Tocilizumab as a Treatment for Cytokine Storm in COVID-19 Patients: A systematic review

Abstract

Tocilizumab is a competitive interleukin-6 inhibitor agent that has been proposed to combat the COVID-19-related hyperinflammatory state, known as a cytokine storm. This systematic review was and Netherland) with different study designs (observational (80%) and randomized controlled trials (20%)) involving 649 patients (48% received TCZ) among moderate to severe COVID-19 patients. There were variabilities in the TCZ dosage given with some combination with other medication (methylprednisolone, azithromycin, hydroxychloroquine, lopinavir and ritonavir). TCZ reduce death cases significantly. It improves respiratory function, reduces the incidence of respiratory syndrome and less-invasive mechanical ventilation usage. The level of inflammatory markers such as C-reactive protein, ferritin and lactate dehydrogenase were significantly higher in the TCZ group. Tocilizumab may increase survival and favourable clinical course, improved hypoxia, accelerate respiratory recovery, lower hospital mortality, reduce the likelihood of invasive mechanical ventilation, improve clinical symptoms, represses the deterioration of patients (prolonging survival) and improve inflammation and immune cell function.

Full text

Tocilizumab as a Treatment for Cytokine Storm in COVID-19 Patients: A
systematic review
Muhammad Huzaimi Haron1, Mohamad Rodi Isa2*, Hanisa Syahirah Mohd Rashid3, Nur Amanina Adam3, Nur Aliah
Awang3, Muhammad Hairul Faez Halip3
1Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia.
2Department of Public Health Medicine, Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai Buloh, Selangor,
Malaysia.
3 Faculty of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia.
Journal of Public Health Issues and Practices
Haron, M.H., et al (2022). J Pub Health Issue Pract, 6(1): 204
https://doi.org/10.33790/jphip1100204
Article Details
Article Type: Review Article
Received date: 11th April, 2022
Accepted date: 06th May, 2022
Published date: 09th May, 2022
*Corresponding Author: Mohamad Rodi Isa, MBBS, DAP&E, MPH, DrPH, Department of Public Health Medicine, Faculty
of Medicine, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai Buloh, Selangor, Malaysia. E-mail: rodi@uitm.edu.
my
Citation: Haron, M.H., Isa, M.R., Mohd Rashid, H.S., Adam, N.A., Awang, N.A., & Faez Halip, M.H., (2022). Tocilizumab
as a Treatment for Cytokine Storm in COVID-19 Patients: A systematic review. J Pub Health Issue Pract 6(1): 204. doi:
https://doi.org/10.33790/jphip1100204
Copyright: ©2022
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J Pub Health Issue Pract JPHIP, an open access journal
Volume 6. 2022. 204 ISSN- 2581-7264
Abstract
Tocilizumab is a competitive interleukin-6 inhibitor agent that has
been proposed to combat the COVID-19-related hyperinammatory
state, known as a cytokine storm. This systematic review was
conducted to study the treatment of cytokine storm by Tocilizumab
in COVID-19 patients. The search strategy (“COVID-19” OR
“COVID19” OR SARS-CoV-2”) AND “tocilizumab” AND
“cytokine storm” AND “inammatory markers” AND (“ICU stay
duration” OR “intensive care unit stay duration”) AND “mechanical
ventilation requirement” AND (mortality OR death) were manually
searched through Web of Science, Scopus, and PubMed databases
spanned from March 2020 to November 2021. The inclusion criteria
were: research articles, human study, clinical trial, and articles in
English. The exclusion criteria were: review articles, case reports,
early access, editorial materials, letters, short survey, in vivo or
in vitro studies. Five articles were included in the analysis. There
were four countries had conducted the studies (Italy, China, USA
and Netherland) with different study designs (observational (80%)
and randomized controlled trials (20%)) involving 649 patients (48%
received TCZ) among moderate to severe COVID-19 patients. There
were variabilities in the TCZ dosage given with some combination
with other medication (methylprednisolone, azithromycin,
hydroxychloroquine, lopinavir and ritonavir). TCZ reduce death cases
signicantly. It improves respiratory function, reduces the incidence
of respiratory syndrome and less-invasive mechanical ventilation
usage. The level of inammatory markers such as C-reactive protein,
ferritin and lactate dehydrogenase were signicantly higher in the
TCZ group. Tocilizumab may increase survival and favourable
clinical course, improved hypoxia, accelerate respiratory recovery,
lower hospital mortality, reduce the likelihood of invasive mechanical
ventilation, improve clinical symptoms, represses the deterioration
of patients (prolonging survival) and improve inammation and
immune cell function.
Keywords: Tocilizumab, Cytokine storm, COVID-19 patients
Introduction
Coronavirus disease 2019 (COVID-19) is a contagious illness
caused by a novel coronavirus which is now known as severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The
virus spreads primarily by droplets of saliva or discharge from the
nose when an infected person coughs or sneezes. The symptoms
exhibited varies among COVID-19 patients with the most common
symptoms being fever, dry cough, and tiredness. Additionally, some
patients may show less typical symptoms such as aches, sore throat,
diarrhoea, conjunctivitis, headache, loss of taste or smell, and rashes
on the skin [2].
In the wake of COVID-19, the term ‘cytokine storm’ becomes more
familiar than ever before. It is a common term among members of
the scientic community, but now the general public is also aware
of it [3]. It is dened as a severe immune reaction in which the body
releases too many cytokines into the blood too quickly. Cytokines
play an important role in normal immune responses, but they can
be harmful when it released in a large amount simultaneously in
the body [4]. A cytokine storm can occur as a result of an infection,
autoimmune condition, or other diseases. It may also occur after
treatment with some types of immunotherapies. In the development
of the cytokine storm, there are many main components involved
such as Interferons, interleukins, chemokines, Colony-stimulating
factors and TNF-alpha [5]. In COVID-19, approximately 2% of
mortality is due to cytokine storms throughout the world [1].
Interleukin-6 (IL-6) plays the biggest role in the pathogenesis of
cytokine storms and the progression of COVID-19 related cytokine
storms [6]. It binds to two forms of IL-6 receptor (IL-6R) i.e.,
membrane-bound interleukin-6 receptor (mIL-6R) and soluble
interleukin-6 receptor (SIL-6R) forming a receptor-ligand complex.
The complex will then bind to gp130 on the cell membrane of the
alveolar epithelial tissue to proceed with signal transduction resulting
in a pro-inammatory response [7].
Ferritin is an acute protein that escalates in response to the broad
spectrum of inammatory states including infections, malignancy,
iron overload, and liver and kidney disease. Hyperferritinaemia can
be used as a screening tool for the early diagnosis of cytokine storms
(Melo et al, 2021). A signicantly elevated ferritin level in the

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blood of in-patients is often associated with haemophagocytic
lymphohistiocytosis (HLH) syndrome but it cannot be considered
as a specic marker [8]. HLH is a severe systemic inammatory
syndrome due to the strong activation of the immune system that
can be fatal [9]. The SARS-CoV-2 infection can lead to features of
cytokine storms that are reminiscent of secondary HLH [10].
Based on several studies, tocilizumab (TCZ), a humanized
monoclonal antibody is needed in invasive mechanical ventilation
and ICU intervention. It has been suggested as a favourable agent
for moderate to severe COVID-19 cases. It was designed to inhibit
the JAK-STAT or MAPK/NF-κB-IL-6 signaling pathway and nally
stops the cytokine storms syndrome [11]. Therefore, it can reduce
the mortality rate and length of hospital stay. This systematic review
is conducted to study the treatment of cytokine storms by TCZ in
COVID-19. This review was conducted to determine the impact of
the use of TCZ on inammatory marker level, ICU stay duration,
mechanical ventilation requirement and mortality rate among patients
with COVID-19 related cytokine storm.
Material and Methods
A systematic review was performed and reported according to the
reporting standards documented in the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statement. This
review was registered with the PROSPERO database (Registration
number: CRD42022303727).
Comprehensive Literature Review
The searching procedure was conducted using bibliographic
databases and other evidence sources which can address the review
question. The procedure of comprehensive literature search involved
looking for the eligible articles, searching strategy for identication
of studies, study selection, and data extraction.
Search strategy
A comprehensive search of the literature was undertaken using three
biomedical electronic databases which were Web of Science (WoS),
Scopus, and PubMed complete Library to perform our research. The
search aimed to identify relevant articles published in peer-reviewed
journals written in English, with the assumption that most of the
important ndings will be reported in English regardless of country
of origin. The process of searching strategy for identication of
studies included all published studies.
The formulated question was performed by identifying the type
of evidence needed to answer the question. The strategy by using
Domain, Determinant, and Outcome (DDO) format was used in the
study to obtain relevant answers and to identify the question and
concentrate the mind. The Boolean search was performed on each
database as follows:
(“COVID-19” OR “COVID19” OR SARS-CoV-2”) AND
“tocilizumab” AND “cytokine storm” AND “inammatory markers”
AND (“ICU stay duration” OR “intensive care unit stay duration”)
AND “mechanical ventilation requirement” AND (mortality OR
death).
Eligibility Criteria
This research examined the TCZ as the treatment for Cytokine
Storm in COVID-19 patients of published articles. The electronic
databases (“COVID-19” OR “COVID19” OR SARS-CoV-2”) AND
“tocilizumab” AND “cytokine storm” AND “inammatory markers”
AND (“ICU stay duration” OR “intensive care unit stay duration”)
AND “mechanical ventilation requirement” AND (mortality OR
death). The studies that did not meet the specic inclusion criteria
for this study were eliminated. The decision to include all employees
was made so that all available studies could be included in this study.
The inclusion criteria in this study are research article, human study,
clinical trial stud, and article in English. The exclusion criteria are
review articles, systematic review, case report, early access, editorial
materials, letters, short survey, in vivo or in vitro study, and other
languages.
Published Articles
The published articles refer to any article that has been published in
any published journal articles. The rst step was to locate the published
articles for this research using a computer-based information search.
The established databases in this study are Web of Science (WoS),
Scopus, and PubMed. The references of the chosen studies were
analysed manually by all researchers to obtain additional research
articles for this review.
Screening Titles and Abstract
All citations were identied by screening titles and abstracts of
the published articles studies. The relevant articles were downloaded
into the Endnote Software. The citations were organized accordingly.
Besides, the duplication of the studies was identied and deleted.
The coding studies guide was used to screen for relevant articles and
theses. Theoretically, study screening looking for suitable titles and
abstracts was conducted by at least two independent researchers.
When all researchers have agreed on the suitable title and abstract,
the articles were considered for full-text retrieval. The articles which
did not full the criteria were excluded from the study.
Obtaining Full text Published Articles Studies
All published articles were searched. Full-text articles were obtained
and downloaded from the established resources (Web of Science
(WoS), Scopus, and PubMed) with a search term. Articles searched
in this study were only obtained in a free article. The articles without
full text were excluded from the study.
Selecting Suitable Full text Published Articles
The process of selecting suitable full text published articles was
done and selected by the corresponding author who are experts in
methodology and topic under review. An agreement of inclusion and
exclusion criteria was made before starting the reviews process.
After searches were performed, articles were then organized into
Endnote Software. Duplication of the articles was identied and
removed by Zotero software. This was performed by one reviewer,
via the “Find and Remove Duplicate References” function at rst,
followed by manual screening, as some of the same articles were
entered slightly differently into different databases. After duplication
of articles was removed, articles were assessed for eligibility
independently by two reviewers in two stages. In the rst stage, the
title and abstract of search results were screened and assessed for
relevance. In the second stage, the full text of potentially relevant
publications was retrieved and reviewed for inclusion. Both stages of
the study selection were performed independently by two reviewers
and cross-validated to assess for disagreements. The list of studies
included and excluded based on the inclusion and exclusion criteria
described earlier was cross-validated to assess for disagreements. If
there was disagreement between both reviewers a third reviewer was
assigned. Only full-text articles were included in the review to enable
quality assessments.
Critical Appraisal
Critical appraisal was performed by two researchers to assess study
quality and most methods encompass issues such as appropriateness
of study design to the research objective. The articles with poor-
quality studies were excluded and discussed in detail. The critical
appraisal of articles was performed using the Consolidated Standards
of Reporting Trials (CONSORT) checklist for randomized controlled
trials and Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) for epidemiological observational study as
guidelines to assess to quality of the articles that have been selected.
The agreement between the two independent research was assessed
using Kappa statistics. The value of kappa with more than 0.80 is
considered a good agreement.
Data extraction
Data extractions were performed by all two independent researchers

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Volume 6. 2022. 204 ISSN- 2581-7264
to establish inter-rater reliability and to avoid data entry errors.
Study context factors of published articles include the information
describing the study and its subjects. Reported ndings of the
remaining studies were extracted onto a data extraction form. Lists of
included studies were created stratied by study name. study design,
patient type, dose, sample size and result independently.
Flowchart of the study
The process of article searches and selection that was performed in
this study is shown in Figure 1:
Data Management
All relevant articles were manually coded in Google Docs as
described in evidence tables. The electronic Google Docs were
utilised to import the data into word form for data analysis.
Statistical analysis
Data were analysed using descriptive statistics. The numerical
outcome was be analysed using mean and standard deviation.
Categorical outcomes were analysed using frequency and percentage.
Results
A total of 237 records were identied through searches in three
databases (Web of Science (WoS), Scopus, and PubMed). After
excluding the duplicates, titles and abstracts were screened, 150
articles were selected for the eligibility of the study. However, 140
articles were removed due to various reasons such: review article
(n = 75), systematic review articles (n = 15), short survey (n = 21),
editorial materials (n = 27) and In vivo / in vitro studies (n = 17).
5 articled were selected for the quality assessment and all articles
were included in the study. An overview of these selected studies
in research characteristics created in the PRISMA chart is shown in
Figure 1.
A total of ve articles were reviewed in this study and summarized
in Table 1. The studies were conducted in Italy [12], China [13, 14],
the Netherlands [15], and the United States of America (USA) [16].
All of the studies involved patients infected with COVID-19 ranging
from severe COVID-19 patients [16], moderate to the severe stage
(cytokine storm syndrome) associated with either pneumonia [12],
moderate (bilateral pulmonary lesions) or severe COVID-19 [13],
Severe COVID-19 patients with extensive lung lesions [14] and
Severe COVID-19 associated cytokine storm syndrome [15].
Figure 1: Flowchart of the study
Published Articles
(“COVID-19” OR “COVID19” OR SARS-CoV-2”) AND
“tocilizumab” AND “cytokine storm” AND “clinical trial*”
Published Articles
(“COVID-19” OR “COVID19” OR SARS-CoV-2”) AND “tocilizumab”
AND “cytokine storm” AND “clinical trial*”
Scopus (n =176)
Scopus (n =176)
Web Of Science (n = 57)
PubMed (n = 4)
Studies found with the search criteria (n = 237)
Duplicate records removed (n = 13)
Number of studies after merge duplicates: 224
Number of studies after merge duplicates: 224
Number of studies after merge duplicates: 224
Number of studies after merge duplicates: 224
Articles excluded for reasons of (n = 145):
- Review article (n = 75)
- Systematic review articles (n = 15)
- Short survey (n = 21)
- Editorial materials (n = 27)
- In vivo / in vitro studies (n = 17)
Duplicate records removed (n = 13)
Web Of Science (n = 57) PubMed (n = 4)
Studies found with the search criteria (n = 237)
Duplicate records removed (n = 13)
Number of studies aer merge duplicates: 224
Articles removed because not suitable titles and abstract (n =
74)
Number of studies aer removing unsuitable title and abstract (n = 150)
Articles excluded for reasons of (n = 145):
• - Review article (n = 75)
• - Systematic review articles (n = 15)
• - Short survey (n = 21)
• - Editorial materials (n = 27)
• - In vivo / in vitro studies (n = 17)
Studies assessed for the quality (n = 5)
Studies included in systemic review (n = 5)

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Study Name Study
Design
Patient
Type
Dose Sample Size Result
Tsai A,
Diawara O
[16]
Single-centre
matched
cohort study
Severe
COVID-19
patients
All patients received
hydroxychloroquine
and azithromycin in
both groups + for
TCZ group:
- 10 (15.1%)
received TCZ 800
mg
- 3 (4.5%) received
TCZ 600 mg
- 53 (80.3%)
received TCZ 400
mg.
- 4 patients received
a second dose of
tocilizumab•
Total 132
patients:
- 66 TCZ
treated (50%)
- 66 no-TCZ
treated (50%)
- Inammatory markers:
a Ferritin – TCZ: 1432.30 (1307.96);
848.35 (684.84), p<0.001
b. CRP – TCZ: 13.01 (7.79); no-TCZ:
9.95 (5.71), p=0.002
c. LDH – TCZ: 42905 (154.50);no-TCZ:
331.19(128.75), p<0.001
- Ventilator use – TCZ: 16 (24.2%); no-
TCZ: 12 (18.2%) , p = 0.450
- Intubation - TCZ (9 patients)
- Mortality – TCZ: 18 deaths (27.3%);
no-TCZ: 18 deaths (27.3%) (OR: 1.0;
95% CI: 0.465–2.151; p = 1.00).
Capra, De
Rossi [12]
Multicentre,
retrospective
case-control
study
COVID-19
related
pneumonia
and
respiratory
failure, not
needing
mechanical
ventilation
patients
- Standard care:
hydroxychloroquine
(400 mg daily) +
lopinavir (800 mg
daily) ritonavir (200
mg daily)
- Treated group:
Standard care
+ TCZ (did not
mention dose)
Total of 85
patients:
- 62 treated
(73%) with
TCZ
- 23 controls
- Survival rate - greater in patients
received TCZ, with (hazard ratio for
death, 0.035; 95% condence interval
[CI], 0.004 to 0.347; p = 0.004)
- Death - 2 (3.22%) - treated group; 11
(47.8%) - control group
- Recovery rate - 92% - treated group
(discharged after 12,5 days); 42.1% -
control group.
- Improvement in respiratory function -
64.8% in hospitalized TCZ group while
none from the control group
- Conclusion: TCZ results have a positive
impact if used early during Covid-19
pneumonia with severe respiratory
syndrome in terms of increased survival
and favourable clinical course.
-
Wang D, Fu
B [13]
Multicentre,
A
randomized,
controlled
trial, open-
label study
Moderate
(bilateral
pulmonary
lesions)
or severe
COVID-19
2 doses given:
- 1st dose: TCZ 400
mg, diluted in 100
ml of 0.9% saline
- 2nd dose is given
if the patients still
febrile for 24 hours
Total of 65
patients:
- 33 treated
(51%) with
TCZ
- 32 controls.
- Cure rate - TCZ (94.12%); control
(87.10%) (p=0.4133, 95%CI: -7.19%,
21.23%)
- Hypoxia -
a. severe patients: TCZ - higher from
day 4 onward and statistically signicant
from day 12 (P = 0.0359).
b. Moderate diseases: TCZ (8.33%);
control 66.67%) (p=0.0217; 95%CI:
-99.17%, -17.50)
- Mild temporary adverse effect - TCZ
(58.82%); control (12.90%).
- Conclusion: TCZ improves hypoxia
without an unacceptable side effect
prole and signicant inuences on the
time virus load become negative. For
patients with bilateral pulmonary lesions
and elevated IL-6 levels, tocilizumab
could be recommended to improve
outcome
Table 1. to be cont...

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Tian J, Zhang
M [14]
Multicentre,
retrospective
cohort study
Severe
COVID-19
patients with
extensive lung
lesions
- IV 400 mg up to
a maximum of 800
mg. Dilution was to
100 ml with 0.9%
normal saline, and
the infusion time
was more than 1 h.
- If fever continues
within 12 hours an
additional dose is
given
Total of 195
patients:
- 65 treated
(33%) with
TCZ
- 130 did not
receive
- In-hospital death - TCZ group
(21.54%): non-tocilizumab group
(32.31%) (p = 0.012); hazard ratio =
0.47; 95% CI: 0.25, 0.90; p = 0.023)
- ICU stay - TCZ (10 days); non-TCZ
(12.00 days) (p=0.27)
- Hospital stays - TCZ (40 days); non-
TCZ (26.5 days) (p = 0.001)
- Incidence Respiratory distress
syndrome - TCZ (36.92); non-TCZ
(70.77%) (p < 0.001); Adj OR: 0.23
(95%CI: 0.11, 0.45; p < 0.001) (odds
ratio = 0.23; 95% CI: 0.11, 0.45; p <
0.001)
- Inammatory markers:
a. IL-10 - TCZ (5.00pg/ml); non-TCZ
(7.35 pg/ml) (p = 0.013)
b. C-reactive protein – TCZ (1.52mg/l);
non-TCZ (22.55 mg/l) (p < 0.001)
- Conclusion:
- TCZ improves clinical symptoms and
represses the deterioration of patients
(prolonging survival) with severe
COVID-19.
- TCZ was associated with a lower risk
of the in-hospital proportion of death.
- TCZ improves inammation and
immune cell function
Ramiro S,
Mostard RLM
[15]
Single-centre,
Retrospective
case-control
study
Severe
COVID-19
associated
cytokine
storm
syndrome
- IV 250mg high
methylprednisolone
(MP) (D1) + 80mg
(D2–D5).
- If the respiratory
condition had
not improved,
the interleukin-6
receptor blocker
TCZ (8mg/kg body
weight, single
infusion) was
added.
Total of 172
patients:
- 86 treated
(50%)
- 86 control
(50%)
- Improvement respiratory status - 79%
higher likelihood (HR: 1.79; 95%CI:
1.20, 2.67), 7 days earlier.
- Hospital mortality - 65% lower (HR:
0.35; 95% CI: 0.19, 0.65)
- Ventilation:
a. 71% less invasive mechanical
ventilation (HR: 0.29; 95% Cl 0.14 to
0.65).
b. Among patients not mechanically
ventilated at baseline, the daily incidence
of mechanical ventilation (new start)
was 1.3% vs 5.4% (p=0.0003).
c. Once mechanically ventilated, the
duration of mechanical ventilation was
not signicantly different.
- Conclusion: strategy involving a course
of high-dose MP, followed by TCZ
in case of insufcient improvement,
may accelerate respiratory recovery,
lower hospital mortality and reduce
the likelihood of invasive mechanical
ventilation
Table 1: Summary of study
Two of the studies (40%) were conducted at a single centre and three
of the studies (60%) were conducted in a multi-centre study. One of the
studies (20%) was conducted via a randomized controlled trial [13]
and the other four studies (80%) were conducted via an observational
study i.e., matched case-control study [12], retrospective cohort
study [14], matched cohort study [16] and retrospective case-control
study [15]. The total number of COVID-19 patients involved was
649, where 312 (48%) patients received TCZ and 338 (52%) patients
was in the control group.
There were variabilities of the TCZ dosage given to the treated
patients. A study by Wang D, Fu B [13] gave 400mg TCZ diluted
in 100 ml of 0.9% saline for the rst dose and the second dose was
only given if the patients still had febrile for 24 hours. Tian J, Zhang
M [14] intervened by giving intravenous (IV) 400mg TCZ and
infusing for one hour and an additional dose was given if the fever
continue within 12 hours. Ramiro S, Mostard RLM [15] intervened
by giving IV 8mg/kg body weight with a combination of 250 mg IV
250 methylprednisolone (MP) on day 1 and 80mg MP on day -2 to

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mechanical ventilation [15]. TCZ also can improve clinical
symptoms and represses the deterioration of patients (prolonging
survival), lower the risk of an in-hospital proportion of death and
improve inammation and immune cell function [14]. However, only
a study by Tsai A, Diawara O [16] did not support the use of TCZ
for the management of cytokine storms in patients with COVID-19.
Discussion
In this systematic review, we summarised and analysed the effect of
TCZ as a treatment for COVID-19 patients related to cytokine storms.
There were many studies found and have been conducted in ve
countries in various types of moderate and severe COVID-19. The
activation of various cytokines is reected by clinical manifestations
in COVID-19 infection. Pyrexia, malaise and chills may convey
an increase in the interferon levels while acute symptoms such as
vascular damage and lung contusions along with general symptoms
may indicate high TNF levels [17]. A high concentration of
interleukins may lead to cytokine storms.
Randomized controlled trials are considered to be the “gold-
standard” method to estimate the treatment effect [18]. However,
in the emergency of COVID-19 worldwide, RCT was not possible
to conduct. Many researchers conducted an observational study to
determine the impact of TCZ with one group as a comparison group
[12, 14-16]. However, ethical approval and informed consent must
be obtained before conducting the study. The ethical review protects
participants and also the researcher. By obtaining ethical approval,
the researcher is demonstrating that they have adhered to the ethical
standard of a research study [19].
TCZ is a key cytokine leading to an inammatory storm act by
inhibiting the IL-6 receptor which may result in increased alveolar-
capillary blood glass exchange dysfunction [20]. There are about
more than 30 drugs have been introduced to treat COVID-19
including TCZ and many research investigate further the efcacy of
TCZ for different patients [21]. A review by Samaee, Mohsenzadegan
[21] of 15 studies found many variabilities of dosages prescribed to
the patients for their treatment which is also the same nding in this
review. The US Food and Drug Administration (FDA) recommended
dosage of TCZ is a single 60-minute intravenous infusion for patients
less than 30kg weight is 12mg/kg and to patients at or above 30kg
weight is 8mg/kg with maximum dosage is 800mg per infusion for
COVID-19 patients [22].
Untreated cytokine storms can progress from respiratory failure to
cardiovascular collapse, multiorgan dysfunction, and death [23]. In
this review, the survival rate was greater in the treated group with
a 92% recovery rate and discharged after 12.5 days [12]. However,
Wang D, Fu B [13] did not nd any signicant cure rate although the
percentage in the TCZ group was higher than the non-TCZ group
and there was a signicant difference in hospital stays where TCZ
groups had longer stays compared to the non-TCZ group (40 days
versus 26.5 days, p=0.001) [14]. Gokhale Yojana, Mehta Rakshita
[23] concluded that the warranted improvement was due to a
hyperinammatory state.
Mortality in COVID-19 patients has been linked to the presence
of the so-called “cytokine storm” induced by the virus [24]. The
majority of the studies reviewed found that TCZ can reduce death,
lower hospital mortality or in-hospital death [12, 14, 15] except a
study by Tsai A, Diawara O [16] did not found any signicant
difference in death. The mortality is due to an excessive production
of pro-inammatory cytokines which leads to ARDS aggravation
and widespread tissue damage [24, 25]. In addition to that, fatal
pneumonia can also be a result of mortality in COVID-19 patients
after the SARS-CoV-2 completes replication in the lower respiratory
tract [25].
Invasive mechanical ventilation is a lifesaving tool commonly used
in the care of hospitalized patients [26]. Adults with COVID-19 who
day-5. A study by Tsai A, Diawara O [16] intervened by giving
hydroxychloroquine and azithromycin and different mg of TCZ i.e.
10 (15.1%) patients received TCZ 800 mg, 3 (4.5%) patients received
TCZ 600 mg, 53 (80.3%) patients received TCZ 400 mg and four
patients received a second dose of TCZ. However, a study by Capra,
De Rossi [12] did not mention the dosage of TCZ but it was given in
a combination of hydroxychloroquine (400 mg daily), lopinavir (800
mg daily) and ritonavir (200 mg daily).
Capra, De Rossi [12] found a greater survival rate in patients who
received TCZ (HR: 0.035; 95%CI: 0.004, 0.347) and a 92% recovery
rate with discharged after 12.5 days compared to just 42.1% in the
control group. Wang D, Fu B [13] found 94.12% cure rate in TCZ
group compared to 87.10% in the control group (p=0.4133, 95%CI:
7.19%, 21.23%). There was no signicant difference in the ICU
stay between TCZ and the control group (10 days versus 12 days,
p=0.270). However, there was a signicant difference in hospital
stays where TCZ groups had longer stays compared to the non-TCZ
group (40 days versus 26.5 days, p=0.001)[14].
For death, Capra, De Rossi [12] found 3.22% in TCZ group
compared to 47.8% in control group. Whereas, Tian J, Zhang M [14]
found 21.54% death in TCZ group and 32.31% in non-TCZ group (p
= 0.012); hazard ratio = 0.47; 95% CI: 0.25, 0.90; p = 0.023) for the
in-hospital death. Ramiro S, Mostard RLM [15] found 65% lower
hospital mortality in TCZ group than control groups (HR: 0.35; 95%
CI: 0.19, 0.65). However, Tsai A, Diawara O [16] did found any
signicant different in the death case between both (OR: 1.0; 95%
CI: 0.465–2.151; p=1.000).
Capra, De Rossi [12] found an improvement in respiratory
function in 64.8% in the TCZ group but none in the control group
and Ramiro S, Mostard RLM [15] found a 79% higher likelihood
of improvement in respiratory status compared to the control group
(HR: 1.79; 95%CI: 1.20, 2.67), 7 days earlier and Tian J, Zhang M
[14] found less incidence of respiratory distress syndrome in TCZ
group (36.92%) compared to the control group (70.77%) (adj OR:
0.23 (95%CI: 0.11, 0.45; p < 0.001).
Ramiro S, Mostard RLM [15] found 71% less-invasive mechanical
ventilation usage in the TCZ group (HR: 0.29; 95% Cl 0.14 to 0.65).
There was also a signicant difference in the incidence of mechanical
ventilation use were less in the TCZ group (1.3% vs 5.4% (p=0.0003).
However, Ramiro S, Mostard RLM [15] reported that once the
patients were mechanically ventilated, the duration of mechanical
ventilation was not signicantly different. Tsai A, Diawara O [16]
found no signicant difference in ventilator use (24.2% versus 18.2%,
p=0.450) although nine patients in the TCZ group need intubation.
Wang D, Fu B [13] found an improvement in the hypoxia from day
4 to day 12 (p=0.0359) in severe COVID-19 patients. In moderate
COVID-19 patients, only 8.33% of hypoxia was reported compared
to 66.67% in control group (p=0.0217; 95%CI: -99.17%, -17.50).
However, Wang D, Fu B [13] found 58.82% mild temporary adverse
effects in the TCZ group than only 12.90% in the control group.
There were some inammatory markers monitored in the treatment
for cytokine storm in COVID-19 patients. The level of C-reactive
protein (CRP) was signicantly higher in the TCZ group than in the
non-TCZ group [16]. However, a study by Tian J, Zhang M [14] did
not nd the same result. The ferritin level and lactate dehydrogenase
(LDH) were signicantly higher in the TCZ group than in the non-
TCZ group [16]. However, the IL-10 level was signicantly higher in
the non-TCZ group than TCZ group [14].
In the overall conclusion, most of the ndings show a positive
impact of TCZ on the COVID-19 patients such as increased survival
and favourable clinical course [12], improved hypoxia without
unacceptable side effects and inuences on the time virus load
becomes negative [13] and may accelerate respiratory recovery,
lower hospital mortality and reduce the likelihood of invasive

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Volume 6. 2022. 204 ISSN- 2581-7264
develop acute respiratory distress syndrome (ARDS) are managed
by intubation and invasive mechanical ventilation as a conventional
oxygen therapy may be insufcient to full their oxygen needs [27].
ARDS is frequently characterized by high levels of plasma IL-6,
which will stimulate lung epithelial cells and inammatory cells
response thus leading to pulmonary damage COVID-19 patients with
cytokine storm syndrome treated with TCZ had 71% less used and
incidence of invasive mechanical ventilation [15]. Several studies
have shown that inhibition of IL-6 with TCZ may help to improve the
respiratory status and survival of patients with COVID-19 requiring
mechanical ventilation [28]. However, Tsai A, Diawara O [16] found
no signicant difference in ventilator use in treated and without
treated TCZ group and Ramora et al. [15] found no difference found
no difference in the duration of using mechanical ventilation once
the patients were mechanically ventilated. Although advanced aged
COVID19 patients are presented with greater pneumonia severity
scores, need for oxygen therapy, lymphopenia and need of mechanical
ventilation it was not associated with age [29].
Prolong intensive care unit (ICU) admission led COVID-19 patients
to worse outcomes. Studies from early in the pandemic have found
statistically one in ve infected individuals are hospitalised and one
in ten may get admitted to an ICU, with most of these critically ill
patients experiencing ARDS and requiring mechanical ventilation
[30]. However, Tian J, Zhang M [14] did not nd any signicant
difference in the ICU stay between TCZ and control group but TCZ
groups had longer stays compared to the non-TCZ group.
Hypoxia and respiratory failure were considered as important causes
of exacerbation and even death of COVID-19 [31]. The “Cytokine
storm” leads to immune dysregulation and tissue damage in the lungs
that cause hypoxia and respiratory failure [32]. With the treatment by
TCZ, it was found an improvement in the hypoxia in day-4 to day-12
in severe and moderate COVID-19 patients and it revealed that an
increased IL-6played an important role in the “cytokine storm” [13].
Although Wang D, Fu B [13] found TCZ group had more adverse
effects including leukopenia, neutropenia and abnormal hepatic
function, all of these side effects remitted spontaneously and no
serious adverse events occurred.
Mostly, serum CRP will increase in bacteria compared to viral
infection but a current study on COVID-19 patients revealed a
signicant rise of serum CRP levels in severe cases than in non-
severe patients. It can be suggested that CRP can be the biomarker for
assessing disease progression and mortality in COVID-19 patients
[33]. Besides CRP, ferritin is another biomarker for inammation in
COVID-19 patients. Ferritin has been characterized as an acute phase
reactant and mediator of immune dysregulation in severe COVID-19
[34]. The remarkable increase of serum ferritin level routinely
indicates liver damage. However, a study by Tsai A, Diawara O [16]
found the level of ferritin raise than the normal level in COVID-19
patients which species more risk of liver injury and severe illness.
Therefore, analysis of ferritin at an early stage can recognise liver
damage, disastrous disease, and prognosis of COVID-19 patients
[35]. Cytokine can induce ferritin expression and ferritin can induce
expression of pro-inammatory cytokine as well. Patients with
higher ferritin levels have been associated with more severe lung
involvement in COVID-19 due to the development of lung damage
resulting from activation of the inammatory response induced by
high ferritin levels [34].
There are several limitations in conducting this systematic review.
The summary provided is only reliable depending on the methods used
to estimate the effect in each of the primary studies. The systematic
review also relied on the relatively limited number of databases for
the identication of potentially eligible studies therefore there may
not be enough research in the literature to analyse. The systematic
review can quickly become outdated because COVID-19 is a newly
emerged disease in which many ongoing types of research are
conducted. The quality of the systematic review depends on what has
been published in the literature.
Conclusion
It can be concluded that TCZ was associated with cytokine storm
syndrome. It may reduce mortality rate, mechanical ventilation
requirement, ICU stay duration, and IL-6 level if it is administered
before entering the moderate to severe inammatory state as a
treatment for COVID-19.
Competing of interest: All authors declare that there is no
conict of interest.
List of abbreviation
ARDS: Acute Respiratory Distress Syndrome; CONSORT:
Consolidated Standards of Reporting Trials; COVID-19: Coronavirus
disease 2019; CRP: C-reactive protein; DDO: Domain, Determinant,
and Outcome; FDA: The US Food and Drug Administration; ICU:
Intensive care unit; HLH: Haemophagocytic lymphohistiocytosis;
IL=6: Interleukin-6; IL-6R: IL-6 receptor; IV: Intravenous: LDH:
Lactate dehydrogenase; OR: Odds ratio; PRISMA: Preferred
Reporting Items for Systematic Reviews and Meta-Analyses;
STROBE: Randomized controlled trials and Strengthening the
Reporting of Observational Studies in Epidemiology; TCZ:
Tocilizumab; WoS: Web of Science;
Acknowledgement
This abstract has been presented in the International Conference on
Post COVID Healthcare, Medical Research and Education 2022 and
Creation de UiTM, International Mega Innovation Carnival 2022.
Funding
This is self-funded research and did not receive any funding.
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