabolism [15]. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
are biomarkers for hepatocellular damage. Bilirubin and albumin levels assess the
liver’s secretory and synthetic capacities, respectively [16]. Increased levels of serum
creatinine can indicate renal dysfunction. Serum ferritin, creatine kinase (CK), lactate
dehydrogenase (LDH), inflammatory factors, and electrolytes (sodium, potassium) can be
used as indicators for COVID-19 [17]. As observed with other viral infections, increasing
cytokine levels have emerged as early parameters in COVID-19 disease advancement
[18]. Hence, estimating increased serum cytokine levels and abnormalities in the hepatic,
renal, and cardiac biomarkers can be important in predicting poor outcomes in COVID-
19 patients. The levels of IL-6, IL-10, and TNF in the serum can also predict the severity of
the disease, as cytokines play an important role in host immunity and immunopathology
during the infection. The present study thus attempts to correlate cytokine levels with
biomarkers of vital body organs in COVID-19 patients.

2. Methods

2.1. Patients and data collection

A total of 60 COVID-19 patients were randomly selected from the Ohud Hospital,
Madinah, Saudi Arabia. A healthy control group of similar age (50 subjects) was selected
from Taibah University, Madinah, Saudi Arabia. The clinical and laboratory data of the
patients were analyzed and documented. All the cases were assessed according to the
inclusion and exclusion criteria. Individuals with a history of endocrine diseases were
excluded. Patients with confirmed COVID-19 were categorized into two groups (severe
and non-severe) based on clinical characteristics, symptoms, and results obtained from
chest radiography [19].

Blood samples (3 ml) were collected in serum separator tubes and allowed to clot
for 2 h at room temperature before centrifugation at 1000×g for 15 min. Serum was
collected and stored at -80∘C. The serum concentrations of TNF-α, IL-10, and IL-6 were
determined in the subjects. Biochemical assays (kidney and liver function tests) were
performed to estimate the concentration of creatinine, urea, Na, K and Ca, troponin I,
C-reactive protein (CRP), LDH, CK, ALT, AST, bilirubin, albumin, and ferritin using the
automated ARCHITECT c4000, as per the manufacturer’s guidelines.

DOI 10.18502/sjms.v18i2.13603 Page 192



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

2.2. Enzyme-linked immunosorbent assays (ELISA)

Cytokine concentrations were determined using ELISA development kits (CUSABIO
Technology LLC, Houston, USA) in adherence with the manufacturer’s instructions for
TNF-α, IL-10, and IL-6. The antibody specific for each cytokine was pre-coated onto
a microplate. The optical density was verified using a Mindray mr-96a/Mindray ELISA
reader microplate reader (Mindray, Guangdong, China) set at 450 nm. The experiment
was carried out twice, with duplicate samples within each experiment.

2.3. Statistical analysis

Quantitative data were normally distributed and expressed as mean with standard
deviations (± SD). Student’s t-test evaluated differences between groups. The Spearman
correlation coefficient calculations were used to investigate the association between
the different parameters. All statistical analyses were performed using the Statistics
Package of Social Science (SPSS 20, SPSS Inc., Chicago, IL) and two-tailed p-values.

3. Results

3.1. Patient characteristics and cytokine levels

The mean age of the COVID-19 patients was comparable (50 ± 10.6 years) to that of the
healthy controls (52 ± 12.8 years) and included subjects from both genders equally. The
serum concentrations of liver enzymes ALT and AST in the patients were high (60.44
± 33.07 U/L and 49.20 ± 25.17 U/L) in comparison to healthy controls, where the values
were 10.8 ± 4.6 U/L and 15.7 ± 7.3 U/L, respectively. Similarly, in COVID-19 patients
the concentrations of albumin and bilirubin were 45 ± 15.35 g/L and 50.34 ± 21.80
mg/dL, respectively, while healthy controls were 40.7 ± 31.9 g/L and 1.4 ± 0.8 mg/dL,
respectively. Thus, the serum concentrations of liver function biomarkers in COVID-19
patients were much higher than in healthy controls.

The serum levels of creatinine, urea, Na, K, and Ca (biomarkers of renal function) in
COVID-19 patients were 292.95 ± 86.73 µmol/L, 20.83 ± 10.98 mmol/L, 149.35 ± 22.96
mmol/L, 1.33 ± 1.2 mmol/L, and 2.15 ± 0.87 mmol/L, respectively. Serum concentrations
for the same in healthy controls were 55.67 ± 20.93 µmol/L, 8.10 ± 5.13 mmol/L, 130.87
± 8.77 mmol/L, 3.77 ± 0.77 mmol/L, and 2.10 ± 0.52 mmol/L, respectively. Except for
Ca and K, the concentrations of renal function biomarkers were significantly higher in

DOI 10.18502/sjms.v18i2.13603 Page 193



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

COVID-19 patients compared to controls. The serum levels of LDH (391.84 ± 75.9 U/L),
CK (393.88 ± 75.27 U/L), CRP (50 ± 15.35 mg/L), and ferritin (599.64 ± 51.90 ng/mL),
although not troponin (0.5 ± 0.20 ng/L), were significantly increased in the patients in
comparison to healthy controls where these values were respectively, 110.57 ± 27.6 U/L,
50.44 ± 40.17 U/L, 6.9 ± 3.35 mg/L, 107.69 ± 55.80 ng/mL, and 0.2 ± 0.10 ng/L (Table
1). Also, the levels of cytokines IL-6 (0.8 ± 0.75 pg/mL), IL-10 (3.2 ± 2.05 pg/mL), and TNF
(6.1 ± 3.32 pg/mL) in healthy controls were found to increase to 30.27 ± 13.35 pg/mL,
17.6 ± 7.2 pg/mL and 15.4 ± 6.4 pg/mL in the diseased individuals, p < 0.001**.

Table 1: Clinical characteristics and cytokine levels in COVID-19 patients and the healthy population.

Parameters COVID-19 patients n = 60) Control (n = 50) P-value

Age 50 ± 10.6 52 ± 12.8
Sex (number) Male = 30 Male = 25

Female = 30 Female = 25

ALT (U/L) 60.44 ± 33.07 10.8 ± 4.6 0.01*
AST (U/L) 49.20 ± 25.17 15.7 ± 7.3 0.02*
Bilirubin (mg/dL) 50.34 ± 21.80 1.4 ± 0.8 <0.001**
Albumin (g/L) 45 ±15.35 40.7 ± 31.9 0.06
Creatinine (µmol/L) 292.95 ± 86.73 55.67 ± 20.93 0.01*
Urea (mmol/L) 20.83 ± 10.98 8.10 ± 5.13 0.06
Na (mmol/L) 149.35 ± 22.96 130.87 ± 8.77 0.04*
K (mmol/L) 1.33 ± 1.2 3.77 ± 0.77 0.04*
Ca (mmol/L) 2.15 ± 0.87 2.10 ± 0.52 0.072
CK (U/L) 393.88 ± 75.27 50.44 ± 40.17 <0.001**
LDH (U/L) 391.84 ±75.9 110.57 ± 27.6 0.002**
Troponin (ng/L) 0.5 ± 0.20 0.2 ± 0.10 0.08
Ferritin (ng/mL) 599.64 ± 51.90 107.69 ± 55.80 <0.001**
CRP (mg/L) 50 ± 15.35 6.9 ± 3.35 0.003*
IL-6 (pg/mL) 30.27 ± 13.35 0.8 ± 0.75 <0.001**
IL-10 (pg/mL) 17.6 ± 7.2 3.2 ± 2.05 <0.001**
TNF (pg/mL) 15.4 ± 6.4 6.1 ± 3.32 <0.001**
Data are presented as mean ± SD. *P < 0.05, **P < 0.001.

3.2. Cytokine levels and other biomarkers in severe and
non-severe COVID-19 patients

Table 2 shows the comparative variations in the concentrations of hepatic, renal, and
cardiac biomarkers with that of cytokines (IL-6, IL-10, and TNF) between severe and
non-severe COVID-19 cases. The mean IL-6 concentration in severe COVID-19 patients
was 20.17 ± 10.35 pg/mL, statistically greater than in non-severe patients (10.8 ± 5.75

DOI 10.18502/sjms.v18i2.13603 Page 194



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

pg/mL). Similarly, the mean concentrations of IL-10 (15.03 ± 5.62 pg/mL) and TNF (17.25
± 6.47 pg/mL) in severe COVID-19 patients were again significantly higher than in non-
severe patients (10.21 pg/mL and 11.21 ± 4.32, respectively). Compared to non-severe
COVID-19 patients, the severe cases showed significantly higher levels of serum ALT,
AST, and bilirubin, which were 65.22 ± 50.91 mmol/L and 53.95 ± 46.50 mmol/L and
50.89 ± 32.62 mg/dl, respectively. In the case of non-severe cases, the serum levels
of ALT, AST, and bilirubin were 12.8 ± 8.6, 15.7± 7.3, and 20.4 ± 1.5, respectively. The
serum levels of creatinine and Na were significantly higher (184.28 ± 34.89 µmol/L and
148.10 ± 20.71 mmol/L, respectively) in severe cases, while the values in non-severe
cases were 78.45 ± 50.99 and 138.17 ± 78.99, respectively. The concentration of K
was slightly higher (2.99 ± 2.92 mmol/L) in non-severe cases than in severe ones
(1.25 ± 0.92 mmol/L). The levels of cardiac biomarkers were again significantly higher in
severe cases compared to non-severe patients (Table 2). The concentrations of CK, LDH,
ferritin, and CRP were 55.94 ± 100.07 U/L, 100.54 ± 25.9 U/L, 100.64 ± 45.80 ng/mL,
and 15.9 ± 4.35 mg/L in non-severe cases. The concentration of the same biomarkers
was considerably increased in severe COVID-19 cases. In patients with severe disease,
the serum concentration values for CK, LDH, ferritin, and CRP were 350.88 ± 45.17 U/L,
362.44 ± 45.9 U/L, 750.60 ± 81.80 ng/mL, and 29 ± 9.35 mg/L, respectively.

Table 2: Alterations in cytokine levels and other biomarkers in severe and non-severe COVID-19 patients.

Biomarkers Non-severe cases, n = 22 Severe cases, n = 38 P-value

Mean ± SD Mean ± SD
IL-6 10.8 ± 5.75 20.17 ± 10.35 0.01*
IL-10 10.21 ± 4.05 15.03 ± 5.62 0.03*
TNF 11.21 ± 4.32 17.25 ± 6.47 0.01*
ALT 12.8 ± 8.6 65.22± 50.91 0.001**
AST 15.7 ± 7.3 53.95 ± 46.50 0.001**
Bilirubin (mg/dl) 20.4 ± 1.5 50.89 ± 32.62 0.002**
Creatinine(µmol/L) 78.45 ± 50.99 184.28 ± 34.89 0.003**
Na(mmol/L) 138.17 ± 78.99 148.10 ± 20.71 0.04*
K(mmol/L) 2.99 ± 2.92 1.25 ± 0.92 0.06
CK (U/L) 55.94 ± 100.07 350.88 ± 45.17 0.003**
LDH (U/L) 100.54 ± 25.9 362.44 ± 45.9 0.001**
Ferritin (ng/mL) 100.64 ± 45.80 750.60 ± 81.80 0.0001**
CRP (mg/L) 15.9 ± 4.35 29 ± 9.35 0.05*
Data were analyzed using t-test. The values indicate statistical significance (p < 0.001** and p < 0.05*)

DOI 10.18502/sjms.v18i2.13603 Page 195



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

3.3. Correlation between cytokine levels and biochemical markers
in COVID-19 patients

The relationship between serum cytokines and other biochemical markers in COVID-19
patients is in Table 3. The values indicated that serum IL-6 showed significant positive
correlations with ALT (r = 0.750, p = 0.02), AST (r = 0.659, p = 0.04), CK (r = 0.569, p =
0.04), Ferritin (r = 0.704, p = 0.02), and CRP (r = 0.859, p = 0.001). On the other hand,
IL-10 showed significant positive correlations with only ALT (r = 0.636, p = 0.04) and AST
(r = 0.672, p = 0.5). Interestingly, TNF showed a positive correlation with ALT (r = 0.726
p = 0.05), AST (r = 0.682 p = 0.03), CK (r = 0.619 p = 0.04), Ferritin (r = 0.604 p = 0.02)
and CRP (r = 0.784, p = 0.03). Our results showed no significant positive correlations
between serum cytokines with biological parameters like bilirubin, creatinine, Na, and
LDH.

Table 3: Relationship between serum cytokine levels and other biochemical parameters in COVID-19
patients.

IL-6 IL-10 TNF

r P r P r P

ALT 0.750 0.02* 0.636 0.04* 0.726 0.05*

AST 0.659 0.04* 0.672 0.05* 0.682 0.03*

Bilirubin 0.210 0.060 0.329 0.07 0.043 0.08

Creatinine 0.082 0.073 0.257 0.06 0.257 0.09

Na 0.201 0.025 0.078 0.08 0.068 0.06

CK 0.569 0.04* 0.319 0.07 0.619 0.04*

LDH 0.122 0.06 0.136 0.07 0.123 0.09

Ferritin 0.704 0.02* 0.257 0.08 0.604 0.02*

CRP 0.859 0.001** 0.426 0.06 0.646 0.03*

IL-6 0.741 0.002** 0.784 0.003**

IL-10 0.741 0.002** 0.604 0.02*

TNF 0.784 0.003** 0.604 0.02*

Correlation is statistically significant (P < 0.05* and P < 0.001**)

4. Discussion

Under normal conditions, cytokines coordinate the host’s immune response against
microbial infections. Insufficient cytokines are incapable of modulating inflammation and
dealing with pathogenic invasion. Similarly, excessively high amounts can sometimes
cause irreparable damage. COVID-19 patients discharged from the ICU seem to have
more elevated levels of inflammatory cytokines than individuals who are less severely

DOI 10.18502/sjms.v18i2.13603 Page 196



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

infected. Cytokine storm generation is not a universal feature of all infections. It has been
observed to be triggered by the influenza A virus and may have been the cause of death
during the 1918 influenza pandemic [20]. Immunotherapy, organ transplantation, cancer
therapy, AIDS, and sepsis are some conditions that can trigger the overproduction
of cytokines and inflammatory molecules, affecting multiple organs and become life-
threatening [21]. In the case of COVID-19, the selective behavior of the host response
toward the virus needs to be investigated. Although unclear, the expression of specific
genes may generate a cytokine storm besides other factors [22]. The severity of
the disease depends on underlying health conditions like diabetes, heart disease,
hypertension, and other comorbidities. Early diagnosis can be made by estimating
the level of cytokines before the body organs are affected, specifically the heart,
liver, and kidneys. Elevated cytokine levels and anomalies in the blood profiles of
patients can be helpful indicators of disease progression [23] . Previous reports have
implicated excessively high levels of IL-6 in disease severity and high mortality in COVID-
19 patients [24]. The available clinical data have indicated that moderate and severe
COVID-19 patients display abnormal liver function with increased levels of AST and
ALT [25]. However, the impact of COVID-19 on liver and kidney function is yet to be
completely understood. Studies have shown that cytokine storms generated in non-
COVID-19 cases also lead to acute liver injury [26-27]. Early measurement of serum
cytokines is thus a reliable predictor of disease outcome and, hence, is critical for
early diagnosis and treatment. A model based on cytokine levels can help optimize
therapeutic strategies and design clinical trials to modulate the released inflammatory
molecules [28]. Increased amounts of LDH and CK enzymes in the blood indicate
cellular damage. Similarly, the release of cardiac biomarkers (CK, troponin, myoglobin)
in the blood indicates a damaged heart. Their levels can be estimated in diagnosing
cardiac ischemia, a condition common in SARS-CoV2 infection. The protein troponin
is the most commonly used biomarker, with very high sensitivity as it remains in the
blood for longer periods. Although not specific, the concentration of CK often doubles
when the heart is damaged [25]. In the present study, the serum concentrations of
cytokines IL-6, IL-10, and TNF were all found to be elevated in COVID-19 patients. The
concentration of IL-6 was found to be elevated 37-fold, which is extremely high in
comparison to the other two cytokines. Ferritin and IL-10 were elevated by 5.5-fold, while
TNF was only 2.5-fold higher compared to the healthy controls. TNF is a proinflammatory
cytokine largely released by activated macrophages, T lymphocytes, and natural killer
cells. It displays a complex network of interactions with other cytokines and further
stimulates their release. IL-10, on the other hand, is an inhibitor of pro-inflammatory

DOI 10.18502/sjms.v18i2.13603 Page 197



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

cytokine production and antigen presentation in activated monocytes/macrophages
[29]. Along with elevated serum cytokine levels, COVID-19 patients displayed increased
levels of liver enzymes (ALT and AST). Interestingly, ALT, a more specific indicator
of liver inflammation [15], was found in higher concentrations than AST. Compared to
healthy individuals, the serum of COVID-19 patients showed elevated levels of AST, ALT,
bilirubin, creatinine, urea, K, CK, LDH, troponin, ferritin, and CRP. Elevation of serum AST
and ALT levels (3-5-fold) can be due to hepatocellular damage, but a 36-fold higher
bilirubin level in COVID-19 patients suggests obstruction of bile flow (cholestasis). We
also found the patients’ CK and CRP levels to be 7-8-fold elevated. Although there was
no change in the Na and Ca ion concentrations, the level of K was slightly lower, which
may be due to its loss in urine [30]. Ferritin is a cytosolic protein that is released into
the serum. Usually, it is used as a diagnostic marker for anemia, but high serum ferritin
levels may indicate acute inflammatory reactions. Ferritin, CRP, and IL-6 have been
considered possible immunological biomarkers for severe COVID-19 and probable tools
for screening and early diagnosis [23]. As expected, the comparison of severe and non-
severe COVID-19 cases revealed that the serum cytokine levels and biomarkers were
slightly higher in the former cases. Severe cases showed around 7.5 times higher levels
of ferritin. The liver enzyme ALT and CK concentrations were 5-6 times higher in severe
cases indicating greater liver damage here.

5. Conclusion

Managing the host’s immune status and other biological parameters can significantly
combat the SARS-CoV-2 infection. Screening patients for hyperinflammation and man-
aging cytokine storms in immunocompromised patients, along with other biomarkers
of vital organs, can improve the mortality rate. Therapeutic strategies may include a
combination of antibiotics, immunoglobulins, and inhibition of cytokine overproduction.
In order to understand the mechanisms and factors involved in COVID-19 disease
progression, a comparative analysis of the serum cytokine levels should be done
in patients and healthy individuals. Estimating increased serum cytokine levels and
abnormalities in the hepatic, renal, and cardiac biomarkers can play an important role
in predicting poor outcomes in COVID-19 patients. The levels of IL-6, IL-10, and TNF in
the serum can also predict the severity of the disease, as cytokines play an important
role in host immunity and immunopathology during the infection. Since there is no
effective treatment for COVID-19 to date, the estimation of cytokine levels and biomarker

DOI 10.18502/sjms.v18i2.13603 Page 198



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

molecules in patients may be used as indicators for early detection and appropriate
treatment.

Acknowledgments

We highly appreciate the hospital team’s efforts in treating the patients and the lab-
oratory staff for data and sample collection. Our sincere thanks are also extended to
Dr. Bander Suliman and his team (Ms. Araig Aljohani, bioscience and technologist) from
Bander Gene Center, Madinah, KSA, for dedicating their time to analyzing the laboratory
experiments.

Ethical Considerations

The study was approved by the Ethics Committee, Faculty of Applied Medical Sciences,
Taibah University (SREC/AMS 2020/63/CLD) and Saudi Arabia Ministry of Health, Gen-
eral Administration for Research & Studies (IRB 452).

Competing Interests

The authors declare no conflict of interest.

Availability of Data and Material

The data supporting this study’s findings are available in the Ministry of Health, Madinah,
Saudi Arabia. Restrictions apply to the availability of these data, which were used under
license for this study. Data are available from the authors, with the permission of the
Ministry of Health, Saudi Arabia.

Funding

The author declares that this research received no specific grant from funding agencies.

References

[1] Wang, C., Wang, Z., Wang, G., Lau, J. Y., Zhang, K., & Li, W. (2021). COVID-19 in
early 2021: Current status and looking forward. Signal Transduction and Targeted

DOI 10.18502/sjms.v18i2.13603 Page 199



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

Therapy, 6, 114.

[2] Mokhtari, T., Hassani, F., Ghaffari, N., Ebrahimi, B., Yarahmadi, A., & Hassanzadeh, G.
(2020). COVID-19 and multiorgan failure: A narrative review on potential mechanisms.
Journal of Molecular Histology, 51, 613–628.

[3] Rothan, H. A., & Byrareddy, S. N. (2020). The epidemiology and pathogenesis of
coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity, 109, 102433.

[4] Wang, C., Horby, P. W., Hayden, F. G., & Gao, G. F. (2020). A novel coronavirus
outbreak of global health concern. Lancet, 395, 470–473.

[5] Lopes-Pacheco, M., Silva, P. L., Cruz, F. F., Battaglini, D., Robba, C., Pelosi, P., Morales,
M. M., Caruso Neves, C., & Rocco, P. R. M. (2021). Pathogenesis of multiple organ
injury in COVID-19 and potential therapeutic strategies. Frontiers in Physiology, 12,
593223.

[6] Nicholls, J. M., Poon, L. L., Lee, K. C., Ng, W. F., Lai, S. T., Leung, C. Y., Chu, C. M.,
Hui, P. K., Mak, K. L., Lim, W., Yan, K. W., Chan, K. H., Tsang, N. C., Guan, Y., Yuen, K.
Y., & Peiris, J. S. (2003). Lung pathology of fatal severe acute respiratory syndrome.
Lancet, 361, 1773–1778.

[7] Zhang, Y., Li, J., Zhan, Y., Wu, L., Yu, X., Zhang, W., Ye, L., Xu, S., Sun, R., Wang, Y., &
Lou, J. (2004). Analysis of serum cytokines in patients with severe acute respiratory
syndrome. Infection and Immunity, 72, 4410–4415.

[8] Velazquez-Salinas, L., Verdugo-Rodriguez, A., Rodriguez, L. L., & Borca, M. V. (2019).
The role of interleukin 6 during viral infections. Frontiers in Microbiology, 10, 1057.

[9] Brydon, E. W., Morris, S. J., & Sweet, C. (2005). Role of apoptosis and cytokines in
influenza virus morbidity. FEMS Microbiology Reviews, 29, 837–850.

[10] Kany, S., Vollrath, J. T., & Relja, B. (2019). Cytokines in inflammatory disease.
International Journal of Molecular Sciences, 20, 6008.

[11] Mortaz, E., Tabarsi, P., Varahram, M., Folkerts, G., & Adcock, I. M. (2020). The immune
response and immunopathology of COVID-19. Frontiers in Immunology, 11, 2037.

[12] Ye, Q., Wang, B., & Mao, J. (2020). The pathogenesis and treatment of the ‘Cytokine
Storm’ in COVID-19. The Journal of Infection, 80, 607–613.

[13] Sinha, P., Matthay, M. A., & Calfee, C. S. (2020). Is a “cytokine storm” relevant to
COVID-19? JAMA Internal Medicine, 180, 1152–1154.

[14] Rismanbaf, A., & Zarei, S. (2020). Liver and kidney injuries in COVID-19 and their
effects on drug therapy; a Letter to Editor. Archives of Academic Emergency
Medicine, 8, e17.

[15] Martinez, M. A., & Franco, S. (2021). Impact of COVID-19 in liver disease progression.
Hepatology Communications, 5, 1138–1150.

DOI 10.18502/sjms.v18i2.13603 Page 200



Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

[16] Clark, R., Waters, B., & Stanfill, A. G. (2021). Elevated liver function tests in COVID-
19: Causes, clinical evidence, and potential treatments. The Nurse Practitioner, 46,
21–26.

[17] Ghahramani, S., Tabrizi, R., Lankarani, K. B., Kashani, S. M. A., Rezaei, S., Zeidi, N.,
Akbari, M., Heydari, S. T., Akbari, H., Nowrouzi-Sohrabi, P., & Ahmadizar, F. (2020).
Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations:
A systematic review and meta-analysis. European Journal of Medical Research, 25,
30.

[18] Zhang, X., Tan, Y., Ling, Y., Lu, G., Liu, F., Yi, Z., Jia, X., Wu, M., Shi, B., Xu, S., Chen,
J., Wang, W., Chen, B., Jiang, L., Yu, S., Lu, J., Wang, J., Xu, M., Yuan, Z., . . . Lu, H.
(2020). Viral and host factors related to the clinical outcome of COVID-19. Nature,
583, 437–440.

[19] MOH-approved scientific instruction manuals and guidelines for healthcare providers
on how to deal with COVID-19 patients, 2020. Available from https://www.moh.
gov.sa/en/Ministry/MediaCenter/Publications/Pages/covid19.aspx; 2020 [accessed
20 June 2020]).

[20] Wang, X., Yang, K., Wei, C., Huang, Y., & Zhao, D. (2010). Coinfection with EBV/CMV
and other respiratory agents in children with suspected infectious mononucleosis.
Virology Journal, 7, 247.

[21] Ye, Q., Wang, B., & Mao, J. (2020). The pathogenesis and treatment of the ‘cytokine
storm’ in COVID-19. The Journal of Infection, 80, 607–613.

[22] Forbester, J. L., & Humphreys, I. R. (2021). Genetic influences on viral-induced
cytokine responses in the lung. Mucosal Immunology, 14, 14–25.

[23] Melo, A. K. G., Milby, K. M., Caparroz, A. L. M. A., Pinto, A. C. P. N., Santos, R. R.
P., Rocha, A. P., Ferreira, G. A., Souza, V. A., Valadares, L. D. A., Vieira, R. M. R. A.,
Pileggi, G. S., & Trevisani, V. F. M. (2021). Biomarkers of cytokine storm as red flags
for severe and fatal COVID-19 cases: A living systematic review and meta-analysis.
PLoS One, 16, e0253894.

[24] Ghazavi, A., Ganji, A., Keshavarzian, N., Rabiemajd, S., & Mosayebi, G. (2021).
Cytokine profile and disease severity in patients with COVID-19. Cytokine, 137,
155323.

[25] Ponti, G., Maccaferri, M., Ruini, C., Tomasi, A., & Ozben, T. (2020). Biomarkers
associated with COVID-19 disease progression. Critical Reviews in Clinical
Laboratory Sciences, 57, 389–399.

[26] Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012).
Into the eye of the cytokine storm. Microbiology and Molecular Biology Reviews, 76,

DOI 10.18502/sjms.v18i2.13603 Page 201

https://www.moh.gov.sa/en/Ministry/MediaCenter/Publications/Pages/covid19.aspx
https://www.moh.gov.sa/en/Ministry/MediaCenter/Publications/Pages/covid19.aspx


Sudan Journal of Medical Sciences Walaa Mohammedsaeed et al

16–32.

[27] Lee, D. W., Gardner, R., Porter, D. L., Louis, C. U., Ahmed, N., Jensen, M., Grupp, S.
A., & Mackall, C. L. (2014). Current concepts in the diagnosis and management of
cytokine release syndrome. Blood, 124, 188–195.

[28] Del Valle, D. M., Kim-Schulze, S., Huang, H. H., Beckmann, N. D., Nirenberg, S.,
Wang, B., Lavin, Y., Swartz, T. H., Madduri, D., Stock, A., Marron, T. U., Xie, H., Patel,
M., Tuballes, K., Van Oekelen, O., Rahman, A., Kovatch, P., Aberg, J. A., Schadt, E., .
. . Gnjatic, S. (2020). An inflammatory cytokine signature predicts COVID-19 severity
and survival. Nature Medicine, 26, 1636–1643.

[29] Islam, H., Chamberlain, T. C., Mui, A. L., & Little, J. P. (2021). Elevated interleukin-10
levels in COVID-19: Potentiation of pro-inflammatory responses or impaired anti-
inflammatory action? Frontiers in Immunology, 12, 677008.

[30] Alfano, G., Ferrari, A., Fontana, F., Perrone, R., Mori, G., Ascione, E., Magistroni,
R., Venturi, G., Pederzoli, S., Margiotta, G., Romeo, M., Piccinini, F., Franceschi,
G., Volpi, S., Faltoni, M., Ciusa, G., Bacca, E., Tutone, M., Raimondi, A., . . .
Guaraldi, G., & the Modena Covid-19 Working Group (MoCo19). (2021). Hypokalemia
in patients with COVID-19. Clinical and Experimental Nephrology, 25, 401–409.
https://doi.org/10.1007/s10157-020-01996-4

DOI 10.18502/sjms.v18i2.13603 Page 202


	Introduction
	Methods
	Patients and data collection
	Enzyme-linked immunosorbent assays (ELISA) 
	Statistical analysis

	Results
	Patient characteristics and cytokine levels 
	Cytokine levels and other biomarkers in severe andnon-severe COVID-19 patients 
	Correlation between cytokine levels and biochemical markers in COVID-19 patients

	Discussion 
	Conclusion
	Acknowledgments
	Ethical Considerations
	Competing Interests
	Availability of Data and Material
	Funding
	References