Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review.

Original Research

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Washington on 12/01/14 For personal use only.

Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review 1.

Introduction

2.

Data sources

3.

Study selection criteria

4.

Data extraction

5.

Definitions

6.

Methodological quality of the

Metehan Ozen, Gonca Kocabas Sandal & Ener Cagri Dinleyici† †

Eskisehir Osmangazi University Faculty of Medicine, Department of Pediatrics, Eskisehir,Turkey

included RCTs 7.

Selected RCTs

8.

Discussion

9.

Expert commentaries and future implications

Background: Acute upper respiratory tract infections (URTIs) contribute substantially to pediatric morbidity and mortality worldwide. Prevention of these infections in childhood is a very important public health challenge. Previous systematic reviews, including both adult and childhood populations, have reported that probiotics seem promising, but with modest evidence. This study aimed to focus on prophylactic probiotic use in the prevention of URTIs in childhood. Methods: Relevant trials on two databases were identified in a systematic review, from inception to June 2014. Study selection, data extraction and quality assessment were carried out by two reviewers. In this review, the effects of probiotics, particularly the Lactobacillus and Bifidobacterium strains, on the incidence and symptom scores of URTI in otherwise healthy children were evaluated for the first time. This review comprises 14 randomized controlled trials (RCTs) applied to a pediatric population with high-quality methodology. Results: This systematic review suggests that probiotics in immunocompetent children have a modest effect both in diminishing the incidence of URTIs and the severity of the infection symptoms. Conclusions: At least one beneficial effect of prophylactic probiotic was observed in the majority of RCTs. Even a minimal reduction of 5 -- 10% in the incidence of URTIs would have an important clinical and economic mpact on societies. Furthermore, the long-term administration of probiotics appeared to have a good safety profile in childhood and none of the studies reported any serious adverse events related to the probiotic strain. Keywords: children, incidence, prevention, probiotics, respiratory tract infection Expert Opin. Biol. Ther. [Early Online]

1.

Introduction

Acute upper respiratory tract infections (URTIs), one of the most common reasons for physician visits, are a major cause of morbidity and absence from daily life, particularly in children and the elderly [1-3]. Any intervention that would lessen or shorten respiratory infection (RTI) episodes will display an important life-saving and cost--effective impact on societies. Probiotics have been defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” [4]”. Lactobacillus and Bifidobacterium strains are the most commonly used probiotics in supplements to treat a wide range of diseases, ailments and conditions that affect humans and animals. The clinical uses of probiotics are extensive in daily life, but the clinical indications based on evidence-based studies are much narrower and are open to ongoing discussion and evaluation. Until recently, the majority of clinical research regarding the clinical efficacy of probiotic microorganisms has focused on the treatment of

10.1517/14712598.2015.980233 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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gastrointestinal diseases, such as acute gastroenteritis (AGE) and irritable bowel symptoms. The rationale for the use of probiotics in the management of infectious diseases has been supported in numerous studies by their potential to influence and stabilize the composition of gut microbiota, enhance colonization resistance and modulate immune function parameters [5]. Preventing and reducing symptoms of respiratory and gastrointestinal illness are the primary reason that dietary supplementation with probiotics are becoming increasingly popular with healthy active individuals. Current evidence suggests a modest effect of probiotics in the prevention of URTIs in the general population (6). However, there has been no systematic review focusing solely on the prevention of acute URTIs in childhood. To the best of our knowledge, this paper is the first review in literature to evaluate the appropriate studies that have reported the effectiveness and safety of probiotic supplementation in children. 2.

Data sources

Study selection criteria

Randomized controlled trials (RCTs) referring to the clinical utility or safety of the administration of probiotics for the prevention of upper RTIs were considered eligible for inclusion in this review. The studies published in languages other than English, German, French, Italian and Spanish were excluded from the review. Two reviewers independently performed the literature search, evaluation of the eligibility of the retrieved studies and data extraction. A systematic review was performed to identify relevant trials from inception to June 2014. According to the recently published International Scientific Association for Probiotics and Prebiotics consensus statement, the RCTs evaluated were those that studied the use of probiotics as supplements in the form of capsules, sachets, droplets or drinks, and “infant formulas with probiotics” were excluded [6]. 4.

Data extraction

Data extracted from each of the included RCTs referred to the study design, the characteristics of the included populations, the type of RTI, the type and form of the administered probiotic, the duration and dosing schedule of the probiotic treatment, any concomitantly administered therapy, the primary and all secondary outcomes regarding the RTI and any treatment-related adverse events observed. 2

Definitions

Respiratory tract infections RTIs were infections of the upper respiratory tract, including common cold, acute otitis media (AOM), tonsillitis/tonsillopharyngitis, sinusitis and recurrent sinusitis. 5.1

Probiotics A product that contains a sufficient number of viable microorganisms to alter the microbiota of the host and has the potential for beneficial health effects [7]. Commonly used probiotics include lactic acid bacteria (such as Lactobacillus acidophilus, L. casei, L. lactis, L. plantarum, L. reuteri, L. rhamnosus, L. salivarius and L. johnsonii) as well as various bifidobacteria (such as Bifidobacterium animalis, B. infantis, B. lactis, B. longum and B. breve), non-pathogenic strains of Escherichia coli or Enterococcus spp., and Saccharomyces spp. 5.2

Prebiotics A non-digestible food ingredient that benefits the host by selectively stimulating the favorable growth and/or activity of one or more indigenous probiotic bacteria [8]. 5.3

The PubMed and Scopus databases were systematically searched to identify clinical trials eligible for inclusion in this review. The literature search strategy used in PubMed was ‘respiratory tract infections AND (probiotics OR Lactobacillus OR Bifidobacterium)’ AND children. The search term applied to Scopus was ‘(respiratory tract infections) AND (probiotics) AND children’. 3.

5.

Synbiotics A product that contains both probiotics and prebiotics. Evidence for synergy of a specific prebiotic for a probiotic in the product is not essential. Synbiotics may be separate supplements or may exist in functional foods as food additives. The most commonly used products are fructo-oligosaccharides, inulin, and transgalactosylated and soybean oligosaccharides [9]. 5.4

Adverse events Any adverse event reported during the study period. 5.5

Methodological quality of the included RCTs

6.

The Jadad score was used to assess the methodological quality of studies [10]. This validated score lies in the range 0 -- 5. Studies are scored according to the presence of three key methodological features of randomization, blinding and accountability of all patients, including withdrawals. In addition, one point is assigned or subtracted depending on whether the quality of each one of the randomization and blinding procedures is deemed adequate. Five points is the maximum score that can be attributed to a trial. A score equal or higher than 3 points was used to denote adequate methodological quality of a trial. 7.

Selected RCTs

The searches performed in PubMed, Scopus and CENTRAL databases generated a total of 53, 22 and 4 results, respectively. From those, 14 individual RCTs were regarded as qualifying for inclusion in this review [11-24]. The detailed

Expert Opin. Biol. Ther. (2014) 15(1)


Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review

Potantially relevant articles retrieved from Pubmed (n = 74)

Potantially relevant articles from Scopus (n = 149)

Articles selected for further evaluation after first screening of title and abstract (n = 41)

Articles selected for further evaluation after first screening of title and abstract (n = 33)

Articles excluded after detailed screening according spesific criteria (n = 27)

Articles excluded after detailed screening according spesific criteria (n = 26)

Reviews (n = 12) Different outcome RCT (n = 8) Animal studies (n = 1) Duplicate publications (n = 1) Inappropriate age (n = 3) Low Jadad score (n = 2)

Reviews (n = 10) Different outcome RCT (n = 6) Different language (n = 2) Infant formula studies (n = 3) Inappropriate age (n = 3) Low Jadad score (n = 2)

RCTs qualifying for inclusion (n = 14)

RCTs qualifying for inclusion (n = 7)

Individual RCTs selected for inclusion (n = 14)

Figure 1. Flow diagram of trials for inclusion in the systematic review.

process of the selection of eligible trials is depicted graphically in Figure 1. Characteristics of the included RCTs The main characteristics of the 14 studies included in this review (Jadad score, study design, characteristics of study population, type/form of administered probiotics, duration/dose of probiotic treatment, concomitant treatments, type of infections studied) are summarized in Table 1. Outcomes regarding the prevention, severity and duration of RTIs and adverse events attributed to the study treatments are presented in Table 2. All the 14 included RCTs had a double-blind, placebo controlled, randomized design [11-24]. All the studies were evaluated by the Jadad scoring system, and 12 of the 14 studies received full scores of 5 and the remaining 2 studies scored 4 on the scale of 5 [21,23]. 7.1

Characteristics of the studied populations Of the total 14 RCTs, 13 involved healthy children or infants [11-16,18-24] and 1 involved hospitalized children [17]. Eight of the 14 included RCTs studied specific populations of children attending daycare. The total number of subjects examined in the 14 studies was 5857.

Probiotic treatment The probiotics evaluated were strains of Lactobacillus spp. as a single strain in seven RCTs [13,16,17,20-22,24], strains of Bifidobacterium spp. in four RCTs [11,12,14,15] and different combinations of Lactobacillus and Bifidobacterium strains in three RCTs [18,19,23]. The duration of probiotic treatment varied between 3 and 12 months. The dosing schedule as well as the form of administration of probiotics varied considerably between RCTs. Concomitant treatments included prebiotics in two studies [15,19] and iron supplement in one RCT [15]. The compliance of study participants with the assigned treatments was difficult to evaluate as, in the majority of included trials, study treatments were administered at home or in daycare centers and the participating individuals themselves or their parents recorded the amount of probiotic taken. Data regarding the appearance or severity of RTI-related symptoms were also mainly recorded by the parents of study participants. 7.3

7.2

7.4

Outcomes regarding respiratory tract infections Incidence of respiratory tract infections

7.4.1

In 5 of the 14 RCTs, no difference was found regarding the incidence of RTIs between the probiotic and placebo arms [13,20-22,24]. On the other hand, a significant decrease in


3

4


1. Double-blinded 2. Randomized 3. Placebo-controlled


1. Double-blinded 2. Cluster-randomized 3. Placebo-controlled

1. Double-blinded 2. Cluster-randomized 3. Placebo-controlled




1. Double-blinded 2. Randomized into three groups 3. Placebo-controlled



5

5

5

5

5

5

5

5

5

5

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

B. animalis ssp. lactis (BB-12) 1 1010 CFU in 100 ml bottle of the strawberry yogurt-based drink B. lactis (BB12), 5 109 CFU/ tablet versus xylitol control L. casei DN-114 001/ CNCMI-1518, 1 108 CFU/g/in 200 ml bottle of yogurt-based drink B. animalis ssp. lactis (BB-12) 1 1010 CFU in 100 ml bottle of the strawberry yogurt-based drink B. lactis HN019, a total of daily 1.9 107 CFU in three milk powder sachets

172 children (2 -- 4 years old) attending daycare/ school centers

638 children (3 -- 6 years old) in daycare/schools

1) L. acidophilus NCFM (ATCC 70039), 5 109 CFU/sachet 2) L. acidophilus NCFM, 0,5 109 CFU + B animalis subsp lactis Bi-07 (ATCC PTA-4802) 0,5 109/sachet Probiotic mixture (L.rhamnosus GG + L. rhamnosus LC705 + B. breve Bb99 + Propionibacterium shermanii JS) 8 -- 9 109 CFU/ capsule L. rhamnosus GG, 1.9 106 CFU in 100 ml milk product

326 children (3 -- 5 years of age) who attend daycare center

501 children (2 -- 6 years old) attending daycare centers

1018 infants (0 -- 6 months)

28 weeks/threemeals per day

6 months after birth/ one capsule per day

6 months/one sachet twice per day

Each day of hospitalization/one bottle per day

L. rhamnosus GG, 1 109 CFU in 100 ml fermented milk product

742 hospitalized children > 1 year of age

281 healthy children (1 -- 7 years) who attend daycare centers

90 consecutive days/ One bottle per day

1 year/three sachets per day

90 consecutive days/ one bottle per day


6 months/2 tablets per day


Duration/dose of probiotic

L. rhamnosus GG, 1 109 CFU in 100 ml fermented milk product

624 healthy children (1 -- 3 years)

182 children (1 -- 3 years old) attending daycare/ school

109 healthy infants (2 -- 8 months)

Type/form of probiotic

Study population

NA

0,8 g of prebiotic galactoligosaccharide in liquid form

NA

NA

A total of daily 2.4 g oligosaccharide, Iron only for severely anemic patients NA

NA

NA

NA

NA

Concomitant Tx

B. animalis: Bifidobacterium animalis; B. bifidum: Bifidobacterium bifidum; B. breve: Bifidobacterium breve: B. lactis: Bifidobacterium lactis; CFU: Colony forming unit; L. acidophilus: Lactobacillus acidophilus; L. casei: Lactobacillus casei; L. rhamnosus: Lactobacillus rhamnosus.

Design of randomized controlled trial

Jadad score

Ref.

Table 1. The main demographics of the 14 studies included in this review.


M. Ozen et al.

B. animalis: Bifidobacterium animalis; B. bifidum: Bifidobacterium bifidum; B. breve: Bifidobacterium breve: B. lactis: Bifidobacterium lactis; CFU: Colony forming unit; L. acidophilus: Lactobacillus acidophilus; L. casei: Lactobacillus casei; L. rhamnosus: Lactobacillus rhamnosus.

NA 3 months/once daily 398 children (1 -- 5 years old) attending daycare centers 5 [24]


4 [23]


80 healthy children (8 -- 13 years old)

L. acidophilus and B. bifidum/ each 1 109 in one capsule

L. rhamnosus HN0001/1 108 in 100 ml bottle of milk based product

NA

NA

7 months (winter)/ three times a day (minimum 250 ml)/five days a week 3 months/two capsules per day 5 [22]

1. Double-blinded 2. Multicentric randomized 3. Placebo-controlled

513 healthy children (1 -- 6 years old) attending daycare centers

L. rhamnosus GG (ATCC53103)/ 5 10 105 CFU

NA 20 weeks/two bottles per day L. casei (DN-114001) ? CFU in a 100 ml bottle of yogurt-type drink 4 [21]

1. Double-blinded 2. Cluster randomized 3. Placebo-controlled

251 healthy children (3 -- 12 years old) in 2 different schools

Duration/dose of probiotic Type/form of probiotic Study population Design of randomized controlled trial Jadad score Ref.

Table 1. The main demographics of the 14 studies included in this review (continued).


Concomitant Tx


the incidence of URTIs was reported in seven RCTs [12,15-19,23] and there was no information on this in the remaining two studies [11,14]. The incidence parameters were different in all the RCTs, including incidence of URTIs, incidence of middle ear infection, incidence of URTIs in the study period, incidence of URTIs in follow-up period and incidence of recurrent (‡ 3) URTIs. Severity of symptoms related to respiratory tract infections

7.4.2

A significant reduction regarding the severity of symptoms of RTIs associated with probiotic treatment was found in 7 of 11 RCTs [12,15-18,22,23] that provided relevant data, while no difference was noted in the remaining 4 of 11 RCTs [11,14,20,24]. Three RCTs did not report data on the severity of symptoms. The symptoms and their severity scaling were different in all RCTs, including duration of fever, cough, runny nose, rate of severe URTI symptoms, earache and ratio of subjects with at least one URTI symptom. Missed days of school because of illness Data regarding missed days of daycare or school due to the severity of the clinical manifestations of URTIs were included in 8 of the total 14 RCTs. Of these eight studies, four reported no difference [11,14,21,24] and four showed significantly decreased absenteeism [16,18,22,23] between the probiotic and placebo groups. 7.4.3

Incidence of antibiotic use Five of the 14 trials provided data regarding the incidence of antibiotic treatments for URTIs. Of these five, in two RCTs [18,19], a significant difference in favor of the probiotic groups was reported, whereas in the remaining three [12,20,24], no difference was found between the placebo and probiotic groups. 7.4.4

Outcomes regarding the safety of probiotic treatment

7.4.5

Data regarding adverse events were reported in all but 2 [21,24] of the 14 RCTs. In 6 of 12 RCTs [15-18,22,23], no adverse events were noted that could be attributed to study treatments. Adverse events of minor clinical severity, mainly vomiting, diarrhea and rash were reported in the remaining six RCTs. Of these six studies, the adverse events were only higher in two [11,12] in favor of the probiotic groups. No serious adverse events were reported in any of the included RCTs. 8.

Discussion

The interaction of microbiota with the mucosal immune system throughout the body provides both local and systemic immunomodulation (5 -- 6). Understanding the role of microbiota in human immunity, including resistance against infections, a major role in auto-immune disorders, certain allergic conditions and cancers has further evolved thanks to


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Table 2. Primary and secondary outcomes regarding the prevention, severity and duration of RTIs, as well as the adverse events attributable to the study protocol. Ref.

Outcomes (probiotic vs control)

Adverse events (probiotic vs control)

[11]

i) Missed days of school due to illness per 100 person days; 2.54 versus 2.42, p = 0.873 ii) Rate of fever per 100 person days; 1.48 versus 1.62, p = 0.724 iii) Rate of runny nose per 100 person days; 12.25 versus 14.26, p = 0.458

ITT analysis

i) With at least one AEs 8 versus 3 ii) With at least one SAEs 0 versus 0

[12]

i) Cumulative incidence of acute URTIs; 65 versus 94%, RR: 0.69, p = 0.014 ii) Cumulative incidence of AOM; 26 versus 17%, RR: 1.54, p = 0.455 iii) Antibiotic use: 29 versus 23% (RR:1.29, p = 0.535)

PP analysis


[13]

i) Incidence rate of common infectious disease per 100 person days; 7.8 versus 9.8, RR: 0.81, p = 0.046 ii) Incidence rate of upper URTIs per 100 person days; 2.7 versus 3.3 RR: 0.82, p = 0.036

ITT analysis


[14]

i) Missed days of school due to illness per 100 person days; 2.82 versus 2.51, p = 0.374 ii) Rate of runny nose per 100 person days; 16.50 versus 13.41, p = 0.231 iii) Rate of cough per 100 person days; 7.86 versus 6.27, p = 0.251

ITT analysis


[15]

i) Days with severe illness per year; 1.8 versus 2.14, RR:0.84, p = 0.004 ii) Days with high fever per year; 10.6 versus 11.2 RR: 0.95, p= 0.05

ITT analysis


[16]

i) Number of children with URTIs; 43.2 versus 67.6%, RR:0.63, p < 0.001 ii) Number of children with RTIs > 3 days; 28.1 versus 49.3%, RR:0.57, p < 0.001 iii) Absent days from care center due to infections; 3.1 days versus 5.1 days, p < 0.001

ITT analysis


[17]

i) Number of URTIs; 2.1 versus 5.5%, RR: 0.38, p < 0.05 ii) Duration of respiratory infection > 3 days; 2.1 versus 5.2%, RR: 0.40; p < 0.05

ITT analysis


[18]

i) Incidence of fever; 16.1 versus 28.2 versus 63.5%, (RR:), p = 0.0009, p = 0.0085 ii) Incidence of rhinorrhea; 31.3 versus 55.5 versus 81.7%, p = 0.03, p = 0.68 iii) Incidence of antibiotics use; 8.0 versus 16.4% versus 54.8; (RR:) p = 0.0001, p = 0.0002 iv) Absent days from care center due to infections; -1.6 days and -1.4 days; p = 0.01 and p = 0.01

ITT analysis

i) With at least one AEs 3 versus 0 versus 0 ii) With at least one SAEs 0 versus 0 versus 0

[19]

i) Incidence of RTIs in 6 months: 66 versus 68%, (OR; ?), p > 0.05 ii) Incidence of middle ear infection in 6 months: 72 versus 76%, (OR: ?), p > 0.05 iii) Incidence of antibiotic use in 6 months; 23 versus 28%; (OR: 0.74), p = 0.049 iv) Incidence of RTIs in 24 months: 93 versus 97%, (OR; 0.49), p = 0.023 v) The total number of RTIs in 24 months: 3.7 versus 4.2, (OR: 0.87), p = 0.009 vi) Incidence of middle ear infection in 24 months: 72 versus 76%, (OR: 0.83), p = 0.204 vii) The total numbers of middle ear infections in 24 months: 1,7 versus 1,9, (OR: 0.89), p = 0.068

ITT analysis


[20]

i) Ratio of subjects with URTI symptoms: 95 versus 94%, (RR:?), p = 0.89 ii) Number of days with symptoms: 5.03/month versus 5.17/ month (IRR:0.97), p = 0.098 iii) Number URTI episodes; 0.59/month versus 0.55/month, (RR:1.06), p = 0.24 iv) Ratio of subjects on antibiotic therapy; 35 versus 34%, (RR:?), p = 0.80

PP analysis


?: No data available; AOM: Acute otitis media; RTI: Respiratory infection; URTI: Upper respiratory tract infections.

6




Table 2. Primary and secondary outcomes regarding the prevention, severity and duration of RTIs, as well as the adverse events attributable to the study protocol (continued). Ref.

Outcomes (probiotic vs control)

Adverse events (probiotic vs control)

[21]

i) Incidence of at least one URTIs; 92.2 versus 87.5%, (RR: ?), p > 0.05 ii) Incidence of recurrent (‡ 3) URTIs: 50.6 versus 58.6% (RR: ?), p > 0.05 iii) Incidence of school absenteeism; 37 versus 45%, (RR:?), p > 0.05

ITT analysis

i) With at least one AEs? versus? ii) With at least one SAEs? versus?

[22]

i) Number of absent days; 4,9 versus 5,8, (RR: 0.85), p = 0.03 ii) Incidence of AOM episodes: 31 versus 39%, (RR:?), p = 0.08

PP analysis


[23]

i) Number of subjects with at least 1 symptom of URTI; 77 versus 95%, p = 0.048 ii) Incidence of fever; 35 versus 63%, (RR: ?), p = 0.025 iii) Incidence of school absenteeism; 5 versus 35%, (RR:?), p = 0.001

PP analysis


[24]

i) No of episodes of upper ARI: 0.44 versus 0.45, (RR:?), p = 0.66 ii) Duration of the ARI episodes (day): 19.4 versus 20.4, (RR:?), p = 0.44 iii) Absenteeism (day): 4.05 versus 4.70, (RR:?), p = 0.37 iv) No of days with antibiotics (days): 1.45 versus 1.54, (RR:?), p = 0.95

ITT analysis

i) With at least one AEs? versus ? ii) With at least one SAEs? versus?

?: No data available; AOM: Acute otitis media; RTI: Respiratory infection; URTI: Upper respiratory tract infections.

recent sophisticated studies, particularly metagenomic techniques. Since RTIs are common among children and contribute substantially to pediatric morbidity and mortality worldwide [25], prevention of these infections is a very important public health challenge. In many countries, children experience 3 -- 6 URTIs per year and 40% of them suffer at least one episode of AOM, which are the main reasons for antibiotic treatment in childhood [26]. Thus, a 5 -- 10% reduction in the incidence of URTIs would have important clinical, public health and economic consequences [27]. According to CDC, 22 million school days and 20 million working days for adults are lost annually due to URTIs and the economic impact of colds has been estimated to be 40 billion dollars per annum in the USA [27]. One of the most important current global health concerns is increasing antibiotic resistance as a result of injudicious antibiotic use in the treatment of acute URTIs [28,29]. The inappropriate use of antibiotics for the treatment of these infections often reinforces further dysbiosis in human microbiota [30]. These changes in the human microbiome, particularly in the early years of life, unfortunately result in the emergence of new childhood epidemics, such as allergic conditions, certain auto-immune disorders, obesity and most probably cancers [31-35]. A cold prevention method should be simple, low cost and without adverse reactions in order to be clinically useful and thereby publicly acceptable. There have been many randomized controlled studies investigating whether taking vitamin C, garlic or Echinacea has any effect on the prevention of colds. According to three systematic reviews performed by the Cochrane Library, there was no significant effect from these supplements in most cases [36-39].

The administration of specific probiotic bacteria has been reported to support both the local and systemic immune system by various methods [40-45], including colonization resistance, trans-epithelial resistance, increased number and activity of natural killer cells, release of certain cytokines and bacteriocins, enhanced antibody response, enhanced vaccine response, stimulation of nonspecific immunity and enhancing humoral and cellular immunity. Different probiotic bacteria have been associated with variable stimuli to the human innate and adaptive immune system and co-mediate metabolic and immune homeostasis with different levels of success. Probiotic strain identity and host genetic differences may account for differential modulation of immune responses [46]. The past few years have seen a surge in the number of research initiatives investigating the association between gut microbiota and our health [47]. Most clinical trials have assessed the therapeutic effects of probiotics but their prophylactic role in the prevention of certain disorders and maintaining good health has been somewhat neglected. The dramatic increase in the number of studies addressing the potential effect of probiotics in reducing the risk of common URTIs in childhood, engendered this systematic review. In view of the extreme diversity of probiotic strains, dosage and duration of administration, the differences in ages and socioeconomic parameters and in research design, it was not appropriate to perform a formal systematic meta-analysis. A Cochrane meta-analysis of 10 clinical trials involving a total of 3451 infants [48], children and adults, found that probiotics were more beneficial than placebo in terms of infection prevention, and reduced the rate of acute URTI and the frequency of antibiotic use, but did not decrease the duration


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of each single episode. The number of participants experiencing at least one URTI episode had an odds ratio (OR) of 0.58; 95% confidence interval (CI) 0.36 -- 0.92; at least three episodes, OR 0.53; 95% CI 0.36 -- 0.80; rate ratio of episodes of acute URTI: rate ratio 0.88; 95% CI 0.81 -- 0.96; and reduced antibiotic prescription rates for acute URTIs: OR 0.67; 95% CI 0.45 -- 0.98 (24). The side effects of probiotics were minor and gastrointestinal symptoms were the most commonly encountered complaints. On the other hand, a previous systematic review [49], including 14 adult and childhood studies, reported that only four RCTs favored the use of probiotics in respect of the incidence of RTIs. In that review, the reduction in severity of symptoms related to RTIs was noted in five of the six RCTs that provided relevant data. The final quote of the manuscript reported that probiotics might have a beneficial effect on the severity and duration of symptoms but no reduction in the incidence of RTIs, which clearly conflicts with the previously mentioned Cochrane report. A recent meta-analysis targeting 10 studies in 7 articles with similar output, the preventive effect of probiotics against respiratory diseases also reported contradictory results. In that paper, only four studies reported that the incidence of respiratory disease was reduced in the probiotic group [50]. According to that meta-analysis, the studies of which, with the all exception of one (one childhood study by Leyer et al.) were all adult population studies, there was no statistically significant effect on the incidence of RTIs, but probiotics seemed to have borderline preventive effects. Several limitations should be taken into consideration in the interpretation and extrapolation of the findings of these systematic reviews and meta-analyses. The most important issue is that these different results absolutely depend on the selection of the primary and secondary outcomes, such as the incidence of one RTI or recurrent infections, specific infections such as AOM, antibiotic consumption, absenteeism, symptom scores, hospitalization, duration of single or total episodes and various others. There is substantial heterogenity between these articles, but the results of the childhood studies are more consistent than those of adults because the methodology is more alike than that used on adults. Finally, the strain, the dose and duration of the probiotic bacteria administration might be the main explanation of these contradictory results, as it is very well known that the effects of probiotics on immune responses are species and strain specific [51,52]. Despite these above-mentioned issues, probiotics are better than placebo in reducing the incidence of acute URTIs and antibiotic use in childhood. The majority of these studies have reported significant improvements on specific sicknessrelated outcome parameters when data are available. In a recent review by Weizman, the immune-stimulatory effect of probiotic bacteria has previously been shown to prevent recurrent infections in the majority of the studies, including children attending daycare centers [6]. He reported that 8

probiotic supplementation was found to be a safe and effective tool in the prevention of gastrointestinal and respiratory infections in daycare infants and children in the majority of the 12 studies involved in his review. It is considered by many authors that meta-analysis is possible if there is a sufficient number of studies and participants with the same strain and/or primary outcome results. A Chinese group recently published a solid meta-analysis of four studies with 1805 participants on L. rhamnosus GG (LGG), one of the most studied strains against common infectious disease (CID). Compared with the placebo group, the pooled data in the LGG group had a significantly reduced risk of AOM (four RCTs, n = 1805, RR 0.76, 95% CI 0.64 -- 0.91, fixed effects model, number need to treat 17, 95% CI 11 -- 46) and a reduced risk of URTIs (one RCT, n = 281, RR 0.62, 95% CI 0.50 -- 0.78, number need to treat 4, 95% CI 3 -- 8). However, there was no effect on lower respiratory infections, perhaps due to the small number of infections affecting the lower respiratory tract [53]. Current data suggests that consumption of LGG appears to be an effective strategy for reducing the risk of AOM and URTIs in basically healthy children. Another strain, L. casei DN-114 001, which has been studied extensively in humans, is a reminder of the necessity to study a strain at different ages before recommending it for all age group immunity. Double-blind RCTs (DBRCTs) of this strain reported beneficial effects both in children (638 children, 3 -- 6 years old in daycare/schools, the incidence rate for CIDs in probiotic group [0.0782] was 19% lower than the control group [0.0986] [13], [incidence rate ratio = 0.81, 95% CI: 0.65, 099] p = 0.046) and in adults (1072 elderly, reduced the mean duration of CID episode to 6.5 versus 8 days, p = 0.008) [54]. The latter author published another study in adults, reporting that daily consumption of a fermented dairy product containing L. casei DN-114 001 could reduce the risk of common infections in stressed individuals such as shift workers (OR = 0.75, 95% CI 0.59 -- 0.95, p = 0.017) [55]. The reduction in the incidence and duration of CID episodes at different ages suggested that this strain is effective throughout the lifetime, which might not be the case with other strains and different probiotics, since it is well known that human microbiota change with age, diet and chronic disease [56,57]. Arising from this review, there are two major sets of problems to be agreed upon for future studies on immunity to CIDs (Table 3). First, some studies have reported the probiotic effect on incidence/recurrence of RTIs and/or antibiotic use, whereas others have reported the total days of single/total episodes of CIDs and the daycare absenteeism. Primary and secondary outcome parameters should be better unified to enable a meta-analysis on this topic. The second set of problems is related to probiotic administration. The strain, dose, administration route, total duration of the study and total follow-up time have been completely different in previous studies. Therefore, there is an urgent need for DBRCTs




Table 3. Future implications for further studies. Study demographics Studies in populations with underlying diseases, who have anomalies that are prone to infections, individuals with or without influenza virus and pneumococcal vaccinations are lacking Risk factors should be clarified and subgroups must be well documented such as allergy in the family, parental smoking, siblings in the family Studies in primary school and teenage populations are lacking Studies in immune-compromised populations, particularly in HIV subjects must be planned Study follow-up should last until RTI season is over Study interpretation Primary and secondary outcomes must be similar at least in three parameters in order to enable to perform a meta-analysis: Incidence of RTIs, ratio of antibiotic use and duration of episodes Study parameters Immunological tests should be planned to show how the probiotics are effective on systemic immune system and which parameters are helpful in prevention of RTIs Stool samples must be collected before and after the study to evaluate the phylum composition Product related Multiple strains with well documented experimental or clinical parameters should be studied Synbiotic studies should be encouraged as prebiotics seem promising in prevention studies Local application of probiotics must be studied and encouraged if the technological solutions are available Product administration period must cover the beginning and disappearing of RTI epidemics in the relevant country and climate The observation period must be long enough to see distant results No matter how long the study and follow-up period, the results might be evaluated every 3 months and the total RTI: Respiratory infection.

with a sufficient number of participants to be able to evaluate the health benefits of each probiotic strain [58]. Taken as a whole, this systematic review suggests that probiotics in otherwise healthy children have a modest effect on the prevention of URTIs and diminish the severity of infection symptoms and seem more promising than other interventions. At least one beneficial effect of prophylactic probiotic use on the incidence of RTIs and antibiotic prescription and/or the severity of a single episode was observed in the majority (10/14 RCTs) of these highquality studies. It should be remembered that even a minimum reduction in the number of CIDs in childhood would have a great impact on societies in terms of morbidity and cost-saving. Therefore, the prophylactic use of certain specific probiotic strains can be recommended to prevent URTIs, particularly in immunocompetent children with the complaint of frequent URTIs and antibiotic use. The recommended strains are those that have been shown to decrease either the incidence of recurrent URTIs or the symptom severity. Finally, the long-term administration of probiotics appeared to have a good safety profile in childhood and none of the studies reported any serious adverse events related to a probiotic strain. A safe, relatively inexpensive and effective intervention to prevent respiratory tract infections in childhood would have significant public health implications, and reducing antibiotic resistance would be a great achievement in particular. Additional placebo-controlled, double-blind clinical trials should carefully evaluate the clinical efficacy of this promising mode of therapy in a short time.

Expert commentaries and future implications

9.

The majority of the studies in this systematic review assessed the safety of probiotic intervention in childhood. No significant adverse event was reported with regards to growth or any kind of clinical side effects attributable to studied strains (Table 3). The endpoint studies should be combined with the investigation of biomarkers that might explain the underlying mechanisms of action in the immune process. Implementing research to understand the mechanisms of action of the strains to be used is critical. Clinical trials in the future should monitor the composition and diversity of the fecal and respiratory microbiota. This might reveal the transient colonization with ingested probiotic agents, if any. All actual available data show that the combination of different micro-organisms does not always induce more favorable immune modulation. The combination should be well documented so as not to inhibit each other. Cost--effectiveness and quality of life studies must be undertaken in order to apply to the reimbursement process of social security systems.

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. M Ozen is a speaker for Pfizer and EC Dinleyici is an advisory board member of Biocodex.


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Affiliation Metehan Ozen1, Gonca Kocabas Sandal2 & Ener Cagri Dinleyici†3 † Author for correspondence 1 Professor, Department of Pediatrics, Acibadem University Faculty of Medicine, Istanbul, Turkey 2 Suleyman Demirel University Faculty of Medicine, Department of Pediatrics, Isparta, Turkey 3 Professor, Eskisehir Osmangazi University Faculty of Medicine, Department of Pediatrics, Eskisehir, Turkey E-mail: [email protected]

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