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\begin{document}

\title{Febuxostat as an alternative therapy in COVID-19: A double-blind
randomized clinical trial}



\author[1]{Lotfollah Davoodi}%
\author[1]{Seyed Mohammad Abedi}%
\author[2]{Ebrahim Salehifar}%
\author[1]{Reza Alizadeh-Navai}%
\author[1]{Hamed Rouhanizadeh}%
\author[3]{Ghasemali Khorasani}%
\author[2]{Seyed Jalal Hosseinimehr}%
\affil[1]{Mazandaran University of Medical Sciences Faculty of Medicine}%
\affil[2]{Mazandaran University of Medical Sciences Faculty of Pharmacy}%
\affil[3]{Tehran University of Medical Sciences School of Medicine}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Aims: The aim of this double-blind randomized clinical trial was to
determine the effects of FBX in comparison with hydroxychloroquine (HCQ)
on clinical symptoms, laboratory tests and chest CT findings in patients
with COVID-19-causing moderate symptomatic disease. Methods: We
conducted a randomized, double blind clinical trial involving adult
outpatients' patients with COVID-19 infection, which causes the moderate
respiratory illness. Sixty patients were randomly assigned to receive
either FBX or HCQ for 5 days. The measured variables were clinical and
laboratory data including rate of fever, cough, berating rate,
C-Reactive Protein level, lymphocytes count at onset of admission and
was well as at 5 days of treatments. In addition, CT lesions were
evaluated on admission and 14 days of treatments in both groups.
Results: Fever, cough and tachypnea significantly mitigated in both
groups after five days of treatments. The lymphocytes count
significantly increased in both treatment groups and the CRP values were
dropped in normal range (negative) in major of patients receiving FBX or
HCQ treatment. It was not observed any significantly difference between
FBX and HCQ in frequency of these symptoms. The mean percentages of CT
abnormality scores were significantly reduced to 7.3\% and 8\% after 14
days of FBX and HCQ treatments, respectively. In adult outpatients with
moderate symptomatic Covid-19, the effectiveness of FBX was same to HCQ
in improvement of clinical manifestations, laboratory tests and CT
lesions. Conclusion: These findings suggest FBX as an alternative
treatment for Covid-19 infection in patients with contraindication or
precaution to HCQ.%
\end{abstract}%



\sloppy


\textbf{1.Introduction}

Coronavirus (Covid-19)--caused respiratory tract illness may result to
severe progressive pneumonia, multiorgan failure and death in critically
ill patients {[}1, 2{]}. There is no specific antiviral treatment
against covod-19 infection but some antiviral drugs have been used as
empirical {[}3{]}. The treatments are usually symptomatic and
supportive. Severe patients with coronavirus disease had lower
lymphocytes counts, higher leukocytes count and lower percentages of
monocytes, eosinophils, and basophils. Elevation in inflammatory
cytokines including IL-2R, IL-6, IL-8, IL-10, and TNF-\selectlanguage{greek}α. \selectlanguage{english}IL-6 and
dysregulation of immune system were observed {[}4{]}. The expression
levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum were
associated with severity of coronavirus diseases when were analyzed
among critical, severe and mild groups. s {[}5{]}. In addition, virus
infection causes NF-kB over expression that has a central role in
massive overproduction of pro-inflammatory cytokines as well as
triggering a variety of cellular responses, including cell phagocytosis,
maturation of dendritic cells, and chemotaxis of cells {[}6{]}. The
uncontrolled inflammatory response may result in pulmonary tissue
damage, functional impairment, and reduced lung capacity. Hence,
scientists believe that an excessive production of IL-6 is acted as a
key role of chronic inflammation and is associated with severe lung
damage observed with COVID-19 infections and acute respiratory illness.
In this way, ACTEMRA\selectlanguage{ngerman}® (tocilizumab) as an anti-IL-6R MAb binds to both
the membrane-bound and soluble forms of IL-6R and rapidly depletes
circulating levels of IL-6 in the blood. It is a FDA-approved
anti-interleukin (IL)-6 receptor therapy for rheumatoid arthritis
{[}7{]}. Febuxostat (FBX) is a novel non-purine xanthine oxidase
(XO)-specific inhibitor that is used for treating hyperuricemia in
patients with gout. FBX by inhibiting oxidation, reduces the
inflammation stress {[}8{]}. Several studies have already demonstrated
the anti-inflammatory {[}9{]}, anti-oxidant {[}10{]} and anti-apoptosis
effects of FBX {[}11{]}. Several preclinical studies showed that FBX
therapy can remarkably inhibit inflammatory responses through reducing
the levels of pro-inflammatory cytokines such as tumor necrosis factor
(TNF)-\selectlanguage{greek}α, \selectlanguage{english}interleukin (IL)-1\selectlanguage{greek}β, \selectlanguage{english}IL-6 as well as decreasing the nuclear
factor kappa B (NF-\selectlanguage{greek}κ\selectlanguage{english}B) as a key regulator of inflammation {[}12-14{]}.
Several studies have shown FBX markedly protects animal against
toxic-induced lung inflammation through downstream inflammatory
mediators and oxidative stress {[}15-17{]}. FBX markedly accelerates
pulmonary endothelial barrier recovery and improves survival in
lipopolysaccharide-induced murine sepsis {[}18{]}. This double-blind
randomized clinical trial was conducted to assess the effects of FBX and
hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and
chest CT findings of patients with COVID-19 infection.

\textbf{2.Material}

2.1.Study Design

A randomized, double-blind clinical trial, recruited patients from March
16, 2020, to April 10, 2020, at Mostafavian Fever Clinic in Sari (Iran).
Sixty patients who had inclusion criteria entered into the study after
the goals of the study were explained to them. This study was approved
by the Ethical and Research Committee of Mazandaran University of
Medical Sciences (ID\#7294) and was registered with Ethical number as
IR.MAZUMS.REC.1398.7294. This study was submitted and approved by the
Iranian Registry of Clinical Trials with the IRCT number:
IRCT2019072704434N1 (the full trial protocol can be accessed at:
http://www.irct.ir). The study was performed in accordance with
declaration of Helsinki. All patients signed the informed consent form.
The study was a randomized double-blind clinical trial. Patients were
randomized using the balance block method. Boxes were numbered (1 to 60)
and divided into two groups; HCQ (30 patients) and FBX (30 patients).
HCQ subjects were taken one tablet of HCQ 200 mg twice daily (Amin
Pharmaceutical Company, Iran) and the FBX group received one tablet of
FBX 80 mg per day (Jalinus Pharmaceutical Company, Iran). The treatment
duration was five days. Both patients and physician did not know the
contents of tables. All patients were taken acetaminophen 325 mg, as
needed, for controlling the fever. Sample size were determined 30
patients in both group based on p1=0.9, p2=0.6, a=0.05 and b=0.2 by
related sample size formula.

2.2.Inclusion Criteria

The inclusions criteria include: 1; CT scan suggestive of lung's
parenchymal involvement, 2; any symptoms of respiratory tract
involvement include cough, dyspnea or tachypnea and history of COVID-19
patients contacting 3; Creatinine clearance greater than 60 ml/min.

2.3.Exclusion Criteria

Suspicious patients for COVID-19 pneumonia, who had severe underlying
diseases such as cardiovascular, lung and kidney diseases, sever
pneumonia that needs hospitalization, unable to taken oral medication
and patients using azathioprine, didanosine, mercaptopurine or
pegloticase (due to drug interaction with FBX) exclude from the study.

2.4.Outcome measures

Patients were assessed for temperature, number of breathing per minute,
cough, dyspnea, CRP, WBC and lymphocyte counts at onset of admission and
5\textsuperscript{th} day of treatment. In addition, the lung CT scans
were evaluated at first and 14 days after the onset of treatment.

2.5.Statistical analysis

Normality of data was checked with Shapiro-Wilk~Test. Independent sample
t-test and Mann-Whitney U test (comparison of continuous variables
between two groups), Wilcoxon matched-pair signed-rank test (comparison
of continuous variables before and after treatment), and
Chi\textsuperscript{2} test (comparing the qualitative data) were used
for analysis. The method of analysis was intention-to-treat. The SPSS
software version 21.0 (SPSS, Inc., Chicago, IL) was applied for
statistical analysis.

\textbf{3.Results}

\textbf{3.1.Patients}

A total of sixty subjects were enrolled in this study including FBX
group (N = 30) and HCQ group (N = 30) (Figure 1). Six patients
(1patients in FBX group and 5 patients in HCQ group) were excluded,
because patients had indisposition in this study after 1 day or did not
interest in follow-up (Figure 1). Six patients were hospitalized with
presented features in in the next result subtitle. Table 1 shows
baseline demographic and clinical characteristics of the 54 patients who
enrolled in this study. The mean age of patients was 57.7 \selectlanguage{ngerman}± 8.4 years,
and 59\% of the patients were men. Among these patients, the most common
symptom was fever, followed by cough and shortness of breath. On
admission, fever as temperature \selectlanguage{english}[?]37.8 (66.7\%), cough (87\%), higher
breathing rate \textgreater{} 20 (44.4\%), dyspnea (35\%), positive CRP
(94.4\%), lung injury with CT involvement (100\%) were found in enrolled
patients. The WBC counts were 4578 +- 1539. On admission, lymphopenia
(lymphocytes count \textless{}1500/microL) was found in 44(81.5\%) of
patients. On admission, most patients had a mild to moderate pneumonia
as documented by clinical manifestations and CT findings. There were not
between-group differences in demographic characteristics baseline
laboratory test results (e.g., CRP, WBC and lymphocytes counts) and CT
scores for lung lesions (Table 1).

\textbf{3.2.Primary outcome}

Patients were re-evaluated at five days after admission, when they took
FBX or HCQ, as ordered. The sign/symptoms of fever, cough and higher
breathing rate significantly mitigated in patients treated with FBX or
HCQ (Table 2) after five days of treatment in both groups (\emph{P}
\textless{}0.01). It was not observed any significantly difference
between FBX and HCQ in frequency of these symptoms. The lymphocytes
count significantly increased in both treatment groups after 5 days. The
mean lymphocytes counts were 1308 +- 617 and 1258 +- 498 for FBX and HCQ
groups at first days of admission whereas they were increased to 1962 +-
478 and 1911 +- 798 after 5 days with FBX and HCQ treatments,
respectively. No significant differences were observed between FEB and
HCQ in lymphocytes counts. The CRP values were dropped in normal range
(negative) in most of patients after receiving FBX or HCQ treatment. FBX
and HCQ treatments showed insignificant difference in the percentages of
negative CRP values after 5 days after treatments.

\textbf{3.3.Secondary outcome}

As all patients infected with COVID-19 had chest CT abnormality,
symptoms or changes on chest CT scans was monitored for COVID-19
progression or mitigation. The lung injuries were evaluated after 14
days of first admission in patients. The CT abnormalities were 16\% and
19.2\% in FBX and HCQ groups at first of admission, while these scores
significantly reduced to 7.3\% and 8\% after 14 days, respectively, in
which efficacies of reduction were 47.4\% and 58.3\% as compared to
first admission (\emph{P} = 0.004 and \textless{}0.001, respectively).

\textbf{3.4.Hospitalization and mortality}

Six patients (11\%) were hospitalized because of increased symptoms (3
patients in FBX group and 3 patients in HCQ group). The hospitalization
rates of patients were nearly the same in both groups. These patients
were taken 2-5 days of FBX or HCQ treatments. All of hospitalized
patients were released from hospitals between 1 to 7 days of
hospitalization. It was not observed any mortality and no patients
needed to admit in intensive care unit (ICU).

\textbf{4.Discussion}

This randomized clinical trial found that FBX treatment showed equal
effectiveness with HCQ in improvement of clinical manifestations and
para-clinical abnormalities after 5 days' administration in outpatients
with COVID-19. It is notable that none of patients took antiviral
medicine in this study, whereas patients received only FBX or HCQ in
combination with acetaminophen (as needed order for fever). Six patients
including 3 out of 29 (10\%) patients in FBX group and 3 out of 25
(12\%) patients in HCQ were admitted to hospital because of progressing
symptoms, but none needed ICU admission, a totally 11\% of study
patients needed to be hospitalized. In China, 15-20\% of cases required
hospitalization, with around 15\% severe and 5\% requiring ICU {[}19{]}.
In Italy, approximately 40\% of patients have been hospitalized, whereas
nearly 7\% admitted to ICU {[}20{]}. There is significant variation in
the rate of hospitalization of patients with COVID-19 in the world.
However, sample size of our clinical trial was smaller than these
studies, in addition patients with significant comorbidities such as
sever cardiovascular and renal diseases were excluded in our clinical
trial. Clinical symptoms such as fever, cough and shortness of breath
were observed in a large proportion of patients at admission, but these
manifestations markedly reduced or resolved (e.g., fever and dyspnea)
after 5 days of using FBX or HCQ. It was not observed any statistically
difference in mitigating of clinical symptoms between FBX and HCQ
treatments. In a systematic review included 656 patients (from 58
articles), fever (88.7\%), cough (57.6\%) and dyspnea (45.6\%) were the
most prevalent manifestations {[}21{]}.

Blood lymphocyte count has shown one of the most significant and
consistent trend, suggesting that this indicator might reflect the
disease progression, and lymphopenia is a predictor of prognosis in
COVID-19 patients {[}22{]}. Lymphopenia (lymphocytes \textless{} 1500
per mm\textsuperscript{3}) is the most common lab finding in COVID-19
and is found in as many as 80\% of the nonsevere patients on admission.
Most of the patients had elevated levels of CRP (56\%). Patients with
severe disease had more prominent laboratory abnormalities (including
lymphopenia and elevated CRP) than those with nonsevere disease
{[}23{]}. Lymphopenia was observed in 81.5\% of patients {[}FBX (79.3\%)
and HCQ (84\%), P=0.66{]} at onset of admission, while lymphocyte counts
significantly increased after 5 days of treatments to normal range, and
lymphopenia was observed on 28.6\% and 30.4\% of patients in FBX and HCQ
treatment after 5 days, respectively (\emph{P} \textless{} 0.002). It is
shown that both treatments significantly improved lymphocyte counts
during 5 days of treatments. At 5 days of treatment, the mean of
lymphocyte count in FBX was greater than HCQ; however, it was
statistically non-significant (\emph{P} = 0.88). Elevated CRP as
positive CRP was observed in 96.6\% patients {[}FBX (96.6\%) and HCQ
(92\%), \emph{P} = 0.47{]} at onset of admission, while FBX and HCQ
significantly reduced after 5 days of treatment to negative range to
50\% (\emph{P} \textless{} 0.001) and to 40\% (P=0.03) of patients,
respectively; however, there was no statistically significant difference
between two group in CRP's response to treatment after 5 days (\emph{P}=
0.49).

Chest CT images from patients with COVID-19 typically demonstrate
bilateral, peripheral ground glass opacities. In China report, of 975 CT
scans that were performed at the time of admission, 86.2\% revealed
abnormal results {[}23{]}. In our study, diagnosis was based on clinical
symptoms, laboratory findings, history of COVID-19 patients contacting
and lung CT abnormalities consistent with coronavirus pneumonia at early
phase. Due to a high sensitivity of lung CT in detecting lung
involvement and also the importance of initiating the treatment as soon
as possible, we included patients who were COVID-19 infection. The real
time Reverse Transcription Polymerase Chain Reaction~(rRT-PCR) were not
performed due to some limitation in our study. We believe that this
limitation would not affect the validity of our results. High
sensitivity of lung CT in diagnosis of COVID-19 infection was frequently
reported in previous studies. For instance, Long \emph{et al,} reported
97.2\% sensitivity for CT whereas the sensitivity of initial rRT-PCR was
only 83.3\% and rRT-PCR may produce initial false negative results. Only
one patient was observed with positive rRT-PCR but negative CT.
Considering that the results of rRT-PCR may be false-negative, and the
relatively long assay time, they suggested that patients with typical CT
findings but negative rRT-PCR results should be isolated and rRT-PCR
repeated to avoid misdiagnosis {[}24{]}. In our study, at admission all
patients showed chest CT abnormalities (100\%), while FBX or HCQ
treatments significantly cleared CT abnormalities in 31\% and 32\% of
patients after 14 days of treatments, respectively. All data show that
FBX is affective as HCQ in improvement of clinical symptoms and also
laboratory and radiographic abnormalities in outpatients with COVI-19.
No FDA-approved drug has demonstrated safety and efficacy in randomized
controlled trials for patients with COVID-19. Multiple drugs
with\emph{in vitro} antiviral activity against SARS-CoV-2 and/or
immunomodulatory effects that have been suggested to be clinically
beneficial. In our protocol, HCQ is prescribed in combination with
acetaminophen for controlling fever. However, antiviral drug is
sometimes added to this medicine protocol, there is challenge the
effectiveness of available anti-viral medicine for management of
Covid-19, then infectious specialist medical doctor has not prescribed
antiviral medicine to patients in this study. Recent publication showed
the \emph{in vitro} activity of chloroquine (CQ) as known antimalarial
drug against SARS-CoV-2. CQ effectively blocked virus infection at low
micromolar concentration and showed high selectivity index. Several
mechanism actions are suggested for CQ are including a widely-used
anti-malarial and autoimmune disease drug as well as anti-viral drug. CQ
is known to block virus infection by increasing endosomal pH required
for virus/cell fusion, as well as interfering with the glycosylation of
cellular receptors of SARS-CoV-2 {[}25{]}. Several clinical studies were
conducted in Chinese hospitals for use of CQ or HCQ in treatment of
SARS-CoV-2-caused pneumonia. The first results obtained from more than
100 patients showed the superiority of CQ compared with treatment of the
control group in terms of reduction of exacerbation of pneumonia,
duration of symptoms and delay of viral clearance, without severe side
effects. This has led in China to include CQ in the recommendations
regarding the prevention and treatment of COVID-19 pneumonia. The
anti-viral and anti-inflammatory activities of CQ may account for its
efficacy in treating patients with COVID-19 pneumonia {[}26-28{]}. HCQ,
as similar to CQ, increases the pH and confers anti-viral effects. As
compared to CQ, HCQ has fewer side effects, better safety profile and
less drug interactions {[}29{]}. A study has demonstrated that HCQ is
more potent than CQ in inhibiting SARS-CoV-2 \emph{in vitro} {[}30{]}.
Gautret, \emph{et al} , were the first to report promising \emph{in
vivo}data of HCQ in a non-randomized clinical trial in France. A total
of 20 patients received HCQ and 16 were control patients who were
analyzed. They used 200 mg of HCQ three times a day for 10 days, plus
azithromycin (AZM) if deemed necessary. A higher frequency of SARS-CoV-2
clearance was noticed after 6 days of treatment with HCQ alone or
HCQ+AZM versus the untreated control group (70\% vs 12.5\%;
P\textless{}0.001). In this study, PCR results in nasopharyngeal samples
and clearing viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19
patients were evaluated. None clinical symptoms, laboratory tests and
lung CT features were reported in both groups of patients. Some
limitations of this study were a small sample size and limited long-term
outcome follow-up {[}31{]}. In other study, Gautret, \emph{et al}
studied an uncontrolled non-comparative observational study in a cohort
of 80 relatively mildly infected inpatients treated with a combination
of HCQ and AZT over a period of at least three days. Patients were
prescribed a combination of 200\selectlanguage{english} mg of oral HCQ sulfate, three times per
day for ten days combined with AZT. A rapid fall of nasopharyngeal viral
load tested by qPCR was noted, with 83\% negative at Day7, and 93\% at
Day8. The number of patients presumably contagious (with a PCR Ct
value\selectlanguage{english} \textless{}\selectlanguage{english} 34) steadily decreased overtime and reached zero on
Day 12. A marked decrease was observed after six days of treatment. Only
15\% required oxygen therapy during their stay in out infectious disease
(ID) ward. Authors claimed that for all other patients in this cohort of
80 people, the combination of HCQ and AZT resulted in a clinical
improvement that appeared superior when compared to outcomes of other
hospitalized patients, as described in the literature. Authors concluded
that they have provided evidence of a beneficial effect of
co-administration of HCQ with AZT in the treatment of COVID-19 and its
potential effectiveness in the early reduction of contagiousness
{[}32{]}. On March 2020, medRxiv.org published data of the first
completed randomized clinical trial in Wuhan investigating the efficacy
of HCQ in patients with COVID-19. Sixty patients were randomized equally
into two groups. The treatment group received oral HCQ 400mg/d (200
mg/bid) from day 1 to 5. Their article is currently under revision. The
body temperature recovery time and the cough remission time were
significantly shorter in the HCQ treatment group. Besides, a larger
proportion of patients with improved pneumonia were in the HCQ treatment
group (80.6\%, 25 of 31) compared with the control group (54.8\%, 17 of
31). Notably, all four patients progressed to severe illness occurred in
the control group. There were two patients with mild adverse reactions
in the HCQ treatment group. Among patients with COVID-19, the use of HCQ
could significantly shorten time to clinical recovery (TTCR) and promote
the absorption of pneumonia {[}33, 34{]}. To date, despite some
promising results associated to efficacy and safety of HCQ in COVID-19,
the evidence regarding its effect remains limited {[}35{]}. Infrequent
and rare side effects include retinal toxicity, cardiac toxicity, QT
interval prolongation and agranulocytosis have been observed with HCQ
and CQ in patients. Life threatening arrhythmias associated with CQ and
HCQ appear to be rare but if these drugs were to be used much more
extensively then caution and appropriate monitoring are necessary {[}36,
37{]}. Patients and their physicians prescribing HCQ need to be keenly
aware of retinal toxicity risks and the importance of regular screening,
and ophthalmologists who see these patients should keep retinal toxicity
in the front of their minds {[}38-40{]}. However, chronic use of HCQ can
result in an acquired lysosomal storage disorder, leading to a
drug-induced cardiomyopathy characterized by concentric hypertrophy and
conduction abnormalities associated with increased adverse clinical
outcomes and mortality {[}41{]}. Considering the short time use of HCQ,
these side effects are probably no critical in patients with COVID-19.

In addition, HCQ has immunomodulatory and anti-inflammatory effects
{[}42-44{]}, which may be beneficial in patients with Covid-19 who
inflammatory response and storm cytokine production make damaged lung
worse. HCQ interfere with lysosomal activity and autophagy, interact
with membrane stability and alter signaling pathways and transcriptional
activity, which can result in inhibition of cytokine production and
modulation of certain co-stimulatory molecules {[}43{]}. The NF-\selectlanguage{greek}κ\selectlanguage{english}B
transcription factor has emerged as the central regulator of
inflammatory processes. It achieves this status through numerous
important pro-inflammatory factors under its transcriptional control.
NF-\selectlanguage{greek}κ\selectlanguage{english}B plays a central role in inflammatory diseases such as rheumatoid
arthritis, inflammatory bowel disease, and autoimmunity. NF-\selectlanguage{greek}κ\selectlanguage{english}B is
activated through microbial products and pro-inflammatory cytokines, as
well as endogenous ligands that function as its trigger during tissue
injury, the latter of which may promote inflammation in the absence of
infection {[}45-47{]}. In addition, viral infections cause NF-\selectlanguage{greek}κ\selectlanguage{english}B
overexpression, which plays a crucial role in the production of
pro-inflammatory cytokine storms and triggers various cellular
responses, including cell phagocytosis, dendritic cell maturation, and
chemotaxis {[}6{]}. NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling is also a key regulator of
lipopolysaccharide-induced pulmonary inflammation {[}48, 49{]}. There is
strong crosstalk between NF-\selectlanguage{greek}κ\selectlanguage{english}B and cytokine activation and production,
in which cytokines and pro-inflammatory mediators activate NF-\selectlanguage{greek}κ\selectlanguage{english}B, and
NF-\selectlanguage{greek}κ\selectlanguage{english}B also activates cytokine production. This cycle can enter an
uncontrolled, positive feedback loop, resulting in the production of a
cytokine storm. It is suggested that downregulation of NF-\selectlanguage{greek}κ\selectlanguage{english}B results in
the attenuation of inflammatory cytokine signaling. In addition, several
pre-clinical studies have demonstrated the beneficial effects of
NF-\selectlanguage{greek}κ\selectlanguage{english}B-targeting inhibitors in the prevention and treatment of lung
inflammation induced by toxic agents in preclinical models {[}49-55{]}.
HCQ inhibits IL-6, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β \selectlanguage{english}and NF-\selectlanguage{greek}κ\selectlanguage{english}B {[}44, 56-58{]}, also it
inhibits the activation of NF-\selectlanguage{greek}κ\selectlanguage{english}B in the lung of bleomycin-treated rats
{[}59{]}. HCQ prevents the TNF-alpha-induced translocation of NF-kB p65
into the nucleus and the phosphorylation of the p65 subunit. HCQ
administration also suppresses TNF-alpha induced lung injury in mice by
reducing neutrophil infiltration in pulmonary interstitial tissue
{[}60{]}. It seems that downregulation of NF-\selectlanguage{greek}κ\selectlanguage{english}B results in the
attenuation of inflammatory cytokine signaling and may be a promising
target for lung protection {[}61{]}. FBX is in a class of medications
called xanthine oxidase (OX) inhibitors leading to decrease in uric acid
production. Beside decreasing serum uric acid in gout by FBX, there are
well documents that FBX suppresses pro-inflammatory cytokines such as
IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6 MCP-1 and TNF-\selectlanguage{greek}α \selectlanguage{english}as well as inhibits the oxidative stress and
inflammatory responses through NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway in animal models {[}12, 14,
62, 63{]}. FBX is able to improve lung damage induced by toxic agents
through down-regulation of oxidative stress pathway and suppression of
inflammatory mediators {[}10, 18, 64{]}. In addition, FBX ameliorates
histopathological changes in lung tissue {[}65{]}. There is not any
report associated to anti-viral activity of FBX. Xanthine oxidase, which
is responsible for the generation of oxygen free radicals, was elevated
in serum and lung tissue of mice infected with influenza virus
{[}66-68{]}. Due to the crucial roles of cytokines and pro-inflammatory
mediators in severe acute respiratory syndrome induced by coronavirus 2
(SARS-CoV-2), with respect to beneficial effects of FBX in blockading
the activation of cytokines and NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway, this medicine seems an
effective drug for the prevention and treatment of lung inflammation in
patients with COVID-19 in same efficacy with HCQ. However, future
studies are needed to find exact mechanism of FBX in treatment of
COVID-19 infection. The adverse effects associated with FBX therapy
include nausea, diarrhea, arthralgia, headache, increased hepatic serum
enzyme levels, rash and heart-related problems. These side effects were
not observed in this study, which may be due to short time consuming of
FBX, also we excluded patients with cardiovascular and chronic kidney
diseases. The limitation of our study was the absence of placebo group.
Considering ethical issues, we designed this study without a placebo
group due to the life-threatening nature of COVID-19 infection.

\textbf{5.Conclusion}

We have provided evidence of a beneficial effect of administration of
FBX as the same efficacy with HCQ in the treatment of COVID-19. Based on
this study, FBX is effective in the reduction of clinical symptoms,
modifying laboratory tests and chest CT abnormalities in COVID-19
outpatients. Given the urgent manage of outpatients and reducing
entrance of sever patients to hospital, it is necessary to manage this
disease with effective, safe, low cost drugs such as FBX.
Immunemodulatory and anti-inflammatory effects of FBX may be involved in
mitigating the initiating of cytokines storm which results to prevent
severe acute respiratory disease in patients with COVID-19.

\textbf{Acknowledgments}

This study was supported by a grant from Mazandaran University of
Medical Science, Sari, Iran (ID\#7294). We thank all patients who
participated in this trial and their families. We thank Adel Heidari for
assistance in this project. We appreciated the health care personals who
have given their lives in the care of patients with Covid-19.

\textbf{DATA AVAILABILITY STATEMENT}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{Conflict of interest statement}

The authors declare no potential conflicts of interest with respect to
authorship, and/or publication of this study.

\textbf{Contributors}

L.D. and S.J.H. were involved in the conception of the study and
obtaining funding. L.D., S.M.A., E.S, R.A, H.R, G.K and S.J.H
contributed to the study and intervention designs. L.D., S.M.A., E.S.
and S.H.J. contributed to the data collection. E.S and S.J.H.
contributed to data analysis. All authors contributed to drafting and
revising manuscript.

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\textbf{Figure 1:} CONSORT diagram, including the number of patients who
started and continued trial treatment, and stopped.

\textbf{Table 1.} Demographic and clinical characteristics of the
patients at Baseline\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Characteristic}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Total (N = 54 )}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Febuxostat (N = 29)}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Hydroxychloroquine (N =25 )}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (Mean \selectlanguage{ngerman}± SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
57.7 \selectlanguage{ngerman}± 8.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 \selectlanguage{ngerman}± 7.3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
57.3 \selectlanguage{ngerman}± 9.7\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.47\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male sex; no (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (59.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (55.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (64)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.51\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Current smoking; no. (\%)\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
1 (3.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.35\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Coexisting conditions Diabetes; no. (\%) Lung disease; no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (27.8) 1 (1.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (27.6) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (28) 1 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.97 0.28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Fever (T\textgreater{} 37.8 \selectlanguage{ngerman}°C)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36 (66.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (55.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.054\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Body temperature; \selectlanguage{ngerman}°C Mean\\
SD\\
Median\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
37.7 0.48 38\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
37.6 0.48 37.9\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
37.9 0.46 38\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Respiratory rate Mean\\
SD\\
Median\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
19.7 1.8 19\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
19.8 1.7 19.5\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
19.6 1.9 19\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.57\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Respiratory rate [?]20/min; no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (44.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.47\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cough; no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47 (87\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (93.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (80)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.15\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Dyspnea; no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19 (35.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (35)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9 (36)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
White Blood Cell count Mean\\
SD\\
median\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
4578 1539 4100\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
4689 1729 4300\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
4444 1299 4050\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.57\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Lymphocyte count Mean\\
SD\\
median\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1285 561 1195\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1308 617 1196\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1258 498 1194\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.75\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Lymphopenia (\textless{} 1500 /microL)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44 (81.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (79.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (84)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.66\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CRP (positive); no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51 (94.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
28 (96.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (92)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.47\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Lung CT (\%involvement) mean\\
SD\\
median\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
17.5 9.9 17.5\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
16 6.5 20\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
19.2 12.8 15\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.72\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Outcomes in the febuxostat and hydroxychloroquine
treatments\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Characteristic}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Febuxostat} \textbf{(N = 29)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Febuxostat} \textbf{(N = 29)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Febuxostat} \textbf{(N = 29)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Hydroxychloroquine} \textbf{(N = 25 )}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Hydroxychloroquine} \textbf{(N = 25 )}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Hydroxychloroquine} \textbf{(N = 25 )}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{P-value} \textbf{(between groups; Day 1)}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{P-value} \textbf{(between groups; Day 5)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Day 1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Day 5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
P-value (within group)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Day 1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Day 5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
P-value (within group)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Fever (T\textgreater{} 37.8 \selectlanguage{ngerman}°C); n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
16 (55.2)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\selectlanguage{greek}\textsuperscript{ζ}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
20 (80)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\selectlanguage{greek}\textsuperscript{ζ}\selectlanguage{english}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.054\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
NA\selectlanguage{greek}\textsuperscript{ζ}\selectlanguage{english}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Body temperature; \selectlanguage{ngerman}°C Mean\\
SD\\
Median\\
Range\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
37.6 0.48 37.9 37-38.2\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
37.1 0.27 37 36.8-37.7\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
37.9 0.46 38 37-39\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
37 0.23 37 36.7-37.7\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Respiratory rate; Mean\\
SD\\
Median\\
Range\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
19.8 1.7 19 18-22\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
17.3 2.6 16 16-26\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
19.5 1.85 19 18-24\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
17.4 2.4 16 16-24\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.57\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.88\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Respiratory rate [?]20/min; no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2 (6.9)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.04\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.47\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Cough; n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
27 (93.1)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
13 (44.8)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
20(80)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (43.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.008\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.15\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.92\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Dyspnea; n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
10 (34.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (10.7)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.07\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9 (36)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 (17.4)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.06\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.49\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
White-cell count; mean \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4689 \selectlanguage{ngerman}± 1729\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6111 \selectlanguage{ngerman}± 1511\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4444\selectlanguage{ngerman}± 1299\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6130 \selectlanguage{ngerman}± 1421\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.57\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.96\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Lymphocyte count; mean \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1308 \selectlanguage{ngerman}± 617\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1962 \selectlanguage{ngerman}± 748\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1258 \selectlanguage{ngerman}± 498\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1911 \selectlanguage{ngerman}± 798\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.002\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.75\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.82\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Lymphopenia (\textless{} 1500/microL) Positive; n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
23 (79.3)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 (28.6)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
21 (84)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7 (30.4)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.66\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.88\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
CRP positive; n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
28 (96.6)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
14 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
23 (92)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
12 (60)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.03\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.47\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.49\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Lung CT (\% involvement); Mean\\
SD\\
Median\\
Range\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
16 6.5 20 5-25\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
7.3 11.7 5 0-50\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.004\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
19.2 12.8 15 5-50\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
8 11.8 5 0-50\textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\textless{} 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.72\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.89\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Reduced lung CT involvement; not adjusted\textsuperscript{\&}; Mean\\
SD\\
Median\\
Range\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 8.4 13 -10 -25 to + 30 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 8.4 13 -10 -25 to + 30 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 8.4 13 -10 -25 to + 30 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 10.8 11.4 -10 -45 to + 10 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 10.8 11.4 -10 -45 to + 10 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
- 10.8 11.4 -10 -45 to + 10 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.86\textsuperscript{\#}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
0.86\textsuperscript{\#}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Reduced lung CT involvement; adjusted\textsuperscript{\&}; Mean\\
SD\\
Median\\
Range\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
47.4 91 80 -200 to +100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
47.4 91 80 -200 to +100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
47.4 91 80 -200 to +100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
58.3 67 80 -200 to + 100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
58.3 67 80 -200 to + 100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
58.3 67 80 -200 to + 100 \textsuperscript{\&}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
1\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
CT day14 involvement, Negative; n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9 (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9 (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
9 (31)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.94\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.94\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hospitalization no. (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (10.3)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (10.3)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (10.3)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.81\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.81\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\&: indicate the Lung CT data on day 14; P-value indicates the
difference of CT changes, Day 14 compared to Day 1, for both row data
and adjusted percent changes; NA\selectlanguage{greek}\textsuperscript{ζ}: \selectlanguage{english}not applicable

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

