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\begin{document}

\title{Effects of Infliximab on patients with COVID-19: a systematic review and
meta-analysis}



\author[1]{Aboalfazl Ataei}%
\author[1]{Amirhossein Orandi}%
\author[1]{Ebadallah  Shiri Malekabad }%
\author[1]{MohammadHossein  Sharbafi}%
\author[1]{Payam Hashemi}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Despite the control of the COVID-19 pandemic, it remains one of the main
concerns of healthcare systems throughout the world. Inflammation and
hyper-reactive immune system play an essential role in developing
SARS-CoV-2 infection, particularly in immunocompromised patients.
Infliximab, an anti-TNF\selectlanguage{greek}α \selectlanguage{english}antibody that is used in autoimmune disorders,
may exert an important role in alleviating inflammation and
hyper-reactive immunity. In this systematic review and meta-analysis, we
have concluded that Infliximab can significantly decrease the mortality
rate in patients with COVID-19. Conversely, it did not have a
significant effect on the rate of hospitalization, mechanical
ventilation, and adverse events during SARS-CoV-2 infection. More
studies on the influence of Infliximab on patients with COVID-19 are
warranted.%
\end{abstract}%



\sloppy


\textbf{Effects of Infliximab on patients with COVID-19: a systematic
review and meta-analysis}

1. Abolfazl Ataei, Department of Medical Entomology and Vector Control,
School of Public Health, Tehran University of Medical Sciences, Tehran,
Iran.

2. Amirhossein Orandi, Associate Professor, School of Medicine, Imam
Khomeini Hospital Complex, Tehran University of Medical Sciences,
Tehran, Iran.

3. Ebadallah Shiri Malekabad Epidemiologist, School of Nursing, AJA
University of Medical Sciences, Tehran, Iran.

4. MohammadHossein Sharbafi, Department of Immunology, School of
Medicine, Tehran University of Medical Sciences, Tehran, Iran.

5. Payam Hashemi, Faculty of Medicine, Tehran University of Medical
Sciences, Tehran, Iran.

* Corresponding author: Payam Hashemi, Faculty of Medicine, Tehran
University of Medical Sciences, Tehran, Iran. Email:
payamhashemimd@gmail.com



\section*{Abstract}

{\label{abstract}}

Despite the control of the COVID-19 pandemic, it remains one of the main
concerns of healthcare systems throughout the world. Inflammation and
hyper-reactive immune system play an essential role in developing
SARS-CoV-2 infection, particularly in immunocompromised patients.
Infliximab, an anti-TNF\selectlanguage{greek}α \selectlanguage{english}antibody that is used in autoimmune disorders,
may exert an important role in alleviating inflammation and
hyper-reactive immunity. In this systematic review and meta-analysis, we
have concluded that Infliximab can significantly decrease the mortality
rate in patients with COVID-19. Conversely, it did not have a
significant effect on the rate of hospitalization, mechanical
ventilation, and adverse events during SARS-CoV-2 infection. More
studies on the influence of Infliximab on patients with COVID-19 are
warranted.

\section*{Introduction}

{\label{introduction}}

Despite the reduction in the mortality rate of COVID-19, SARS-CoV-2
infection remains one of the major worldwide health concerns,
particularly in older adults, unvaccinated individuals, and patients
with underlying diseases, or immunocompromised conditions {[}1{]}. Few
medications with antiviral properties including Nirmatrelvir/Ritonavir
(Paxlovid), Remdesivir, and Molnupiravir have been authorized for
treatment of mild to moderate COVID-19 in high-risk patients {[}2{]}.
Because of the detrimental role of inflammation and excessive immune
response in COVID-19 patients, it's crucial to lessen the side effects
of SARS-CoV-2 infection by pharmacological agents {[}3{]}. Accordingly,
corticosteroids such as dexamethasone have beneficial effects on
hospitalized patients with COVID-19 who need respiratory support
{[}4{]}. Other therapies for COVID-19 such as monoclonal antibodies,
anti-thrombotics, and immunotherapies are also under investigation
{[}5{]}.

Infliximab, a chimeric monoclonal antibody against TNF-\selectlanguage{greek}α \selectlanguage{english}indicated for
management of inflammatory/autoimmune disorders like Rheumatoid
Arthritis and Psoriasis, has demonstrated promising role in the
management of SARS-CoV-2 infection {[}6{]}.

Current studies on the pathophysiologic mechanisms of COVID-19 propose
that hyper-reactive immune response and increased generation of
cytokines such as TNF-\selectlanguage{greek}α, \selectlanguage{english}interleukin (IL)-6, IL-2, IL-7, and IL-10
(called cytokine release syndrome) play a pivotal role in worsening the
signs and symptoms of this disease {[}7{]}. TNF-\selectlanguage{greek}α, \selectlanguage{english}one of the essential
pro-inflammatory cytokines during cytokine release syndrome, intensifies
the severity of COVID-19 infection mainly through inducing interaction
of the SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE-2) in
respiratory system, cytokine release syndrome {[}7{]}, and auto-immune
response {[}8{]}. Therefore, TNF-\selectlanguage{greek}α \selectlanguage{english}is a potential target in COVID-19
patients with inappropriate activity of immune system and may lead to
better management of this infection {[}9{]}. Infliximab binds to TNF-\selectlanguage{greek}α
\selectlanguage{english}and thereby inhibits the biological activity of soluble and
transmembrane forms of this inflammatory cytokine {[}10{]}. Infliximab
can also lyse inflammatory immune cells through binding transmembrane
TNF-\selectlanguage{greek}α \selectlanguage{english}and subsequently impair the excessive inflammatory response
{[}11{]}.

Herein, we set out a systematic review and meta-analysis on the role of
Infliximab in terms of its effectiveness, and safety in the management
of COVID-19.

\section*{Method}

{\label{method}}

This review was prepared in accordance with the Preferred Reporting
Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline which
is an evidence-based protocol for rapid review of major studies.

\textbf{Literature search}

A literature searches of the full text or abstracts available on PubMed,
Cochrane Library, Web of Science, medRxive, and Google Scholar was
conducted to identify relevant evidence through September 20, 2023. A
reference list of studies was scanned for additional citations. In
addition, we searched clinical trial databases including
ClinicalTrials.gov and the European Union Register of Clinical Trials to
discover additional records. All these steps were conducted by two
authors independently. There was no restriction on language. The key
search terms used were SARS-CoV-2, COVID-19, Infliximab, safety, and
efficacy. The search strategy used in PubMed is as follows:
(Coronavirus{[}Title/Abstract{]}) OR (Coronavirus {[}MeSH Terms{]}) OR
(COVID-19 {[}Title/Abstract{]}) OR (SARS-CoV-2 {[}Title/Abstract{]}) OR
(COVID-19{[}MeSH Terms{]}) OR (SARS-CoV-2 {[}MeSH Terms{]}) OR (2019
novel coronavirus infection{[}Title/Abstract{]}) OR (2019-nCoV
infection{[}Title/Abstract{]}) AND (Infliximab {[}Title/Abstract{]} OR
(Remicade {[}Title/Abstract{]}).

\section*{Study selection}

{\label{study-selection}}

We included studies if they fulfilled the following criteria: Patients
with a confirmed diagnosis of COVID-19

Intervention: Infliximab

Control: placebo, standard of care (SOC), any treatment

Efficacy outcomes of interest: mortality rate, need for mechanical
ventilation, and ICU admission

Safety outcomes of interest: the incidence of any adverse events (AEs)

The studies which conducted on animal models, case reports, case series,
and letters to the editor were excluded.

\section*{Data Extraction and Quality
Assessment}

{\label{data-extraction-and-quality-assessment}}

\section*{}

{\label{section-1}}

Two of the five review authors extracted data independently and in
duplicate, using a customized data extraction form developed in
Microsoft Excel (Microsoft Excel). Disagreements during the review
process were resolved through discussion between the two review authors.
In cases where consensus could not be reached, a third review author was
consulted to help resolve the disagreement and make a final decision.
The Risk of Bias in Non-Randomized Interventions (ROBINS-I) tool was
used to assess the quality of non-randomized studies (table 2). The Risk
of Bias (RoB2) tool was also used to assess the quality of randomized
studies (table 3). We used the same data extraction form to extract the
data. We extracted data including (1) study characteristics (author,
year, place, and study design); (2) patient's characteristics (sample
size, and sex); (3) intervention and comparison (sample size and
treatment dose); and (4) safety outcomes. All steps stated above were
performed independently by two authors.

\section*{Evidence synthesis}

{\label{evidence-synthesis}}

Comprehensive Meta-analysis software is used to compare the efficacy and
safety of and control. The Odds ratio (OR) with 95\% confidence interval
(CI) was used for dichotomous variables. We conducted a pairwise
meta-analysis for our analysis and reported summary effect estimates
along with 95\% confidence intervals (CIs) for each direct comparison.
We included studies that provided data for at least two comparisons. The
heterogeneity is defined as I2\textgreater{}50\% and P \textless{}0.1.
The random and fixed effect models were used for high and low
heterogeneity studies, respectively.

\textbf{Results}

\section*{3.1 Search findings}

{\label{search-findings}}

The identification of evidence, removal of duplicated records, screening
by title, abstract, and full text, eligibility, and final inclusion
process is depicted in Figure 1. A total of 138 articles were identified
in the literature search. Following screening by title and abstract, 8
studies underwent full-text review. Three studies were excluded due to
combination treatment and irrelevant reported outcomes, resulting in
five articles being included in the study. Table 1 presents the main
characteristics of the included studies. We implemented a meta-analysis
on the role of Infliximab in COVID-19 patients within the investigations
of Farrokhpour et. al., and Stallmach et. al., O'Halloran et. al.,
(randomized double blind clinical trial), Taleng et. al. (observational
studies), Fisher et. al., (randomized open-label clinical trial),
(retrospective cohort study) {[}12{]} {[}13{]} {[}14, 15{]}. These
studies compared Infliximab with various treatment interventions.

\textbf{Efficacy outcomes}

\textbf{Mortality rate}

A total of five studies involving 1224 patients reported cases of death
among COVID-19 patients receiving Infliximab or no Infliximab. The
pooled analysis of these studies revealed no significant difference in
mortality rates between the Infliximab and no Infliximab groups (RR=
0.70, 95\% CI: 0.53 to 0.91; P \textless{} 0.001, I2 = 0\%) (Figure 2).

\textbf{Hospitalization rate}

The combined estimate from two studies indicated no significant
difference in ICU admission between the Infliximab and no Infliximab
groups (RR= 0.37, 95\% CI: 0.11 to 1.16; P = 0.09, I2 = 20\%) (Figure
3).

\textbf{Need for Mechanical Ventilation}

Three studies reported on the need for mechanical ventilation in
patients treated with Infliximab and no Infliximab. The meta-analysis
demonstrated no significant difference between the Infliximab and no
Infliximab groups in terms of need for mechanical ventilation (RR= 0.98,
95\% CI: 0.65 to 1.48; P = 0.94, I2 = 30\%) (Figure 4).

\textbf{ICU Admission}

The combined estimate from three studies showed no significant
difference in ICU admission between the Infliximab and no Infliximab
groups (RR= 0.92, 95\% CI: 0.67 to 1.26; P = 0.61, I2 = 30\%) (Figure
5).

\textbf{Adverse events}

The pooled estimate from two studies indicated no significant difference
in the incidence of adverse events between the Infliximab and no
Infliximab groups (RR= 1.09, 95\% CI: 0.79 to 1.51; P = 0.51, I2 = 56\%)
(Figure 6)

\section*{Results}

{\label{results}}

\section*{Efficacy outcomes}

{\label{efficacy-outcomes}}

\section*{Mortality rate}

{\label{mortality-rate}}

A total of five studies involving 1224 patients reported cases of death
among COVID-19 patients receiving Infliximab or no Infliximab. The
pooled analysis of these studies revealed significant difference in
mortality rates between the Infliximab and no Infliximab groups (RR=
0.70, 95\% CI: 0.53 to 0.91; P \textless{} 0.001, I2 = 0\%) (Figure 2).

\section*{Hospitalization rate}

{\label{hospitalization-rate}}

The combined estimate from two studies indicated no significant
difference in ICU admission between the Infliximab and no Infliximab
groups (RR= 0.37, 95\% CI: 0.11 to 1.16; P = 0.09, I2 = 20\%) (Figure
3).

\section*{Need for mechanical
ventilation}

{\label{need-for-mechanical-ventilation}}

Three studies reported on the need for mechanical ventilation in
patients treated with Infliximab and no Infliximab. The meta-analysis
demonstrated no significant difference between the Infliximab and no
Infliximab groups in terms of need for mechanical ventilation (RR= 0.98,
95\% CI: 0.65 to 1.48; P = 0.94, I2 = 30\%) (Figure 4).

\section*{ICU admission}

{\label{icu-admission}}

The combined estimate from three studies showed no significant
difference in ICU admission between the Infliximab and no Infliximab
groups (RR= 0.92, 95\% CI: 0.67 to 1.26; P = 0.61, I2 = 30\%) (Figure
5).

\section*{Adverse events}

{\label{adverse-events}}

The pooled estimate from two studies indicated no significant difference
in the incidence of adverse events between the Infliximab and no
Infliximab groups (RR= 1.09, 95\% CI: 0.79 to 1.51; P = 0.51, I2 = 56\%)
(Figure 6).

\section*{Discussion}

{\label{discussion}}

Other indices including the rate of adverse events, hospitalization,
mechanical ventilation, and ICU admission were not statistically
significant between the two groups.

\section*{The impact of Infliximab on mortality rate of COVID-19
patients:}

{\label{the-impact-of-infliximab-on-mortality-rate-of-covid-19-patients}}

Our meta-analysis has revealed that Infliximab administration could
significantly decrease the mortality rate compared to non-infliximab
group in patients with SARS-CoV-2 infection.

According to Kokkotis et. al., meta-analysis, anti-TNF\selectlanguage{greek}α \selectlanguage{english}treatment has
helpful effects in terms of reducing the risk of hospitalization and
severe COVID-19 in patients with underlying inflammatory disease
{[}16{]}. Tocilizumab, a kind of anti- TNF\selectlanguage{greek}α \selectlanguage{english}which primarily used in
Rheumatoid disorders, could also decrease all-cause mortality in 6481
individuals with generally severe, non-critical COVID-19 infection based
on Avni et. al., meta-analysis {[}17{]}. Based on Halim et. al.,
meta-analysis, the mortality rate in COVID-19 patients is strongly
correlated with higher levels of serum concentrations of TNF-\selectlanguage{greek}α. \selectlanguage{english}Each 1
picogram (pg)/mL surge in TNF-\selectlanguage{greek}α \selectlanguage{english}level significantly increases the risk
of mortality rate in patients with COVID-19 according to this study
(with crude hazard ratio = 1.0640; 95\% CI: 1.0259--1.1036; p = 0.0009)
{[}18{]}. Baricitinib, a Janus kinase (JAK) inhibitor primarily used in
moderate to severe active rheumatoid arthritis, could significantly
decrease the 28-day mortality rate of COVID-19 in hospitalized patients
rather than standard treatment (RR, 0.69, 95\% CI, 0.50--0.94, p = 0.02,
i2 = 64.86\%) {[}19{]}. According to Amstutz et. al., meta-analysis
remdesivir reduces the mortality rate in hospitalized patients with
COVID-19 who needed no or conventional respiratory oxygen support. In
this study, 662 (12\selectlanguage{ngerman}·5\%) of 5317 patients of remdesivir group and 706
(14·1\%) of 5005 patients of no remdesivir group died (aOR 0·88, 95\% CI
0·78-1·00, p=0·045). However, the results of the study were not
influential enough to recommend remdesivir for ventilated patients with
COVID-19 (aOR 1·10 {[}0·88-1·38{]}) {[}20{]}.

According to Gohda et. al., study which utilized multivariate logistic
regression analysis, the mortality rate in patients with COVID-19 were
correlated with increased serum levels of TNFR1 and TNFR2 (p value =
0.08, p value = 0.03, respectively) {[}21{]}. Combination of Infliximab
with tocilizumab has superior therapeutic function rather than
tocilizumab alone in decreasing mortality rate and serum levels of
inflammatory factors in hospitalized patients with severe Covid-19
{[}22{]}. According to CLARITY study, levels of antibodies against
SARS-CoV-2 and anti- SARS-CoV-2 immune reactivity can be declined by
administration of Infliximab in patients with inflammatory bowel disease
(IBD) {[}23{]}.

\section*{Infliximab and rate of adverse events in COVID-19
patients:}

{\label{infliximab-and-rate-of-adverse-events-in-covid-19-patients}}

The rate of adverse events was not statistically significant between the
two groups according to our study.

According to Hernandez et. al., meta-analysis, the adverse effects of
monoclonal antibodies on hospitalized patients with COVID-19 was
uncertain (RR 1.31; 95\% CI, 1.02-1.67; I2 = 77\%). In non-hospitalized
patients, monoclonal antibodies could marginally decrease the serious
adverse events (RR 0.47; 95\% CI, 0.22-1.01; I2 = 33\%) {[}24{]}. The
risk of any adverse events (OR, 0.90; 95\% CI: 0.79--1.03; p = 0.14) and
drug-related adverse events (OR, 1.43; 95\% CI: 0.85--2.41; p = 0.18) in
the three groups of non-hospitalized patients with COVID-19 managed by
nirmatrelvir plus ritonavir, remdesivir, and molnupiravir were similar
to placebo counterparts based on Lai et. al., meta-analysis {[}25{]}.



\section*{Infliximab and rate of hospitalization in COVID-19
patients:}

{\label{infliximab-and-rate-of-hospitalization-in-covid-19-patients}}

The rate of hospitalization was not statistically significant between
the two groups based on our meta-analysis.

Monoclonal antibodies have desirable effects in terms of decline in
hospitalization of outpatients with COVID-19 (RR 0.30; 95\% CI,
0.17-0.53; I2 = 0\%) {[}24{]}. Both baricitinib and tocilizumab decrease
the length of hospitalization in hospitalized patients with COVID-19
(baricitinib: mean difference, \selectlanguage{english}-1.13 days (95\% CI, \selectlanguage{english}-1.51 to \selectlanguage{english}-0.76), p
\textless{} 0.001, i2 = 0.00\%; tocilizumab: mean difference, \selectlanguage{english}-2.80 days
(95\% CI, \selectlanguage{english}-4.17 to \selectlanguage{english}-1.43), p \textless{} 0.001, i2 = 55.47\%) and also
result in significant clinical recovery of them by day 28 (baricitinib:
RR, 1.24 (95\% CI, 1.03--1.48),~\emph{p} ~= 0.02, i\textsuperscript{2}~=
27.20\%; tocilizumab: RR, 1.41 (95\% CI, 1.12--1.78),~\emph{p}
~\textless{} 0.001, i\textsuperscript{2}~= 34.59\%)~in comparison with
standard care {[}19{]}. Lai et. al., network meta-analysis revealed that
nirmatrelvir plus ritonavir treatment had the least risk of
hospitalization or death (OR, 0.12; 95\% CI: 0.06--0.24), following
remdesivir (OR, 0.13; 95\% CI: 0.03--0.57) and molnupiravir (OR, 0.67;
95\% CI: 0.46--0.99) in non-hospitalized patients with SARS-CoV-2
infection compared with placebo treatment {[}25{]}.

According to Halim et. al., meta-analysis, the risk of COVID-19
infection severity is insignificantly associated with higher serum
levels of TNF-\selectlanguage{greek}α. \selectlanguage{english}The results of this study also indicated that every 1
picogram (pg)/mL surge in TNF-\selectlanguage{greek}α \selectlanguage{english}level is correlated with severity of
COVID-19 infection (with adjusted odds ratio = 1.0304; 95\% CI:
0.8178-1.2983; p value = 0.80) {[}18{]}.

\textbf{Infliximab and rate of ICU admission in COVID-19 patients:}

The rate of ICU admission was not statistically significant between the
two groups according to our study.

Based on Gohda et. al., retrospective study, the ICU-admitted patients
with SARS-CoV-2 infection had significantly increased blood
concentrations of Tumor Necrosis Factor receptor 1 and 2 (TNFR1, 2)
rather than patients who did not hospitalize in ICU section after
adjustment the confounding factors {[}21{]}.

\section*{Infliximab and rate of mechanical ventilation in COVID-19
patients:}

{\label{infliximab-and-rate-of-mechanical-ventilation-in-covid-19-patients}}

The rate of mechanical ventilation was not statistically significant
between the two groups according to this meta-analysis.

Monoclonal antibodies could slightly decrease the rate of mechanical
ventilation in hospitalized patients with COVID-19 (relative risk 0.74;
95\% confidence interval {[}CI{]}, 0.60-0.9; I2 = 20\%) {[}24{]}.

Infliximab may potentially induce pulmonary complications like
non-infectious interstitial lung disease and thereby should be
cautiously prescribed in patients with SARS-CoV-2 {[}26{]}.

\section*{Limitations of this study}

{\label{limitations-of-this-study}}

Interpretive bias may occur due to the different study methods reported
in the clinical articles (which are used in our meta-analysis) {[}27{]}.
The other limitation of our study is the limited numbers of
meta-analysis that investigated the impact of infliximab on COVID-19
patients.

\textbf{Conclusion}

We conclude that Infliximab exerts favorable impact in terms of lowering
the mortality rate of SARS-CoV-2 infection. More studies on the effects
of Infliximab on severe COVID-19 should be conducted {[}28{]}.

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21. Gohda, T., et al., \emph{Circulating tumor necrosis factor receptors
are associated with mortality and disease severity in COVID-19
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versus tocilizumab among COVID-19 patients with cytokine storm
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23. Ray, K., \emph{Antibody responses to SARS-CoV-2 infection are
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24. Hernandez, A.V., et al., \emph{Beneficial and Harmful Effects of
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p. 1349-1361.e18.

25. Lai, C.C., et al., \emph{The Clinical Efficacy and Safety of
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Syndrome during Infliximab Therapy in a Patient with Crohn Disease.}Case
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27. Yoo, J.Y., et al., \emph{Comparative analysis of COVID-19 guidelines
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28. Coldewey, S.M., et al., \emph{Infliximab in the treatment of
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2022. \textbf{23} (1): p. 737.

\textbf{Table 1}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
SARS-COV-2 variant & COVID-19 vaccination rate (\%) & Control(s) &
Intervention & M & N & Design & Place & First author,
year\tabularnewline
\midrule
\endhead
& & SOC & Infliximab & 17 & 24 & Observational & Germany & Stallmach,
2020\tabularnewline
& & Control; IVIg; infliximab + IVIg & Infliximab & 68 & 104 &
Observational & Iran & Farrokhpour, 2021\tabularnewline
& & Placebo & Infliximab & 40 & 69 & RCT & UK & Fisher,
2021\tabularnewline
& & Placebo & Infliximab & 637 & 1061 & RCT & USA & O'Halloran,
2023\tabularnewline
& & SOC & Infliximab & 50 & 190 & observational & Italy & Taleng,
2021\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: M, male, N, number; NR, not reported; RCT, randomized
controlled trial; SOC, standard of care

\textbf{Table 2 Risk of bias of included studies (ROBINS-I)}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Study\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Confounding\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Selection\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Classification of interventions\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
deviations from intended interventions\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Missing Data\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Measurement of outcomes\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Reported Result\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Overall\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Farrokhpour,2021\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Taleng,2021\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Stallmach, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Moderate\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Serious\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3 Risk of bias of included studies (RoB2)}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Study & Random sequence generation & Allocation concealment & Blinding
of participants and personnel & Blinding of outcome assessment &
Incomplete outcome data & Selective reporting\tabularnewline
\midrule
\endhead
Fisher,2021 & Low & Unclear & Unclear & high & Low & Low\tabularnewline
O'Halloran,2023 & Low & Unclear & Low & Low & Low & Low\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1. PRISMA flow diagram of study selection process\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2 Forest plot of Infliximab versus control group for outcome of
mortality rate\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 3 Forest plot of Infliximab versus control group for outcome of
hospitalization rate\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 4 Forest plot of Infliximab versus control group for outcome of
Need for mechanical ventilation\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

Figure 5 Forest plot of Infliximab versus control group for outcome of
ICU admission\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

Figure 6 Forest plot of Infliximab versus control group for outcome of
Adverse Events

\selectlanguage{english}
\FloatBarrier
\end{document}

