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Effectiveness of probiotics on the duration of illness in healthy children
and adults who develop common acute respiratory infectious conditions:
a systematic review and meta-analysis
Sarah King1
, Julie Glanville1
*, Mary Ellen Sanders2
, Anita Fitzgerald1
and Danielle Varley1
1
York Health Economics Consortium, York, UK
2
Dairy and Food Culture Technologies, Centennial, CO 80122, USA
(Submitted 10 June 2013 – Final revision received 14 November 2013 – Accepted 8 January 2014 – First published online 29 April 2014)
Abstract
Recent systematic reviews have reported a positive, although modest, effect of probiotics in terms of preventing common cold symptoms.
In this systematic review, the effect of probiotics, specifically Lactobacillus and Bifidobacterium strains, on the duration of acute respiratory
infections in otherwise healthy children and adults was evaluated. To identify relevant trials, eight databases, including MEDLINE, Embase,
the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of
Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Science Citation Index (SCI) and OAISTER, were searched
from inception to 20 July 2012. Details regarding unpublished studies/databases were also obtained from probiotic manufacturers. Study
selection, data extraction and quality assessment were carried out by two reviewers. Risk of bias was assessed using criteria adapted from
those published by the Centre for Reviews and Dissemination. In this review, twenty randomised controlled trials (RCT) were included, of
which twelve were considered to have a low risk of bias. Meta-analysis revealed significantly fewer numbers of days of illness per person
(standardised mean difference (SMD) 20·31 (95 % CI 20·41, 20·11), I 2
¼ 3 %), shorter illness episodes by almost a day (weighted mean
difference 20·77 (95 % CI 21·50, 20·04), I 2
¼ 80 %) (without an increase in the number of illness episodes), and fewer numbers of days
absent from day care/school/work (SMD 20·17 (95 % CI 20·31, 20·03), I 2
¼ 67 %) in participants who received a probiotic intervention
than in those who had taken a placebo. Reasons for heterogeneity between the studies were explored in subgroup analysis, but could not
be explained, suggesting that the effect sizes found may differ between the population groups. This systematic review provides evidence
from a number of good-quality RCT that probiotics reduce the duration of illness in otherwise healthy children and adults.
Key words: Probiotics: Respiratory infections: Systematic reviews
Respiratory infectious conditions place a substantial health
and economic burden on society. In a 6-month survey of
3249 university students, upper respiratory tract infections
(RTI) resulted in 6023 bed-days, 4263 missed school days,
3175 missed workdays and 45 219 d of illness(1)
. According
to the United States Centers for Disease Control and Pre-
vention, twenty-two million school days and twenty million
workdays in adults are lost annually due to the common
cold in the USA(2)
. The economic impact of colds has been
estimated to be $40 billion dollars in the USA annually(3)
.
Probiotics are defined as live micro-organisms that confer a
health benefit on the host when administered in adequate
amounts(4)
. Several studies(5–8)
have evaluated the effectiveness
of probiotics on the symptoms and incidence of common
infectious respiratory diseases. Recent meta-analyses(9,10)
have
reported a positive, although modest, effect of probiotics in
terms of preventing common cold symptoms.
The objective of this systematic review was to assess the
effect of probiotics on the duration of an acute RTI in other-
wise healthy children and adults. We evaluated probiotics
that belong to the Lactobacillus and Bifidobacterium genera,
but not probiotics such as yeast and Gram-negative probiotics
(e.g. Escherichia coli), which are taxonomically distinct. Thus,
for the purposes of this review, ‘probiotic’ hereafter refers to
Lactobacillus and Bifidobacterium strains.
Methods
Studies eligible for inclusion in this systematic review were ran-
domised controlled trials (RCT) of any duration that compared
* Corresponding author: J. Glanville, fax þ44 1904 323628, email yhec@york.ac.uk
Abbreviations: Bentley_unpublished, C. Bentley unpublished results; RTI, respiratory tract infections; SMD, standardised mean differences.
British Journal of Nutrition (2014), 112, 41–54 doi:10.1017/S0007114514000075
q The Authors 2014. The online version of this article is published within an Open Access environment subject to the conditions of the
Creative Commons Attribution licence http://creativecommons.org/licenses/by/3.0/
BritishJournalofNutrition
Lactobacillus and/or Bifidobacterium strains consumed orally
with placebo or ‘no treatment’ in apparently healthy children
(aged between 1 and 18 years) or adults who developed acute
RTI at some point during the study. Open-label studies were
eligible as long as the patients were randomised. The probiotic
strains could be administered at any dose and could be
combined with or not be combined with non-Lactobacillus
or non-Bifidobacterium strains. Studies carried out using pro-
biotics combined with other functional ingredients (such as
prebiotics and vitamins) were also eligible as long as the com-
parator included the other functional ingredients, so that the
overall effects could be attributed to the probiotic. To be
eligible for inclusion, the trials had to report on a measure of
illness duration, such as the length of illness episodes,
number of days of illness per person, number of days off sick
from day care, school or work, or time without an infection.
‘Acute respiratory infections’ were considered to include
upper RTI and/or lower RTI, colds or influenza-like symp-
toms. Trials that reported on ‘common infectious disease’
were also included if RTI were defined within this umbrella
term by the trial authors. Studies conducted in infants (aged
,1 year), trained athletes, seriously ill people and institutiona-
lised elderly adults were excluded from this review as they
were considered to be immunologically distinct.
To identify relevant trials, we searched a number of data-
bases including MEDLINE, Embase, the Cochrane Database
of Systematic Reviews (CDSR), the Cochrane Central Register
of Controlled Trials (CENTRAL), the Database of Abstracts of
Reviews of Effects (DARE), Health Technology Assessment
(HTA) database, Science Citation Index (SCI) and OAISTER
from inception to 20 July 2012. The search was not restricted
by country or language. Search terms included (but were not
limited to) ‘Probiotics’, ‘Lactobacillus’ and ‘Bifidobacterium’.
The search results were combined with those obtained by
searching for terms including (but not limited to) ‘Common
Cold’, ‘Sinusitis’, ‘Pharyngitis’, ‘Laryngitis’ and ‘Respiratory
Tract Infections’. The full set of search terms is presented in
online Supplementary File S1.
Information on ongoing or recently completed trials,
unpublished research and research reported in the grey litera-
ture was obtained by searching trial registers and selected
major conference proceedings (3 years before search date).
Unpublished studies were included in accordance with estab-
lished approaches to the systematic review process(11,12)
. The
resources searched are also listed in online Supplementary
File S1. The references of recent reviews and eligible studies
were checked for additional trials not identified by the elec-
tronic search. Unpublished papers were also sought from
the manufacturers within the funding organisation (Global
Alliance for Probiotics), which included Yakult, Danone,
Probi, Lallemand, Chr. Hansen, DuPont and Valio. Studies
published only as abstracts or conference presentations were
included if adequate data were provided.
An initial screening of search results was done by one
reviewer to exclude obviously irrelevant records. The remain-
ing records were screened by two reviewers independently to
identify potentially relevant records meeting the inclusion/
exclusion criteria. Full papers were obtained for these
records and were assessed for relevance by two reviewers
independently. Any discrepancies were resolved through
discussion and/or by consulting a third reviewer.
For each eligible trial, data on study and population character-
istics and results were extracted by one reviewer and checked by
a second reviewer (Table 1). Quality assessment, using quality
criteria adapted from the Centre for Reviews and Dissemina-
tion(11)
, was also conducted by one reviewer and checked by a
second reviewer (summaries are given in Table 2 and full assess-
mentsareprovidedin online SupplementaryFileS2).Anydiscre-
pancies in data extraction or quality assessment were resolved
through discussion or by consulting a third reviewer. If any of
the quality criteria were unclear in the trial publications, study
authors were contacted for further (documented) information.
Means and standard deviations were collected for continuous
outcomes. In the absence of information, authors were con-
tacted for further details. If no further data could be obtained,
a standard deviation was imputed using P values or SD from
other similar studies (where possible). For studies involving
twoprobiotictreatment arms,themeansandstandarddeviations
from the two groups were combined using statistical software to
create a single pairwise comparison with the placebo group.
Where appropriate, data from all the studies were pooled in a
meta-analysis to determine the overall effect size (weighted
mean difference) with 95 % CI using a random-effects model.
When the same outcome was measured in different ways, the
data were pooled using a standardised mean difference (SMD)
statistic. When continuous and dichotomous data were pre-
sented for an outcome, SMD (or log OR) and their standard
errors were computed for all the studies to facilitate pooling of
the data. Meta-analysis was conducted using RevMan software
(The Nordic Cochrane Centre, The Cochrane Collaboration)(13)
.
Heterogeneityacrossthestudieswasinvestigatedusingthe x 2
test (significance set at P,0·1) and the I 2
statistic (with a value
$50 %) and by examining the random-effects between-study
variance (t 2
). When significant heterogeneity was evident, sub-
group analysis planned a priori was used to explore differences
among the trials for specific variables including age (children
and adults), sex, country of study, treatment dose, intervention
duration, and single-strain v. combination interventions. We
also evaluated studies by their overall risk of bias (low, high or
unclear) based on the Cochrane Risk of Bias tool. For the pur-
poses of this review, a study was assumed to have a ‘low risk
of bias’ when all the key quality criteria (i.e. randomisation
method, allocation concealment and blinding) as well as most
of the other criteria were adequately met; an ‘unclear risk’ of
bias when most of the key criteria were not reported or unclear;
and a ‘high risk’ of bias when one or more of the key criteria were
not adequately met. The category ‘some risk of bias’ was
assigned when all aspects of the key criteria were adequate,
but either (1) an intention-to-treat analysis was not conducted
and when one criterion was not met or (2) when two key criteria
were adequate, but an intention-to-treat analysis was not con-
ducted. The category ‘unclear/low risk of bias’ was assigned
when two key criteria were adequately met and the rest of
the criteria were adequate. Publication bias was assessed
using funnel plots when more than ten studies were included
in a meta-analysis(12)
.
S. King et al.42
BritishJournalofNutrition
Table 1. Characteristics of the included studies
Intervention Comparator
Study
Country
of study Population group Condition Detail(s)
Number
randomised
(included in
the analysis) Details
Number
randomised
(included in
the analysis)
Bentley (2008,
unpublished results)
Germany Adults at an increased risk
of infection (at least two
episodes in the previous
6 months)
Common cold Lactobacillus plantarum
HEAL9 and L. paracasei
8700:2 in maltodextrin
155 (146) Placebo: sachet contain-
ing maltodextrin
without living cultures
155 (138)
Berggren et al.(5)
Sweden Healthy adults aged
18–65 years
Common cold L. plantarum HEAL9 and
L. paracasei 8700:2 in
maltodextrin
159 (137) Placebo: sachet contain-
ing maltodextrin
without living cultures
159 (135)
Ca´ceres et al.(23)
Chile Children (aged 1–5 years)
attending day-care
centres
Acute respiratory tract
infections
L. rhamnosus HN001 203 (170) Placebo: milk product
with no probiotic
195 (179)
Cazzola et al.(20)
France Children (aged 3–7 years)
attending school
Common winter
diseases (URTI, LRTI
and gastrointestinal
tract infections)
L. helveticus R0052, Bifido-
bacterium infantis R0033
and Bifidobacterium bifi-
dum R0071
52 (62) Placebo: contained only
common excipients
73 (50)
de Vrese et al.(6)
Germany Healthy adults (aged
18–67 years)
Common cold L. gasseri PA 16/8, Bifido-
bacterium longum SP
07/3 and B. bifidum MF
20/5
238 (225) Placebo: vitamin mineral
preparation without
probiotic
241 (229)
Guillemard et al.(24)
Germany Healthy shift workers CID* Actimel, L. paracasei subsp.
casei DN-114001
combined with Strepto-
coccus thermophilus þ
L. delbrueckii subsp.
bulgaricus
500 (500) Placebo: dairy drink with-
out active components
500 (500)
Guillemard et al.(25)
France Elderly (not living in an
institution)
URTI Actimel, L. paracasei subsp.
casei DN-114001
combined with
S. thermophilus þ
L. delbrueckii subsp.
bulgaricus
537 (535) Placebo: dairy drink with-
out active components
535 (535)
Hatakka (2007,
unpublished results)
and Hatakka et al.(18)
Finland Children (aged 1–6 years)
attending day-care
centres
Gastrointestinal and
respiratory infections
L. rhamnosus GG Unclear (282) Placebo: milk without
probiotic
Unclear (289)
Hojsak et al.(28)
Croatia Hospitalised children aged
12 months and older
Respiratory symptoms L. rhamnosus GG 376 (376) Placebo: fermented milk
product without
L. rhamnosus GG
366 (366)
Hojsak et al.(29)
Croatia Children attending
day-care centres
Respiratory symptoms L. rhamnosus GG 139 (139) Placebo: fermented milk
product without
L. rhamnosus GG
142 (142)
Kloster et al.(27)
Norway Children (aged 12–36
months) attending
day-care centres
Gastrointestinal and
respiratory
symptoms
Biola with L. rhamnosus GG,
L. acidophilus LA-5
and Bifidobacterium
lactis BB-12
117 (97) Placebo: fermented milk
drink without probiotic
bacteria
123 (102)
Kumpu et al.(19)
Finland Children (aged 2–6 years)
attending day-care
centres
Respiratory symptoms L. rhamnosus GG 261 (251) Placebo: fresh milk
without L. rhamnosus
262 (250)
Probioticsandacuterespiratoryinfections43
British Journal of Nutrition
Table 1. Continued
Intervention Comparator
Study
Country
of study Population group Condition Detail(s)
Number
randomised
(included in
the analysis) Details
Number
randomised
(included in
the analysis)
Leyer et al.(7)
China Children (aged 3–5 years) Cold and influenza-like
symptoms
Two interventions: Placebo: sucrose added
to 1 % fat milk
104 (104)
L. acidophilus NCFM
(ATCC 700396)
110 (110)
L. acidophilus NCFM and
Bifidobacterium animalis
subsp. lactis Bi-07
(ATCC PTA-4802)
112 (112)
Merenstein et al.(21)
USA Healthy children (aged
3–6 years) attending
day care/school
CID* DanActive, L. paracasei
subsp. casei DN-114001
with S. thermophilus and
L. bulgaricus
314 (250
households)
Placebo: non-fermented
acidified dairy drink
324 (250
households)
Niborski (2008,
unpublished results)
France Healthy adults (mostly
men) recruited from a
fireman training course
CID* L. paracasei subsp.
casei DN-114001 with
S. thermophilus þ
L. delbrueckii subsp.
bulgaricus
118 (118) Placebo: acidified milk
(no bacteria)
121 (121)
Prodeus (2008,
unpublished results)
Russia Children (aged 3–5 years)
attending day-care
centres
URTI L. paracasei subsp.
casei DN-114001 with
S. thermophilus þ
L. delbrueckii
subsp. bulgaricus
300 (300) Placebo: acidified milk
(no bacteria)
299 (299)
Smith et al.(22)
USA Apparently healthy college
students
URTI L. rhamnosus GG and
B. lactis BB-12
114 (101) Placebo: powder without
probiotic
117 (97)
Tiollier et al.(15)
France Male cadets undergoing
commando training
Respiratory tract
infections
L. paracasei subsp.
casei DN-114001
24 (24) Placebo: non-fermented
milk
23 (23)
Tubelius et al.(16)
Sweden Healthy employees
working at TetraPak
Respiratory and/or
gastrointestinal tract
infections
Probiotic drinking straw with
L. reuteri protectis
132 (94) Placebo: drinking straw
without probiotic
130 (87)
Turchet et al.(17)
Italy Free-living elderly aged
above 60 years
CID* L. casei DN-114001 180 (180) No treatment 180 (180)
URTI, upper respiratory tract infections; LRTI, lower respiratory tract infections.
* CID included URTI, LRTI and gastrointestinal tract infections.
S.Kingetal.44
British Journal of Nutrition
Table 2. Quality criteria and study risk of bias assessment
Reference
Was
randomisation
carried out
appropriately?
Was the
concealment of
treatment allocation
adequate?
Were the care
providers, participants
and outcome
assessors blind to
treatment allocation?
Were the groups
similar at the onset
of the study in terms
of prognostic factors,
for example, severity
of the disease?
Were there any
unexpected imbalances
in dropouts between the
groups? If so, were they
explained or adjusted for?
Is there any evidence
to suggest that the
authors measured
more outcomes than
they reported?
Did the analysis
include an ITT
analysis? If so,
was this appropriate?
Bentley (2008,
unpublished results)
L L L L L? L L
Berggren et al.(5)
L L L L L L H
Ca´ceres et al.(23)
L L L L H Y H
Cazzola et al.(20)
L L L L L L L
de Vrese et al.(6)
L L L L L L H
Guillemard et al.(24)
L L L L L L L
Guillemard et al.(25)
L L L L L L L
Hatakka (2007,
unpublished results)
and Hatakka et al.(18)
L L L? L? L L H
Hojsak et al.(28)
L L L L L L L
Hojsak et al.(29)
L L L L L L L
Kloster et al.(27)
L L? L? L L L H
Kumpu et al.(19)
L L L? L? ? L H
Leyer et al.(7)
L L L? L L L L
Merenstein et al.(21)
L L L L L? L L
Niborski et al.(14)
L L L L L L L
Prodeus et al.(26)
L L L L? L L L
Smith et al.(22)
L L L L H L H
Tiollier et al.(15)
L L L L L L L
Tubelius et al.(16)
L L L L L L H
Turchet et al.(17)
L L? H L? H L L
ITT, intention-to-treat; L, low risk; L?, low risk with some areas of uncertainty; H, high risk; ?, unclear risk.
Probioticsandacuterespiratoryinfections45
British Journal of Nutrition
Results
A total of 3069 records were retrieved and 1888 remained
after deduplication. Following assessment based on title and
abstract, seventy-five records were considered to be poten-
tially relevant. Inclusion criteria were met by twenty-one
RCT, but for one trial, data were not available after request
(N. P. West, P. L. Horn, D. B. Pyne, V. J. Gebski,
S. J. Lahtinen, P. A. Fricker and A. W. Cripps, unpublished
results ‘Probiotic supplementation for respiratory and gastro-
intestinal illness symptoms in healthy physically active individ-
uals’). Twenty trials were included in this systematic review
(full details are provided in online Supplementary File S3):
Berggren et al.(5)
; de Vrese et al.(6)
; Leyer et al.(7)
; Niborski
et al.(14)
; Tiollier et al.(15)
; Tubelius et al.(16)
; Turchet et al.(17)
;
Hatakka et al.(18)
and K. Hatakka (unpublished results 2007
‘Probiotics in the prevention of clinical manifestations of
common infectious diseases in children and in the elderly’);
Kumpu et al.(19)
; Cazzola et al.(20)
; Merenstein et al.(21)
;
Smith et al.(22)
; Ca´ceres et al.(23)
; Guillemard et al.(24)
; Guille-
mard et al.(25)
; Prodeus et al.(26)
; Kloster et al.(27)
; Hojsak
et al.(28,29)
; C. Bentley (unpublished results ‘Double blind, ran-
domized, placebo-controlled, multicentric nutritional study to
prove the efficacy and safety of a probiotic for common
colds’)(Bentley_unpublished)
. Of these trials, ten investigated the
use of probiotics in children who ranged in age from
12 months to 12 years and ten were conducted in adults, of
which two were conducted in elderly free-living adults.
Approximately half of the trials were carried out in Western
Europe: Germany; Sweden; France; Finland; Norway; Italy.
The remaining trials were carried out in several different
countries including the USA, Chile, Russia, Croatia and China.
The duration of probiotic treatment ranged from 3 weeks to
7 months, although the majority of trials were carried out for
approximately 3 months – over the winter months. Only three
trials(14–16)
did not report the season in which the trial was
conducted, butthese trialswere conducted in settings such asa fire-
man training course, a military training course and employees
working at TetraPak. Other settings included day-care centres,
schools,auniversity,apaediatrichospitalorthegeneralpopulation.
Lactobacillus strains were investigated by fifteen
trials(Bentley_unpublished, 5,7,14 – 19,21,23,24,26,28,29)
and strains of
Lactobacillus administered concurrently with Bifidobacterium
strains by five trials(6,20,22,25,27)
. Of those trials that evaluated
Lactobacillus strains, seven(6,14,17,21,24 –26)
investigated the use
of the fermented milk drink ‘Actimel’ (DanActive in the USA).
All but one of the trials(17)
compared probiotics with a placebo.
Quality assessment of the studies is summarised in Table 2,
and full assessments are provided in online Supplementary
File S2. All the trials used appropriate randomisation methods,
such as a computer-generated randomisation list or referring
to a random number. Appropriate allocation concealment
methods were reported in most of the studies, including the
use of sealed envelopes(7,16,18,19)
, central allocation(6,20 –22)
,
and/or the use of coded packaging/containers that were
identical in appearance(5,15,21 –23)
. Subjects were included
sequentially in accordance with the randomisation list
in four trials(14,24–26)
. Allocation concealment was only
partially addressed by two trials(17,27)
. Among the nineteen
trials(Bentley_unpublished,5 – 7,14 –16,18 – 20,22 –29)
that were described
as double blind, descriptions of blinding methods were
provided in most. However, due to colour coding of the
study product and placebo in three trials(18,19,27)
, it was
unclear whether blinding was maintained. In this review,
one open label study(17)
was included, so although partici-
pants were randomised, the study was not blinded.
Overall, twelve trials(Bentley_unpublished,5,6,14,16,20,21,24–26,28,29)
were
considered to have a ‘low’ risk of bias, one(8)
had an ‘unclear/low’
risk of bias as all the quality criteria were well-reported except for
the methods of blinding, and seven(16–1922,23,27)
had ‘some’ risk of
bias due to imbalances in dropout rates between the treatment
groups and an intention-to-treat analysis not being conducted,
three studies(18,19,27)
due to blinding and an intention-to-treat
analysis not being conducted, one study(17)
due to lack of blinding
and imbalances in dropouts, and one study(15)
due to a small
sample size (n 47). No trials had a ‘high’ risk of bias.
The included trials evaluated ‘colds’, ‘respiratory tract infec-
tions’ and ‘common infectious diseases’. The majority (n 17)
of the trial authors reported clear descriptions of the symp-
toms and diagnoses of these conditions. In eleven of the
trials(15,17 –20,22 –25,28,29)
, a physician confirmed the presence
of an infection, and in an additional two trials(5,7)
, symptoms
were reported by the participants in a diary with a diagnosis
confirmed by a trial investigator.
In the included trials, three main outcomes were reported:
duration of illness episodes; number of days of illness per
person; absenteeism from day care/school/work. The results of
studies carried out in children are reported in Table 3, of those
in adults in Table 4 and of those in elderly people in Table 5.
Duration of illness episodes
Among the included trials, ten(Bentley_unpublished,
5,6,14,17,19,23–25,27)
reported on the duration of illness episodes,
defined as the overall sum of illness episode lengths (in d)
divided by the total number of illness episodes experienced
by the study participants. Data that could be pooled in a
meta-analysis were presented by nine trials(Bentley_unpublished,
5,6,14,17,19,23 –25,27)
(Fig. 1). This figure also shows the number
of illness episodes in each arm of each study; the numbers
are generally balanced between the arms, although slightly
more illness episodes were observed in the placebo groups.
Given that all the studies were randomised in a 1:1 fashion,
the numbers of participants are approximately the same in
each arm, and thus the numbers of illness episodes are not
likely to reflect differences in sample sizes. The meta-analysis
revealed that participants who received a probiotic interven-
tion had significantly shorter illness episodes than those
who received a placebo: weighted mean difference 20·77
(95 % CI 21·50, 20·04), P¼0·04. This suggests that the
mean difference in illness duration between those who take
probiotics and those who do not is between half and 1 d.
However, there was statistical heterogeneity among these
trials (t 2
¼ 0·81; P,0·00 001; I 2
¼ 80 %).
To explore potential sources of heterogeneity, sub-
group analyses were conducted. Studies carried out in
S. King et al.46
BritishJournalofNutrition
Table 3. Results of included studies conducted in children
(Mean values and standard deviations)
Study Condition
Duration of
treatment
(months) Treatments
Age (years)
Number
randomised
(included in
the analysis)
Percentage
of females
Number (%) of
participants with
at least one
illness episode
Number of
illness
episodes
Duration
of illness
episodes (d)
Number of days
of illness
Number of
days absent
Mean SD Mean SD Mean SD Mean SD
Ca´ceres
et al.(23)
Acute RTI 3 L. rhamnosus
HN001
3·1 1·1 203 (170) 52·7 NR 172* 20·4 14·4 NR 4·70 5·5
Placebo 3·2 1·0 195 (179) 50·8 NR 181 19·4 14·8 NR 4·05 5·6
Cazzola
et al.(20)
Common winter
diseases
3 L. helveticus R0052,
Bifidobacterium
infantis R0033,
and Bifido-
bacterium bifidum
R0071 þ 750 mg
FOS†
4·1 1·0 62 (62) 46·8 29‡ (47 %) 64§ NR NR 2·11 2·1
Placebo 4·2 1·1 73 (50) 46·6 43 (86 %) 87§ 2·88 2·8
Hatakka (2007,
unpublished results)
and Hatakka et al.(18)
GI and RI 7 L.rhamnosus GG 4·6 1·5 Unclear (282) 46 97 (34 %) NR NR NRk 4·9 NR{
Placebo 4·4 1·5 Unclear (289) 52 123 (43 %) 5·8 NR
Hojsak et al.(28)
Respiratory
symptoms
Median: 5 d L. rhamnosus GG 9·9 5·1 376 (376) 49·2 8 (2 %) NR NR r 8 (2·1 %)** NR
Placebo 10·6 5·0 366 (366) 44·3 20 (6 %) NR NR r 19 (5·2 %)** NR
Hojsak et al.(29)
Respiratory
symptoms
3 L. rhamnosus GG 51·9 months
(13–86)
139 (139) 43·9 60 (43 %) NR NR 39 (28·1 %)** 3·1 3·6††
Placebo 53·6 months
(13–83)
142 (142) 44·4 96 (68 %) 70 (49·3 %)** 5·1 3·6
Kloster Smerud
et al.(27)
Gastrointestinal
and
respiratory
symptoms
7 Biola (L. rhamnosus
GG with
L.acidophilus
LA-5 and
Bifidobacterium
lactis BB-12)
Over both
groups: 18
months
117 (97) NR 92‡ (95 %) 492 5·39 7·89‡ 5·35 3·97‡ 7·5 5·0††
Placebo Over both
groups: 18
months
123 (102) NR 95 (93 %) 564 4·69 5·19 5·94 3·77 8·5 5·0
Kumpu et al.(19)
Respiratory
symptoms
28 weeks L. rhamnosus GG 4·0 1·3 261 (251) 47 239 (95 %) NR Median 8 d
(IQR 5–12)
5·03‡‡ 0·88 NR
Placebo 4·0 1·4 262 (250) 47 236 (94 %) NR Median 8 d
(IQR 5–12)
5·17 0·96 NR
Leyer et al.(7)
Cold and
influenza-like
symptoms
6 L. acidophilus
NCFM
3·7 0·7 110 (110) 57 NR NR NR 4·5 4·7 3·6 3·7‡
L. acidophilus
NCFM and
Bifidobacterium
animalis subsp.
lactis Bi-07
3·8 0·6 112 (112) 52·7 NR NR NR 3·4 3·7 3·8 3·9
Placebo 4·1 0·54 104 (104) 57·7 NR NR NR 6·5 7·3 5·2 5·7
Probioticsandacuterespiratoryinfections47
British Journal of Nutrition
Table 3. Continued
Study Condition
Duration of
treatment
(months) Treatments
Age (years)
Number
randomised
(included in
the analysis)
Percentage
of females
Number (%) of
participants with
at least one
illness episode
Number of
illness
episodes
Duration
of illness
episodes (d)
Number of days
of illness
Number of
days absent
Mean SD Mean SD Mean SD Mean SD
Merenstein
et al.(21)
CID§§ 90 d DanActive
(L. paracasei
subsp. casei
DN-114001 with
Streptococcus
thermophilus and
L. bulgaricus)
4·86 1·12 314 (250
households)
50 NR NR NR NR 421·5 d
‡absent
(1·69 d/
household)
Placebo 4·94 1·13 324 (250
households)
46·9 NR NR NR NR 463·0 d absent
(1·85 d/
household)
Prodeus
et al.(26)
Upper RI 3 L. paracasei subsp.
casei DN-114001
with S.
thermophilus þ
L. delbrueckii
subsp. bulgaricus
Over both
groups: 4
300 (300) Overall
45·7
66 (22 %) 98kk NR NR 5·68 4·01‡
Placebo Over both
groups: 4
299 (299) 73 (24 %) 93kk NR NR 5·64 3·67
RTI, respiratory tract infections; NR, not reported; FOS, fructo-oligosaccharides; GI, gastrointestinal infections; RI, respiratory infections; IQR, interquartile range; CID, common infectious diseases.
* The total number of illness episodes was calculated from the total number of illness episodes per child (included in the analysis).
† Although this study used FOS along with probiotic and did not use it in the control, the level of FOS was only 750 mg, which is considered to be below an active dose(32,33)
.
‡ Data obtained from the study authors.
§ ‘Health events’.
k The authors stated that the number of days with symptoms was lower in the treatment group, but the difference was not significant.
{ To calculate mean difference and 95 % CI, standard deviation was calculated from the CI.
** Children with a RTI that lasted .3 d.
†† Standard deviation was calculated from the P value.
‡‡ Number of days with at least one respiratory symptom per subject per month.
§§ CID included upper RTI, lower RTI and gastrointestinal tract infections.
kk Number of CID.
S.Kingetal.48
British Journal of Nutrition
Table 4. Results of included studies conducted in adults
(Mean values and standard deviations)
Study Condition
Duration of
treatment
(weeks) Treatments
Age (years)
Number
randomised
(included in
the analysis)
Percentage
of females
Number (%) of
participants with
at least one
illness episode
Number
of illness
episodes
Duration
of illness
episodes (d)
Number
of days
of illness Number of days absent
Mean SD Mean SD Mean SD Mean SD
Bentley (2008,
unpublished
results)
Common
cold
12 Lactobacillus plantarum
HEAL9 (DSM 15312) and
L. paracasei 8700:2 (DSM
13434)
45·3 17·1 155 (146) Overall 66·5 72 (49 %) 87 5·6 1·3 NR NR
Placebo 46·6 17·2 155 (138) 76 (55 %) 98 6·7 0·8 NR NR
Berggren
et al.(5)
Common
cold
12 L. plantarum HEAL9 (DSM
15312) and L. paracasei
8700:2 (DSM 13434)
46·5 159 (137) 65·7 76 (55 %) 121 7·0 NR* 6·2 9·27† NR
Placebo 43·7 159 (135) 66·7 91 (67 %) 170 7·0 NR‡ 8·6 10·45 NR
de Vrese
et al.(6)
Common
cold
3–5·5
months
L. gasseri PA 16/8, Bifido-
bacterium longum SP
07/3, and Bifidobacterium
bifidum MF 20/5 with
Tribion harmonis
37 12 238 (225) 63·9 NR 158 7·0 (SEM 0·5)§ NR NR
Placebo 38 14 241 (229) 58·9 NR 153 8·9 (SEM 1·0) NR NR
Guillemard
et al.(24)
CID 3 months Actimel (L. paracasei subsp.
casei DN-114001 þ
S. thermophilus þ
L. delbrueckii subsp.
bulgaricus)
31·8 8·9 500 (500) 57 213 (43 %) Unclear 6·9 4·5 NR 2·0 4·3k
Placebo 32·5 8·9 500 (500) 56 256 (51 %) Unclear 6·5 4·5 NR 1·6 4·0
Niborski
et al.(14)
CID{ 7 L. paracasei subsp. casei
DN-114001 þ
S. thermophilus þ
L. delbrueckii subsp.
bulgaricus
Overall median
21 years (range
18–29 years)
118 (118) Overall 1·3 28 (24 %) 32 3 2·04** 3 2·29** 0·18 0·61k
Placebo Overall median
21 years (range
18–29 years)
121 (121) Overall 1·3 34 (28 %) 38 4 2·04 4 2·29 0·24 0·61
Smith et al.(22)
Upper RTI 12 s L. rhamnosus GG and
Bifidobacterium lactis
BB-12
Overall median
19 years (range
18–24 years)
114 (101) 80·2 Not clear 83 ‘cases’ NR 5·58 4·41 23 d missed
work and school
(0·27/‘case’)
Placebo Overall median
19 years (range
18–24 years)
117 (97) 72·2 Not clear 84 ‘cases’ NR 7·11 5·07 45 d missed
work and school
(0·54/‘case’)
Tiollier et al.(15)
RTI 4 L. paracasei subsp. casei
DN-114001
21·3 (0·2) 24 (24) 100 % male 11 (46 %) 17 NR 5·5 1·6 NR
Placebo 21·3 (0·4) 23 (23) 13 (57 %) 30 NR 6·1 1·7 NR
Tubelius
et al.(16)
RTI and GI 80 d L. reuteri protectis 44 132 (94) 35 % NR NR NR NR Median 3 d
Placebo 44 130 (87) 29 % NR NR NR NR Median 3 d
NR, not reported; CID, common infectious diseases; RTI, respiratory tract infections; GI, gastrointestinal infections.
* To calculate mean difference with 95 % CI, standard deviations were imputed based on the method of de Vrese et al.(6)
.
† Standard deviations were obtained from the study authors.
‡ No P value reported.
§ To calculate mean difference with 95 % CI, standard deviations were calculated from the SEM.
k Data obtained from the study authors.
{ CID included upper RTI, lower RTI and GI.
** Standard deviation was calculated from the P value.
Probioticsandacuterespiratoryinfections49
British Journal of Nutrition
adults(Bentley_unpublished,5,7,14,17,24,25)
revealed statistical differ-
ences between the treatment groups, but heterogeneity
remained. By contrast, studies carried out in children (based
on only two trials(23,27)
) did not reveal significant differences
between the treatment groups. Studies conducted only in
European countries (including Scandinavia) also revealed
significant differences, but again, the studies were statistically
heterogeneous.
A subgroup analysis was also conducted by the illness as
described by the study authors (i.e. acute RTI, colds and
‘common infectious diseases’) and by the duration of the
trial (,3 months, 3–5 months, 6 months or longer), but few
significant effects were observed (data not shown). Finally,
an analysis of six studies considered to have a ‘low’ risk of
bias yielded a significant result similar to the overall pooled
analysis (weighted mean difference 20·96 (95 % CI 21·79,
20·13), P¼0·02), but heterogeneity remained (Fig. 2).
In addition to the nine trials included in the meta-
analysis, one study(19)
compared Lactobacillus rhamnosus
with a placebo in 523 children aged 2–6 years attending
day-care centres in Finland. The authors reported that, after
28 d of treatment, the median duration of respiratory symptom
episodes was 8 d (interquartile range 5–12) in both groups
(the authors did not report the number of illness episodes).
However, this study had some risk of bias, so there is uncer-
tainty regarding its results.
Number of days of illness per person
Duration of illness per person was calculated as the overall
number of days with symptoms divided by the number of
individuals with an illness. In some studies, it was unclear
whether all individuals were included in the analysis (i.e.
participants with and without illness). To account for the
possibility that different units were used to calculate this
outcome, data were pooled using a SMD. We found that the
numbers of people with an illness episode were either similar
between the probiotic and placebo groups or slightly higher
in the placebo group.
Overall, eleven trials reported on the number of days the
participants were ill, of which ten could be pooled in a
meta-analysis (Fig. 3). The results demonstrated a significant
difference in favour of probiotics, suggesting fewer numbers
of days of illness per person compared with that in parti-
cipants who had taken a placebo (SMD 20·31 (95 % CI
20·41, 20·11), P,0·00 001). There was no statistical hetero-
geneity among these studies (t 2
¼ 0·00; P¼0·42; I 2
¼ 3 %).
In addition to these trials, Hatakka et al.(18)
examined the
effects of L. rhamnosus GG v. placebo for 7 months in 571
healthy children aged 1–6 years from 18 day-care centres in
Finland. They reported that the number of days with res-
piratory and gastrointestinal symptoms was lower in the
L. rhamnosus GG group than in the placebo group, but that
the difference did not reach statistical significance (no data
were reported in the paper or could be obtained). They did
report that the duration without respiratory symptoms was
5 weeks (95 % CI 4·1, 5·9) in the probiotic group and 4
weeks (95 % CI 3·5, 4·6) in the placebo group (P¼0·03).
Table5.Resultsofincludedstudiesconductedinelderlypeople
(Meanvaluesandstandarddeviations)
StudyCondition
Durationof
treatment
(months)Treatments
Age(years)
Number
randomised
(includedin
theanalysis)
Percentage
offemales
Number(%)of
participantswith
atleastone
illnessepisode
Number
ofillness
episodes
Duration
ofillness
episodes
(d)
Number
ofdays
ofillness
Number
ofdays
absent
MeanSDMeanSDMeanSDMeanSD
Guillemard
etal.(25)
Upper
RTI
3Actimel(Lacto-
bacillusparacasei
subsp.casei
DN-114001þ
Streptococcus
thermophilusþ
L.delbrueckii
subsp.bulgaricus)
Median76·0537(535)63·161(11%)1207·77·28·57·2NR
PlaceboMedian76·0535(535)62·266(12%)13511·07·711·67·9NR
Turchet
etal.(17)
CID*3Milk-fermented
yogurtcultureand
L.caseiDN-114001
67·16·0180(180)Overall6752(29%)NR7·03·2NRNR
Notreatment69·35·6180(180)Overall6750(28%)NR8·73·7NRNR
CID,commoninfectiousdiseases;RTI,respiratorytractinfections;NR,notreported.
*CIDincludedupperRTI,lowerRTIandgastrointestinaltractinfections.
S. King et al.50
BritishJournalofNutrition
This trial had some risk of bias, so that there is uncertainty
with regard to the reliability of the results.
Absenteeism (days away from day care/school/work)
Absenteeism appears to have been largely calculated as the
number of days absent from day care/school/work divided
by the number of participants with at least one illness episode
(i.e. absenteeism/ill person). In some trials, it was unclear how
absenteeism was calculated. To account for potential differ-
ences in units, we pooled the data using a SMD.
Overall, twelve trials reported on absenteeism due to respir-
atory infections/common infectious diseases, of which eleven
could be pooled in a meta-analysis (Fig. 4). The results
demonstrated that there was a significant difference in
favour of probiotics, suggesting fewer numbers of days
absent from day care/school/work compared with that in
participants who had taken a placebo (SMD 20·17 (95 % CI
20·31, 20·03), P¼0·02). However, there was statistical
heterogeneity among the studies (t 2
¼ 0·04; P¼0·0009;
I 2
¼ 67 %).
Very few subgroup differences were observed in the sub-
group analyses (data not shown). A statistically significant
result was obtained for eight trials conducted in children,
suggesting fewer numbers of days absent from day care/
school in participants who had taken probiotics than in
those who had taken a placebo (SMD 20·18 (95 % CI
20·34, 20·02), P¼0·03), although again significant hetero-
geneity remained. Analysis by risk of bias demonstrated
no pattern. While only eleven trials were included in this
analysis, the funnel plot was roughly symmetrical, indicating
no publication bias (data not shown).
In the meta-analysis, one trial that evaluated absenteeism
could not be included. A well-conducted trial by Tubelius et al.(16)
Study or subgroup
Bentley (unpublished results)
Berggren et al.(5)
Cáceres et al.(23)
de Vrese et al.(6)
Guillemard et al.(24)
Guillemard et al.(25)
Kloster Smerud et al.(27)
Niborski et al.(14)
Turchet et al.(17)
Total (95% CI)
Heterogeneity: τ2
= 0·81; χ2
= 40·60, df = 8 (P < 0·00001); I2
= 80%
Test for overall effect: Z = 2·06 (P = 0·04)
5·6
7
20·4
7
6·9
7·7
5·39
3
7
1·3
6·29
14·4
6·29
4·5
7·2
7·89
2·04
3·2
87
121
172
158
213
120
492
32
180
1575
6·7
7
19·4
8·9
6·5
11
4·69
4
8·7
0·8
9·73
14·8
12·37
4·5
7·7
5·19
2·04
3·7
98
170
181
153
256
135
564
38
180
1775
Total Weight (%)
16·6
8·2
4·3
6·7
14·1
8·2
14·1
13·2
14·7
100·0
(95% CI)
−1·10 (−1·42, −0·78)
0·00 (−1·84, 1·84)
1·00 (−2·05, 4·05)
−1·90 (−4·09, 0·29)
0·40 (−0·42, 1·22)
−3·30 (−5·13, −1·47)
0·70 (−0·12, 1·52)
−1·00 (−1·96, −0·04)
−1·70 (−2·41, −0·99)
−0·77 (−1·50, −0·04)
Mean difference Mean difference
IV, random, 95% CI
−4 −2 0 2 4
Favours probiotics Favours placebo
Mean SD Total Mean SD
Probiotics Placebo
Fig. 1. Mean duration of illness episodes (d). The ‘total’ is the overall number of illness episodes experienced by the participants (randomised in a 1:1 ratio) in
each treatment group. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn).
Study or subgroup
4.5.1 Low risk of bias
Bentley (unpublished results)
Berggren et al.(5)
de Vrese et al.(6)
Guillemard et al.(24)
Guillemard et al.(25)
Niborski et al.(14)
Subtotal (95% CI)
Heterogeneity: τ2
= 0·67; χ2
= 19·42, df = 5 (P = 0·002); I2
= 74%
Test for overall effect: Z = 2·27 (P = 0·02)
4.5.4 Some risk of bias
Cáceres et al.(23)
Kloster Smerud et al.(27)
Turchet et al.(17)
Subtotal (95% CI)
Heterogeneity: τ2
= 2·51; χ2
= 19·86, df = 2 (P < 0·0001); I2
= 90%
Test for overall effect: Z = 0·18 (P = 0·85)
Test for subgroup differences: χ2
= 0·49, df = 1 (P = 0·48), I2
= 0%
5·6
7
7
6·9
7·7
3
20·4
5·39
7
1·3
6·29
6·29
4·5
7·2
2·04
14·4
7·89
3·2
87
121
158
213
120
32
731
172
492
180
844
6·7
7
8·9
6·5
11
4
19·4
4·69
8·7
0·8
9·73
12·37
4·5
7·7
2·04
14·8
5·19
3·7
Total
98
170
153
256
135
38
850
181
564
180
925
Weight (%)
26·0
11·6
9·4
21·4
11·7
19·9
100·0
21·3
39·1
39·7
100·0
95% CI
−1·10 (−1·42, −0·78)
0·00 (−1·84, 1·84)
−1·90 (−4·09, 0·29)
0·40 (−0·42, 1·22)
−3·30 (−5·13, −1·47)
−1·00 (−1·96, −0·04)
−0·96 (−1·79, −0·13)
1·00 (−2·05, 4·05)
0·70 (−0·12, 1·52)
−1·70 (−2·41, −0·99)
−0·19 (−2·19, 1·82)
Mean difference Mean difference
IV, random, 95% CI
−4 −2 0 2 4
Favours probiotics Favours placebo
Mean SD Total Mean SD
Probiotics Placebo
Fig. 2. Mean duration of illness episodes (d) – analysis by risk of bias. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn).
Probiotics and acute respiratory infections 51
BritishJournalofNutrition
examined the effects of Lactobacillus reuteri (ATCC55730)
v. placebo on the length of sick leave due to respiratory or
gastrointestinal infections in 262 healthy employees working
at TetraPak in Sweden. They reported a median duration of
3 d sick leave in both groups (no other statistical results
were reported and nor was it clear how many individuals
experienced an illness episode).
Discussion
We identified a number of studies that evaluated the effec-
tiveness of probiotics on the duration of illness episodes.
A meta-analysis of the data showed that the mean duration
of illness episodes decreased by between half and 1 d in
participants who received probiotics compared with those
who did not. We also found significantly fewer numbers of
days of illness per person and significantly fewer numbers of
days absent from day care/school/work in participants who
had taken probiotics than in those who had taken a placebo.
However, there was significant statistical heterogeneity between
the studies that reported on the duration of illness episodes
and those that reported on absenteeism from day care/school/
work, but not for studies that reported on the number of
days of illness per person. This unexplained heterogeneity
means that the effect size (i.e. the difference in the duration of
illness episodes between treated and untreated individuals)
may differ between the population groups.
Subgroup analyses did not elucidate sources of statistical
heterogeneity among the studies. As many trials were not car-
ried out in each subgroup, some of the analyses did not have
Study or subgroup
Berggren et al.(5)
Guillemard et al.(25)
Hojsak et al.(28)
Hojsak et al.(29)
Kloster Smerud et al.(27)
Kumpu et al.(19)
Leyer et al.(7)
Niborski (unpublished results)
Smith et al.(22)
Tiollier et al.(15)
Total (95% CI)
Heterogeneity: τ2
= 0·00; χ2
= 9·24, df = 9 (P = 0·42); I2
= 3%
Test for overall effect: Z = 6·36 (P < 0·00001)
Std mean
difference
−0·24
−0·41
−0·51
−0·503
−0·15
−0·15
−0·47
−0·43
−0·32
−0·32
SD
0·1582
0·1786
0·2356
0·141
0·148
0·0918
0·1225
0·2551
0·1582
0·4286
Weight
(%)
9·4
7·4
4·3
11·8
10·7
26·6
15·4
3·7
9·4
1·3
100·0
−0·24 (−0·55, 0·07)
−0·41 (−0·76, −0·06)
−0·51 (−0·97, −0·05)
−0·50 (−0·78, −0·23)
−0·15 (−0·44, 0·14)
−0·15 (−0·33, 0·03)
−0·47 (−0·71, −0·23)
−0·43 (−0·93, 0·07)
−0·32 (−0·63, −0·01)
−0·32 (−1·16, 0·52)
−0·31 (−0·41, −0·22)
Std mean difference
(95% CI)
Mean difference
IV, random, 95% CI
−1 −0·5 0 0·5 1
Favours probiotics Favours placebo
Fig. 3. Duration of illness per person. In this meta-analysis, dichotomous and continuous data were pooled. The totals used in this analysis (not shown) were
mostly the number of individuals with at least one illness episode (see Table 3). In one study(7)
, the totals used in the analysis were the numbers of participants
included in the study, and in another study(22)
, the totals used were the numbers of ‘cases’ of illness (in both studies, the number of individuals with illness
episodes was not reported). (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn).
Study or subgroup
Cáceres et al.(23)
Cazzola et al.(20)
Guillemard et al.(24)
Hatakka et al.(18)
Hojsak et al.(29)
Kloster Smerud et al.(27)
Leyer et al.(7)
Merenstein et al.(21)
Niborski (unpublished results)
Prodeus (unpublished results)
Smith et al.(22)
Total (95% CI)
Heterogeneity: τ2
= 0·04; χ2
= 29·90, df = 10 (P = 0·0009); I2
= 67%
Test for overall effect: Z = 2·32 (P = 0·02)
4·7
2·11
2
4·9
3·1
7·5
3·7
1·69
0·18
5·68
0·27
5·5
2·08
4·3
2·5
3·6
5
3·8
13
0·61
4·01
0·6
170
29
213
97
60
92
222
250
28
66
83
1310
4·05
2·88
1·6
5·8
5·1
8·5
5·2
1·85
0·24
5·64
0·54
5·65
2·81
4
2·8
3·6
5
5·7
13
0·61
3·67
0·6
179
43
256
123
96
95
104
250
34
73
84
1337
Total Weight (%)
11·1
5·6
11·8
9·6
8·2
9·2
10·5
12·0
5·2
8·1
8·7
100·0
(95% CI)
0·12 (–0·09, 0·33)
–0·30 (–0·77, 0·17)
0·10 (–0·09, 0·28)
–0·34 (–0·60, –0·07)
–0·55 (–0·88, –0·22)
–0·20 (–0·49, 0·09)
–0·33 (–0·57, –0·10)
–0·01 (–0·19, 0·16)
–0·10 (–0·60, 0·40)
0·01 (–0·32, 0·34)
–0·45 (–0·76, –0·14)
–0·17 (–0·31, –0·03)
Std mean difference Std mean difference
IV, random, 95% CI
–1 –0·5 0 0·5 1
Favours probiotics Favours placebo
Mean SD Total Mean SD
Probiotics Placebo
Fig. 4. Days absent from day care/school/work. The ‘total’ is mostly the number of individuals with at least one illness episode. In two studies(7,23)
, the totals used
were the number of participants included in the study; in one study(21)
, the totals were the number of households randomised, and in another study(22)
, the totals
were the number of ‘cases’ of illness (in all these studies, the number of individuals with illness episodes was not reported). (A colour version of this figure can be
found online at http://www.journals.cambridge.org/bjn).
S. King et al.52
BritishJournalofNutrition
enough power to detect any underlying effects and thus could
not detect significant effects.Where differences were observed,
it is important to note that inferences made according to
between-study differences do not translate into within-study
differences, as this would be making an indirect comparison
of effects. One cannot make the assumption that the effective-
ness of probiotics on the duration of illness episodes is insig-
nificant in children compared with that in adults. Moreover,
other unknown modifying factors in studies conducted in
children may have had an effect on the results that could
potentially be independent of age.
For two of the outcomes evaluated, we pooled the data
using the SMD, which can be difficult to interpret. Based on
research in the social sciences, Cohen(30)
suggested that
effect size indices of 0·2, 0·5 and 0·8 can be used to represent
small, medium and large effect sizes, respectively. Such
generic interpretations may be problematic, as even small
improvements may be important in health-related contexts(12)
.
We also argue that improvements in respiratory illness, even
up to a day, would be of great benefit to an individual and
could potentially have public health benefits.
Furthermore, two systematic reviews(10,31)
that evaluated
the use of probiotics for the prevention of acute RTI also
reported on the duration of illness. Hao et al.(10)
reported
no difference between probiotics and placebo for the mean
duration of illness episodes, but they included only two
trials in their meta-analysis, of which one was conducted in
athletes (which were excluded from this review). However,
the authors did find a difference in the incidence of RTI in
favour of placebo, but this outcome has not been evaluated
here. The review by Vouloumanou et al.(31)
reported that of
nine studies, three showed a significant effect in favour of
probiotics and six found no difference between the probiotic
and comparison groups (the authors did not conduct a
meta-analysis). Again, this systematic review included athletes
and children aged ,1 year, which differs from the inclusion
criteria of our review. No previous systematic reviews
appear to have summarised data on absenteeism from day
care/school/work, and this review provides new evidence
for this outcome.
The present systematic review has some limitations. First,
we included trials that evaluated colds and RTI, as well as
‘common infectious diseases’, so that some of the analyses
will have included patients with gastrointestinal infections.
On the other hand, the significant results may be indicative
of the effectiveness of probiotics in the wider population.
While the majority of trial authors reported clear descriptions
of the symptoms and diagnoses, a confirmed diagnosis by a
physician was made in about half of the trials. It is possible
that acute infections could have been under-reported or
over-reported in some of these trials. As with all systematic
reviews, it is possible that the addition of publications in the
future could alter the results. As this review includes a large
number of high-quality studies that demonstrate a consistent
trend in favour of probiotics, the results are probably reliable.
Further research and meta-analyses are recommended in
different population groups to identify potential sources of
variability in the results. It is also suggested that trial authors
need to more clearly describe how their outcomes were
calculated.
In conclusion, this systematic review provides evidence
from a number of good-quality RCT that the average duration
of respiratory illness episodes, the number of days of illness
per person and the number of days absent from day care/
work/school are significantly reduced with probiotic treatment
compared with placebo.
Supplementary material
To view supplementary material for this article, please visit
http://dx.doi.org/10.1017/S0007114514000075
Acknowledgements
This work was funded by an unrestricted educational grant
from the Global Alliance for Probiotics. The funder provided
the scope to conduct the review and was allowed to comment
on the protocol and draft of the manuscript, but had no
control over the final article. The authors have received other
educational grants from the Global Alliance for Probiotics.
The authors’ contributions are as follows: S. K. (lead author)
conducted the review, analysed and interpreted the data,
drafted the article and gave final approval for publication;
J. G. contributed to the concept, design, conduct and report-
ing of the review and critically revised the article for important
intellectual content and gave final approval for publication;
M. E. S. formulated the research questions and contributed
to the design of the review, critically revised the article for
important intellectual content and gave final approval for pub-
lication; A. F. contributed to the analysis and interpretation of
the data, critically revised the article for important intellectual
content and gave final approval for publication; D. V. carried
out data extraction, checked the review, contributed to the
drafting of the article and gave final approval for publication.
All authors met the requirements set by the BJN.
There are no conflicts of interest.
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Prob 2014

  • 1. Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis Sarah King1 , Julie Glanville1 *, Mary Ellen Sanders2 , Anita Fitzgerald1 and Danielle Varley1 1 York Health Economics Consortium, York, UK 2 Dairy and Food Culture Technologies, Centennial, CO 80122, USA (Submitted 10 June 2013 – Final revision received 14 November 2013 – Accepted 8 January 2014 – First published online 29 April 2014) Abstract Recent systematic reviews have reported a positive, although modest, effect of probiotics in terms of preventing common cold symptoms. In this systematic review, the effect of probiotics, specifically Lactobacillus and Bifidobacterium strains, on the duration of acute respiratory infections in otherwise healthy children and adults was evaluated. To identify relevant trials, eight databases, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Science Citation Index (SCI) and OAISTER, were searched from inception to 20 July 2012. Details regarding unpublished studies/databases were also obtained from probiotic manufacturers. Study selection, data extraction and quality assessment were carried out by two reviewers. Risk of bias was assessed using criteria adapted from those published by the Centre for Reviews and Dissemination. In this review, twenty randomised controlled trials (RCT) were included, of which twelve were considered to have a low risk of bias. Meta-analysis revealed significantly fewer numbers of days of illness per person (standardised mean difference (SMD) 20·31 (95 % CI 20·41, 20·11), I 2 ¼ 3 %), shorter illness episodes by almost a day (weighted mean difference 20·77 (95 % CI 21·50, 20·04), I 2 ¼ 80 %) (without an increase in the number of illness episodes), and fewer numbers of days absent from day care/school/work (SMD 20·17 (95 % CI 20·31, 20·03), I 2 ¼ 67 %) in participants who received a probiotic intervention than in those who had taken a placebo. Reasons for heterogeneity between the studies were explored in subgroup analysis, but could not be explained, suggesting that the effect sizes found may differ between the population groups. This systematic review provides evidence from a number of good-quality RCT that probiotics reduce the duration of illness in otherwise healthy children and adults. Key words: Probiotics: Respiratory infections: Systematic reviews Respiratory infectious conditions place a substantial health and economic burden on society. In a 6-month survey of 3249 university students, upper respiratory tract infections (RTI) resulted in 6023 bed-days, 4263 missed school days, 3175 missed workdays and 45 219 d of illness(1) . According to the United States Centers for Disease Control and Pre- vention, twenty-two million school days and twenty million workdays in adults are lost annually due to the common cold in the USA(2) . The economic impact of colds has been estimated to be $40 billion dollars in the USA annually(3) . Probiotics are defined as live micro-organisms that confer a health benefit on the host when administered in adequate amounts(4) . Several studies(5–8) have evaluated the effectiveness of probiotics on the symptoms and incidence of common infectious respiratory diseases. Recent meta-analyses(9,10) have reported a positive, although modest, effect of probiotics in terms of preventing common cold symptoms. The objective of this systematic review was to assess the effect of probiotics on the duration of an acute RTI in other- wise healthy children and adults. We evaluated probiotics that belong to the Lactobacillus and Bifidobacterium genera, but not probiotics such as yeast and Gram-negative probiotics (e.g. Escherichia coli), which are taxonomically distinct. Thus, for the purposes of this review, ‘probiotic’ hereafter refers to Lactobacillus and Bifidobacterium strains. Methods Studies eligible for inclusion in this systematic review were ran- domised controlled trials (RCT) of any duration that compared * Corresponding author: J. Glanville, fax þ44 1904 323628, email yhec@york.ac.uk Abbreviations: Bentley_unpublished, C. Bentley unpublished results; RTI, respiratory tract infections; SMD, standardised mean differences. British Journal of Nutrition (2014), 112, 41–54 doi:10.1017/S0007114514000075 q The Authors 2014. The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence http://creativecommons.org/licenses/by/3.0/ BritishJournalofNutrition
  • 2. Lactobacillus and/or Bifidobacterium strains consumed orally with placebo or ‘no treatment’ in apparently healthy children (aged between 1 and 18 years) or adults who developed acute RTI at some point during the study. Open-label studies were eligible as long as the patients were randomised. The probiotic strains could be administered at any dose and could be combined with or not be combined with non-Lactobacillus or non-Bifidobacterium strains. Studies carried out using pro- biotics combined with other functional ingredients (such as prebiotics and vitamins) were also eligible as long as the com- parator included the other functional ingredients, so that the overall effects could be attributed to the probiotic. To be eligible for inclusion, the trials had to report on a measure of illness duration, such as the length of illness episodes, number of days of illness per person, number of days off sick from day care, school or work, or time without an infection. ‘Acute respiratory infections’ were considered to include upper RTI and/or lower RTI, colds or influenza-like symp- toms. Trials that reported on ‘common infectious disease’ were also included if RTI were defined within this umbrella term by the trial authors. Studies conducted in infants (aged ,1 year), trained athletes, seriously ill people and institutiona- lised elderly adults were excluded from this review as they were considered to be immunologically distinct. To identify relevant trials, we searched a number of data- bases including MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Science Citation Index (SCI) and OAISTER from inception to 20 July 2012. The search was not restricted by country or language. Search terms included (but were not limited to) ‘Probiotics’, ‘Lactobacillus’ and ‘Bifidobacterium’. The search results were combined with those obtained by searching for terms including (but not limited to) ‘Common Cold’, ‘Sinusitis’, ‘Pharyngitis’, ‘Laryngitis’ and ‘Respiratory Tract Infections’. The full set of search terms is presented in online Supplementary File S1. Information on ongoing or recently completed trials, unpublished research and research reported in the grey litera- ture was obtained by searching trial registers and selected major conference proceedings (3 years before search date). Unpublished studies were included in accordance with estab- lished approaches to the systematic review process(11,12) . The resources searched are also listed in online Supplementary File S1. The references of recent reviews and eligible studies were checked for additional trials not identified by the elec- tronic search. Unpublished papers were also sought from the manufacturers within the funding organisation (Global Alliance for Probiotics), which included Yakult, Danone, Probi, Lallemand, Chr. Hansen, DuPont and Valio. Studies published only as abstracts or conference presentations were included if adequate data were provided. An initial screening of search results was done by one reviewer to exclude obviously irrelevant records. The remain- ing records were screened by two reviewers independently to identify potentially relevant records meeting the inclusion/ exclusion criteria. Full papers were obtained for these records and were assessed for relevance by two reviewers independently. Any discrepancies were resolved through discussion and/or by consulting a third reviewer. For each eligible trial, data on study and population character- istics and results were extracted by one reviewer and checked by a second reviewer (Table 1). Quality assessment, using quality criteria adapted from the Centre for Reviews and Dissemina- tion(11) , was also conducted by one reviewer and checked by a second reviewer (summaries are given in Table 2 and full assess- mentsareprovidedin online SupplementaryFileS2).Anydiscre- pancies in data extraction or quality assessment were resolved through discussion or by consulting a third reviewer. If any of the quality criteria were unclear in the trial publications, study authors were contacted for further (documented) information. Means and standard deviations were collected for continuous outcomes. In the absence of information, authors were con- tacted for further details. If no further data could be obtained, a standard deviation was imputed using P values or SD from other similar studies (where possible). For studies involving twoprobiotictreatment arms,themeansandstandarddeviations from the two groups were combined using statistical software to create a single pairwise comparison with the placebo group. Where appropriate, data from all the studies were pooled in a meta-analysis to determine the overall effect size (weighted mean difference) with 95 % CI using a random-effects model. When the same outcome was measured in different ways, the data were pooled using a standardised mean difference (SMD) statistic. When continuous and dichotomous data were pre- sented for an outcome, SMD (or log OR) and their standard errors were computed for all the studies to facilitate pooling of the data. Meta-analysis was conducted using RevMan software (The Nordic Cochrane Centre, The Cochrane Collaboration)(13) . Heterogeneityacrossthestudieswasinvestigatedusingthe x 2 test (significance set at P,0·1) and the I 2 statistic (with a value $50 %) and by examining the random-effects between-study variance (t 2 ). When significant heterogeneity was evident, sub- group analysis planned a priori was used to explore differences among the trials for specific variables including age (children and adults), sex, country of study, treatment dose, intervention duration, and single-strain v. combination interventions. We also evaluated studies by their overall risk of bias (low, high or unclear) based on the Cochrane Risk of Bias tool. For the pur- poses of this review, a study was assumed to have a ‘low risk of bias’ when all the key quality criteria (i.e. randomisation method, allocation concealment and blinding) as well as most of the other criteria were adequately met; an ‘unclear risk’ of bias when most of the key criteria were not reported or unclear; and a ‘high risk’ of bias when one or more of the key criteria were not adequately met. The category ‘some risk of bias’ was assigned when all aspects of the key criteria were adequate, but either (1) an intention-to-treat analysis was not conducted and when one criterion was not met or (2) when two key criteria were adequate, but an intention-to-treat analysis was not con- ducted. The category ‘unclear/low risk of bias’ was assigned when two key criteria were adequately met and the rest of the criteria were adequate. Publication bias was assessed using funnel plots when more than ten studies were included in a meta-analysis(12) . S. King et al.42 BritishJournalofNutrition
  • 3. Table 1. Characteristics of the included studies Intervention Comparator Study Country of study Population group Condition Detail(s) Number randomised (included in the analysis) Details Number randomised (included in the analysis) Bentley (2008, unpublished results) Germany Adults at an increased risk of infection (at least two episodes in the previous 6 months) Common cold Lactobacillus plantarum HEAL9 and L. paracasei 8700:2 in maltodextrin 155 (146) Placebo: sachet contain- ing maltodextrin without living cultures 155 (138) Berggren et al.(5) Sweden Healthy adults aged 18–65 years Common cold L. plantarum HEAL9 and L. paracasei 8700:2 in maltodextrin 159 (137) Placebo: sachet contain- ing maltodextrin without living cultures 159 (135) Ca´ceres et al.(23) Chile Children (aged 1–5 years) attending day-care centres Acute respiratory tract infections L. rhamnosus HN001 203 (170) Placebo: milk product with no probiotic 195 (179) Cazzola et al.(20) France Children (aged 3–7 years) attending school Common winter diseases (URTI, LRTI and gastrointestinal tract infections) L. helveticus R0052, Bifido- bacterium infantis R0033 and Bifidobacterium bifi- dum R0071 52 (62) Placebo: contained only common excipients 73 (50) de Vrese et al.(6) Germany Healthy adults (aged 18–67 years) Common cold L. gasseri PA 16/8, Bifido- bacterium longum SP 07/3 and B. bifidum MF 20/5 238 (225) Placebo: vitamin mineral preparation without probiotic 241 (229) Guillemard et al.(24) Germany Healthy shift workers CID* Actimel, L. paracasei subsp. casei DN-114001 combined with Strepto- coccus thermophilus þ L. delbrueckii subsp. bulgaricus 500 (500) Placebo: dairy drink with- out active components 500 (500) Guillemard et al.(25) France Elderly (not living in an institution) URTI Actimel, L. paracasei subsp. casei DN-114001 combined with S. thermophilus þ L. delbrueckii subsp. bulgaricus 537 (535) Placebo: dairy drink with- out active components 535 (535) Hatakka (2007, unpublished results) and Hatakka et al.(18) Finland Children (aged 1–6 years) attending day-care centres Gastrointestinal and respiratory infections L. rhamnosus GG Unclear (282) Placebo: milk without probiotic Unclear (289) Hojsak et al.(28) Croatia Hospitalised children aged 12 months and older Respiratory symptoms L. rhamnosus GG 376 (376) Placebo: fermented milk product without L. rhamnosus GG 366 (366) Hojsak et al.(29) Croatia Children attending day-care centres Respiratory symptoms L. rhamnosus GG 139 (139) Placebo: fermented milk product without L. rhamnosus GG 142 (142) Kloster et al.(27) Norway Children (aged 12–36 months) attending day-care centres Gastrointestinal and respiratory symptoms Biola with L. rhamnosus GG, L. acidophilus LA-5 and Bifidobacterium lactis BB-12 117 (97) Placebo: fermented milk drink without probiotic bacteria 123 (102) Kumpu et al.(19) Finland Children (aged 2–6 years) attending day-care centres Respiratory symptoms L. rhamnosus GG 261 (251) Placebo: fresh milk without L. rhamnosus 262 (250) Probioticsandacuterespiratoryinfections43 British Journal of Nutrition
  • 4. Table 1. Continued Intervention Comparator Study Country of study Population group Condition Detail(s) Number randomised (included in the analysis) Details Number randomised (included in the analysis) Leyer et al.(7) China Children (aged 3–5 years) Cold and influenza-like symptoms Two interventions: Placebo: sucrose added to 1 % fat milk 104 (104) L. acidophilus NCFM (ATCC 700396) 110 (110) L. acidophilus NCFM and Bifidobacterium animalis subsp. lactis Bi-07 (ATCC PTA-4802) 112 (112) Merenstein et al.(21) USA Healthy children (aged 3–6 years) attending day care/school CID* DanActive, L. paracasei subsp. casei DN-114001 with S. thermophilus and L. bulgaricus 314 (250 households) Placebo: non-fermented acidified dairy drink 324 (250 households) Niborski (2008, unpublished results) France Healthy adults (mostly men) recruited from a fireman training course CID* L. paracasei subsp. casei DN-114001 with S. thermophilus þ L. delbrueckii subsp. bulgaricus 118 (118) Placebo: acidified milk (no bacteria) 121 (121) Prodeus (2008, unpublished results) Russia Children (aged 3–5 years) attending day-care centres URTI L. paracasei subsp. casei DN-114001 with S. thermophilus þ L. delbrueckii subsp. bulgaricus 300 (300) Placebo: acidified milk (no bacteria) 299 (299) Smith et al.(22) USA Apparently healthy college students URTI L. rhamnosus GG and B. lactis BB-12 114 (101) Placebo: powder without probiotic 117 (97) Tiollier et al.(15) France Male cadets undergoing commando training Respiratory tract infections L. paracasei subsp. casei DN-114001 24 (24) Placebo: non-fermented milk 23 (23) Tubelius et al.(16) Sweden Healthy employees working at TetraPak Respiratory and/or gastrointestinal tract infections Probiotic drinking straw with L. reuteri protectis 132 (94) Placebo: drinking straw without probiotic 130 (87) Turchet et al.(17) Italy Free-living elderly aged above 60 years CID* L. casei DN-114001 180 (180) No treatment 180 (180) URTI, upper respiratory tract infections; LRTI, lower respiratory tract infections. * CID included URTI, LRTI and gastrointestinal tract infections. S.Kingetal.44 British Journal of Nutrition
  • 5. Table 2. Quality criteria and study risk of bias assessment Reference Was randomisation carried out appropriately? Was the concealment of treatment allocation adequate? Were the care providers, participants and outcome assessors blind to treatment allocation? Were the groups similar at the onset of the study in terms of prognostic factors, for example, severity of the disease? Were there any unexpected imbalances in dropouts between the groups? If so, were they explained or adjusted for? Is there any evidence to suggest that the authors measured more outcomes than they reported? Did the analysis include an ITT analysis? If so, was this appropriate? Bentley (2008, unpublished results) L L L L L? L L Berggren et al.(5) L L L L L L H Ca´ceres et al.(23) L L L L H Y H Cazzola et al.(20) L L L L L L L de Vrese et al.(6) L L L L L L H Guillemard et al.(24) L L L L L L L Guillemard et al.(25) L L L L L L L Hatakka (2007, unpublished results) and Hatakka et al.(18) L L L? L? L L H Hojsak et al.(28) L L L L L L L Hojsak et al.(29) L L L L L L L Kloster et al.(27) L L? L? L L L H Kumpu et al.(19) L L L? L? ? L H Leyer et al.(7) L L L? L L L L Merenstein et al.(21) L L L L L? L L Niborski et al.(14) L L L L L L L Prodeus et al.(26) L L L L? L L L Smith et al.(22) L L L L H L H Tiollier et al.(15) L L L L L L L Tubelius et al.(16) L L L L L L H Turchet et al.(17) L L? H L? H L L ITT, intention-to-treat; L, low risk; L?, low risk with some areas of uncertainty; H, high risk; ?, unclear risk. Probioticsandacuterespiratoryinfections45 British Journal of Nutrition
  • 6. Results A total of 3069 records were retrieved and 1888 remained after deduplication. Following assessment based on title and abstract, seventy-five records were considered to be poten- tially relevant. Inclusion criteria were met by twenty-one RCT, but for one trial, data were not available after request (N. P. West, P. L. Horn, D. B. Pyne, V. J. Gebski, S. J. Lahtinen, P. A. Fricker and A. W. Cripps, unpublished results ‘Probiotic supplementation for respiratory and gastro- intestinal illness symptoms in healthy physically active individ- uals’). Twenty trials were included in this systematic review (full details are provided in online Supplementary File S3): Berggren et al.(5) ; de Vrese et al.(6) ; Leyer et al.(7) ; Niborski et al.(14) ; Tiollier et al.(15) ; Tubelius et al.(16) ; Turchet et al.(17) ; Hatakka et al.(18) and K. Hatakka (unpublished results 2007 ‘Probiotics in the prevention of clinical manifestations of common infectious diseases in children and in the elderly’); Kumpu et al.(19) ; Cazzola et al.(20) ; Merenstein et al.(21) ; Smith et al.(22) ; Ca´ceres et al.(23) ; Guillemard et al.(24) ; Guille- mard et al.(25) ; Prodeus et al.(26) ; Kloster et al.(27) ; Hojsak et al.(28,29) ; C. Bentley (unpublished results ‘Double blind, ran- domized, placebo-controlled, multicentric nutritional study to prove the efficacy and safety of a probiotic for common colds’)(Bentley_unpublished) . Of these trials, ten investigated the use of probiotics in children who ranged in age from 12 months to 12 years and ten were conducted in adults, of which two were conducted in elderly free-living adults. Approximately half of the trials were carried out in Western Europe: Germany; Sweden; France; Finland; Norway; Italy. The remaining trials were carried out in several different countries including the USA, Chile, Russia, Croatia and China. The duration of probiotic treatment ranged from 3 weeks to 7 months, although the majority of trials were carried out for approximately 3 months – over the winter months. Only three trials(14–16) did not report the season in which the trial was conducted, butthese trialswere conducted in settings such asa fire- man training course, a military training course and employees working at TetraPak. Other settings included day-care centres, schools,auniversity,apaediatrichospitalorthegeneralpopulation. Lactobacillus strains were investigated by fifteen trials(Bentley_unpublished, 5,7,14 – 19,21,23,24,26,28,29) and strains of Lactobacillus administered concurrently with Bifidobacterium strains by five trials(6,20,22,25,27) . Of those trials that evaluated Lactobacillus strains, seven(6,14,17,21,24 –26) investigated the use of the fermented milk drink ‘Actimel’ (DanActive in the USA). All but one of the trials(17) compared probiotics with a placebo. Quality assessment of the studies is summarised in Table 2, and full assessments are provided in online Supplementary File S2. All the trials used appropriate randomisation methods, such as a computer-generated randomisation list or referring to a random number. Appropriate allocation concealment methods were reported in most of the studies, including the use of sealed envelopes(7,16,18,19) , central allocation(6,20 –22) , and/or the use of coded packaging/containers that were identical in appearance(5,15,21 –23) . Subjects were included sequentially in accordance with the randomisation list in four trials(14,24–26) . Allocation concealment was only partially addressed by two trials(17,27) . Among the nineteen trials(Bentley_unpublished,5 – 7,14 –16,18 – 20,22 –29) that were described as double blind, descriptions of blinding methods were provided in most. However, due to colour coding of the study product and placebo in three trials(18,19,27) , it was unclear whether blinding was maintained. In this review, one open label study(17) was included, so although partici- pants were randomised, the study was not blinded. Overall, twelve trials(Bentley_unpublished,5,6,14,16,20,21,24–26,28,29) were considered to have a ‘low’ risk of bias, one(8) had an ‘unclear/low’ risk of bias as all the quality criteria were well-reported except for the methods of blinding, and seven(16–1922,23,27) had ‘some’ risk of bias due to imbalances in dropout rates between the treatment groups and an intention-to-treat analysis not being conducted, three studies(18,19,27) due to blinding and an intention-to-treat analysis not being conducted, one study(17) due to lack of blinding and imbalances in dropouts, and one study(15) due to a small sample size (n 47). No trials had a ‘high’ risk of bias. The included trials evaluated ‘colds’, ‘respiratory tract infec- tions’ and ‘common infectious diseases’. The majority (n 17) of the trial authors reported clear descriptions of the symp- toms and diagnoses of these conditions. In eleven of the trials(15,17 –20,22 –25,28,29) , a physician confirmed the presence of an infection, and in an additional two trials(5,7) , symptoms were reported by the participants in a diary with a diagnosis confirmed by a trial investigator. In the included trials, three main outcomes were reported: duration of illness episodes; number of days of illness per person; absenteeism from day care/school/work. The results of studies carried out in children are reported in Table 3, of those in adults in Table 4 and of those in elderly people in Table 5. Duration of illness episodes Among the included trials, ten(Bentley_unpublished, 5,6,14,17,19,23–25,27) reported on the duration of illness episodes, defined as the overall sum of illness episode lengths (in d) divided by the total number of illness episodes experienced by the study participants. Data that could be pooled in a meta-analysis were presented by nine trials(Bentley_unpublished, 5,6,14,17,19,23 –25,27) (Fig. 1). This figure also shows the number of illness episodes in each arm of each study; the numbers are generally balanced between the arms, although slightly more illness episodes were observed in the placebo groups. Given that all the studies were randomised in a 1:1 fashion, the numbers of participants are approximately the same in each arm, and thus the numbers of illness episodes are not likely to reflect differences in sample sizes. The meta-analysis revealed that participants who received a probiotic interven- tion had significantly shorter illness episodes than those who received a placebo: weighted mean difference 20·77 (95 % CI 21·50, 20·04), P¼0·04. This suggests that the mean difference in illness duration between those who take probiotics and those who do not is between half and 1 d. However, there was statistical heterogeneity among these trials (t 2 ¼ 0·81; P,0·00 001; I 2 ¼ 80 %). To explore potential sources of heterogeneity, sub- group analyses were conducted. Studies carried out in S. King et al.46 BritishJournalofNutrition
  • 7. Table 3. Results of included studies conducted in children (Mean values and standard deviations) Study Condition Duration of treatment (months) Treatments Age (years) Number randomised (included in the analysis) Percentage of females Number (%) of participants with at least one illness episode Number of illness episodes Duration of illness episodes (d) Number of days of illness Number of days absent Mean SD Mean SD Mean SD Mean SD Ca´ceres et al.(23) Acute RTI 3 L. rhamnosus HN001 3·1 1·1 203 (170) 52·7 NR 172* 20·4 14·4 NR 4·70 5·5 Placebo 3·2 1·0 195 (179) 50·8 NR 181 19·4 14·8 NR 4·05 5·6 Cazzola et al.(20) Common winter diseases 3 L. helveticus R0052, Bifidobacterium infantis R0033, and Bifido- bacterium bifidum R0071 þ 750 mg FOS† 4·1 1·0 62 (62) 46·8 29‡ (47 %) 64§ NR NR 2·11 2·1 Placebo 4·2 1·1 73 (50) 46·6 43 (86 %) 87§ 2·88 2·8 Hatakka (2007, unpublished results) and Hatakka et al.(18) GI and RI 7 L.rhamnosus GG 4·6 1·5 Unclear (282) 46 97 (34 %) NR NR NRk 4·9 NR{ Placebo 4·4 1·5 Unclear (289) 52 123 (43 %) 5·8 NR Hojsak et al.(28) Respiratory symptoms Median: 5 d L. rhamnosus GG 9·9 5·1 376 (376) 49·2 8 (2 %) NR NR r 8 (2·1 %)** NR Placebo 10·6 5·0 366 (366) 44·3 20 (6 %) NR NR r 19 (5·2 %)** NR Hojsak et al.(29) Respiratory symptoms 3 L. rhamnosus GG 51·9 months (13–86) 139 (139) 43·9 60 (43 %) NR NR 39 (28·1 %)** 3·1 3·6†† Placebo 53·6 months (13–83) 142 (142) 44·4 96 (68 %) 70 (49·3 %)** 5·1 3·6 Kloster Smerud et al.(27) Gastrointestinal and respiratory symptoms 7 Biola (L. rhamnosus GG with L.acidophilus LA-5 and Bifidobacterium lactis BB-12) Over both groups: 18 months 117 (97) NR 92‡ (95 %) 492 5·39 7·89‡ 5·35 3·97‡ 7·5 5·0†† Placebo Over both groups: 18 months 123 (102) NR 95 (93 %) 564 4·69 5·19 5·94 3·77 8·5 5·0 Kumpu et al.(19) Respiratory symptoms 28 weeks L. rhamnosus GG 4·0 1·3 261 (251) 47 239 (95 %) NR Median 8 d (IQR 5–12) 5·03‡‡ 0·88 NR Placebo 4·0 1·4 262 (250) 47 236 (94 %) NR Median 8 d (IQR 5–12) 5·17 0·96 NR Leyer et al.(7) Cold and influenza-like symptoms 6 L. acidophilus NCFM 3·7 0·7 110 (110) 57 NR NR NR 4·5 4·7 3·6 3·7‡ L. acidophilus NCFM and Bifidobacterium animalis subsp. lactis Bi-07 3·8 0·6 112 (112) 52·7 NR NR NR 3·4 3·7 3·8 3·9 Placebo 4·1 0·54 104 (104) 57·7 NR NR NR 6·5 7·3 5·2 5·7 Probioticsandacuterespiratoryinfections47 British Journal of Nutrition
  • 8. Table 3. Continued Study Condition Duration of treatment (months) Treatments Age (years) Number randomised (included in the analysis) Percentage of females Number (%) of participants with at least one illness episode Number of illness episodes Duration of illness episodes (d) Number of days of illness Number of days absent Mean SD Mean SD Mean SD Mean SD Merenstein et al.(21) CID§§ 90 d DanActive (L. paracasei subsp. casei DN-114001 with Streptococcus thermophilus and L. bulgaricus) 4·86 1·12 314 (250 households) 50 NR NR NR NR 421·5 d ‡absent (1·69 d/ household) Placebo 4·94 1·13 324 (250 households) 46·9 NR NR NR NR 463·0 d absent (1·85 d/ household) Prodeus et al.(26) Upper RI 3 L. paracasei subsp. casei DN-114001 with S. thermophilus þ L. delbrueckii subsp. bulgaricus Over both groups: 4 300 (300) Overall 45·7 66 (22 %) 98kk NR NR 5·68 4·01‡ Placebo Over both groups: 4 299 (299) 73 (24 %) 93kk NR NR 5·64 3·67 RTI, respiratory tract infections; NR, not reported; FOS, fructo-oligosaccharides; GI, gastrointestinal infections; RI, respiratory infections; IQR, interquartile range; CID, common infectious diseases. * The total number of illness episodes was calculated from the total number of illness episodes per child (included in the analysis). † Although this study used FOS along with probiotic and did not use it in the control, the level of FOS was only 750 mg, which is considered to be below an active dose(32,33) . ‡ Data obtained from the study authors. § ‘Health events’. k The authors stated that the number of days with symptoms was lower in the treatment group, but the difference was not significant. { To calculate mean difference and 95 % CI, standard deviation was calculated from the CI. ** Children with a RTI that lasted .3 d. †† Standard deviation was calculated from the P value. ‡‡ Number of days with at least one respiratory symptom per subject per month. §§ CID included upper RTI, lower RTI and gastrointestinal tract infections. kk Number of CID. S.Kingetal.48 British Journal of Nutrition
  • 9. Table 4. Results of included studies conducted in adults (Mean values and standard deviations) Study Condition Duration of treatment (weeks) Treatments Age (years) Number randomised (included in the analysis) Percentage of females Number (%) of participants with at least one illness episode Number of illness episodes Duration of illness episodes (d) Number of days of illness Number of days absent Mean SD Mean SD Mean SD Mean SD Bentley (2008, unpublished results) Common cold 12 Lactobacillus plantarum HEAL9 (DSM 15312) and L. paracasei 8700:2 (DSM 13434) 45·3 17·1 155 (146) Overall 66·5 72 (49 %) 87 5·6 1·3 NR NR Placebo 46·6 17·2 155 (138) 76 (55 %) 98 6·7 0·8 NR NR Berggren et al.(5) Common cold 12 L. plantarum HEAL9 (DSM 15312) and L. paracasei 8700:2 (DSM 13434) 46·5 159 (137) 65·7 76 (55 %) 121 7·0 NR* 6·2 9·27† NR Placebo 43·7 159 (135) 66·7 91 (67 %) 170 7·0 NR‡ 8·6 10·45 NR de Vrese et al.(6) Common cold 3–5·5 months L. gasseri PA 16/8, Bifido- bacterium longum SP 07/3, and Bifidobacterium bifidum MF 20/5 with Tribion harmonis 37 12 238 (225) 63·9 NR 158 7·0 (SEM 0·5)§ NR NR Placebo 38 14 241 (229) 58·9 NR 153 8·9 (SEM 1·0) NR NR Guillemard et al.(24) CID 3 months Actimel (L. paracasei subsp. casei DN-114001 þ S. thermophilus þ L. delbrueckii subsp. bulgaricus) 31·8 8·9 500 (500) 57 213 (43 %) Unclear 6·9 4·5 NR 2·0 4·3k Placebo 32·5 8·9 500 (500) 56 256 (51 %) Unclear 6·5 4·5 NR 1·6 4·0 Niborski et al.(14) CID{ 7 L. paracasei subsp. casei DN-114001 þ S. thermophilus þ L. delbrueckii subsp. bulgaricus Overall median 21 years (range 18–29 years) 118 (118) Overall 1·3 28 (24 %) 32 3 2·04** 3 2·29** 0·18 0·61k Placebo Overall median 21 years (range 18–29 years) 121 (121) Overall 1·3 34 (28 %) 38 4 2·04 4 2·29 0·24 0·61 Smith et al.(22) Upper RTI 12 s L. rhamnosus GG and Bifidobacterium lactis BB-12 Overall median 19 years (range 18–24 years) 114 (101) 80·2 Not clear 83 ‘cases’ NR 5·58 4·41 23 d missed work and school (0·27/‘case’) Placebo Overall median 19 years (range 18–24 years) 117 (97) 72·2 Not clear 84 ‘cases’ NR 7·11 5·07 45 d missed work and school (0·54/‘case’) Tiollier et al.(15) RTI 4 L. paracasei subsp. casei DN-114001 21·3 (0·2) 24 (24) 100 % male 11 (46 %) 17 NR 5·5 1·6 NR Placebo 21·3 (0·4) 23 (23) 13 (57 %) 30 NR 6·1 1·7 NR Tubelius et al.(16) RTI and GI 80 d L. reuteri protectis 44 132 (94) 35 % NR NR NR NR Median 3 d Placebo 44 130 (87) 29 % NR NR NR NR Median 3 d NR, not reported; CID, common infectious diseases; RTI, respiratory tract infections; GI, gastrointestinal infections. * To calculate mean difference with 95 % CI, standard deviations were imputed based on the method of de Vrese et al.(6) . † Standard deviations were obtained from the study authors. ‡ No P value reported. § To calculate mean difference with 95 % CI, standard deviations were calculated from the SEM. k Data obtained from the study authors. { CID included upper RTI, lower RTI and GI. ** Standard deviation was calculated from the P value. Probioticsandacuterespiratoryinfections49 British Journal of Nutrition
  • 10. adults(Bentley_unpublished,5,7,14,17,24,25) revealed statistical differ- ences between the treatment groups, but heterogeneity remained. By contrast, studies carried out in children (based on only two trials(23,27) ) did not reveal significant differences between the treatment groups. Studies conducted only in European countries (including Scandinavia) also revealed significant differences, but again, the studies were statistically heterogeneous. A subgroup analysis was also conducted by the illness as described by the study authors (i.e. acute RTI, colds and ‘common infectious diseases’) and by the duration of the trial (,3 months, 3–5 months, 6 months or longer), but few significant effects were observed (data not shown). Finally, an analysis of six studies considered to have a ‘low’ risk of bias yielded a significant result similar to the overall pooled analysis (weighted mean difference 20·96 (95 % CI 21·79, 20·13), P¼0·02), but heterogeneity remained (Fig. 2). In addition to the nine trials included in the meta- analysis, one study(19) compared Lactobacillus rhamnosus with a placebo in 523 children aged 2–6 years attending day-care centres in Finland. The authors reported that, after 28 d of treatment, the median duration of respiratory symptom episodes was 8 d (interquartile range 5–12) in both groups (the authors did not report the number of illness episodes). However, this study had some risk of bias, so there is uncer- tainty regarding its results. Number of days of illness per person Duration of illness per person was calculated as the overall number of days with symptoms divided by the number of individuals with an illness. In some studies, it was unclear whether all individuals were included in the analysis (i.e. participants with and without illness). To account for the possibility that different units were used to calculate this outcome, data were pooled using a SMD. We found that the numbers of people with an illness episode were either similar between the probiotic and placebo groups or slightly higher in the placebo group. Overall, eleven trials reported on the number of days the participants were ill, of which ten could be pooled in a meta-analysis (Fig. 3). The results demonstrated a significant difference in favour of probiotics, suggesting fewer numbers of days of illness per person compared with that in parti- cipants who had taken a placebo (SMD 20·31 (95 % CI 20·41, 20·11), P,0·00 001). There was no statistical hetero- geneity among these studies (t 2 ¼ 0·00; P¼0·42; I 2 ¼ 3 %). In addition to these trials, Hatakka et al.(18) examined the effects of L. rhamnosus GG v. placebo for 7 months in 571 healthy children aged 1–6 years from 18 day-care centres in Finland. They reported that the number of days with res- piratory and gastrointestinal symptoms was lower in the L. rhamnosus GG group than in the placebo group, but that the difference did not reach statistical significance (no data were reported in the paper or could be obtained). They did report that the duration without respiratory symptoms was 5 weeks (95 % CI 4·1, 5·9) in the probiotic group and 4 weeks (95 % CI 3·5, 4·6) in the placebo group (P¼0·03). Table5.Resultsofincludedstudiesconductedinelderlypeople (Meanvaluesandstandarddeviations) StudyCondition Durationof treatment (months)Treatments Age(years) Number randomised (includedin theanalysis) Percentage offemales Number(%)of participantswith atleastone illnessepisode Number ofillness episodes Duration ofillness episodes (d) Number ofdays ofillness Number ofdays absent MeanSDMeanSDMeanSDMeanSD Guillemard etal.(25) Upper RTI 3Actimel(Lacto- bacillusparacasei subsp.casei DN-114001þ Streptococcus thermophilusþ L.delbrueckii subsp.bulgaricus) Median76·0537(535)63·161(11%)1207·77·28·57·2NR PlaceboMedian76·0535(535)62·266(12%)13511·07·711·67·9NR Turchet etal.(17) CID*3Milk-fermented yogurtcultureand L.caseiDN-114001 67·16·0180(180)Overall6752(29%)NR7·03·2NRNR Notreatment69·35·6180(180)Overall6750(28%)NR8·73·7NRNR CID,commoninfectiousdiseases;RTI,respiratorytractinfections;NR,notreported. *CIDincludedupperRTI,lowerRTIandgastrointestinaltractinfections. S. King et al.50 BritishJournalofNutrition
  • 11. This trial had some risk of bias, so that there is uncertainty with regard to the reliability of the results. Absenteeism (days away from day care/school/work) Absenteeism appears to have been largely calculated as the number of days absent from day care/school/work divided by the number of participants with at least one illness episode (i.e. absenteeism/ill person). In some trials, it was unclear how absenteeism was calculated. To account for potential differ- ences in units, we pooled the data using a SMD. Overall, twelve trials reported on absenteeism due to respir- atory infections/common infectious diseases, of which eleven could be pooled in a meta-analysis (Fig. 4). The results demonstrated that there was a significant difference in favour of probiotics, suggesting fewer numbers of days absent from day care/school/work compared with that in participants who had taken a placebo (SMD 20·17 (95 % CI 20·31, 20·03), P¼0·02). However, there was statistical heterogeneity among the studies (t 2 ¼ 0·04; P¼0·0009; I 2 ¼ 67 %). Very few subgroup differences were observed in the sub- group analyses (data not shown). A statistically significant result was obtained for eight trials conducted in children, suggesting fewer numbers of days absent from day care/ school in participants who had taken probiotics than in those who had taken a placebo (SMD 20·18 (95 % CI 20·34, 20·02), P¼0·03), although again significant hetero- geneity remained. Analysis by risk of bias demonstrated no pattern. While only eleven trials were included in this analysis, the funnel plot was roughly symmetrical, indicating no publication bias (data not shown). In the meta-analysis, one trial that evaluated absenteeism could not be included. A well-conducted trial by Tubelius et al.(16) Study or subgroup Bentley (unpublished results) Berggren et al.(5) Cáceres et al.(23) de Vrese et al.(6) Guillemard et al.(24) Guillemard et al.(25) Kloster Smerud et al.(27) Niborski et al.(14) Turchet et al.(17) Total (95% CI) Heterogeneity: τ2 = 0·81; χ2 = 40·60, df = 8 (P < 0·00001); I2 = 80% Test for overall effect: Z = 2·06 (P = 0·04) 5·6 7 20·4 7 6·9 7·7 5·39 3 7 1·3 6·29 14·4 6·29 4·5 7·2 7·89 2·04 3·2 87 121 172 158 213 120 492 32 180 1575 6·7 7 19·4 8·9 6·5 11 4·69 4 8·7 0·8 9·73 14·8 12·37 4·5 7·7 5·19 2·04 3·7 98 170 181 153 256 135 564 38 180 1775 Total Weight (%) 16·6 8·2 4·3 6·7 14·1 8·2 14·1 13·2 14·7 100·0 (95% CI) −1·10 (−1·42, −0·78) 0·00 (−1·84, 1·84) 1·00 (−2·05, 4·05) −1·90 (−4·09, 0·29) 0·40 (−0·42, 1·22) −3·30 (−5·13, −1·47) 0·70 (−0·12, 1·52) −1·00 (−1·96, −0·04) −1·70 (−2·41, −0·99) −0·77 (−1·50, −0·04) Mean difference Mean difference IV, random, 95% CI −4 −2 0 2 4 Favours probiotics Favours placebo Mean SD Total Mean SD Probiotics Placebo Fig. 1. Mean duration of illness episodes (d). The ‘total’ is the overall number of illness episodes experienced by the participants (randomised in a 1:1 ratio) in each treatment group. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn). Study or subgroup 4.5.1 Low risk of bias Bentley (unpublished results) Berggren et al.(5) de Vrese et al.(6) Guillemard et al.(24) Guillemard et al.(25) Niborski et al.(14) Subtotal (95% CI) Heterogeneity: τ2 = 0·67; χ2 = 19·42, df = 5 (P = 0·002); I2 = 74% Test for overall effect: Z = 2·27 (P = 0·02) 4.5.4 Some risk of bias Cáceres et al.(23) Kloster Smerud et al.(27) Turchet et al.(17) Subtotal (95% CI) Heterogeneity: τ2 = 2·51; χ2 = 19·86, df = 2 (P < 0·0001); I2 = 90% Test for overall effect: Z = 0·18 (P = 0·85) Test for subgroup differences: χ2 = 0·49, df = 1 (P = 0·48), I2 = 0% 5·6 7 7 6·9 7·7 3 20·4 5·39 7 1·3 6·29 6·29 4·5 7·2 2·04 14·4 7·89 3·2 87 121 158 213 120 32 731 172 492 180 844 6·7 7 8·9 6·5 11 4 19·4 4·69 8·7 0·8 9·73 12·37 4·5 7·7 2·04 14·8 5·19 3·7 Total 98 170 153 256 135 38 850 181 564 180 925 Weight (%) 26·0 11·6 9·4 21·4 11·7 19·9 100·0 21·3 39·1 39·7 100·0 95% CI −1·10 (−1·42, −0·78) 0·00 (−1·84, 1·84) −1·90 (−4·09, 0·29) 0·40 (−0·42, 1·22) −3·30 (−5·13, −1·47) −1·00 (−1·96, −0·04) −0·96 (−1·79, −0·13) 1·00 (−2·05, 4·05) 0·70 (−0·12, 1·52) −1·70 (−2·41, −0·99) −0·19 (−2·19, 1·82) Mean difference Mean difference IV, random, 95% CI −4 −2 0 2 4 Favours probiotics Favours placebo Mean SD Total Mean SD Probiotics Placebo Fig. 2. Mean duration of illness episodes (d) – analysis by risk of bias. (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn). Probiotics and acute respiratory infections 51 BritishJournalofNutrition
  • 12. examined the effects of Lactobacillus reuteri (ATCC55730) v. placebo on the length of sick leave due to respiratory or gastrointestinal infections in 262 healthy employees working at TetraPak in Sweden. They reported a median duration of 3 d sick leave in both groups (no other statistical results were reported and nor was it clear how many individuals experienced an illness episode). Discussion We identified a number of studies that evaluated the effec- tiveness of probiotics on the duration of illness episodes. A meta-analysis of the data showed that the mean duration of illness episodes decreased by between half and 1 d in participants who received probiotics compared with those who did not. We also found significantly fewer numbers of days of illness per person and significantly fewer numbers of days absent from day care/school/work in participants who had taken probiotics than in those who had taken a placebo. However, there was significant statistical heterogeneity between the studies that reported on the duration of illness episodes and those that reported on absenteeism from day care/school/ work, but not for studies that reported on the number of days of illness per person. This unexplained heterogeneity means that the effect size (i.e. the difference in the duration of illness episodes between treated and untreated individuals) may differ between the population groups. Subgroup analyses did not elucidate sources of statistical heterogeneity among the studies. As many trials were not car- ried out in each subgroup, some of the analyses did not have Study or subgroup Berggren et al.(5) Guillemard et al.(25) Hojsak et al.(28) Hojsak et al.(29) Kloster Smerud et al.(27) Kumpu et al.(19) Leyer et al.(7) Niborski (unpublished results) Smith et al.(22) Tiollier et al.(15) Total (95% CI) Heterogeneity: τ2 = 0·00; χ2 = 9·24, df = 9 (P = 0·42); I2 = 3% Test for overall effect: Z = 6·36 (P < 0·00001) Std mean difference −0·24 −0·41 −0·51 −0·503 −0·15 −0·15 −0·47 −0·43 −0·32 −0·32 SD 0·1582 0·1786 0·2356 0·141 0·148 0·0918 0·1225 0·2551 0·1582 0·4286 Weight (%) 9·4 7·4 4·3 11·8 10·7 26·6 15·4 3·7 9·4 1·3 100·0 −0·24 (−0·55, 0·07) −0·41 (−0·76, −0·06) −0·51 (−0·97, −0·05) −0·50 (−0·78, −0·23) −0·15 (−0·44, 0·14) −0·15 (−0·33, 0·03) −0·47 (−0·71, −0·23) −0·43 (−0·93, 0·07) −0·32 (−0·63, −0·01) −0·32 (−1·16, 0·52) −0·31 (−0·41, −0·22) Std mean difference (95% CI) Mean difference IV, random, 95% CI −1 −0·5 0 0·5 1 Favours probiotics Favours placebo Fig. 3. Duration of illness per person. In this meta-analysis, dichotomous and continuous data were pooled. The totals used in this analysis (not shown) were mostly the number of individuals with at least one illness episode (see Table 3). In one study(7) , the totals used in the analysis were the numbers of participants included in the study, and in another study(22) , the totals used were the numbers of ‘cases’ of illness (in both studies, the number of individuals with illness episodes was not reported). (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn). Study or subgroup Cáceres et al.(23) Cazzola et al.(20) Guillemard et al.(24) Hatakka et al.(18) Hojsak et al.(29) Kloster Smerud et al.(27) Leyer et al.(7) Merenstein et al.(21) Niborski (unpublished results) Prodeus (unpublished results) Smith et al.(22) Total (95% CI) Heterogeneity: τ2 = 0·04; χ2 = 29·90, df = 10 (P = 0·0009); I2 = 67% Test for overall effect: Z = 2·32 (P = 0·02) 4·7 2·11 2 4·9 3·1 7·5 3·7 1·69 0·18 5·68 0·27 5·5 2·08 4·3 2·5 3·6 5 3·8 13 0·61 4·01 0·6 170 29 213 97 60 92 222 250 28 66 83 1310 4·05 2·88 1·6 5·8 5·1 8·5 5·2 1·85 0·24 5·64 0·54 5·65 2·81 4 2·8 3·6 5 5·7 13 0·61 3·67 0·6 179 43 256 123 96 95 104 250 34 73 84 1337 Total Weight (%) 11·1 5·6 11·8 9·6 8·2 9·2 10·5 12·0 5·2 8·1 8·7 100·0 (95% CI) 0·12 (–0·09, 0·33) –0·30 (–0·77, 0·17) 0·10 (–0·09, 0·28) –0·34 (–0·60, –0·07) –0·55 (–0·88, –0·22) –0·20 (–0·49, 0·09) –0·33 (–0·57, –0·10) –0·01 (–0·19, 0·16) –0·10 (–0·60, 0·40) 0·01 (–0·32, 0·34) –0·45 (–0·76, –0·14) –0·17 (–0·31, –0·03) Std mean difference Std mean difference IV, random, 95% CI –1 –0·5 0 0·5 1 Favours probiotics Favours placebo Mean SD Total Mean SD Probiotics Placebo Fig. 4. Days absent from day care/school/work. The ‘total’ is mostly the number of individuals with at least one illness episode. In two studies(7,23) , the totals used were the number of participants included in the study; in one study(21) , the totals were the number of households randomised, and in another study(22) , the totals were the number of ‘cases’ of illness (in all these studies, the number of individuals with illness episodes was not reported). (A colour version of this figure can be found online at http://www.journals.cambridge.org/bjn). S. King et al.52 BritishJournalofNutrition
  • 13. enough power to detect any underlying effects and thus could not detect significant effects.Where differences were observed, it is important to note that inferences made according to between-study differences do not translate into within-study differences, as this would be making an indirect comparison of effects. One cannot make the assumption that the effective- ness of probiotics on the duration of illness episodes is insig- nificant in children compared with that in adults. Moreover, other unknown modifying factors in studies conducted in children may have had an effect on the results that could potentially be independent of age. For two of the outcomes evaluated, we pooled the data using the SMD, which can be difficult to interpret. Based on research in the social sciences, Cohen(30) suggested that effect size indices of 0·2, 0·5 and 0·8 can be used to represent small, medium and large effect sizes, respectively. Such generic interpretations may be problematic, as even small improvements may be important in health-related contexts(12) . We also argue that improvements in respiratory illness, even up to a day, would be of great benefit to an individual and could potentially have public health benefits. Furthermore, two systematic reviews(10,31) that evaluated the use of probiotics for the prevention of acute RTI also reported on the duration of illness. Hao et al.(10) reported no difference between probiotics and placebo for the mean duration of illness episodes, but they included only two trials in their meta-analysis, of which one was conducted in athletes (which were excluded from this review). However, the authors did find a difference in the incidence of RTI in favour of placebo, but this outcome has not been evaluated here. The review by Vouloumanou et al.(31) reported that of nine studies, three showed a significant effect in favour of probiotics and six found no difference between the probiotic and comparison groups (the authors did not conduct a meta-analysis). Again, this systematic review included athletes and children aged ,1 year, which differs from the inclusion criteria of our review. No previous systematic reviews appear to have summarised data on absenteeism from day care/school/work, and this review provides new evidence for this outcome. The present systematic review has some limitations. First, we included trials that evaluated colds and RTI, as well as ‘common infectious diseases’, so that some of the analyses will have included patients with gastrointestinal infections. On the other hand, the significant results may be indicative of the effectiveness of probiotics in the wider population. While the majority of trial authors reported clear descriptions of the symptoms and diagnoses, a confirmed diagnosis by a physician was made in about half of the trials. It is possible that acute infections could have been under-reported or over-reported in some of these trials. As with all systematic reviews, it is possible that the addition of publications in the future could alter the results. As this review includes a large number of high-quality studies that demonstrate a consistent trend in favour of probiotics, the results are probably reliable. Further research and meta-analyses are recommended in different population groups to identify potential sources of variability in the results. It is also suggested that trial authors need to more clearly describe how their outcomes were calculated. In conclusion, this systematic review provides evidence from a number of good-quality RCT that the average duration of respiratory illness episodes, the number of days of illness per person and the number of days absent from day care/ work/school are significantly reduced with probiotic treatment compared with placebo. Supplementary material To view supplementary material for this article, please visit http://dx.doi.org/10.1017/S0007114514000075 Acknowledgements This work was funded by an unrestricted educational grant from the Global Alliance for Probiotics. The funder provided the scope to conduct the review and was allowed to comment on the protocol and draft of the manuscript, but had no control over the final article. The authors have received other educational grants from the Global Alliance for Probiotics. The authors’ contributions are as follows: S. K. (lead author) conducted the review, analysed and interpreted the data, drafted the article and gave final approval for publication; J. G. contributed to the concept, design, conduct and report- ing of the review and critically revised the article for important intellectual content and gave final approval for publication; M. E. S. formulated the research questions and contributed to the design of the review, critically revised the article for important intellectual content and gave final approval for pub- lication; A. F. contributed to the analysis and interpretation of the data, critically revised the article for important intellectual content and gave final approval for publication; D. V. carried out data extraction, checked the review, contributed to the drafting of the article and gave final approval for publication. All authors met the requirements set by the BJN. There are no conflicts of interest. References 1. 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