201911 - Pingitore - Quando usare i probiotici in pediatria?

Quando usare
i probiotici
in pediatria
Giuseppe Pingitore, Roma

The World Health Organization defines probiotics as
“live microorganisms that, when
administered in adequate amounts,
confer a health benefit on the host”
(FAO/WHO, 2006; Hill et al., 2014)

Quali sono le situazioni cliniche
per le quali ci sono evidenze che…
…i probiotici conferiscano un
beneficio alla salute dell’ospite?

Selezione delle evidenze
scientifiche
Studi
secondari
Studi primari

Selezione delle evidenze
scientifiche
Studi
secondari
Studi primari
Pubblicati negli
ultimi 5 anni

1 - Dolori addominali ricorrenti

Recurrent abdominal pain in children: summary
evidence from three systematic reviews of
treatment effectiveness
• Between 4% and 25% of school-aged
children complain of recurrent abdominal
pain (RAP) severe enough to interfere with
their daily activities
• Systematic review of RCTs
• Included 55 RCTs, involving 3572 children
with RAP (21 dietary, 15 pharmacological, 19
psychosocial, and 1 multi-arm).
Abbott RA et al. Journal of Pediatric Gastroenterology and Nutrition, 2018

• Children aged 5 to 18 years old with RAP or an
abdominal pain-related functional gastrointestinal
disorder, as defined by the Rome III criteria.
• We judged the evidence of effectiveness to be of
low quality.
• We found probiotic diets, cognitive behavioural
therapy (CBT) and hypnotherapy were reported to
reduce pain in the short-term and medium-term
effectiveness

• Effects of probiotics: 15 studies, 1123 children
• The trials ranged in duration from 4-12 weeks, and
used a range of probiotic preparations (5 used
Lactobacillus rhamnosus GG; 5 used Lactobacillus reuteri DSM 17938; 2
used Bacillus coagulans with fructo-oligosaccharides; 1 used a patented
mixture called VSL#3 containing 8 different strains (Bifidobacterium
breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus
acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus
bulgaris, Streptococcus thermophiles); one used a combination of three
Bifidobacterium species (Bifidobacterium longum BB536,
Bifidobacterium infantis M-63 and Bifidobacterium breve M-16V; and
one used Lactobacillus plantarum LP299V).

Improvement in pain post-intervention for probiotics compared to placebo
NNT = 8
The evidence regarding relative effectiveness of different strains of probiotics
is currently insufficient to guide clinical practice

Positive Effect of Probiotics on Constipation in
Children: A Systematic Review and Meta-Analysis of
Six Randomized Controlled Trials
• Eligible studies were RCT that compared the effect
of probiotics interventions to any control
intervention on stool frequency and consistency.
• Children < 18 y.
• Six studies were identified. The use of probiotics
significantly increased the stool frequency [mean
difference (MD), 0.73; 95% CI, 0.14–1.31; P = 0.02].
However, there was significant heterogeneity (I2=
84%, P = 0.02).
Huang R et al. Front Cell Infect Microbiol. 2017 Apr 28;7:153

Frequenza delle evacuazioni

• Included 4 trials reporting data on 382 children with
functional constipation.
• There were no significant differences in treatment success
(P=.697), spontaneous bowel movements per week
(P=.571), fecal soiling episodes per week (P=.642), straining
at defecation (P=.408), use of lactulose (P=.238), use of
laxatives (P=.190), fecal incontinence (P=.139), pain during
defecation (P=.410), flatulence (P=.109), and adverse events
(P=.979) between probiotics and placebo.
• The use of probiotics was associated with lower frequency
of glycerin enema use (weighted MD 2.40, P=.004) and
abdominal pain (weighted MD 4.80, P<.001).
Jin L et al. Medicine (2018) 97:39(e12174)
Systematic review and meta-analysis of the effect
of probiotic supplementation on functional
constipation in children

Systematic review and meta-analysis of the effect
of probiotic supplementation on functional
constipation in children
Jin L et al. Medicine (2018) 97:39(e12174)

Effectiveness of Probiotics in Children With
Functional Abdominal Pain Disorders and
Functional Constipation. A Systematic Review
• A systematic review was conducted,
searching PubMed and Cochrane databases
from inception to January 2018 for RCTs
investigating the efficacy of probiotics in
children aged 4 to 18 years with FAPD or
children aged 0 to 18 years with FC.
• 11 RCTs for FAPD and 6 RCTs for FC were
included
Wheg CAM et al. J Clin Gastroenterol. 2018 Nov/Dec;52 Suppl 1

• Some evidence exists for Lactobacillus rhamnosus GG
(n=3) in reducing frequency and intensity of
abdominal pain in children with irritable bowel
syndrome (IBS)
• There is no evidence to recommend L. reuteri DSM
17938 (n=5), a mix of Bifidobacterium infantis,
Bifidobacterium breve and Bifidobacterium longum
(n=1), Bifidobacterium lactis (n=1) or VSL#3 (n=1) for
children with FAPD.
• No evidence exists to support the use of Lactobacillus
casei rhamnosus LCR35 (n=1), B. lactis DN173 010
(n=1), B. longum (n=1), L. reuteri DSM 17938 (n=1), a
mix of B. infantis, B. breve and B. longum (n=1), or
Protexin mix (n=1) for children with FC.
Wheg CAM et al. J Clin Gastroenterol. 2018 Nov/Dec;52 Suppl 1
Effectiveness of Probiotics in Children With
Functional Abdominal Pain Disorders and
Functional Constipation. A Systematic Review

Probiotics for management of infantile colic:
a systematic review of randomized controlled trials
• Infantile colic is a common pediatric problem.
• The cause of infantile colic remains unclear.
• Treatment options are limited.
• Evidence suggests that probiotics might offer
some benefit.
• The aim of the study was to systematically assess
the effectiveness of probiotics supplementation in
the management of infantile colic
Dryl R et al. Arch Med Sci 2018; 14, 5: 1137–1143

• MEDLINE and the Cochrane Library
were searched up to April 2016 for
RCTs evaluating the efficacy of
probiotics (any well-defined strain)
compared with placebo for the
management of infantile colic.
• The outcome measures of interest
were treatment success and the
duration of crying at the end of the
intervention.
• Seven RCTs (471 participants) were
included.

• Results: Compared with placebo the administration
of Lactobacillus reuteri DSM 17938 at a daily dose
of 108 CFU was associated with the treatment
success (relative risk = 1.67, 95% CI: 1.10–2.81,
NNT=5, 95% CI: 4–8) and reduced crying times at
the end of the intervention (mean difference: –49
min, 95% CI: –66 to –33); however, the effect was
mainly seen in exclusively breastfed infants.

Treatment
success
Conclusions: Some probiotics, primarily L.
reuteri DSM 17938, may be considered for the
management of infantile colic in breastfed inf.
Data on other probiotics are limited.

4 - Diarrea acuta/Gastroenterite

Florez ID et al. PLoS ONE 13(12): e0207701, 2018
Comparative effectiveness and safety of interventions for
acute diarrhea and gastroenteritis in children: A systematic
review and network meta-analysis
• Eligible trials compared zinc (ZN), vitamin A,
micronutrients (MN), probiotics, prebiotics,
symbiotics, racecadotril, smectite(SM), loperamide,
diluted milk, lactose-free formula(LCF), or their
combinations, to placebo or standard treatment
(STND), or among them.
• The primary outcome was diarrhea duration.
• Secondary outcomes were stool frequency at day
2, diarrhea at day 3, vomiting and side effects

• A total of 174 studies (32,430 children) proved
eligible. Studies were conducted in 42 countries of
which most were low-and middle-income countries
(LMIC).
• Interventions were grouped in 27 categories.
• Most interventions were better than STND
• The combinations Saccharomyces boulardii
(SB)+ZN, and SM+ZN were considered the best
interventions

Ianiro G et al. Nutrients 2018, 10, 1074; doi:10.3390/nu10081074
Bacillus clausii for the Treatment of Acute Diarrhea
in Children: A Systematic Review and Meta-Analysis
of Randomized Controlled Trials
• Six RCT (1298 patients) met the eligibility criteria.
• Data arising from pooled analysis showed that Bacillus
clausii significantly reduced the duration of diarrhea (MD =
-9.12 h; 95% CI: -16.49 to-1.75, p = 0.015), and the duration
of hospitalization (MD = -0.85 days; 95% CI: -1.56 to -0.15, p
= 0.017), compared with control.
• There was a trend of decreasing stool frequency after
Bacillus clausii administration compared with the control
group (MD = -0.19 diarrheal motions; 95% CI: -0.43 to -0.06,
p = 0.14).
• Bacillus clausii may represent an effective therapeutic
option in acute childhood diarrhea, with a good safety
profile

Ianiro G et al. Nutrients 2018, 10, 1074; doi:10.3390/nu10081074
Durata della diarrea Durata del ricovero
Bacillus clausii for the Treatment of Acute Diarrhea
in Children: A Systematic Review and Meta-Analysis
of Randomized Controlled Trials

Freedman SB et al. N Engl J Med 2018;379:2015-26
Multicenter Trial of a Combination Probiotic
for Children with Gastroenteritis
• We conducted a randomized, double-blind trial involving 886 children 3
to 48 months of age with gastroenteritis who presented to six pediatric
EDs in Canada.
• Participants received a 5-day course of a combination probiotic product
containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a
dose of 4.0×109 CFU twice daily or placebo.
• The primary outcome was moderate-to-severe gastroenteritis, which
was defined according to a post-enrollment modified Vesikari scale
symptom score of 9 or higher (scores range from 0 to 20, with higher
scores indicating more severe disease).
• Secondary outcomes included the duration of diarrhea and vomiting,
the percentage of children who had unscheduled physician visits, and
the presence or absence of adverse events

• Moderate-to-severe gastroenteritis within 14 days
after enrollment occurred in 108 of 414 participants
(26.1%) who were assigned to probiotics and 102 of
413 participants (24.7%) who were assigned to placebo
(OR 1.06; 95% CI, 0.77 to 1.46; p = 0.72).
• There were no significant differences between the
probiotic group and the placebo group in the median
duration of diarrhea or vomiting the percentages of
participants with unscheduled visits to a health care
provider and the percentage of participants who
reported an adverse event.

In conclusion, we found that a twice-daily, 5-day course of 4.0×109
CFU of a combined L. rhamnosus and L. helveticus probiotic did
not prevent the development of moderate-to-severe
gastroenteritis within 14 days after enrollment

Schnadower D et al. N Engl J Med 2018;379:2002-14
Lactobacillus rhamnosus GG versus Placebo
for Acute Gastroenteritis in Children
• Prospective randomized double-blind trial involving
children 3 months to 4 years of age with acute
gastroenteritis who presented to one of 10 U.S.
pediatric ED
• Participants received a 5-day course of Lactobacillus
rhamnosus GG at a dose of 1×1010 colony-forming units
twice daily or matching placebo
• The primary outcome was moderate-to-severe
gastroenteritis (Vesikari scale of 9 or higher, scores
range from 0 to 20, with higher scores indicating more
severe disease), within 14 days after enrollment

RESULTS
• Among the 971 participants, 943 (97.1%) completed the
trial. The median age was 1.4 years.
• The Vesikari scale score for the 14-day period after
enrollment was 9 or higher in 55 of 468 participants (11.8%)
in the L. rhamnosus GG group and in 60 of 475 participants
(12.6%) in the placebo group (RR 0.96; 95% CI, 0.68 to 1.35;
p = 0.83).
• There were no significant differences between the L.
rhamnosus GG group and the placebo group in the duration
of diarrhea (median, 49.7 hours in the L. rhamnosus GG
group and 50.9 hours in the placebo group; P = 0.26),
duration of vomiting (median, 0 hours in both groups; P =
0.17), or day-care absenteeism (median, 2 days in both
groups; P = 0.67).

RESULTS
• Among the 971 participants, 943 (97.1%) completed the
trial. The median age was 1.4 years.
• The Vesikari scale score for the 14-day period after
enrollment was 9 or higher in 55 of 468 participants (11.8%)
in the L. rhamnosus GG group and in 60 of 475 participants
(12.6%) in the placebo group (RR 0.96; 95% CI, 0.68 to 1.35;
p = 0.83).
• There were no significant differences between the L.
rhamnosus GG group and the placebo group in the duration
of diarrhea (median, 49.7 hours in the L. rhamnosus GG
group and 50.9 hours in the placebo group; P = 0.26),
duration of vomiting (median, 0 hours in both groups; P =
0.17), or day-care absenteeism (median, 2 days in both
groups; P = 0.67).
CONCLUSIONS
Among preschool children with acute gastroenteritis,
those who received a 5-day course of L. rhamnosus GG
did not have better outcomes than those who received
placebo

LI Y-T et al. World J Gastroenterol 2019 September 7; 25(33): 4999-5016
RESULTS
• Nineteen RCTs met the inclusion criteria and showed that
compared with the control group, LGG administration
notably reduced the diarrhea duration [ MD -24.02 h, 95%
(CI) (-36.58, -11.45)].
• More effective results were detected at a high dose ≥ 1010
CFU per day vs a lower dose.
• A similar reduction was found in Asian and European
patients
• High-dose LGG effectively reduced the duration of
rotavirus-induced diarrhea [MD -31.05 h, 95%CI (-50.31, -
11.80)] and the stool number per day [MD -1.08, 95%CI (-
1.87, -0.28)].
Efficacy of Lactobacillus rhamnosus GG in treatment
of acute pediatric diarrhea: A systematic review
with meta-analysis

LI Y-T et al. World J Gastroenterol 2019 September 7; 25(33): 4999-5016
Efficacy of Lactobacillus rhamnosus GG in treatment
of acute pediatric diarrhea: A systematic review
with meta-analysis

Goldenberg JZ et al. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD004827
Probiotics for the prevention of pediatric
antibiotic associated diarrhea (Review)
• The primary objectives were to assess the efficacy
and safety of probiotics (any specified strain or
dose) used for the prevention of AAD in children.
• Randomized, parallel, controlled trials in children (0
to 18 years) receiving antibiotics, that compare
probiotics to placebo, active alternative
prophylaxis, or no treatment and measure the
incidence of diarrhea secondary to antibiotic use
were considered for inclusion

• Twenty-three studies (3938 participants) met the
inclusion criteria.
• Trials included treatment with either Bacillus spp.,
Bifidobacterium spp., Clostridium butyricum,
Lactobacilli spp., Lactococcus spp., Leuconostoc
cremoris, Saccharomyces spp., or Streptococcus
spp., alone or in combination.
• The risk of bias was determined to be high or
unclear in 13 studies and low in 10 studies.

• The incidence of AAD in the probiotic group was 8%
(163/1992) compared to 19% (364/1906) in the control
group (RR 0.46, 95% CI 0.35 to 0.61; I2 = 55%, 3898
participants).
• A GRADE analysis indicated that the overall quality of
the evidence for this outcome was moderate.
• Moderate quality evidence suggests a protective effect
of probiotics in preventing AAD (NNT=10).
• Among the various probiotics evaluated, Lactobacillus
rhamnosus or Saccharomyces boulardii at 5 to 40
billion colony forming units/day may be appropriate.

Hojsak L et al. Journal of Pediatric Gastroenterology and Nutrition, 2018, 66(1), 3–9.
Probiotics for the prevention of nosocomial
diarrhea in children
• This document provides recommendations
developed by the ESPGHAN Working Group (WG)
on Probiotics and Prebiotics on the role of
probiotics in the prevention of nosocomial
diarrhea in children based on a systematic review
and of subsequently published RCTs.
• The quality of evidence was assessed using the
Grading of Recommendations Assessment,
Development and Evaluation (GRADE) guidelines

• The primary outcome measure was nosocomial
diarrhea regardless of the cause.
• The secondary outcome was nosocomial gastroenteritis
caused by Rotavirus.
• Included participants were infants and children up to
18 years of age. Neonates and premature babies were
excluded from the analysis.
• As in previous guidelines, the focus was on 6 taxonomic
probiotic groups (Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and/or
Bacillus).

preventing
nosocomial
diarrhea

preventing
nosocomial
rhotavirus
diarrhea

preventing
nosocomial
rhotavirus
diarrhea
RECOMMENDATION. If probiotics for preventing nosocomial
diarrhea in children are considered, the WG recommends using
L. rhamnosus GG (at least 109 CFU/day, for the duration of
hospital stay).
QUALITY OF EVIDENCE: Moderate
STRENGTH OF RECOMMENDATION: Strong

7 - Infezione da Clostridium Difficile

Johnston BJ et al. Infect Control Hosp Epidemiol 2018;1–11
Microbial Preparations (Probiotics) for the Prevention of
Clostridium difficile Infection in Adults and Children: An
Individual Patient Data Meta-analysis of 6,851 Participants
• Identified 32 RCTs (n= 8,713); among them, 18 RCTs (n
=6,851 participants) compared probiotic prophylaxis to
placebo or no treatment (standard care).
• Probiotics reduced CDI odds in the unadjusted model
(n =6,645; odds ratio [OR] 0.37; 95% confidence
interval [CI], 0.25–0.55) and the adjusted model (n=
5,074; OR, 0.35; 95% CI, 0.23–0.55).
• Using 2 or more antibiotics increased the odds of CDI
(OR, 2.20; 95% CI, 1.11–4.37)
• Multispecies probiotics were more beneficial than
single-species probiotics

Johnston BJ et al. Infect Control Hosp Epidemiol 2018;1–11
Microbial Preparations (Probiotics) for the Prevention of
Clostridium difficile Infection in Adults and Children: An
Individual Patient Data Meta-analysis of 6,851 Participants
Conclusions. Moderate quality evidence suggests that probiotic
prophylaxis may be a useful and safe CDI prevention strategy,
particularly among participants taking 2 or more antibiotics
and in hospital settings where the risk of CDI is ≥5%.

Is It Useful to Administer Probiotics Together With
Proton Pump Inhibitors in Children With
Gastroesophageal Reflux?
• Gastroesophageal reflux disease (GERD) is a frequent
condition diagnosed in children and treated with
proton pump inhibitors (PPI).
• Long-term PPI administration can alter intestinal
bacterial population by suppressing the gastric acid
barrier and may cause diarrhea.
• The aim of this study is to evaluate the prevalence of
small intestinal bacterial overgrowth assessed by
glucose hydrogen breath test among children that
received 12 weeks of PPI with or without probiotics
(Lactobacillus reuteri DSM 17938) associated,
compared to controls
Belei O et al. J Neurogastroenterol Motil, Vol. 24 No. 1 January, 2018

• Glucose hydrogen breath test was performed
before PPI treatment and after 12 weeks of PPI
treatment to 128 consecutive children with GERD
(1-18 years old) and a control group (120 healthy
children).
• The children with GERD were randomized into 2
groups:
• placebo group (64 who received PPI and placebo for 12
weeks) and
• probiotics group (64 who received PPI and probiotics for
12 weeks).

• Results: after 12 weeks of treatment, dysbiosis was detected among
56.2% of children from placebo group (36/64), compared to 6.2% of
children from the probiotics group (4/64, P < 0.001). Bacterial
overgrowth was detected in 5% of controls (6/120). Probiotics group
had a lower prevalence of dysbiosis, similar to controls (P = 0.740).

• Results: after 12 weeks of treatment, dysbiosis was detected among
56.2% of children from placebo group (36/64), compared to 6.2% of
children from the probiotics group (4/64, P < 0.001). Bacterial
overgrowth was detected in 5% of controls (6/120). Probiotics group
had a lower prevalence of dysbiosis, similar to controls (P = 0.740).
Conclusion: Probiotics administration decreased the
rate of dysbiosis among children treated with PPI

9 - Dermatite atopica (trattamento)

Probiotics for the Treatment of Atopic Dermatitis in
Randomized Controlled Trials
• Thirteen studies were identified.
• Significantly higher SCORAD
values favoring probiotics over
controls were observed (mean
difference [MD], −3.07; 95%
confidence interval [CI], −6.12 to
−0.03; P < 0.001).
• Subgroup analyses showed that
in Europe SCORAD revealed no
effect of probiotics, whereas
significantly lower SCORAD
values were reported in Asia
(MD, −5.39; 95%CI, −8.91 to
−1.87).
Huang R et al. Front Cell Infect Microbiol. 2017 Sep 6;7:392

• Lactobacillus fermentum
(MD, −11.42; 95%CI,
−13.81 to −9.04),
Lactobacillus salivarius
(MD, 7.21; 95%CI, −9.63
to −4.78), and a mixture of
different strains (MD,
−3.52; 95%CI, −5.61 to
−1.44) showed significant
effects on SCORAD values
in children with AD.
Huang R et al. Front Cell Infect Microbiol. 2017 Sep 6;7:392
Probiotics for the Treatment of Atopic Dermatitis in
Randomized Controlled Trials

10 - Dermatite atopica (Prevenzione)

Lactobacillus rhamnosus GG in the Primary
Prevention of Eczema in Children: A
Systematic Review and Meta-Analysis
Szajewska H et al. Nutrients 2018, 10, 1319
• Current guidelines recommend the use of probiotics to
reduce the risk of eczema (Fiocchi, WAO J 2015).
• It remains unclear which strain(s) to use
• We systematically evaluated data on the efficacy of
Lactobacillus rhamnosus GG (LGG) supplementation
prenatally and/or postnatally for the primary prevention of
eczema
• The primary outcome was eczema
• The GRADE criteria were used to assess the overall quality
of evidence

• Seven publications reporting 5 RCTs (889 participants)
were included.
• High to moderate certainty in the body of evidence
suggests that LGG supplementation (regardless of the
timing of administration) did not reduce the risk of
eczema.
• There was also no consistent effect on other allergic
outcomes.
• This meta-analysis shows that LGG was ineffective in
reducing eczema. It does not support the general
recommendation to use probiotics for preventing
eczema, unless specific strains would be indicated

eczema asma

Probiotics supplementation in children with
asthma: A systematic review and meta-
analysis
• Eleven studies with a total
of 910 children
• No statistical significance
was observed in childhood
ACT, asthmatic symptom,
in symptom-free days,
FEV1
• The pooled data revealed
that the proportion of
children with fewer
episodes of asthma was
significantly higher in the
probiotics group than in
the control group
ACT
Score day
Score night
Lin J et al. Journal of Paediatrics and Child Health (2018)

Effects of pro-/synbiotic supplementation on
anthropometric and metabolic indices in overweight or
obese children and adolescents: A systematic review and
meta-analysis
• Overall 9 randomized trials including 410 subjects
(2-18 y) were identified for the present meta-
analysis
• Supplementation with pro-/synbiotics for 4–16
weeks
• Conclusion: Based on our findings, modulation of
gut microbiota composition through pro-/ synbiotic
supplements did not have favorable effects to
manage overweight or obese children and
adolescents
Mohammadi H et al. Complementary Therapies in Medicine 44 (2019) 269–276

Effects of pro-/synbiotic supplementation on
anthropometric and metabolic indices in overweight or
obese children and adolescents: A systematic review and
meta-analysis
Mohammadi H et al. Complementary Therapies in Medicine 44 (2019) 269–276

13 - Prevenzione malattie
allergiche nel pretermine

Plummer E et al. Allergy 2019 Oct 14
Postnatal probiotics and allergic disease in
very preterm infants: sub-study to the
ProPrems randomized trial
• Alteration of the gut microbiota composition in
early life have been associated with increased risk
of allergic diseases such as eczema and atopic
sensitization
• Compared with term infants, preterm infants
typically have a low diversity gut microbiota with
low abundance of anaerobes
• Preterm infants have been shown to have an
increased risk of asthma and wheeze by meta-
analysis compared to term infant

• In this study 1099 very preterm infants (<32 weeks’
gestation and weighing <1500g) were randomized
1:1 to receive a probiotic combination
Bifidobacterium infantis, Streptococcus
thermophilus and Bifidobacterium lactis once daily
or placebo (maltodextrin), from soon after birth
until discharge from hospital
• The primary outcomes of this sub-study were
incidence of allergic diseases (eczema, atopic
eczema, food allergy and wheeze) and atopic
sensitization in the first two years of life

14 - Infezioni respiratorie ricorrenti

Network Meta-Analysis of Probiotics to
Prevent Respiratory Infections in Children
and Adolescents
• RCT assessing the effect of probiotics on RTIs in
children and adolescents were included.
• Two reviewers, working independently, to identify
studies that met the eligibility criteria.
• Main and secondary outcomes were RTIs and
adverse effects, respectively.
• Twenty-one trials with 6.603 participants were
included
Amaral MA et al. Pediatric Pulmonology, 2017

• The probiotics used in the included studies are:
Lactobacillus casei rhamnosus (LCA), Lactobacillus
rhamnosus T cell-1 (RHT), Lactobacillus reuteri
(LRE), Bifidobacterium lactis (BB-12), Lactobacillus
rhamnosus GG (LGG), Lactobacillus fermentum
CECT5716 (LFC), Streptococcus salivarius K12 (SSK),
Bacillus clausii (BCL), and placebo (PLA).
• Some studies used a mixture of probiotics as an
intervention
• The study has received financial aid from Brazilian
governmental agencies that support research
and Adolescents

and Adolescents

• Pairwise meta-analysis suggested that Lactobacillus
casei rhamnosus (LCA) was the only effective probiotic
to the rate of RTIs compared to placebo (RR=0.38; Cl
0.19–0.45).
• LCA showed no better effect compared to other
probiotic strains by indirect analysis.
• This systematic review found a lack of evidence to
support the effect of probiotic on the incidence rate of
respiratory infections in children and adolescents;
there is insufficient evidence to support the general
use of both isolated and mixtures of probiotics in the
prevention and treatment of respiratory tract infections
and Adolescents

Probiotics for respiratory tract infections in children
attending day care centers-a systematic review
• Evaluate strain-specific probiotic effects on RTIs in
children attending day care.
• We included 15 RCTs with 5121 children in day care
settings (aged 3 months to 7 years)
• Twelve RCTs (n = 4527) reported results which could be
compared in at least one outcome of the meta-analysis.
• Compared to placebo, Lactobacillus rhamnosus GG
(LGG) significantly reduced duration of RTIs (three
RCTs, n = 1295, mean difference − 0.78 days, 95%
confidence interval (CI) − 1.46; − 0.09), whereas no
effect was found on other evaluated outcomes (acute
otitis media (AOM), antibiotic use, duration of respiratory tract
infections, and days missed)
Laursen RP et al. Eur J Pediatr. 2018 May 12. doi: 10.1007/s00431-018-3167-1

Laursen RP et al. Eur J Pediatr. 2018 May 12. doi: 10.1007/s00431-018-3167-1
Probiotics for respiratory tract infections in children
attending day care centers-a systematic review
Conclusion: LGG is modestly effective in decreasing
the duration of RTIs. More RCTs investigating specific
probiotic strains or their combinations in prevention
of RTIs are needed

Probiotic supplementation in children
with cystic fibrosis: a systematic review
• Probiotics may benefit in cystic fibrosis (CF) as gut
dysbiosis is associated with gastrointestinal
symptoms and exacerbation of respiratory
symptoms in CF
• Systematic review of RCTs and non- RCTs of
probiotic supplementation in children with CF
• Primary outcomes were pulmonary exacerbations,
duration of hospitalization and antibiotics, and all-
cause mortality.
Ananthan A et al. Eur J Pediatr, 2016

• A total of nine studies (RCTs 6, non-RCTs 3; N = 275) with some
methodological weaknesses were included in the review.
• The pooled estimate showed significant reduction in the rate
of pulmonary exacerbation (fixed effects model, two parallel
group RCTs and one cross-over trial: RR 0.25, (95 % CI
0.15,0.41); p < 0.00001; level of evidence: low) and decrease
in fecal calprotectin (FCLP) levels (fixed effect model, three
RCTs: MD −16.71, 95 % CI −27.30,−6.13); p = 0.002; level of
evidence: low) after probiotic supplementation.
• Conclusion: Limited low-quality evidence exists on the effects
of probiotics in children with CF

Sintomi respiratori

Calprotectina fecale

16 - Ittero neonatale patologico

Probiotics Supplementation Therapy for
Pathological Neonatal Jaundice: A Systematic
Review and Meta-Analysis
• Neonatal jaundice is a relatively prevalent disease and
affects approximately 2.4–15% newborns.
• This study aims at systematically evaluating the efficacy
and safety of probiotics supplement therapy for
pathological neonatal jaundice.
• RCTs of probiotics supplementation for pathological
neonatal jaundice
• The cochrane tool was applied to assessing the risk of
bias of the trials.
• The relative risks (RR) or mean difference (MD) with a
95% confidence interval (CI) was used to measure the
effect
Chen Z et al Front. Pharmacol. 2017, 8:432

• 13 RCTs involving 1067 neonatal with jaundice were
included in the meta-analysis.
• Probiotics supplementation treatment showed efficacy [RR:
1.19, 95% CI (1.12, 1.26), P < 0.00001] in neonatal jaundice.
• It not only decreased the total serum bilirubin level after 3
day [MD: −18.05, 95% CI (−25.51, −10.58), P < 0.00001], 5
day [MD: -23.49, 95% CI (−32.80, −14.18), P < 0.00001], 7
day [MD: −33.01, 95%CI (−37.31, −28.70), P < 0.00001]
treatment, but also decreased time of jaundice fading [MD:
−1.91, 95% CI (−2.06, −1.75), P < 0.00001], as well as the
duration of phototherapy [MD: −0.64, 95% CI (−0.84,
−0.44), P < 0.00001] and hospitalization [MD: −2.68, 95% CI
(−3.18, −2.17), P < 0.00001], when compared with the
control group.
• Additionally, no serious adverse reaction was reported

Conclusion: This meta-analysis shows that probiotics
supplementation therapy is an effective and safe
treatment for pathological neonatal jaundice

Probiotics for management of neonatal
hyperbilirubinemia: a systematic review of
randomised controlled trials
• SR of RCT of probiotic supplementation for prevention
or treatment of jaundice in neonates (any gestation or
weight) using the Cochrane methodology
• Primary outcome was the duration of phototherapy.
• Secondary outcomes included incidence of jaundice,
total serum bilirubin level (TSB) at 24, 48, 72, 96 hours
and day 7, duration of hospital stay, and adverse effects
(e.g. probiotic sepsis).
• Results were summarized as per GRADE guidelines
Deshmukh J et al. The Journal of Maternal-Fetal & Neonatal Medicine, 2017

• Nine RCTs (Prophylactic: 6 trials, N=1761; Therapeutic: 3
trials, N=279) were included
• Meta-analysis (Random effects model) showed
probiotics supplementation reduced duration of
phototherapy (N=415, MD: -11.80(-17.47, -6.13)
p<0.0001; Level of evidence (LOE): Low]. TSB was
significantly reduced at 96 hours [MD: -1.74(-2.92, -
0.57) p=0.004], and 7 days [MD: -1.71(-2.25, -1.17)
p<0.00001; LOE: Low] after probiotic treatment.
• Prophylactic probiotics didn’t reduce the incidence of
jaundice significantly [N=1582, RR: 0.56 (0.25, 1.27)
p=0.16; LOE: Low].
• There were no probiotic related adverse effects.

• Nine RCTs (Prophylactic: 6 trials, N=1761; Therapeutic: 3
trials, N=279) were included
• Meta-analysis (Random effects model) showed
probiotics supplementation reduced duration of
phototherapy (N=415, MD: -11.80(-17.47, -6.13)
p<0.0001; Level of evidence (LOE): Low]. TSB was
significantly reduced at 96 hours [MD: -1.74(-2.92, -
0.57) p=0.004], and 7 days [MD: -1.71(-2.25, -1.17)
p<0.00001; LOE: Low] after probiotic treatment.
• Prophylactic probiotics didn’t reduce the incidence of
jaundice significantly [N=1582, RR: 0.56 (0.25, 1.27)
p=0.16; LOE: Low].
• There were no probiotic related adverse effects.
Conclusion: Limited low-quality evidence indicates
that probiotic supplementation may reduce the
duration of phototherapy in neonates with
jaundice. Routine use of probiotics to prevent or
treat neonatal jaundice cannot be recommended.
Large well-designed trials are essential to confirm
these findings

17 - Terapia eradicante Helicobacter

Feng J et al. Eur J Clin Pharmacol (2017) 73:1199–1208
Efficacy and safety of probiotic-supplemented triple therapy
for eradication of Helicobacter pylori in children: a
systematic review and network meta-analysis
• The aim of this study was to identify the best probiotic
supplementation in triple therapy for pediatric
population with Helicobacter pylori infection.
• Twenty-nine trials (3122 participants) involving 17
probiotic regimens were identified.
• Compared with placebo, probiotic-supplemented
triple therapy significantly increased H. pylori
eradication rates (relative ratio (RR) 1.19, 95% CI 1.13–
1.25) and reduced the incidence of total side effects
(RR 0.49, 95%CI 0.38–0.65).
• Furthermore, to supplemented triple therapy,
Lactobacillus casei was identified the best for H. pylori
eradication rates (P score = 0.84),

Eradicazione H. pylorii Effetti collaterali terapia con probiotici

Eradicazione H. pylorii Effetti collaterali terapia con probiotici
Conclusions: Probiotics are recommended to
supplement triple therapy in pediatrics, and the
effectiveness of triple therapy is associated with
specific probiotic supplementation

18 - Potenziamento della risposta
immunitaria indotta dalle vaccinazioni

Kwak JY et al. Benef Microbes. 2017 Oct 13;8(5):657-670
Can probiotics enhance vaccine-specific
immunity in children and adults?
• Enhanced immune
function is among the
touted health benefits
conferred by probiotics
but has not yet been
fully established
• This review evaluates
recent clinical trials of
probiotics used to
enhance vaccine-specific
immune responses in
adults and infants

Conclusions: In summary, based upon
the results of 21 clinical trials examining
the effect of probiotics on vaccine-
specific immunity, the positive effect of
probiotics remains inconclusive.

19 - Infezioni delle vie urinarie

Hosseini M et al. Journal of Pediatric Urology (2017)
The efficacy of probiotics in prevention of urinary
tract infection in children: A systematic review and
meta-analysis
• This systematic review and meta-analysis was
designed to assess the efficacy of probiotics in
prevention UTI in children.
• Results: data from 10 studies were entered in the
present meta-analysis.
• Probiotic therapy did not have any beneficial effect
on the incidence of UTI (RR = 0.94; 95% CI 0.85–
1.03; p = 0.19) and its recurrence (RR = 0.93; 95% CI
0.85–1.02; p = 0.14).

Hosseini M et al. Journal of Pediatric Urology (2017)
The efficacy of probiotics in prevention of urinary
tract infection in children: A systematic review and
meta-analysis

CONDIZIONI PATOLOGICHE RISULTATI
POSITIVO bassa qualità, NNT=8 (più dati per L. Rhamnosus GG)
INCERTO (POS solo L. Rhamnosus GG in BIS)
POSITIVO (solo L. Reuteri DSM 17938 solo se alimentati al seno)
POS S. Boulardii e B. Clausii – POS L. Rhamn GG alte dosi
POSITIVO (solo S. Boulardii e L. Rhamnosus, NNT=10)
POSITIVO (solo L. Rhamnosus GG)
POSITIVO (meglio più ceppi, setting ospedaliero)
POSITIVO (meno disbiosi i trattati con PPI)
INCERTO (POS solo L. Fermentum e L. Salivarius)
INCERTO (NEG L. Rhamnosus GG) (POS solo LG WAO ma non specif ceppi)
NEGATIVO
NEGATIVO
NEGATIVO
INCERTO (POS solo L. Rhamnosus GG)
POSITIVO (bassa qualità, dati limitati)
INCERTO (alcuni dati POS, no uso routinario in prevenzione)
POSITIVO (da preferire L. Casei)
INCERTO (dati non conclusivi)
NEGATIVO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

201911 - Pingitore - Quando usare i probiotici in pediatria?

201911 - Pingitore - Quando usare i probiotici in pediatria?

More Related Content

What's hot (20)

Similar to 201911 - Pingitore - Quando usare i probiotici in pediatria? (20)

More from Asmallergie (20)

Recently uploaded (20)

201911 - Pingitore - Quando usare i probiotici in pediatria?