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\begin{document}

\title{Next-Gen Biotherapeutics: A Systematic Review and Network Meta-Analysis
on Postbiotics as Treatment For Pediatric Atopic Dermatitis}



\author[1]{Carol Stephanie Tan-Lim}%
\author[2]{Ma. Easter Joy V. Sajo}%
\author[2]{Khianne Ed Miguel P. Orteza}%
\author[2]{Patricia Barbara A. Fernandez}%
\author[2]{Ma. Junella C. Vila}%
\affil[1]{University of the Philippines Manila Department of Clinical Epidemiology}%
\affil[2]{University of the Philippines Baguio College of Science}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Due to the recency of the postbiotic field, there
are no head-to-head postbiotic studies investigating its biotherapeutic
potential for atopic dermatitis (AD). No network meta-analysis (NMA) has
yet been conducted to synthesize relevant studies to compare postbiotic
interventions for AD. \textbf{Objective:} To assess the comparative
efficacy and safety of postbiotic strains for treating pediatric AD.
\textbf{Methodology:} This is an NMA of randomized controlled studies
that evaluate postbiotics in treating pediatric AD. Systematic search of
databases and registers from inception to November 30, 2022. Three
authors independently performed the search, screening, appraisal using
the Cochrane risk of bias tool version 2 and data extraction. Data
analysis was done using STATA14 software. \textbf{Results:} There were 9
studies that evaluated 8 postbiotic preparations. \emph{Lactobacillus
rhamnosus} IDCC 3201 (LR) ranked highest in the efficacy outcome.
Compared to placebo, LR may be effective in reducing symptoms of atopic
dermatitis both in the main analysis (SMD -0.53, 95\%CI -1.02 to -0.04)
and sensitivity analysis involving studies that used SCORAD (MD -5.52,
95\% CI -10.46 to -0.58), based on low-certainty evidence. Based on
moderate-certainty evidence, LR probably does not increase the risk of
adverse events (RR 0.97, 95\% CI 0.79 to 1.21). Although
\emph{Lactobacillus paracasei} GM080 (LP2) ranked highest in the safety
outcome, it may not reduce AD symptoms compared to placebo (SMD -0.03,
95\% CI -0.37 to 0.32) based on low-certainty evidence.
\textbf{Conclusion:} LR showed significant benefits for children with
AD, based on low-certainty evidence. Further investigation on LR is
recommended.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Atopic dermatitis (AD) is the most common skin disorder among children.
As a chronic inflammatory disorder, it is considered a psychologically
burdensome pediatric concern and affects 15 to 20\% of children
worldwide.\textsuperscript{1-3} Probiotics are live microbial agents
that have been increasingly used for various disease conditions over the
past two decades.\textsuperscript{4} While its effect on AD has been
studied extensively, concerns about the safety of administering live
microbes in children instigated further research for alternative
approaches in AD management.\textsuperscript{1}

Recent studies show increasing interest in the potential clinical
application of postbiotics to prevent and treat
AD.\textsuperscript{5-13} Postbiotics are defined as ``preparations of
inanimate microorganisms and/or their components that confer a health
benefit on the host''.\textsuperscript{14} Aside from mutually
benefiting hosts, another similarity between probiotics and postbiotics
is their high strain-specificity. In postbiotics, exopolysaccharides and
lipoteichoic acid production are strain-specific
behavior.\textsuperscript{15.}

Postbiotics are promising alternatives to probiotics since these
eliminate the risk of using live microbial strains, especially among
individuals with weakened immune systems, and address product longevity
concern\textsuperscript{14,16}. Several randomized controlled trials
(RCTs) have been conducted on this topic, with conflicting evidence. As
of the writing of this paper, no systematic review and meta-analysis
that evaluate the efficacy of postbiotic therapy for atopic dermatitis
in children have been conducted. This network meta-analysis (NMA) aims
to synthesize all available evidence and determine the efficacy and
safety of various postbiotics preparations in treating pediatric AD.

\textbf{METHODOLOGY}

This SR/NMA followed the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses 2009 (PRISMA) incorporating the Extension
Statement for Reporting of Systematic Reviews incorporating Network
Meta-analysis of Health Care Interventions.\textsuperscript{17}

\textbf{Eligibility criteria}

RCTs from the earliest record to November 30, 2022, that evaluated
postbiotics in pediatric patients with AD were included. The
intervention should involve postbiotics compared to other postbiotic
preparations or placebo. No restrictions were made on the strain type,
dose, and treatment length.

The primary outcome was a relief of AD symptoms which may be reported
using several scoring systems such as SCORAD, EASI, POEM, Pruritus-NRS,
TIS, IGA, and SASSAD.\textsuperscript{18-22} While scoring systems
attribute different weights for various symptoms, lower scores always
indicate less severe AD. The secondary outcome was the adverse event
occurrences (AEO), defined as any untoward medical condition observed
among study participants during postbiotic administration.

Studies where participants had concomitant diseases were excluded.
Quasi-randomized trials and observational studies were excluded.

\textbf{Information sources and search strategy}

Three reviewers independently searched the databases PubMed, Cochrane
Library, Science Direct, Ovid, Springer Link, Google Scholar, and
ClinicalTrials.gov (https://clinicaltrials.gov). The search algorithm
includes: (((((((Postbiotics) OR (Paraprobiotics)) OR (Ghost
probiotics)) OR (Parapsychobiotics)) OR (Tyndallized probiotics)) OR
(Metabiotics)) OR (Bacterial lysates)) AND (Atopic dermatitis). Some
studies involve postbiotics but may not explicitly mention this term or
its related terms; instead, they may only describe its inanimation
process and the specific microorganism used. Thus, individual probiotic
strains reported in the SR on the probiotics of Tan-Lim \emph{et al.,}
\textsuperscript{23} were also used as search terms for the PubMed
database. Search for additional references cited in the screened
full-text papers was also performed.\textsuperscript{24} Search for
unpublished articles was done by correspondence with content experts in
the field.

\textbf{Study selection}

Three authors independently reviewed studies from six databases,
resolving conflicts with a 4\textsuperscript{th} author. The PICO
(Population, Intervention, Comparison, Outcome) framework was used to
evaluate titles and abstracts of initially selected studies. A narrowed
number of studies that met eligibility criteria were selected for
full-text review. The same process was used for data extraction, quality
assessment, and manual search. Study consolidations were done manually
using Microsoft Excel.

\textbf{Data collection process}

Data including study author(s), country of publication, sample size
(\emph{n} ), age range, microorganism(s) of interest, treatment dosage,
mode, and treatment length, and results for both the experimental and
placebo groups were tabulated in an Excel sheet. Three reviewers
independently assessed the risk of bias assessment using the Cochrane
risk of bias tool version 2.0. The outcome for efficacy and safety were
tabulated by three authors and independently reviewed by the
4\textsuperscript{th} author. Original investigators were contacted via
email to seek unreported or underreported information.

\textbf{Data items}

The primary outcome, relief of symptoms, was measured as a continuous
variable as change in AD severity score from baseline to end of
treatment. Safety outcomes based on AEO were reported as rates/counts;
information whether these were intervention-related was also noted.

This study employed the intention-to-treat principle in order to
minimize type-1 error.\textsuperscript{25} Missing data were not
imputed. The outcome measures reported at the end-of-treatment were used
for analysis. Probable effect modifiers may stem from the population and
intervention characteristics, including age and dosage.

\textbf{Review of network geometry}

Each postbiotic strain was represented in the network geometry as a
node. The placebo was also represented as a node. The nodes' links
represent studies comparing the postbiotic strain with a different
strain or placebo.

\textbf{Risk of bias within individual studies}

The revised Cochrane risk-of-bias tool for randomized trials (RoB-2) was
used for independent appraisal of included studies by three
authors.\textsuperscript{26} Issues were resolved through collaborative
discussions to achieve consensus. The risk-of-bias assessment of the
individual studies was done for both efficacy and safety outcomes.

\textbf{Summary measures}

Effect sizes for the efficacy outcome were summarized using Standardized
Mean Difference (SMD) and 95\% confidence interval (CI) since studies
used different AD relief indices. Safety data was summarized using
relative risk (RR) and 95\% CI. Interval plots were generated to
visualize the efficacy and safety effect estimates for the different
postbiotic preparations compared to placebo. Forest plots were generated
to inspect the relative effects of each strain-specific treatment.

A league table was generated for the outcomes, showing NMA summary
estimates with 95\% CI. Ranking of interventions was assessed using
cumulative ranking probabilities and SUCRA values.

\textbf{Data analysis}

Comparisons of postbiotic preparations using direct and indirect
evidence for efficacy and safety was to be conducted. In trials where
postbiotics were administered at different doses, the main analysis used
the results of the higher dose group to avoid the generation of an
auto-loop. Sensitivity analysis on the dose-response was conducted to
determine if there was a difference in results when used as high- or
low-dose.

STATA 14 software was used for data analysis and synthesis, employing
the frequentist approach using random effects model incorporated in
STATA 14. Heterogeneity of studies was measured quantitatively using the
software Review Manager 5.4.

For studies with missing summary statistics, the study authors were
contacted. If they were unresponsive, the guide for data collection in
section 5.5.8 of the Cochrane Handbook for systematic reviews of
interventions was followed.\textsuperscript{27} Data from figures
reported in journal articles\textsuperscript{28} was electronically
extracted using WebPlotDigitizer. Missing means and/or SD were derived
from the available data in the studies following the section on data
extraction for continuous outcomes in the Cochrane Handbook
(Higgins\emph{et al.,} 2022), the formula derived by Wan \emph{et al.,}
\textsuperscript{29} and using MedCalc Comparison of Means Statistical
Software (www.medcalc.org/calc/), as appropriate.

Sensitivity analysis was conducted with studies that reported the
efficacy outcome using SCORAD. Results were reported as mean difference
with 95\% CI. This sensitivity analysis was done to facilitate ease of
interpretation of results in the clinical setting since SCORAD has an
established minimal clinically important difference (MCID) at 8.7
points.

Publication bias was to be assessed using comparison-adjusted funnel
plots.

\textbf{Assessment for NMA Assumptions}

\emph{Directness}

The PICO of the included studies was qualitatively assessed for
directness with the research question.

\emph{Heterogeneity}

Heterogeneity was assessed qualitatively by evaluating the similarity of
studies for each pairwise comparison and quantitatively using the
inconsistency statistic (I\selectlanguage{ngerman}²) and the chi-square test. Heterogeneity was
considered significant for I² \textgreater{}50\% and p-value
\textless{}0.10.

\emph{Transitivity}

Assessment of transitivity was done qualitatively by analyzing
similarity of the PCO of adjacent edges to ensure the validity of the
indirect comparisons.\textsuperscript{28}

\emph{Coherence}

Coherence was assessed qualitatively by analyzing similarity of
interventions of direct and indirect links. Quantitative assessment of
coherence was to be done by assessing loop inconsistency through node
splitting (if with closed loops) and design inconsistency (if with
multi-arm studies).

\textbf{Rating strength of evidence through GRADE CoE}

The Grading of Recommendations Assessment, Development, and Evaluation
(GRADE) approach was used for the assessment of certainty of evidence
(CoE). The GRADE approach considers five domains, namely: risk of bias,
inconsistency, indirectness, imprecision, and publication bias.
Intransitivity and inconsistency were also considered in the rating of
certainty of evidence.\textsuperscript{30}

\textbf{RESULTS}

\textbf{Study selection}

A total of 434 studies from six databases were identified through
electronic and manual searches. Nineteen duplicate studies were
excluded, and 371 studies did not pass the title and abstract screening.
From 44 studies eligible for full-text assessment, 36 were excluded due
to deviation from the PICO, of which two papers were excluded due to the
study subjects having concomitant diseases and
allergies.\textsuperscript{31-32} One study was a duplicate, and the
full-text of one study could not be retrieved despite maximal efforts.
An additional 3 studies were identified through manual search of
relevant articles. Finally, nine studies were included in this SR/NMA
(Figure 1).

\textbf{Presentation of Network Geometries}

\emph{Efficacy of postbiotic strains on AD}

The network geometry for the efficacy outcome at the strain-specific
level is shown in Figure 2a. There were seven postbiotic preparations
evaluated, which were all compared to placebo. Six were supported by one
study and one (comparison of MV1 and placebo) was supported by two
studies.

\emph{Safety of postbiotic strains on AD}

Of the seven postbiotic preparations that were compared to placebo, the
link between MV1 and placebo is the thickest, with two studies
supporting the comparison. The rest each have one study to support the
comparison (Figure 2b).

\textbf{Characteristics of Included Studies}

This SR includes nine RCTs with a total of 793 children with AD, whose
ages ranged from four months to 18 years old. The main characteristics
of the nine eligible studies are summarized in Table 1. Of the nine
RCTs, five reported the efficacy outcome using SCORAD, and four used
SASSAD. Eight studies reported the safety outcome. Five studies
administered the interventions orally and four intradermally.

\textbf{Risk of bias within studies}

Figure 3a displays risk of bias assessment for the efficacy outcome in
nine studies. Three had low overall risk of bias, three were high, and
three were unclear. Randomization processes were adequate in all
studies, but only four followed the intended interventions for the
participants. Two studies had high risk of bias due to intervention
deviations for failure to report the analysis used to estimate the
effect of assignment to intervention and failure to analyze participants
in the group to which they were randomized. Three had unclear risk of
bias for not reporting blinding or possible deviations.

One study did not report the reason for missing outcomes. Two studies
may have used inappropriate outcome measurement methods.~ Three studies
had unclear risks due to selective reporting and insufficient result
detail.

Figure 3b shows bias risk for safety outcomes in eight studies. Three
had low overall bias risk, three high, and two were unclear. Unclear and
high risks were due to intended intervention deviations, missing outcome
data, inappropriate outcome measurement, and selective reporting of
results.

\textbf{Synthesis of Results}

\emph{Efficacy of strain-specific postbiotic administration on relief of
AD symptoms}

All nine studies reported the reduction of AD symptoms. However, only
eight were included in the network meta-analysis as one study provided
insufficient data to allow pooling. This study reported that SCORAD
values were significantly lower at 6 months of treatment using Mix
postbiotic preparation (median 11.4 points for Mix, 19.4 points for
placebo; p=0.02) but not at 9 months of treatment (median 9.5 points for
Mix, 14.8 points for placebo, p=0.08).\textsuperscript{9}

Figure 4a shows the interval plot containing the SMD and 95\% CI of each
postbiotic strain compared to placebo. LR had the most favorable effect
with SMD -0.53 (95\% CI of -1.02 to -0.04), indicating statistically
significant reduction in symptoms compared to placebo. MV2 had the least
favorable effect with SMD= 0.03, indicating possible increase in
symptoms. However, MV2, LP1, LP2, LS, MV1, and MV3, have wide CIs which
preclude definite conclusions from being made.

The league table, ranking probabilities and SUCRA values are in the
Supplementary File. LR was the highest-ranked while MV2 was the
lowest-ranked strain for the efficacy outcome.

\emph{Adverse effects of strain-specific postbiotic administration for
AD}

Figure 4b shows the interval plot containing the RR and 95\% CI of seven
postbiotic preparations compared with placebo. LP2 had the lowest RR for
adverse events; however, the 95\% CI is wide and precludes definite
conclusions from being made (RR 0.32, 95\% CI 0.01 to 7.78). MV3 and MV2
had statistically significant increase in adverse events (MV3 RR 25.77,
95\% CI 1.63 to 406.64; MV2 RR 3.37, 95\% CI 2.48 to 4.58). LR showed no
significant difference with placebo (RR = 0.97 95\% CI 0.79 to 1.21).

LP2 was the highest-ranked while MV3 was the lowest-ranked strain for
the safety outcome.

\textbf{Assessment of NMA Assumptions}

\emph{Directness}

All included studies were direct. All trials involved the administration
of postbiotics compared to placebo among pediatric patients with AD and
reported reduction in AD symptoms.

\emph{Heterogeneity}

Only the pairwise comparison between MV1 and placebo had more than one
study contributing evidence. Qualitative assessment showed that the PICO
and effect modifiers in the two studies comprising the edge had no
substantial variation. Quantitative assessment also showed no
heterogeneity, with I\textsuperscript{2}=0\% and p-value=0.33.

\emph{Transitivity}

All postbiotic preparations were compared to placebo. The population and
outcomes reported were similar; thus, there was no violation of the
transitivity assumption.

\emph{Inconsistency}

There is no source of loop and design inconsistency in this network.

\textbf{Results of GRADE CoE Assessments}

The CoE assessments for the efficacy and safety outcomes are presented
in Table 2. Compared to placebo, LR may reduce the symptoms of AD based
on low CoE, and does not cause a significant increase in adverse events
based on moderate CoE.

\textbf{Results of Additional Analyses}

\emph{Sensitivity analysis}

In the sensitivity analysis including only studies that used SCORAD, 3
postbiotic strains (LP, LR, LS) were evaluated in four studies. The
network geometry is shown in Supplementary Figure 5a and the interval
plot is shown in Supplementary Figure 5b. Compared to placebo, LR
decreased the SCORAD value by 5.52 points (95\% CI --10.46 to --0.58).
Although statistically significant, results were not clinically
significant since the mean difference (MD) was smaller than the MCID of
8.7 points. LS and LP had negative MD values indicating reduction in AD
symptoms; however, the 95\% CI are wide and inconclusive.

One dose-response-controlled trial was included in this NMA. Sensitivity
analysis found no difference in results when using data from the
low-dose and high-dose groups in reducing AD
severity.\textsuperscript{7}

\emph{Publication bias}

Comparison-adjusted funnel plot was not generated given the limited
number of studies supporting each pairwise comparison.

\textbf{DISCUSSION}

This NMA synthesizes evidence on the efficacy and safety of various
postbiotic strains for treatment of pediatric AD. Only LR showed
significant benefit compared to placebo. Evidence suggests LR may reduce
AD symptoms, but CoE is low. LR had a statistically significant effect
in reducing SCORAD values in the sensitivity analysis, but results did
not reach clinical significance. The MD and upper limit of the 95\% CI
were less than the MCID. A reduction of least 8.7 points in SCORAD is
considered clinically significant. \textsuperscript{33}

Effectiveness is a crucial factor in clinical decision-making, but other
factors including safety and cost-effectiveness are also
important.\textsuperscript{34} In this study, there was no significant
difference in adverse events between LR and placebo, based on moderate
certainty of evidence. Although LP2 was the highest-ranked postbiotic
strain in terms of safety, it only ranked 6\textsuperscript{th} (out of
7 postbiotic preparations) in the efficacy outcome and did not
demonstrate significant benefit when compared to placebo.

MV2 and MV3 demonstrated significant harm, which may be explained by the
route of administration since \emph{Mycobacterium vaccae} was
administered intradermally. The other postbiotic species were
administered orally. Injection site reactions such as induration and
erythema were common and dose-related.\textsuperscript{7-8}

Only one study that tested a mixed preparation of postbiotics was
included in the review. However, it was not included in the NMA due to
inadequate data. Their study showed favorable effect on AD at 6 months
of treatment, with no major safety concerns. This finding is similar to
the NMA of Tan-Lim \emph{et al. 2020} that compared probiotic
preparations for the treatment of pediatric AD, three of the six mixed
probiotic preparations demonstrated significant reduction in AD
symptoms. This effect was hypothesized to be due to the synergistic
activity of the bacteria included in the mix.\textsuperscript{23}

Furthermore, of the 17 probiotic preparations included in the NMA
of\emph{Tan-Lim et al. 2020} , probiotic Mix 1
(ProbioMix1;\emph{Bifidobacterium animalis} subsp. \emph{lactis} CECT
8145,\emph{Bifidobacterium longum, CECT 7347, Lactobacillus casei CECT
9104} ) had the most favorable effect in reducing AD symptoms (SMD =
-1.94 (95\% CI of -2.65 to -1.94). None of the strains included in this
Mix1 were included in this NMA on postbiotics. ProbioMix1 had
MD\textsubscript{SCORAD} of -19.2 (95\% CI of -24.76 to -13.64) compared
to placebo, which was clinically significant. In this NMA on
postbiotics, LR had the most favorable effect in reducing AD symptoms,
but results were not clinically significant.

In the Tan-Lim \emph{et al. 2020} study, \emph{Lactobacillus
rhamnosus}MP 108 also showed significant benefit in reducing AD symptoms
(SMD --0.62, 95\% CI --1.12 to --0.13).\textsuperscript{23} Although the
LR postbiotic evaluated in this NMA consists of a different strain
(\emph{L. rhamnosus} IDCC 3201), the \emph{L. rhamonsus} species seem to
have a promising effect on atopic dermatitis both in probiotic and
postbiotic form.

There is one study that evaluated the effect of live and
heat-inactivated \emph{Lactobacillus rhamnosus} GG (LGG) compared to
placebo,\textsuperscript{31} but this was not included in this NMA since
participants had concomitant cows' milk allergy. This trial showed
significant benefit only with the viable LGG supplementation. The
authors emphasized the importance of including the safety variable for
future research on heat-inactivated LGG, as adverse gastrointestinal
symptoms were observed.

One of the main limitations of this study is the limited number of
studies supporting each pairwise comparison and the absence of direct
evidence providing head-to-head comparisons of the postbiotic strains.
Multiple treatment comparisons could not be performed for the
interventions. The imprecise results found in most pairwise comparisons
may be due to the limited available data. However, this is expected
given the recentness of the postbiotic field. Consensus on the naming
and defining the concept of `killed microorganism that benefits its
host' was only recently established.\textsuperscript{14}A recent
convention attended by foremost experts in the field was organized last
December 2022 for further discussion\textsuperscript{35}. Nevertheless,
the study sheds light on postbiotic treatments' potential benefits and
safety concerns for AD management.

\emph{Impact in Healthcare}

The specific strain RHT3201, here known as LR, may potentially confer
benefits to pediatric patients with AD to relieve symptoms, based on low
certainty of evidence. Although the effect did not reach clinical
significance, further research on the optimal dose and duration of
treatment using LR may be explored. LR showed favorable safety outcomes
based on moderate certainty of evidence. As the age of the participants
in the trials included for this study are considerably broad,
suggestions on the optimal age for postbiotic administration in AD
treatment cannot be made.

\emph{Impact on microbiological research}

Exploration of the effects of postbiotics on different AD phenotypes and
endotypes, as well as patients' ages and immune mechanisms, is essential
for better understanding of their role in AD treatment. Future studies
on LR compared with other postbiotic preparations could enrich the
quality of evidence. Evaluating LR as part of a mixed postbiotic
preparation is also a potential research interest. Using a standard
reporting method and common scoring system is recommended for easier
pooling and interpretation of data.

\textbf{ACKNOWLEDGMENTS}

Our gratitude is extended to Ms. Micah Dispo, Mr. Jeno Rey Pagaduan, and
Asst. Prof. Jhunas Paul Viernes for their valuable contributions in this
study.

\textbf{IMPACT STATEMENT}

Concerns on the long-term efficacy and safety of current treatments for
pediatric AD have propelled the search for therapeutic alternatives,
including postbiotics. This study compares the efficacy and safety of
different postbiotic preparations for treating pediatric AD. This NMA
shows biotherapeutic potential of inanimate \emph{Lactobacillus
rhamnosus.} Our findings may assist healthcare professionals in making
evidence-based decisions for pediatric AD patients and enrich our
current microbial research focusing on \emph{biotics} .

\textbf{REGISTRATION}

This study was registered through the Science Research Center (SRC) of
the University of the Philippines Baguio with registration number
04032023152822. The review protocol and study data may be accessed upon
request with the corresponding author. There were no protocol
amendments.

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\textbf{TABLES}

\textbf{Table 1.} Characteristics of included studies.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
\textbf{Study} & \textbf{Country} & \textbf{N} \textbf{(experimental,
control)} & \textbf{Age range} & \textbf{Postbiotic intervention} &
\textbf{Dosage} & \textbf{Mode of administration} & \textbf{Treatment
length} & \textbf{Control group} & \textbf{Outcome} & \textbf{Assessment
time intervals}\tabularnewline
\midrule
\endhead
Arkwright 2001 & United Kingdom & 41 (21, 20) & 5 -- 18 y & MV3
(Heat-killed \emph{Mycobacterium vaccae} SRL 172) & 0.3 mL & Intradermal
& 3 mo & Placebo & SASSAD index, adverse events & 1, 3 mo\tabularnewline
Arkwright 2003 & United Kingdom & 56 (29, 27) & 2 -- 6 y & MV1
(Heat-killed \emph{Mycobacterium vaccae} SRP 299) & 10 mg/mL &
Intradermal & 6 mo & Placebo & SASSAD index, adverse
events\selectlanguage{ngerman}\emph{\textsuperscript{§}} & 1, 3, 6 mo\tabularnewline
Berth-Jones 2006 & United Kingdom, Croatia & 101 (52, 49) & 5 -- 16 y &
\textbf{High dose MV1 (Heat-killed \emph{Mycobacterium vaccae} SRP
299)\emph{~\textsuperscript{+}}} Low dose (Heat-killed
\emph{Mycobacterium vaccae} SRP 299) & \textbf{1 mg} 0.1 mg &
Intradermal & 12 wk & Placebo & SASSAD index, adverse
events\emph{\textsuperscript{++}} & 12, 24 wk\tabularnewline
\textbf{} & & & & & & & & & &\tabularnewline
Bodemer 2017 & France & 179 (93, 86) & 6 months -- 7 years & Mix
(Lyophilized \emph{Haemophilus influenzae, Streptococcus pneumoniae, S.
aureus, S. viridans, S. pyogenes, Klebsiella ozaenae, K. pneumoniae,
Neisseria catarrhalis}) & 3.5 mg & Oral & 9 mo & Placebo & Adverse
events\emph{\textsuperscript{+}} & 1, 3, 6, 9 months\tabularnewline
Brothers 2009 & New Zealand & 124 (61, 63) & 5 -- 16 years & MV2
(Heat-killed \emph{Mycobacterium vaccae} AVAC) & 250 \selectlanguage{greek}µ\selectlanguage{english}g/mL & Intradermal
& 6 wk & Placebo & SASSAD index, adverse events & 3, 6
months\tabularnewline
D'Auria 2020 & Italy & 58 (29, 29) & 6 -- 36 mo & LP1 (Heat-killed
\emph{Lactobacillus paracasei} CBA L74) & 8 g & Oral & 12 wk & Placebo &
SCORAD index & 4, 8, 12 weeks\tabularnewline
Jeong 2020 & South Korea & 66 (33, 33) & 1 -- 12 years & LR (Tyndallized
\emph{Lactobacillus rhamnosus} IDCC 3201) & 10\textsuperscript{10}
CFU/day & Oral & 12 wk & Placebo & SCORAD index, adverse events & 6, 12
weeks\tabularnewline
\textbf{} \textbf{} & \textbf{~} & & & & & & & & &\tabularnewline
Rather 2021 & South Korea & 42 (22, 20) & 3 -- 18 years & LS
(Heat-killed \emph{Lactobacillus sakei proBio65}) & 400 mg & Oral & 12
wk & Placebo & SCORAD index, adverse events & 6, 12 weeks\tabularnewline
Yan 2019 & Taiwan & 126 (64, 62) & 4 -- 30 months & LP2 (Heat-treated
\emph{Lactobacillus paracasei} GM-080) & 10\textsuperscript{10} CFU/day
& Oral & 16 wk & Placebo & SCORAD index, adverse
events\emph{\textsuperscript{+}} & 4, 10, 16 weeks\tabularnewline
\bottomrule
\end{longtable}

Bold = \emph{Only dose used in the analysis}

\emph{~\textsuperscript{+}related to treatment}

\emph{\textsuperscript{~++}serious adverse events}

\selectlanguage{ngerman}\emph{\textsuperscript{§}adverse effects}

\textbf{Table 2.} GRADE Certainty of evidence assessments for network
meta-analysis estimates.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Efficacy outcome} & &\tabularnewline
\midrule
\endhead
\textbf{Comparison} & \textbf{Standardized Mean Difference (95\% CI)} &
\textbf{Certainty of Evidence}\tabularnewline
LR and Placebo & -0.53 (-1.02, -0.04) & Low
\textsuperscript{a}\tabularnewline
LS and Placebo & -0.33 (-0.94, 0.27) & Low
\textsuperscript{a}\tabularnewline
LP1 and Placebo & 0.33 (-0.84, 0.19) & Moderate
\textsuperscript{d}\tabularnewline
LP2 and Placebo & -0.03 (-0.37, 0.32) & Low
\textsuperscript{a}\tabularnewline
MV1 and Placebo & -0.12 (-0.44, 0.19) & Low
\textsuperscript{a}\tabularnewline
MV2 and Placebo & 0.03 (-0.32, 0.37) & Low
\textsuperscript{a}\tabularnewline
MV3 and Placebo & -0.28 (-0.90, 0.33) & Very low
\textsuperscript{a}\tabularnewline
\textbf{Safety outcome} & &\tabularnewline
\textbf{Comparison} & \textbf{Relative Risk (95\% CI)} &
\textbf{Certainty of Evidence}\tabularnewline
LR and Placebo & 0.97 (0.79, 1.21) & Moderate
\textsuperscript{d}\tabularnewline
Mix and Placebo & 1.39 (0.24, 8.09) & Low
\textsuperscript{e}\tabularnewline
LS and Placebo & 0.91 (0.02, 43.99) & Very low
\textsuperscript{c}\tabularnewline
LP2 and Placebo & 0.32 (0.01, 7.78) & Very low
\textsuperscript{b}\tabularnewline
MV1 and Placebo & 0.72 (0.15, 3.58) & Very low
\textsuperscript{b}\tabularnewline
MV2 and Placebo & 3.37 (2.48, 4.58) & Low
\textsuperscript{f}\tabularnewline
MV3 and Placebo & 25.77 (1.63, 406.64) & Low
\textsuperscript{a}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} Downgraded due to risk of bias and imprecision.

\textsuperscript{b} Downgraded due to risk of bias and very serious
imprecision.

\textsuperscript{c} Downgraded due to very serious risk of bias and
imprecision.

\textsuperscript{d} Downgraded due to imprecision.

\textsuperscript{e} Downgraded due to very serious imprecision.

\textsuperscript{f} Downgraded due to very serious risk of bias.



\textbf{FIGURES}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.84\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1. Search flow diagram for the systematic review and
network meta-analysis of Postbiotics as Treatment for Pediatric Atopic
Dermatitis.} The diagram summarizes the number of articles identified
during the initial search, screening, retrieval, and inclusion in the
meta-analysis.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.98\columnwidth]{figures/image2/image2}
\caption{{~Figure 2a ~ ~ ~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~%
}}
\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~Figure 2a Figure 2b

\textbf{Figure 2. Network geometry for the efficacy outcome (a) and
safety outcome (b).} Each node represents one strain-specific
intervention. The size of the node is proportional to the number of
participants randomly assigned to the intervention, and the thickness of
the lines is proportional to the number of trials comparing the two
interventions. The largest node is placebo, with a total of 303 patients
for the efficacy outcome and 370 patients for the safety outcome across
all studies.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~Figure 3a~\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~Figure 3b

\textbf{Figure 3. Risk of bias summary for efficacy outcome (a) and
safety outcome (b).} Review authors' judgments about the risk of bias in
all included studies. Positive signs indicate low risk. Exclamation
marks indicate unclear risk. Negative signs indicate high risk.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~Figure 4a\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~Figure 4b

\textbf{Figure 4. Interval plot of postbiotic strains compared to
placebo for the efficacy outcome in standardized mean difference (SMD)
(a) and safety outcome in relative risk (RR) (b).} The plot shows the
strain-specific SMD for efficacy and RR for safety and their respective
95\% confidence interval. For SMD, comparisons with negative treatment
effect estimates at the left of the no-effect line (SMD = 0) favor the
postbiotic strain, whereas positive treatment effect measures at the
right favor the reference treatment, placebo.~Relative risk and 95\% CI
less than 1 is indicative of the superiority of the intervention over
placebo in terms of safety, whereas relative risk and 95\% CI greater
than 1 indicate that the treatment intervention is inferior to placebo.

\selectlanguage{english}
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\end{document}

