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\begin{document}

\title{Efficacy of Oseltamivir in the Treatment of Patients Infected with
Covid-19}



\author[1]{Abolfazl Zendehdel}%
\author[1]{Mohammad  Bidkhori}%
\author[1]{Mohsen  Ansari}%
\author[1]{Saeed Reza  Jamali Moghaddam siyahkali}%
\author[1]{Azadeh  Asoodeh}%
\affil[1]{Tehran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background and purpose: The recent unprecedented pandemic caused by
Sars-Cov-2, is threatening public health over the world. Although
several studies have been performed there is no identified treatment for
Covid-19 patients. Here we assessed the efficacy of oseltamivir in
combination therapy, by comparing two different therapeutic regimens in
hospitalized patients. Experimental approach: This is a retrospective,
according to the date of admission, the patients were divided into two
groups; group 1 (oselta group) from Feb 20, 2020 to March 15, 2020
received Oseltamivir with routine regimen and group 2 (control group)
from March 20, 2020 to April 20, 2020 received routine regimen alone
including Azithromycin 500 mg/daily and Hydroxychloroquine 200 mg/12h.
The endpoints including, the duration of hospitalization, requirement to
intensive care unit (ICU) admission and mechanical ventilation, the
outcome and rate of mortality. Key Results: A total of 285 patients were
enrolled over the two months, 120 patients for group 1 and 165 for group
2. The median time from admission to discharge was significantly shorter
in oselta group in comparison with control Group. Additionally, the
mortality rate was found to be lower in oselta group than control group
which was statistically significant by multivariate analysis. The
incidence of ICU admission and mechanical ventilation were also
decreased in oselta group but were not found to be statistically
significant. Conclusion and implications: This study showed that
administration of oseltamivir was associated with shorter length of
hospital stay and earlier recovery and discharge of hospital, and a
lower mortality rate.%
\end{abstract}%



\sloppy


\textbf{Introduction}

In late (December) 2019 a new pneumonia with unknown origin, detected in
patients who were linked to a seafood wholesale market, where wild
animals were illegally sold in china. After testing the specimens of the
patient's airway epithelial cells, a novel coronavirus was detected and
described as 2019-nCov, and was later named severe acute respiratory
syndrome coronavirus 2 (SARS-COV-2) by WHO, and the disease caused by
this new virus, was named Covid-19 (Zhu et al., 2020).

This new virus is the seventh human coronavirus described to date as
being responsible for respiratory infections (Devaux, Rolain, Colson, \&
Raoult, 2020), and categorized in the Betacoronaviruse subgroup(Zhu et
al., 2020).

Covid-19 rapidly spread in the world and made an unprecedented pandemic
on March 12, 2020, became a big concern for global health with
threatening public health over the world. Thus there was an urgent need
for an effective treatment and conducting clinical trials and studies
for assessing the efficacy of different repurposed drugs for treatment
and prevention of transmission of this infection (Kupferschmidt \&
Cohen, 2020). So WHO considered a Solidarity and a major study, on March
20, 2020 to collect scientific data and compare therapeutic strategies
for defining an effective treatment for patients with Covid-19, wants
the hospitals overwhelmed by Covid-19 patients to participate, and from
the physicians to simply record their results as the duration of
hospital stay, whether the patients required intensive care unit (ICU)
admission or ventilation and the day patient left the hospital or died.
''That's all'' says Ana Maria Henao Restrepo, a medical officer at WHO's
Emergencies Programme (Kupferschmidt \& Cohen, 2020).

There for we decided to do our duty in this Solidarity and describe the
result of our therapeutic regimens in this hospital, as a center for
Covid-19 patients.

Antiviral drugs, may be the best candidates for the treatment of
Covid-19, until we have specific therapeutic drugs (Kivrak, Ula\selectlanguage{polish}ş, \selectlanguage{english}\&
Kivrak, 2021). Oseltamivir (brand name Tamiflu) is a neuraminidase
inhibitor that is approved for treatment and prophylaxis of influenza A
and B ((Yousefi, Mashouri, Okpechi, Alahari, \& Alahari, 2021),(Agrawal,
Goel, \& Gupta, 2020)).It can inhibit the spread of the influenza virus
and reduce viral shedding in respiratory secretions in the human body
(Agrawal et al., 2020), and is considered as a therapeutic option in
several clinical trials and studies but the results remain controversial
((Zhou et al., 2020),(Ungogo, Mohammed, Umar, Bala, \& Khalid, 2021)).
There for further studies are required to demonstrate the efficacy of
antiviral drugs for the treatment of Covid-19 patients.

In this study we aimed to evaluate the efficacy of Oseltamivir, by
comparing two different combination therapeutic regimens, based on
length of hospital stay, need for ICU admission, mechanical ventialation
and mortality rate.

\textbf{Material and methods}

\textbf{Study design}

This was a retrospective analysis of a single center, cohort study,
performed between Feb 20, 2020 and April 20, 2020 in patients with
Covid-19 infection, at Ziaeian Hospital, a center for pandemic Covid-19
infected patients, Tehran, Iran.

This study including 285 confirmed, Covid-19 infected patients who were
admitted to this hospital during two months and received two different
therapeutic regimens according to the guidelines issued by Iranian
Ministry of Health and Medical Education (first edition(\emph{Iranian
Ministry of health and Medical Education} , 28 Feb 2020), fifth
edition(\emph{Iranian Ministry of Health and Medical Education} , 25
march 2020)).The first group including 120 inpatients between Feb 20,
2020 and March 15, 2020 who received Oseltamivir in addition with
routine regimen (combination group) (\emph{Iranian Ministry of health
and Medical Education} , 28 Feb 2020).The second group including 165
patients between March 20,2020 and April 20,2020 received routine
regimen alone (control group) (\emph{Iranian Ministry of Health and
Medical Education} , 25 march 2020).

\textbf{Study population}

The confirmed Covid-19 infected inpatients with mild to severe disease
were enrolled in the study, according to their clinical symptoms with a
positive diagnostic kit result (RT-PCR) or typical radiologic changes at
chest computed tomograph (CT) (Fang et al., 2020), with the approval of
the specialist in this hospital for Covid-19 diagnosis, and clinically
requirement of hospitalization(\emph{Iranian Ministry of health and
Medical Education} , 28 Feb 2020).

The patient's medical informations including demographic data, clinical
features, the result of Covid-19 test (PCR), chest CT scans,
comorbidities and underling disease (hypertention, diabete, pulmonary
disease, cardiovascular and kidney disease), the admission to the
intensive care unit (ICU), the requirement of mechanical ventilation,
the duration of hospitalization, their outcome and mortality, extracted
from hospital documented patient's data recorded in this hospital.

Patients with a history of allergic reactions or known contraindications
(QT-prolongation) or drug interactions with routine regimens, or lack of
data in their documents, and the patients who die within the first 24
hours of hospitalization, exclude from study.

Patients in this study were enrolled by simple random sampling without
stratification.

This study was conducted in accordance with the declaration of Helsinki
and was approved by the Ethics committee of Tehran University of Medical
Science (Ethic number : IR.TUMS.MEDICINE.REC.1399.396 ) .

Written informed consent was obtained from all patients when admitted to
the hospital. patients confidentiality was considered by protecting
their data and documents.

\textbf{Intervention and measurement}

The routin regimen include: Azithromycin 500 mg/daily,
Hydroycholoroquine 200 mg/12 h (subgroup A), which can fallowed with
Lopinavir/ritonavir ( 200/50 mg tablets two times/12h) if patients need
and their hospitalization continued and their conditions worsened, with
or with out Ribavirin (1200 mg/daily) (subgroup B).

Patients received Acetaminophen for fever as needed,
Antiacid(Pantoprazole) for prevention of gastritis induced by stress or
drugs, and other antimicrobial empiric treatments for secondary
bacterial pneumonia if they need (Levofloxacin 500 mg/daily, vancomycin
1gr/12h, meropenem 1gr/8h, ceftriaxone 1gr/12h).

The severity of patient's disease evaluated with National Early Warning
Score (NEWS) which is used for standardizing the assessment of acute
illness severity in the NHS (physicians, 2017), in this scoring we gave
scores to patients vital signs (PR,RR,T,SO2,SYS BP), the level of
consciousness and requirement to supplemental oxygen at the first visit
when they admitted, scores between 1-4 show Mild disease, 5-6 show
Moderate disease and \textgreater{}=7 show severe disease, and the
degree of involvement of their lungs at chest CT scans to compare the
severity of disease between our two groups with an expert radiologist in
this hospital, according to this score both lungs divided into 5 lobes
and each lobe can get a score of involvement between 1 to 5 so every CT
scans scored between 1 to 25 (Assistant, 2020).

\textbf{Outcome}

In this study we compare a combination of oseltamivir with routine
regimen (oselta group), with routine regimen alone as a control group
(control group), to evaluate the efficacy of oseltamivir in the
treatment and outcome of Covid-19 infected patients.

The primary endpoint was the duration of hospitalization (length of
hospital stay). The secondary endpoints were, requirement to admission
to the intensive care unit (ICU), mechanical ventilation, and patient's
outcome discharge or mortality.

\textbf{Statistical analysis}

The statistical analysis was performed using statistical package STATA
version 14. A p value of 0.05 or less (\textless{}=0.05) was considered
statistically significant. The power of study was 80\% and alfa was
0.05.

Descriptive statistic was reported as mean, standard deviation,
percentage and frequency. Confidence interval was 0.95 (Cl, 0.95).

Independent samples T test and chi-square test was used to compare the
differences between Baseline characteristics of two groups.

Linear regression analysis was used to investigate the relationship
between continues outcomes and treatment. Besides, a logistic regression
was used to investigate the relationship between binary dependent
variables and treatment. Adjustment for severity was performed by
multiple linear and multiple logistic regression.

\textbf{Result}

\textbf{Patients' characteristics}

A total of 285 confirmed Covid-19 patients, after initial screening and
excluding, were enrolled in the study during two consecutive months of
study period, and subdivided in two groups (fig 1).

The baseline characteristics of all enrolled patients are shown in Table
1. As shown in this table, the patients had no significant differences
between the two groups regarding the demographic data, baseline
characteristics and underlying diseases.

Patient's comorbidities and underlying diseases, including chronic
cardiovascular disease, hypertension, diabetes, chronic pulmonary and
kidney disease.

Overall, 117 (41.1\%) Patients were female and 168 (58.9\%) were male,
their ages ranged from 16 to 91 years old (mean=53.80, sd=16.71).

Of these identified cases, 120 patients were classified in group 1
(oselta group), who received oseltamivir plus routine regimen, while 165
patients were classified in group 2 (control group), who were treated
with routine regimen alone. The flow chart of current study is shown in
figure 1.

The disease severity assessed by NEWS scoring (physicians, 2017) and
chest CT scans findings on the admission day (Assistant, 2020), was
different between two groups and oselta group had a higher severity
score (5.02 vs 4.2, p=0.01) (Table 2).

\textbf{Therapeutic effects of oseltamivir}

However, severity of disease in patients in the oselta group were more
than the control group (5.02 vs 4.2, p=0.01), time to recovery and
length of stay in hospital were significantly shorter in patients in
oselta group (4.9 vs 6.6 days, P\textless{}0.001).

Similarly, the mortality rate was lower in oselta group (1.7\% vs 6.7\%,
p=0.06) and after adjusting the disease severity by multivariate
regression analysis between two groups had a statistically significant
difference (OR=5.29, 95\% cl=1.11,25.02, p=0.03).

By univariate and multivariate regression analysis, the comparison of
the incidence of ICU admission (6.7\%, vs 11.5\%, p=0.1), and the
incidence of mechanical ventilation (2.5\% vs 4.8\%, p=0.3), showed
lower percentage in oselta group but did not differ statistically
significant.

A comparison of length of hospital stays between two subgroup A
together, and two subgroup B together, showed the similar results, were
shorter in oselta group, but the other outcomes did not have a
particular result and cannot be evaluated due to the small sample size
between subgroups A (table 3,4). Our results of multivariate regression
analysis showed that by comparing subgroup A1 with subgroup A2, length
of hospital stay was shorter (AOR=2.2, 95\%Cl=1.48-2.92,
P\textless{}0.001) than comparing group 1 and group2 (AOR=1.89,95\%
Cl=1.03,2.75, P\textless{}0.001), or subgroup B1 with subgroup
B2(AOR=1.5,95\% Cl=0.18-2.83, P=0.02). Therefore, maybe it can show
that, the efficacy of oseltamivir therapy in mild conditions have a
better response in duration of recovery and length of hospital stay.

\textbf{Discussion}

In such an unprecedent pandemy wich affect the global public health and
make a serious crisis in every country around the world, there is an
ergent need to assess the efficacy of different repurposed and antiviral
drugs for treating the patient infected with Covid-19.

Therefor, in this study we evaluate the efficacy of Oseltamivir as a
therapeutic option, for confirmed Covid-19 hospitalized patients with
mild to sever disease. Oseltamivir is a repurposed approved antiviral
drug recommended by CDC for the prevention and treatment of viral
influenza infection (Ishaqui et al., 2020), and is one of the
therapeutic options considered for Covid-19 patients((Ding, Zhu, \& Yao,
2020),(Jiang et al., 2020)).

In one review study in china, revealed that between 96-virus drug and 78
small molecules and after evaluation and compution a complete genomic
sequence similarity of virus and chemical structure similarity of drugs,
the predicted top three antiviral drugs against SARS-COV-2 are
remedesivir, oseltamivir and zanamivir, and after molecular docking
showed that these three drugs have higher molecular binding energies
with ACE2(Zhou et al., 2020).

Similarly in another study, showed that neuraminidase inhibitors
enhances the survival rate of mice in clinically relevant models of
sepsis and regulate neutrophil response by inhibition of
neuraminidase-mediated neutrophil dysfunction (overactivation) in vivo,
resulting in infection control and suggest oseltamivir as it could be
repurposed for the treatment of sepsis or sever infections such as
Covid-19, and it raised the requirement of the clinically used of
neuraminidase inhibitors in sepsis and Covid-19 to explore this
hypothesis (Formiga et al., 2020).

In this study, we showed that oseltamivir in combination therapy within
the first hours of admission (group 1), was associated with a decreased
incidence of ICU admission and mechanical ventilation in compare with
control group (group2) which was not statistically significant, and a
significant lower mortality rate especially in moderate to sever
conditions (subgroup B, p=0.04).

Similar results obtained from a retrospective single center cohort study
including 1190 patients with Covid-19 in wuhan, china showed that
administration of oseltamivir was associated with a lower rate of
mortality in sever patients (Liu et al., 2020).

In addition there are reassuring safety data for use of oseltamivir in
pregnant women that can be prescribe during pregnancy (Louchet et al.,
2020).

In some studies the efficacy of oseltamivir treatment for Covid-19
patients remain controversial and further studies requirements for
evaluating the efficacy of this drug suggested ((Wu et al.,
2020),(Ungogo et al., 2021)). Whereas, in another studies showed that
oseltamivir did not have efficacy for treatment of Covid-19 patients and
was not recommended ((Lam, Lombardi, \& Ouanounou, 2020),(Tan et al.,
2020),(Sanders, Monogue, Jodlowski, \& Cutrell, 2020)).

Since Covid-19 infection is a viral disease, and like most drugs for
acute infections, an antiviral may be much more potent if given early,
says Stanley Perlman, a coronavirus researcher at the University of Iowa
, and he said although remdesivir is the best antiviral drug in many
studies, but the big challenge is how we could give an expensive
intravenous drug like that to people who walk in with mild symptoms and
considering that 85\% of patients won't develop sever disease and need
such a drug like it (Kupferschmidt \& Cohen, 2020). Similarly in another
study showed that early (within 24 hours of fever onset) administration
of oseltamivir in combination with antibiotic help a faster improvement
in patient's symptoms in Covid-19 suspected outpatients without hypoxia
(Chiba, 2020).

There for an important consideration in the effective management of
Covid-19 as a viral infection is to start an antiviral agent in the
first days of infection which is the replication phase of the virus
(\emph{Iranian Ministry of health and Medical Education} , deceber
2020).

In our study, we found patients who were treated with oseltamivir in
combination therapy within the first hours of their admission, showed a
faster recovery and discharge from hospital and have a shorter length of
hospital stay in compare with the control group, which was statistically
significant (B=1.89, p\textless{}0.001) especially in mild conditions
(subgroup A, B=2.2, P\textless{}0.001).

This may show that immunomodulatory and probable antiviral effects of
hydroxychloroquine ((Yao et al., 2020),(Gautret et al.,
2020),(Guastalegname \& Vallone, 2020)), and antibiotic therapy with
Azithromycin with triple therapeutic effects (anti inflammatory,
antiviral, antimicrobial)((Mosquera et al., 2018),(Kakeya et al., 2014))
alone may not be effective in treatment of Covid-19 disease in the
absence of an effective antiviral drugs against this viral infection, to
start and prescribed as soon as possible. So may be oseltamivir as an
oral, nonexpensive antiviaral drug from the repurposed drugs which is
already approved for other disease and have acceptable safety profile
and a few well-known adverse effects, could consider as a therapeutic
option for the initial treatment of Covid-19 patients at the first visit
in the office or in the health care centers in combination with an oral
antibiotic for prevention of probable secondary bacterial infections and
an anti inflammatory agent. Thus, we could have a faster recovery of
disease, and in this way we could prevent the transmission of the virus
from infected patients and progression of the disease in the society for
a better control and management of this disease(Agrawal et al., 2020).

In conclusion, oseltamivir in combination with routine regimen therapy
was found to be more efficacious as compared to routine regimen alone,
in rapid recovery and earlier discharge of hospital, and was associated
with lower mortality rate.

The limitation of our study, is the retrospective nature of this study,
incomplete medical records that we had to remove a number of patients,
small sample size especially for better results in mortality rate, and
the patients were not evaluate at the same time and were reviewed in two
consecutive months.

Further prospective studies are required to clarify the clinical
benefits of oseltamivir in combination therapy and compare oseltamivir
with other antiviral drugs for better management and found a
well-established gold standard therapy for the treatment of diagnosed
Covid-19.

\textbf{Acknowledgment}

We would like to thank the Tehran university of Medical science and
Ziaeian Hospital, and it's research unit for the facilities and
possibility of conducting this study.

\textbf{Conflict of interest} : The authors deny any conflict of
interest in any terms or by any means during the study.

\section*{Ethical approval and consent to
participate}

{\label{ethical-approval-and-consent-to-participate}}

All procedures performed in this study involving human participants were
in accordance with the ethical standards of the institutional and/or
national research committee and with the 1964 Helsinki Declaration and
its later amendments or comparable ethical standards.

\textbf{Consent to participate:} from the under 16 years old was given
by a parent or legal guardian

\textbf{Consent for publication:} Not applicable

\textbf{Availability of data and material:} Data sharing is not
applicable to this article as no datasets were generated or analyzed
during the current study.

\textbf{Funding:} This study had a research project grunt from Tehran
university of Medical science. The authors declare no conflict of
interests.

\textbf{Contributors' Statement Page:}

Dr. Abolfazl Zendehdel: conceptualized and designed the study, drafted
the initial manuscript, and reviewed and revised the manuscript.

Dr. Saeed Reza Jamali Moghaddam siyahkali and Dr. Azadeh Asoodeh:
Designed the data collection instruments, collected data, carried out
the initial analyses, and reviewed and revised the manuscript.

Dr. Mohammad Bidkhori and Dr. Mohsen Ansari: Coordinated and supervised
data collection, and critically reviewed the manuscript for important
intellectual content.

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doi:10.1007/s40495-020-00216-7

Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., . . . Liu, D.
(2020). In Vitro Antiviral Activity and Projection of Optimized Dosing
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Table1-patient demographic data and characteristic for two groups\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
p-value\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Total N=285\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Group2 N=165\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Group 1 N=120\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.5 0.3 0.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53.80(16.71) 168(58.9\%) 117(41.1\%) 130(45.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55.32(17.43) 92(55.8\%) 72(43.6\%) 74(44.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55.09(15.7) 76(63.3\%) 44(36.7\%) 56(46.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age,year Mean(sd) Sex,number(\%) Male Female Underlying disease
Yes,number(\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table2-Clinical outcome comparison of study population for two subgroup
A\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
P-value\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
B(95\%Cl)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
P-value\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
SubgroupA2 N=76\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Subgroup A1 N=55\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.2(1.48-2.92)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.97(2.49)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.1(1.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
3.1(1.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Lohs\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

CL=Confidence interval, B=Regression coefficient, LOHS=Length of
hospital stay

Table3-Clinical outcome comparison of study population for both group\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
p-value\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
AOR/B (95\%CL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
p-value\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Group 2 N=165\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Group 1 N=120\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.2 0.06 0.03 \textless{}0.001 0.01 0.3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.2 0.06 0.03 \textless{}0.001 0.01 0.3\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2.32(o.59,9.11) 2.32(0.94,5.73) 5.29(1.11,25.02) 1.89(1.03-2.75)
-0.81(-1.5,-1.3) -0.06(-1.86,-0.65)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2.32(o.59,9.11) 2.32(0.94,5.73) 5.29(1.11,25.02) 1.89(1.03-2.75)
-0.81(-1.5,-1.3) -0.06(-1.86,-0.65)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.3 0.1 0.06 \textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.3 0.1 0.06 \textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
8(4.8\%) 19(11.5\%) 11(6.7\%) 6.62(3.88) 4.2(2.96) 7.84(5.74)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3(2.5\%) 8(6.7\%) 2(1.7\%) 4.98(3.44) 5.02(2.78) 8.45(4.76)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3(2.5\%) 8(6.7\%) 2(1.7\%) 4.98(3.44) 5.02(2.78) 8.45(4.76)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Mechanical Ventilation Yes(\%) ICU admission Yes(\%) Mortality Yes(\%
LOHS Day(sd) NEWS score Mean(sd) CT scre Mean(sd)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AOR=Adjusted odds ratio, CL=Confidence interval, ICU=Intensive care
unit, SD=Standard deviation B=Regression coefficient, NEWS= National
Early Warning Score, CT=Computed tomography, LOHS=Length of hospital
stay.

Table 4-clinical outcom comparison of study population for subgroups B.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
Multivariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
Univariate analysis\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
P-value\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
AOR/B(95\%CL)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
AOR/B(95\%CL)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
P-value\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
SubgroupB2 N=89\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
SubgroupB2 N=89\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
SubgroupB1 N=65\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
SubgroupB1 N=65\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.3 0.1 0.03 0.02\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.3 0.1 0.03 0.02\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.86(0.45-7.57) 1.87(0.73-4.77) 9.89(1.19-81.83) 1.5(0.18-2.83)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
1.86(0.45-7.57) 1.87(0.73-4.77) 9.89(1.19-81.83) 1.5(0.18-2.83)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.4 0.2 0.04 0.03\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.4 0.2 0.04 0.03\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0.4 0.2 0.04 0.03\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
7(7.9\%) 17(19.1) 10(11.2\%) 8.03(4.29)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
7(7.9\%) 17(19.1) 10(11.2\%) 8.03(4.29)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3(4.6\%) 8(12.3) 1(1.5\%) 6.56(3.81)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3(4.6\%) 8(12.3) 1(1.5\%) 6.56(3.81)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3(4.6\%) 8(12.3) 1(1.5\%) 6.56(3.81)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Mechanical ventilation,N(\%) Icu admission Yes(\%) Mortality Yes(\%)
Lohs\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AOR=Adjusted odds ratio, CL=Confidence interval, ICU=Intensive care
unit, B=Regression coefficient, LOHS=Length of hospital stay

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

