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\begin{document}

\title{Treatment of COVID-19 Patients with Quercetin: A Prospective, Single -
Centre, Randomized, Controlled Trial}



\author[1]{Hasan Onal}%
\author[2]{Bengu Arslan}%
\author[1]{Nurcan Ucuncu Ergun}%
\author[1]{Seyma Topuz}%
\author[1]{Seda Yilmaz Semerci}%
\author[1]{Mehmet Kurnaz}%
\author[1]{Yulet Bolu}%
\author[1]{Mehmet Bozkurt}%
\author[1]{Nurettin Suner}%
\author[1]{Ali Kocatas}%
\affil[1]{Affiliation not available}%
\affil[2]{Kanuni Sultan Suleyman Training and Research Hospital}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim The present study aimed to evaluate the effect of quercetin in
COVID-19 treatment. Methods This was a single-centre, prospective
randomised controlled cohort study. Routine care versus QCB (quercetin,
vitamin C, bromelain) supplementation was compared between 447 patients
with at least one chronic disease and moderate-to-severe respiratory
symptoms. Demographic features, signs, laboratory results and drug
administration data of patients were recorded. The endpoint was that QCB
supplementation was continued throughout the follow-up period from study
baseline to discharge, intubation, or death. Results The most common
complaints at presentation were fatigue (62.4\%), cough (61.1\%),
anorexia (57\%), thirst (53.7\%), respiratory distress (51\%) and chills
(48.3\%). The decrease in CRP, procalcitonin and ferritin levels was
higher in the QCB group (all Ps were \textless{}0.05). In the QCB group,
an increase in platelet and lymphocyte counts were higher (all Ps were
\textless{}0.05). QCB did not reduce the risk of events during
follow-up. Adjustments for statistically significant parameters,
including the lung stage, use of favipiravir and presence of comorbidity
did not change the results. While there was no difference between the
groups in terms of event frequency, QCB group had more advanced
pulmonary findings. QCB supplement is shown to have a positive effect on
laboratory recovery. Conclusion We suggest that suboptimal
bioavailability of QCB may explain this. So, we conclude that if a
stable blood level can be achieved for QCB, it may make a difference in
the treatment of COVID-19.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Scientific research continues on new preventive and therapeutic
strategies against severe acute respiratory syndrome Coronavirus-2
(SARS-CoV-2). So far, there is no proven curative treatment for the
Novel Coronavirus Disease 2019 (COVID-19), and while an effective
vaccine is expected, ''wild'' protocols based on ''ancient''
anti-inflammatory and anti-viral drugs are being offered. A valid and
alternative therapeutic approach needs to be developed.

Affecting the nasopharyngeal cells first, SARS-CoV-2 can target
different tissues such as lung, vascular endothelium, kidney and nervous
at various degrees and it can cause severe illness and death.{[}1,2{]}
With the advantage of the lack of systemic toxicity, flavonoids,
including quercetin, are proven to potentialise routine drugs against
Coronavirus.{[}3{]} Flavonoids owe their antioxidant, anti-inflammatory
and anti-viral properties, against a wide range of DNA and RNA viruses,
to their pleiotropic molecular structure that acts by targeting variable
cells on multiple pathways.{[}4,5{]} Therefore, this study aimed to
determine if quercetin had a curative role in the treatment of COVID-19.

\textbf{Material and Methods:}

\textbf{Design:} This was a single-centre, prospective, randomised
controlled cohort study. This study was conducted in the Health Sciences
University Kanuni Sultan Suleyman Training and Research Hospital, which
was designated as a pandemic hospital. The Ministry of Health and local
ethics committee approved the study (Ethics Committee approval number:
KAEK/2020.05.50).

\textbf{Participants:} Between March 7 and July 8, 2020, adults who were
hospitalised in the pandemic ward with the diagnosis of COVID-19
included upon individual informed written consent. All participants
evaluated with a nasopharyngeal swab polymerase chain reaction (PCR) and
chest computed tomography (CCT). The treatment protocol recommended by
the Ministry of Health was applied for all cases. The recommended
treatment regimen is hydroxychloroquine, 400 mg daily for another 5
days, and/or favipiravir, 2 x 600 mg for 4 days following a 2 x 1600 mg
loading dose on day one. QCB (1000 mg quercetin, 1000 mg vitamin C and
100 mg bromelain) supplementation was added daily in 2 divided doses to
52/447 patients with at least one chronic disease and moderate-to-severe
respiratory symptoms. Computer-generated random numbers used for simple
randomisation. Exclusion criteria determined as severe respiratory
failure, shock and/or combined failure of other organs that required ICU
monitoring and treatment; previous history of allergic reactions against
any component of QCB; pregnant or lactating women; women of childbearing
age with a positive pregnancy test, breastfeeding, miscarriage, or
within 2 weeks after delivery; and participation in another clinical
trial against SARS-CoV-2 treatment currently or in the past 28 days.

The study was reported according to the~\emph{Consolidated Standards of
Reporting Trials} ~guidelines and registered on ClinicalTrials.gov
(number:~ NCT04377789) on March 20, 2020. The primary endpoint of the
study was determined as QCB supplementation was continued throughout the
follow-up period from study baseline to discharge, intubation, or death.
Demographic features, vital signs, laboratory test results during
follow-up, drug administration data, past and current diagnoses of the
patients were recorded. CCT findings of the cases were evaluated in 5
stages: stage 0 is the lung being completely normal, stage 1; light
one-sided ground glass image, stage 2; multifocal double-sided ground
glass image, stage 3; multifocal bilateral ground glass and stage 4;
opacity, air bronchogram, bilateral ground glass and opacity,
respectively.

\textbf{Statistical Analysis}

The quantitative data were described as the mean \selectlanguage{ngerman}±\selectlanguage{english} standard deviation
(SD), or as the median (min-max). A~sample size~calculation~was
performed based on our observed results by using a one-sided McNemar's
test. A sample size of 447 individuals, at least 49 in each arm, is
found to be sufficient to detect a clinically significant difference
between groups with 80\% power and a 5\% level of significance. The
qualitative data were described by the number of cases (proportion, \%).
Patient characteristics were compared using the
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}~test or Fisher's exact test for categorical data
and the Mann Whitney U test for continuous data. Cox
proportional-hazards regression models were used to estimate the
association between QCB use and the composite endpoint of intubation or
death. Statistical significance was accepted when the probability (P)
value was \textless{}0.05 and changes were referred to as significant at
this P-value.

\textbf{Results}

A total of 447 adult covid patients hospitalised in the COVID ward were
included in the study between March 7 and July 8, 2020. Flow chart of
the study was demonstrated as Figure-1 (Figure 1). None of the adverse
effects related to QCB supplement was observed in participants.

The most common symptoms at presentation were fatigue (62.4), cough
(61.1\%), anorexia (57\%), thirst (53.7\%), respiratory distress (51\%)
and chills (48.3\%; Table 1).

There was no significant difference in gender and age distribution
between the standard treatment group and the standard treatment plus QCB
group (p = 0.30; p = 0.19). In terms of comorbid diseases, the standard
treatment plus QCB group had a significantly higher number of chronic
obstructive pulmonary disease (COPD) and tuberculosis infection cases (p
= 0.02; p = 0.07), though there was no significant difference in terms
of other diseases. Both groups did not differ in terms of smoking (p =
0.34; Table 2). Pulmonary findings in the standard therapy plus QCB
group were significantly more severe than in the standard therapy group
(p = 0.04; Table 2). The proportion of patients with an oxygen
saturation \textless{}93 mmHg at admission and/or follow-up was
significantly higher in the group receiving standard therapy plus QCB (p
= 0.021; Table 2). Nasopharyngeal swab SARS CoV2 PCR result was positive
in 40-50\% of cases for both groups (p = 0.84; Table 2).

The decrease in the levels of C-reactive protein, procalcitonin and
ferritin were significantly higher in the group that received standard
treatment plus QCB compared to the other group (Pcrp = 0.001;
Pprocalcitonin = 0.004; Pferritin = 0.021; Table 3, Figure 2). Also, the
increase in thrombocyte and lymphocyte count was significantly higher in
the group receiving standard therapy plus QCB (Pplatelet = 0.009,
Plymphocyte = 0.014; Table 3). It was found that the addition of QCB to
the standard therapy/routine care did not reduce the risk of events
during the service follow-up period (Omnibus tests of model coefficients
p = 0.028, Hazard Ratio: 0.180, p = 0.094, (0.024--1.34); Table 4).

After adjustment for the conditions (CCT lung stage, oxygen saturation,
favipiravir use, presence of comorbid chronic disease), similar results
were observed between the groups (statistically significantly different
values were persisted same as the previous). Therefore, QCB supplement
found to be effective in the treatment of COVID-19.

\textbf{Discussion}

Quercetin, as a common component of many fruits and vegetables such as
high capers, lovage, and tea (Camellia sinensis), is a flavonoid.{[}6{]}
There is a wealth of literature supporting the anti-viral properties of
quercetin in both in vitro and in vivo experiments. Quercetin is proven
to inhibit several respiratory viruses in cell cultures.{[}7, 8{]} Viral
S-protein of SARS-CoV-2 is known to infect the human cell via binding
angiotensin-converting enzyme-2 (ACE-2) receptor. This mechanism of the
virus emerged as a target for several anti-viral therapies. Hence, in
silico studies demonstrated that a variety of small molecules which bind
to either the isolated SARS-CoV-2 Viral S-protein at its host receptor
region or to the S protein-human ACE-2 interface.{[}9{]} Quercetin is
pointed one of those top five small molecules. Having that advantage of
sharing the same receptor (ACE-2) and the accessory protease FURIN with
SARS-CoV to bind the cell, quercetin is suggested to be an effective
drug against COVID-19.{[}11,12{]} Besides, quercetin, due to its similar
biochemical structure, was reported as a competitive inhibitor of
SARS-CoV-2 for entry into human cells like luteolin It, therefore, has
the ability to prevent SARS-CoV-2 infection.{[}10{]} Several natural
polyphenolic compounds like quercetin and kaempferol are revealed as
anti-viral in virtual studies.{[}13{]}

Shukor et al. (1999) showed that flavonoids which include a catechol
group, enact better inhibitory capacity on ACE.{[}14{]} Thus, quercetin
seems to be the most effective inhibitory flavonoid against ACE.
Elimination of quercetin in humans is relatively low, with a half-life
ranging from 11 to 28 hrs.{[}13{]} In parallel with this data, the
bioavailability of oral quercetin widely varies, ranging from 0 to
50\%.{[}14{]} Mostly depending on the individual features, an average
terminal half-life of 3.5 hrs is defined for 500 mg oral
quercetin.{[}17{]} Isoquercetin (glycosylated quercetin) is reported to
be more absorbable than quercetin in the aglycone form, and the
concomitant ingestion of quercetin with vitamin C, folate and additional
flavonoids improves bioavailability.{[}13,15{]} Quercetin has the
ability of spontaneous oxidation to O-semiquinone (antioxidant) or
O-quinone/quinone methide (QQ; prooxidant), and this can result in the
process of ''quercetin paradox.''{[}18{]} Consequently, inadequate
ascorbate or glutathione levels may cause quercetin to convert to QQ,
which has prooxidant effects. Since its co-administration with vitamin C
is crucial.{[}19,20{]} Therefore, a combination of quercetin and vitamin
C would not only provide a viral blockade of SARS-CoV-2 but also
strengthen the immune response.

US Food and Drug Administration described quercetin as GRAS status
(generally recognised as safe).{[}6{]} Besides, the European Food Safety
Authority (EFSA) claimed several beneficial physiological effects of
quercetin, including the protection of DNA, proteins and lipids from
oxidative damage (EFSA, 2011). Bromelain is a crude extract of the
pineapple that is considered as a food supplement and is freely
available to the general public in health food stores and pharmacies
around the world.{[}22{]} Bromelain is also demonstrated to improve oral
bioavailability of quercetin up to 80\% similar to vitamin C.{[}22{]}

Oral supplementation with quercetin up to 1 g/day for 3 months has not
resulted in significant adverse effects.{[}15{]} The safety of
quercetin-based oral supplementation during pregnancy and breastfeeding
has not been established. None of the adverse effects related to QCB
supplement was observed in participants. SARS CoV2 can affect many other
systems along with the lung, and its effect may last after the acute
period of infection resolves. It can cause endothelial dysfunction,
hypercoagulability and cytokine storm.{[}24{]} In the case of
significant blood levels achieved for quercetin, the adverse effects of
SARS CoV2, in both acute and chronic periods, can be overcome.
Inhibitory effect of quercetin on the xanthine dehydrogenase/xanthine
oxidase system is another mechanism to decrease oxidative injury due to
the pathological conditions.{[}24,25{]} As the most potent scavenger of
reactive oxygen species, quercetin also reduces ischemia reperfusion
injury in experimental models.{[}25,26{]} Moreover, quercetin provides
antihypertensive effects and improves endothelial function by inhibiting
endothelin-1.{[}27,28{]} Depending on its structural relation to
disodium cromoglycate, quercetin is a potent antihistamine that can
prevent allergic and asthma attacks.{[}29,30{]} Several studies
demonstrated that quercetin causes a down-regulation of histidine
decarboxylase mRNA in the human mast cell line; it also inhibits the
production of leukotriene B4 in leukocytes.{[}33-35{]} Besides, it
suppresses TNFa and nitric oxide release from macrophages.{[}31,32{]}
Regardless of its antioxidant properties, quercetin noted to have a
positive impact on endothelial function by PDE5A inhibition.{[}36,37{]}
Quercetin has the ability to regulate platelet function by inhibiting
thrombin-induced and collagen-induced platelet activation.{[}37{]}
Possible impacts of quercetin on platelet functions may include
down-regulation of CD40L on platelets and interference with adhesion
molecules.{[}38,39{]} In the current study, although the lung
involvement was more advanced and significantly comorbid COPD was
present in the group with QCB supplement, a significant decrease was
achieved in the acute phase reactants (APRs). Besides, QCB supplement is
suggested to have a role on the elevation of the thrombocyte and
lymphocyte count. The exaggerated release of the pro-inflammatory
cytokines from 'hyper-reactive' monocytes, thought to be the reason for
the increase of APRs in COVID-19.{[}41{]} Therefore, those findings may
be explained by the immune-modulatory properties of flavonoids on
macrophages via contributing their transformation from pro- to
anti-inflammatory phenotypes. {[}42{]} Variable bioavailability, high
bio-transformations due to adsorption in the gut, and complexity of the
gut microbiota make it unlikely for flavonoids and their metabolites to
reach micromolar blood concentrations.{[}43{]} We tried to overcome this
problem with vitamin C and bromelain supplements. Although the lung
findings are more advanced in the patient group receiving QCB, it has a
positive effect in terms of improvement in laboratory markers/results.
We suggest that a similar event rate between groups is due to the
non-optimal bioavailability of quercetin. Furthermore, the possible
effect of hydroxychloroquine which is included in the standard
treatment, on the bioavailability of QCB has not been well described.

\textbf{Conclusion} We suggest that QCB has a positive effect in
addition to routine treatment against COVID-19 even for patients with
more advanced lung involvement, still further studies with isoquercetin,
a different form of quercetin with higher bioavailability, are needed as
a light of hope.

\textbf{Acknowledgement:} None.

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\textbf{Figure Legends}

Figure-1: Flow chart of the study was demonstrated.

Figure-2: Alterations in acute phase reactants and complete blood count
parameters during the follow-up

Table 1. Symptoms of all patients at the time of admission

Table 2. Comparison of demographic characteristics of the groups

Table 3. Comparison of groups in terms of laboratory parameters

Table-4 Average time of hospital follow-up, discharge rate and rate of
events of the groups

\textbf{Table 1. Symptoms of all patients at the time of admission}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Symptoms & N=447 (\%)\tabularnewline
\midrule
\endhead
Cough & 273 (61.1)\tabularnewline
Fever & 160 (35.8)\tabularnewline
Sore throat & 135 (30.2)\tabularnewline
Respiratory distress & 228 (51)\tabularnewline
Fatigue & 279 (62.4)\tabularnewline
Poor appetite & 255 (57.0)\tabularnewline
Loss of smell & 90 (20.1)\tabularnewline
Loss of taste & 123 (27.5)\tabularnewline
Thirst & 240 (53.7)\tabularnewline
Nausea & 168 (37.6)\tabularnewline
Vomiting & 107 (23.9)\tabularnewline
Diarrhae & 129 (28.9)\tabularnewline
Muscle pain & 100 (22.4)\tabularnewline
Joint pain & 174 (38.9)\tabularnewline
Chest pain & 129 (28.9)\tabularnewline
Back pain & 161 (36)\tabularnewline
Headache & 213 (47.7)\tabularnewline
Vertigo & 134 (30)\tabularnewline
Syncope & 15 (3.4)\tabularnewline
Chill & 216 (48.3)\tabularnewline
Insomnia & 159 (35.6)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Comparison of demographic characteristics of the
groups}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Standard treatment Group n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
Standard treatment plus QCB Group n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
N\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
395\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Standard therapy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hydroxychloroquine\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
387 (98)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49 (94.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.12\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Favipiravir\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45 (11.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (26.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.004\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
220 (55.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (63.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
175 (44.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19 (36.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18-30\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (5.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30-40\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40 (10.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
40-50\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
81 (20.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (19.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50-60\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96 (24.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17 (32.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60-70\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
81 (20.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13 (25.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
70-80\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41 (10.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
80-90\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (7.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (5.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
90-100\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Comorbidities\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
COPD\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (13.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.02\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52 (13.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (19.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cardiac disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
85 (21.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (30.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.16\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
149 (37.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (46.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.29\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Diabetes Mellitus\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
110 (27.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (30.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Malignity\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (3.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (3.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.91\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Obesity\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (0.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.39\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Rheumathologic Disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
22 (5.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (5.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.95\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Chronic liver disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (0.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Chronic renal disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (1.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Tuberculose\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (5.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
229(58)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (51.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
+\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36 (9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Past history of smoking\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
130 (32.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17 (32.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.04\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CCT at admission\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0: Totally normal 1: Slight, one-sided ground-glass 2-Multifocal
two-sided ground-glass 3- Multifocal two-sided ground-glass and opasity
4- Air bronchogram, bilateral ground-glass and opacity\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
25 (6.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2 (3.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46 (11.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
123 (31.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (26.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
166 (42.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30 (57.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (8.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (11.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Partially Oxygen saturation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.021\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textgreater{}93\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
263 (66.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}93\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
132 (33.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SARS-CoV-2 test result\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.84\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Positive\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
180 (45.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (44.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Negative\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
199 (50.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (50.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Test result not yet known\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (4.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (5.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3. Comparison of groups in terms of laboratory parameters}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& & Standard treatment & Standard treatment plus QCB & P\tabularnewline
\midrule
\endhead
& & Median (min-max) & Median (min-max) &\tabularnewline
C-reactive protein (mg/liter) & & & &\tabularnewline
& 1.measurement & 20.15 (0.1-352.9) & 49.18 (4.6-339) &\tabularnewline
& 2.measurement & 15.27 (0.1-326.0) & 22.23 (0.4-88.8) &\tabularnewline
& Difference between the results (2-1) & -2.21 & -34.64 &
0.001\tabularnewline
Procalsitonin (ng/ml) & & & &\tabularnewline
& 1.measurement & 0.09 (0.02-305.7) & 0.15 (0.04-10.5) &\tabularnewline
& 2.measurement & 0.06 (0.00-39) & 0.06 (0.02-55) &\tabularnewline
& Difference between the results (2-1) & -0.00 & -0.06 &
0.004\tabularnewline
LDH (U/liter) & & & &\tabularnewline
& 1.measurement & 265.5 (20-1247) & 309 (140-556) &\tabularnewline
& 2.measurement & 242 (41-972) & 233.5 (37-566) &\tabularnewline
& Difference between the results (2-1) & -33 & -47.5 &
0.23\tabularnewline
Hgb & & & &\tabularnewline
& 1.measurement & 13.5 (4.8-17.5) & 13.3 (8.9-16) &\tabularnewline
& 2.measurement & 12.5 (4.2-20.5) & 12.4(8.5-16) &\tabularnewline
& Difference between the results (2-1) & -0.7 & -0.8 &
0.46\tabularnewline
Leukocyte count per mm3 & & & &\tabularnewline
& 1.measurement & 6.73 (0.4-39.3) & 7.16 (3.1-43) &\tabularnewline
& 2.measurement & 5.94 (1.8-21.6) & 6.81 (4.0-18.9) &\tabularnewline
& Difference between the results (2-1) & -0.69 & -0.5 &
0.44\tabularnewline
Neutrophil count per mm3 & & & &\tabularnewline
& 1.measurement & 4.36 (0.01-79) & 4.20 (0.9-40) &\tabularnewline
& 2.measurement & 3.57 (1.0-40.8) & 4.64 (2.3-17.91) &\tabularnewline
& Difference between the results (2-1) & -0.52 & -0.08 &
0.33\tabularnewline
Lymphocyte count per mm3 & & & &\tabularnewline
& 1.measurement & 1.50 (0.00-26.8) & 1.30 (0.5-3.80) &\tabularnewline
& 2.measurement & 1.40 (0.2-21.5) & 1.55 (0.4-3.5) &\tabularnewline
& Difference between the results (2-1) & -0.10 & 0.10 &
0.014\tabularnewline
Platelet count per mm3 & & & &\tabularnewline
& 1.measurement & 214.5 (9-768) & 232 (114-471) &\tabularnewline
& 2.measurement & 242 (4-698) & 309.5 (64-687) &\tabularnewline
& Difference between the results (2-1) & 14 & 69 & 0.009\tabularnewline
D-dimer (\selectlanguage{greek}µ\selectlanguage{english}g/dl) & & & &\tabularnewline
& 1.measurement & 0.68 (0.16-48.0) & 0.94 (0.19-7.1) &\tabularnewline
& 2.measurement & 0.76 (0.17-14.5) & 0.81 (0.17-35.2) &\tabularnewline
& Difference between the results (2-1) & -0.03 & 0.08 &
0.20\tabularnewline
Ferritin (ng/ml) & & & &\tabularnewline
& 1.measurement & 199.6 (3.9-15029) & 370 (65.9-2166) &\tabularnewline
& 2.measurement & 257 (3.3-80503) & 375.3 (23.5-1621) &\tabularnewline
& Difference between the results (2-1) & 25.7 & -8.1 &
0.021\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table-4 Average time of hospital follow-up, discharge rate and
rate of events of the groups}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& & Standard treatment & Standard treatment and QCB\tabularnewline
\midrule
\endhead
& & Median (min-max) & Median (min-max)\tabularnewline
Outcomes & & &\tabularnewline
Follow-up (days) & & 6 (2-57) & 8 (2-30)\tabularnewline
Discharge & & 371 (93.9) & 51 (98.1)\tabularnewline
Events & & &\tabularnewline
& Need for intensive care & 14 (3.5\%) & 0 (0)\tabularnewline
& Death in the ward & 10 (2.5\%) & 1 (1.9\%)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1.} Flow diagram of the study\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure-2:} Alterations in acute phase reactants and complete
blood count parameters during the follow-up\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

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

