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\begin{document}

\title{Synbiotic for prevention of SARS-Cov2 infection in high risk hospital
staffs: A randomized controlled trial}



\author[1]{hamid ahanchian}%
\author[2]{Alireza ranjbar}%
\author[1]{Hamidreza Reihani}%
\author[1]{Arash Peyvandi}%
\author[1]{Seyedali Jafari}%
\author[1]{Moahammadali Kiani}%
\author[1]{Rana  Tafrishi}%
\author[1]{Nasrinsadat Motevalihaghi}%
\author[1]{Ali Kakshour}%
\author[1]{Nasrin Moazzen}%
\author[1]{Zahra  Abbasi Shaye}%
\author[1]{Sadegh Ebrahimi}%
\author[1]{Hamidreza Kianifar}%
\affil[1]{Mashhad University of Medical Sciences}%
\affil[2]{Institute for interventional Allergology and Immunology}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Introduction: COVID-19 pandemic caused by the novel coronavirus
SARS-CoV-2 increasingly involves people worldwide. Probiotics can
improve immune system functions via different mechanisms. We proposed
that Synbiotic Lactocare\selectlanguage{ngerman}® may also reduce SARS-Cov2 infection in high
risk medical staff working in COVID-19 hospital wards. Method: In a
randomized, controlled trial, 60 hospital staff without any history of
clinical or laboratory evidence of SARS-Cov2 infection were received
either once daily oral synbiotic capsule (Lactocare®) that contains 1
billion CFU/Cap of L. (Lactobacillus) casei, L. rhamnosus, Streptococcus
thermophilus, Bifidobacterium breve, L. acidophilus, Bifidobacterium
infantis, L. bulgaricus, and Fructooligosacharide (Zist Takhmir, Tehran,
Iran) or placebo with the same appearance for 30 days. They were
followed for two months. Result: During the two month period of this
study, SARS-COV-2 RT-PCR test results were positive in three
participants (9.67\%) in placebo group compared to zero positive test in
synbiotic group. The differences were not statistically significant (p=
0.238). During the study, two persons (7 \%) of placebo group had
respiratory complaint such as cough, rhinorrhea and/or dyspnea, compared
with one in synbiotic group (p= 0.492). Conclusion: This study showed
that overall frequency of SARS-COC2 infection in participants receiving
synbiotic and those receiving placebo did not differ significantly.
However, 3 hospital staff in placebo group compared to no one in
synbiotic group had SARS-COV2 infection. Further studies with greater
power and alternative probiotic strains and mixture are warranted to
determine whether Synbiotic can prevent COVID-19 in at-risk hospital
staff. Keywords: COVID-19, Synbiotic, prevention, Lactocare, SARS-Cov2%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


Synbiotic for prevention of SARS-Cov2 infection in high risk hospital
staffs: A randomized controlled trial

\textbf{Authors:}

\textbf{Hamid Ahanchian} \textsuperscript{1, \textbf{2}} \textbf{,
Alireza Ranjbar\textsuperscript{3}, Hamidreza
Reihani\textsuperscript{4}, Arash Peyvandi\textsuperscript{5},}

\textbf{Seyed Ali Jafari\textsuperscript{6}, Mohammad Ali
Kiani\textsuperscript{6}, Rana Tafrishi\textsuperscript{6}, Nasrinsadat
Motevalli Haghi\textsuperscript{2}}

\textbf{Nasrin Moazzen\textsuperscript{2}, Ali
Khalshour\textsuperscript{6}, Zahra Abbasi Shaye\textsuperscript{6},
Sadegh Ebrahimi\textsuperscript{4}, Hamidreza
Kianifar\textsuperscript{2}}

\begin{enumerate}
\tightlist
\item
  Child Health Research Centre, University of Queensland, South
  Brisbane, Australia
\item
  Allergy Research Center, Faculty of Medicine, Mashhad University of
  Medical Sciences, Mashhad, Iran
\item
  Institute for Interventional Allergology and Immunology ,
  Cologne/Bonn, Germany
\item
  Department of Emergency Medicine, Faculty of Medicine, Mashhad
  University of Medical Sciences, Mashhad, Iran
\item
  Lung Disease Research Center, Faculty of Medicine, Mashhad University
  of Medical Sciences, Mashhad, Iran
\item
  Department of Pediatrics, Faculty of Medicine, Mashhad University of
  Medical Sciences, Mashhad, Iran
\end{enumerate}

Correspondence to:

Hamidreza Reyhani, MD. Department of Emergency Medicine, Imamreza
Hospital, Bahar Avenue, Mashhad, Iran Reihanihr@mums.ac.ir

\textbf{Abstract} :

\textbf{Introduction:} COVID-19 pandemic caused by the novel coronavirus
SARS-CoV-2 increasingly involves people worldwide. Probiotics can
improve immune system functions via different mechanisms. We proposed
that Synbiotic Lactocare\selectlanguage{ngerman}® may also reduce SARS-Cov2 infection in high
risk medical staff working in COVID-19 hospital wards.

\textbf{Method:} In a randomized, controlled trial, 60 hospital staff
without any history of clinical or laboratory evidence of SARS-Cov2
infection were received either once daily oral synbiotic capsule
(Lactocare®) that contains 1 billion CFU/Cap of L. (Lactobacillus)
casei, L. rhamnosus, Streptococcus thermophilus, Bifidobacterium breve,
L. acidophilus, Bifidobacterium infantis, L. bulgaricus, and
Fructooligosacharide (Zist Takhmir, Tehran, Iran) or placebo with the
same appearance for 30 days. They were followed for two months.

\textbf{Result:} During the two month period of this study, SARS-COV-2
RT-PCR test results were positive in three participants (9.67\%) in
placebo group compared to zero positive test in synbiotic group. The
differences were not statistically significant (p= 0.238). During the
study, two persons (7 \%) of placebo group had respiratory complaint
such as cough, rhinorrhea and/or dyspnea, compared with one in synbiotic
group (p= 0.492).

\textbf{Conclusion:} This study showed that overall frequency of
SARS-COC2 infection in participants receiving synbiotic and those
receiving placebo did not differ significantly. However, 3 hospital
staff in placebo group compared to no one in synbiotic group had
SARS-COV2 infection. Further studies with greater power and alternative
probiotic strains and mixture are warranted to determine whether
Synbiotic can prevent COVID-19 in at-risk hospital staff.

Keywords: COVID-19, synbiotic, prevention, Lactocare, SARS-Cov2

\textbf{Introduction:}

COVID-19 pandemic caused by the novel coronavirus severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly
affecting people worldwide. To date, there is no established prevention
or treatment protocol for this new virus. Millions of people suffer from
COVID 19 despite social distancing, hand hygiene, healthy diet, and life
style and mask wearing. Although several brands of vaccines with
different efficacy have been approved and vaccination started in some
countries, , It won't be available for all people especially
indeveloping countries. It necessary to work on other effective
preventive measures that are able to reduce the risk of SARS-Cov2
infection with negligible side effects. This can be used in community or
at least in high risk groups such as health care providers {[}1{]}.

One of the potential strategies can be probiotics with the ability to
boost human immunity{[}2{]}. Recent studies revealed that
gastrointestinal microbiota have an important role in balance and proper
function of immune system {[}3, 4{]}. Probiotics have been used in
different immune-mediated and inflammatory disorders {[}5-9{]}.
Probiotics can improve immune system functions via different mechanisms.
One of them is increasing IgA secreting plasma cell numbers in lamina
propria of intestine, lung and mammary gland {[}10-12{]}. This
immunoglobulin has a major role in mucosal immune system{[}13{]}.
Besides humoral immunity, healthy commensal microbiota of intestine can
increase CD4+ T cells and regulatory T cells of GI lamina propria.

Bradley et al. in 2019 showed that the intestinal microbiota influence
the IFN-\selectlanguage{greek}α/β \selectlanguage{english}receptor surface expression in respiratory epithelial cells,
which in case of a respiratory virus infection are able to respond more
efficiently to type I IFNs stimulation with enhanced
interferon-stimulated genes (ISGs) levels and impedes early virus
replication{[}14{]}. A high-fiber diet (Prebiotic) increased the
production of acetate by the intestinal microbiota and modulated the
activity of respiratory IFN-\selectlanguage{greek}β \selectlanguage{english}and increased the expression of ISGs in
the lung{[}15{]}. Furthermore, gut microbial components and metabolites
(postbiotic) including short-chain fatty acids (SCFA), are involved in
gut-lung communication.

To date several studies revealed that probiotics could reduce upper
respiratory infections incidence, duration and disease severity{[}16,
17{]}. A Cochrane review concluded that probiotics were better than
placebo in reducing the number of episodes of acute upper respiratory
infection (URTI), the mean duration of an episode of acute URTI,
antibiotic use and school absence{[}18{]}. A recent systematic review
and meta-analysis in 2020 concluded that synbiotic interventions reduced
the incidence rate of respiratory tract infections (RTIs) by 16\% and
the proportion of participants experiencing RTIs by 16\%{[}19{]}. Sly et
al. showed that when using Immunostimulant OM-85 in infants, the
cumulative frequency of severe lower respiratory tract infection and the
number of days with symptoms were significantly lower compared to
placebo, suggesting a reduction in the overall inflammatory burden in
the lower airways {[}20{]}.

The immunomodulatory effects of probiotics are strain-dependent{[}21{]}.
Many trials using Lactobacillus Rhamnosus GG, Lactobacillus Plantarum,
Lactobacillus Casei and Paracasei and some strains of Bifidobacterium
could have preventive effects against respiratory infections. These
scientific evidences have opened the possibility of exploring particular
strains of beneficial probiotic with immunomodulatory capacities
(immunobiotics) in order to increase antiviral defenses in the
respiratory tract, especially the combination of probiotic and
prebiotics which is called synbiotic{[}14, 19{]}.

David Baud and colleagues provided a list of probiotic products with
documentation in human studies that may have relevance to reducing the
burden of the coronavirus pandemic {[}1{]}.We recently showed that
synbiotic Lactocare\selectlanguage{ngerman}® intervention can reduce the episodes of viral
respiratory infections in asthmatic children{[}22{]}. Interestingly,
some probiotic strains in Synbiotic Lactocare® are similar to Strains
suggested by David Baud. After COVID-19 pandemic, we proposed that
Synbiotic Lactocare® may also reduce SARS-Cov2 infection in high risk
medical staff working in COVID-19 hospital wards.

\textbf{Method:}

Participants: This study was a randomized, double blind,
placebo-controlled trial that was done during the second wave of
COVID-19 pandemic (July to August 2020) in Mashhad, the second most
popular city in Iran. Subjects were recruited from employees of
emergency department of Imam Reza and Akbar hospital, COVID 19 referral
centers in Mashhad. Participants were invited through banners. Sixty
persons without any history of clinical or laboratory evidence of
SARS-Cov2 infection participated in the trial. Exclusion criteria
included: History of COVID-19 infection, Positive antibody or RT-PCR
against SARS-Cov2, history of autoimmune disorders, pregnancy,
immunosuppressive drugs use, or any chronic lung diseases. All
participants signed informed consent form.

Figure 1: Flow chart of the study

\begin{enumerate}
\tightlist
\item
  Study design: Participants in synbiotic group received once daily oral
  synbiotic capsule (Lactocare®) that contains 1 billion CFU/Cap of
  Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus
  thermophilus, Bifidobacterium breve, Lactobacillus acidophilus,
  Bifidobacterium infantis, Lactobacillus bulgaricus, and
  Fructooligosacharide (Zist Takhmir, Tehran, Iran) or placebo in the
  same appearance for 30 days. They were followed up at 15 and 45 days
  by phone call and after first and second month visited in clinic. If
  suspected symptoms and signs of COVID-19 were occurred, SARS-Cov2
  RT-PCR with nasal or oral swab was done.
\item
  Sample size and randomization: All participants (60 persons) were
  active hospital staff of emergency department in Imam Reza and Akbar
  hospital, working at least 40 hours per week, and who had no evidence
  of novel coronavirus infection at the time of trial entrance or before
  it. They were randomly divided to synbiotic and placebo groups.
  According to previous studies that showed a 20-30\% reduction{[}22{]}
  in common colds with a probiotic, we estimated a sample size of 28 in
  each group using an \selectlanguage{greek}α \selectlanguage{english}value of 0.05 with a power of 90\% and possible
  20\% follow-up loss.
\item
  Statistical analysis: Statistical analysis was done by statistical
  package for social sciences (SPSS) software version 16.0 (IBM Inc.,
  Chicago, Il, USA). The IBM SPSS Statistical Software for Windows
  version 22.0 (IBM Corp., Armonk, N.Y., USA) was used for the
  statistical analyses. The standard descriptive statistics were applied
  to describe the pattern of the data. The Chi-square and Fisher's exact
  tests were used to examine the significance of associations between
  categorical data. All tests were two-tailed, and the probability value
  of 0.05 was considered significant.
\end{enumerate}

Ethical consideration: This trial protocol was approved by Mashhad
University of Medical Sciences ethical committee (code:
IR.MUMS.REC.1399.240). The study protocol was registered in Iranian
registry of clinical trials. (Code: IRCT20101020004976N6). The authors
have no conflict of interests. This article was funded by the Deputy of
Research at Mashhad University of Medical Sciences.

\textbf{Result:}

Among sixty participants who were enrolled in the study, fourteen (23\%)
of them were physicians, forty- one (68\%) were nurses and five (9\%)
were nurse aids. Most of them (forty- six, 77\%) were older than 30
years. There was no significant difference between two groups. Detailed
distribution between groups are shown in Table 1.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Synbiotic group ( n=29 )\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Placebo group ( n=31 )\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
P-value ( Chi-2)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age \textless{} 30 years \textgreater{} 30 years\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 21\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 25\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.451\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Career (n) Nurse Physician Nurse aid\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 10 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
23 4 4\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.101\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Risk factors\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.393\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 1: Characteristics of study participants. (n= Number, Risk
factors: hypertension, diabetes mellitus, etc.)

During the two month period of this study, SARS-COV-2 RT-PCR test
results were positive in three participants (9.67\%) in placebo group
compared to no positive test in synbiotic group. The difference was not
statistically significant (p= 0.238).

During the study, two persons (7 \%) of placebo group had respiratory
complaint such as cough, rhinorrhea and/or dyspnea, compared with one in
synbiotic group (p= 0.19). Three persons in placebo group revealed
gastrointestinal manifestations like diarrhea, vomiting and abdominal
pain while two patients in intervention group revealed diarrhea, nausea
and/or vomiting (p=0.67). Only one case in placebo group had disturbance
in gustatory and smell senses (Table 2).\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Synbiotic group\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Placebo group\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value ( Chi-2)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
SARS-COV-2 RT-PCR First month Second month Total\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 0 0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 2 3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.238\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Respiratory First month Second month Total\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 1 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 2 4\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gastrointestinal First month Second month Total\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 1 2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 2 3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.67\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fever and Chill First month Second month Total\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 1 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 1 2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.61\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Loss of smell First month Second month Total\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 0 0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 1 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.48\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 2. Comparing Laboratory data and clinical manifestations between
synbiotic and placebo group during the 2 month study period.

\textbf{Discussion:}

This study showed that 3 participants in placebo group got SARS-COV2
infection in comparison to no participant in synbiotic group. Although
there was a lower number of involved persons in synbiotic group, the
difference was not statistically significant. This may be partly due to
small sample size, however, as even a small reduction in COVID-19
involvement is still promising, larger studies are critically needed.

While vaccines will not be widely available in the near future for
general population in many countries, additional preventive strategies
are urgently needed especially in high risk groups including health care
providers and hospital staffs.

There are many evidences that communications exist between gut and lung,
which is called the gut-lung axis. To our knowledge, this is the first
report of synbiotic application for prevention of COVID-19 and there is
no other published trial using probiotic or prebiotic for prevention or
treatment of this novel disease. There are some animal studies and very
nice reviews that suggest specific strains of probiotics are effective
against corona viruses and presumably, SARS-COV2. Julio Villena and
Haruki Kitazawa have summarized the information regarding the effect of
L. rhamnosus CRL1505 in the beneficial modulation of the mucosal
antiviral immune response and suggest that this strain could be
beneficial in the prevention and/or the reduction of the severity of
infections caused by SARS-COV2{[}14{]}. They also concluded that
immunobiotic interventions are mostly effective in the prevention of
respiratory infections while they rarely influence the course of
infection once the pathogen has started its replication in the host and
immunobiotics should be considered as a strategy for prevention rather
than as a therapeutic option.

Some patients with COVID-19 have intestinal microbial dysbiosis with low
numbers of probiotic species such as Bifidobacterium and Lactobacillus
which could be an indicator of their weak immunity, and therefore
prebiotic, probiotic or synbiotic supplementation will help to
re-normalize the intestinal flora balance and decrease the risk of
infection{[}14{]}.

Zuo and coworkers compared the fecal microbiota of fifteen patients
infected with SARS-Cov2 to healthy controls and showed
that\emph{Coprobacillus} spp. \emph{Clostridium ramosum}
and\emph{Clostridium hatherwayi} were associated with severity of
COVID-19 symptoms{[}23{]}. Geva-Zatorsky demonstrated that
\emph{Coprobacillus}spp. can upregulate ACE2 (which is a receptor for
virus entry) in the murine guts{[}24{]}. Beneficial effects include
enhancement of the intestinal epithelial barrier, competition with
pathogens for nutrients and adhesion, production of anti-microbial
agents and modulation of the host immune system{[}25{]}.

A recent systematic review and meta-analysis in 2020 concluded that
synbiotic interventions reduced the incidence rate of respiratory tract
infections (RTIs) by 16\% and the proportion of participants
experiencing RTIs by 16\%{[}19{]}. Interestingly, Synbiotic intervention
reduced the episodes of viral respiratory infections even in asthmatic
children{[}14{]}.

Our study showed that participants in synbiotic had less
gastrointestinal symptoms. This era is another potential beneficial
effect of the application of immunobiotics as diarrhea is a frequent
symptom in 10 to 30\% of patients infected with SARSCoV-2. Animal
studies demonstrated that L. plantarum Probio-38 and L. salivarius
Probio-37 were capable of reducing the replication of transmissible
coronavirus. A mixture of probiotic strains was also capable of
improving the immune system of pigs infected with coronavirus and
improved their reproductive performance (Tsukahara et al., 2018).
Interestingly, it was recently reported that a multi-strain probiotic
mixture significantly reduced the fecal shedding of the feline
coronavirus in cats infected with the pathogen{[}14{]}.

Mak et al. reported that 58--71\% of patients with COVID-19 in China
were consumed antibiotics, and antibiotic-associated diarrhea occurred
in 2--36\% of patients. Probiotics intervention has been proposed to
make these COVID-19 patients less prone to secondary infections{[}26{]}.

In our study, one participant in placebo group versus no one in
synbiotic group had anosmia. Dysgeusia and anosmia are common
comorbidities in COVID-19 patients. Epidemiological studies have
demonstrated that the incidence rate of olfactory problems in COVID-19
patients varies from 33.9-68\% with female dominance {[}27{]}. There are
some ongoing trials using intranasal probiotics for prevention and
treatment of COVID-19. Their results will be interesting as to whether
local use or probiotics produce inhibitory effects on olfactory problems
(ClinicalTrials.gov Identifier: NCT04458519).

In COVID-19 patients, the main manifestations are fever and cough,
lymphocytopenia and ground-glass changes on chest computed tomography
{[}27{]}. In the current trial, fever and chill were seen in two cases
in placebo group compared to one case in synbiotic group with no
statistically significant difference.

Finally, although it seems that probiotics and synbiotic should be used
mainly as a preventive strategy against COVID-19, there are some
evidences that show they may also help patients after infection with
SARS-COV2{[}28{]}. Interestingly, in an RCT of 65 critically ill,
mechanically ventilated patients, a multi-strain synbiotic containing
Pediococcus pentosaceus, Leuconostoc mesenteroides, L. paracasei ssp.
Paracasei 19, L. plantarum plus inulin, oat bran, pectin, and resistant
starch lowered the rate of infections, sepsis, days of admission in the
intensive care unit, days under mechanical ventilation, and
mortality{[}29{]}.

Controversy still exists as some experts believe that blind use of
probiotics for COVID-19 is not recommended until we have a better
understanding of the pathogenesis of SARS-CoV-2 and its effect on gut
microbiota {[}30{]}.

The main limitation of this study was the small sample size. Many
hospital staff were excluded from the study for their positive past
clinical history or laboratory results of COVID-19. The strengths of
this study were the novelty of application of synbiotic in COVID-19 and
the study population, health care workers, which are in high risk group
and any data regarding the prevention of COVID-19 in this population are
highly needed.

\textbf{Conclusion}

This study showed that overall frequency of SARS-COC2 infection in
participants receiving synbiotic and those receiving placebo did not
differ significantly. However, 3 hospital staff in placebo group
compared to no one in synbiotic group had SARS-COC2 infection. This is
encouraging regarding the importance of morbidity and mortality of
COVID-19 especially in health care workers. Further studies with greater
power and alternative probiotic strains and mixture are warranted to
determine whether Synbiotic can prevent COVID-19 in at-risk hospital
staff.

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