MILITARY MEDICINE, 179, 6:580, 2014

Comparative Probiotic Strain Efficacy in the Prevention of Eczema in Infants and Children: A Systematic Review and Meta-Analysis 2LT Joseph A. Mansfield, MSC USA*; 2d Lt Samuel W. Bergin, USAF MSC*; ENS James R. Cooper, MC USN*; Cara H. Olsen, DrPH† ABSTRACT Background: Eczema affects 3.5% of the global population, with peak prevalence during infancy. Eczema has no cure, but probiotics have been suggested as a preventative measure. Objective: To comprehensively analyze the impact of prenatal and postnatal probiotic supplementation on the prevention of infantile and childhood eczema. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and PubMed were searched for randomized controlled trials regarding probiotic usage and eczema development from 1945 to 2013. Participants included were 7 years old or younger with probiotic exposure in utero or below 6 months of age and who was not diagnosed previously. Results: 27 publications describing 16 studies assessing 10 probiotics in 2,797 participants met our criterion. The pooled relative risk of all the studies, 0.74 (95% confidence interval 0.67, 0.82), indicated that probiotic supplementation in the first several years of life did have a significant impact on development of eczema. During evaluation of the studies, heterogeneity of terms and definitions for similar primary and secondary outcomes were identified. Conclusion: The use of probiotic supplements during pregnancy and/or during infancy creates a statistically significant decline in the incidence of eczema. The heterogeneity of terms and definitions regarding eczema is the major limitation of these studies.

INTRODUCTION Use of probiotics for the prophylaxis and treatment of a variety of pathological changes is becoming increasingly common.1–3 Research on the intestinal microbial milieu seems to support the application of certain probiotics to prevent and possibly treat certain pathologies. However, the methodology of optimizing the digestive microbiota remains complex and poorly understood.1,4 The complexity of enriching the microbiota arises from several sources.4,5 One is the preponderance of microorganisms in a host human.6,7 A second source is the normal quantitative variance of microorganisms between healthy individuals.7,8 A third is the lack of knowledge of a necessary and/or sufficient absence that can cause a pathological state. Finally, a fourth source is the deficient understanding of how exactly an individual acquires and retains their microbiota.9,10 Despite the limited research body on probiotics, their impact on a person’s microbiota, and the subsequent impact on that person’s state of health, consumers and health care providers persist in recommending and using probiotics to prevent and treat a myriad of diseases.1,11,12 To help guide

*F. Edward Hebert School of Medicine, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. †Department of Preventative Medicine and Biometrics, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Uniformed Services University, the U.S. Department of Defense, the U.S. Department of the Navy, the U.S. Department of the Army, or the U.S. Department of the Air Force. doi: 10.7205/MILMED-D-13-00546

580

clinicians, researchers, and consumers, a better consensus in the literature is needed. Our objective was to synthesize new and old data from randomized controlled trials (RCTs) performed since 1945 that deal with probiotic exposure and the development of eczema in infants. By reviewing the expanding collective literature instead of isolated individual studies, we sought to establish a more definitive answer regarding the impact of probiotics on eczema. We conducted a meta-analysis of eligible RCTs to determine the impact of probiotic supplementation during gestation and infancy on the incidence of eczema. We analyzed individual probiotics, probiotic mixtures (including 2 or more probiotics within a supplement), pre-/postnatal exposure and whether duration of exposure was greater or less than 6 months. By evaluating the literature, we also sought to establish the most useful definition of “eczema” and “atopic dermatitis.” We aim to improve the accessibility of future studies on probiotics and eczema by identifying the need for a common terminology. METHODS Literature Search Three members of the team independently conducted a systematic literature search of EMBASE, PubMed, MEDLINE, and CENTRAL. The search term for the 4 databases used was ([atopic* Dermat* or eczema*] and probio*). The use of the wildcard “*” Boolean expression allowed for a larger initial pool of studies and decreased the possibility of missing studies because of spelling differences. The search filter limiting results to RCTs was used on the MEDLINE, EMBASE, and PubMed searches. A manual search of the reference lists MILITARY MEDICINE, Vol. 179, June 2014

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Comparative Probiotic Strain Efficacy in the Prevention of Eczema TABLE I. References Abrahamsson, TR, et al13

Diagnostic Term Eczema

IgE-Associated Eczema

Abrahamsson TR, et al15

Abrahamsson TR, et al17 Bottcher MF, et al18

Eczema IgE-Associated Eczema Eczema Eczema

Kalliomaki M, et al19 Kalliomaki M, et al21

IgE Associated Eczema Atopic Eczema Eczema

Kalliomaki M, et al21

Atopic Eczema

Rautava S, et al22 Kukkonen K, et al23

Atopic Eczema Eczema,

Atopic Eczema

Kuitunen M, et al26

Eczema Atopic Eczema

Kukkonen AK, et al27 Marschan E, et al28 Taylor AL, et al30 Jensen MP, et al31 Wickens K, et al32

Eczema Atopic Eczema Eczema AD SPT+ AD Eczema SPT+ and eczema Eczema

IgE-Associated Eczema

Wickens K, et al35

Eczema

Eczema with SCORAD ³10

Diagnostic Terms and Definitions Definition Used

Major features*: (1) Evidence of pruritic dermatitis, (2) Typical facial or extensor eczematous or lichenified or nummular dermatitis, (3) Eczema-free skin of nose–mouth area and/or diaper area, (4) Family history of eczema; Minor features*: (1) Xerosis/ichtyosis/hyperlinear palms, (2). Periauricular fissures, (3) Chronic scalp scaling, (4) Perifollicular accentuation. *At least 2 major and 2 minor criteria must be present.14 Major features*: (1) Evidence of pruritic dermatitis, (2) Typical facial or extensor eczematous or lichenified or nummular dermatitis, (3) Eczema-free skin of nose–mouth area and/or diaper area, (4) Family history of eczema; Minor features*: (1). Xerosis/ichtyosis/hyperlinear palms, (2) Periauricular fissures, (3) Chronic scalp scaling, (4) Perifollicular accentuation. *At least 2 major and 2 minor criteria must be present14 and at least 1 positive SPT and/or detectable circulating allergen-specific IgE antibodies. Pruritic, chronic, or chronically relapsing noninfectious dermatitis with typical features and distribution.16 Pruritic, chronic, or chronically relapsing noninfectious dermatitis with typical features and distribution16 with a positive SPT. A pruritic, chronic, or chronically relapsing noninfectious dermatitis with typical features and distribution. A pruritic, chronic, or chronically relapsing noninfectious dermatitis with typical features and distribution.14 A pruritic, chronic, or chronically relapsing noninfectious dermatitis with typical features and distribution14 and a positive SPT and/or circulating allergen-specific IgE. Pruritus, facial or extensor involvement, or both, and chronic relapsing course.20 Pruritic eczematous lesions with typical location and with relapsing or chronic course during the last 12 months. Itchy eczematous lesions with typical location and with relapsing or chronic course during the last 12 months. Pruritus, typical morphology and distribution, and a chronic relapsing course. United Kingdom Working Party’s criteria (an itchy skin condition plus 3 of the following: history of atopic disease in the family, dry skin during the last year, history of eczema, or visible eczema involving typical sites). United Kingdom Working Party’s criteria (an itchy skin condition plus 3 of the following: history of atopic disease in the family, dry skin during the last year, history of eczema, or visible eczema involving typical sites)24 and IgE associated.25 An itchy skin plus 3 or more of the following: family history of atopic disease, dry skin during the previous 12 months, history of eczema, or visible eczema at typical sites.24 An itchy skin plus 3 or more of the following: family history of atopic disease, dry skin during the previous 12 months, history of eczema, or visible eczema at typical sites24 and positive SPT response or serum-specific IgE test result (>0.7 kU/L). Eczema (NFD) Atopic Eczema (NFD) An itchy skin condition with a dry skin and eczema at typical sites.24,29 Typical skin lesions responsive to topical steroids.16 Typical skin lesions responsive to topical steroids16 and SPT positive. Typical skin lesions responsive to topical steroids.16 Typical skin lesions responsive to topical steroids16 and SPT positive History of scratching or rubbing since the child turned 2 years plus 2 or more of the following: (1) a generally dry skin since turning 2 years, (2) a history of asthma or hay fever ever, (3) flexural involvement since 2 years around the eyes, sides or front of neck, elbow or knee flexures or fronts of ankles, and (4) visible atopic eczema present at any of these sites.33 History of scratching or rubbing since the child turned 2 years plus 2 or more of the following: (1) a generally dry skin since turning 2 years, (2) a history of asthma or hay fever ever, (3) flexural involvement since 2 years around the eyes, sides or front of neck, elbow or knee flexures or fronts of ankles, and (4) visible atopic eczema present at any of these sites33 and positive SPT.34 History of scratching or rubbing and 2 or more of the following occurring since birth or the previous visit: (1) a history of involvement of outer arms or legs, (2) a history of a generally dry skin, or (3) visible atopic eczema present on the cheeks or outer arms or legs with no axillary involvement.24 History of scratching or rubbing and 2 or more of the following occurring since birth or the previous visit: (1) a history of involvement of outer arms or legs, (2) a history of a generally dry skin, or (3) visible atopic eczema present on the cheeks or outer arms or legs with no axillary involvement24 with SCORAD score of 10 or higher.34 (continued)

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Comparative Probiotic Strain Efficacy in the Prevention of Eczema TABLE I. References

Allen SJ, et al36 Boyle RJ, et al37

Diagnostic Term

Definition Used

IgE Assoc. Eczema

History of scratching or rubbing and 2 or more of the following occurring since birth or the previous visit: (1) a history of involvement of outer arms or legs, (2) a history of a generally dry skin, or (3) visible atopic eczema present on the cheeks or outer arms or legs with no axillary involvement24 plus a positive SPT response. Eczema (NFD) Eczema and a postitive SPR (NFD) A history of itchy skin, scratching, or rubbing plus at least 3 of the following: family history of atopic disease; history of generally dry skin; history of skin rash affecting the flexures, cheeks, or outer surfaces of the limbs; onset of rash under the age of 2 years; visible dermatitis at any study visit affecting the flexures, cheeks, or outer surfaces of the limbs.24 A history of itchy skin, scratching, or rubbing plus at least 3 of the following: family history of atopic disease; history of generally dry skin; History of skin rash affecting the flexures, cheeks, or outer surfaces of the limbs; onset of rash under the age of 2 years; visible dermatitis at any study visit affecting the flexures, cheeks, or outer surfaces of the limbs24 and a positive SPT (note 1). A history of itchy skin, scratching, or rubbing plus at least 3 of the following: family history of atopic disease; history of generally dry skin; history of skin rash affecting the flexures, cheeks, or outer surfaces of the limbs; onset of rash under the age of 2 years; visible dermatitis at any study visit affecting the flexures, cheeks, or outer surfaces of the limbs.24 Skin lesions [that] met the criteria of Hanifin and Rajka (NFD).16 Skin lesions [that] met the criteria of Hanifin and Rajka (NFD).16 Skin lesions [that] met the criteria of Hanifin and Rajka (NFD)16 and antigen-specific IgE levels greater than 0.35 kU/L. Skin lesions [that] met the criteria of Hanifin and Rajka (NFD)16 and antigen-specific IgE levels greater than 0.35 kU/L. Pruritus, facial or extensor involvement, or both, and chronic relapsing course by using United Kingdom Working Party criteria.24 Noninfectious dermatitis with typical features [redness, dryness, edema, oozing, and itching (scratching)] and distribution.16 Noninfectious dermatitis with typical features [redness, dryness, edema, oozing and itching (scratching)] and distribution16 plus sensitization, i.e., detectable (>0.35 IU/mL) allergen-specific IgE antibodies or a positive SPT Pruritus, typical morphology and distribution, and a chronic relapsing course.43 United Kingdom Working Party’s diagnostic criteria.45 Eczema43 Pruritic rash over the face and/ or extensors with a chronic relapsing course.14 Pruritic rash over the face and/ or extensors with a chronic relapsing course14 and sensitization (NFD). Itchy rash for at least 2 week with typical distribution and dry skin and/or doctor’s diagnosis of eczema.49,50

Eczema Atopic Eczema Eczema

Atopic Eczema

Dotterud CK, et al38

AD (note 2)

Kim JY, et al39

Eczema AD Atopic Eczema

Kopp MV, et al40

IgE-associated Eczema AD

Niers L et al41

Eczema Atopic Eczema

Rautava S, et al42 Roze JC, et al44 Huurre A, et al46 Soh SE, et al47 West CE, et al48

Continued

Eczema AD Atopic Eczema Eczema Atopic Eczema Eczema

IgE-associated eczema definition given but atopic eczema results provided in article. Though data is provided as AD, the definition of each data set of AD defines it as eczema. Author uses AD and eczema interchangeably.

of all identified review articles retrieved was conducted. Only studies published in English or had English translations provided were included in this study. Study Selection and Eligibility Criteria The articles were reviewed independently by 3 investigators (SB, JC, and JM) for inclusion. Any discrepancies between the inclusion lists of the 3 investigators were discussed with another investigator (CO) and resolved. A multitiered selection criterion was used to select the articles containing usable data. The first tier involved 2 team members (JC and SB) determining the probiotic used and the age at which the participant began use. Articles were excluded that did not use probiotics or that had the participating infant begin the protocol after 6 months of life. With the next tier of selection, any article that had participant infants already diagnosed with either atopic dermatitis 582

(AD) or any form of eczema before beginning supplementation was excluded. For the third tier of selection, any studies that did not assess the participants after 6 months of age were excluded. Data Abstraction Data abstraction from relevant articles was conducted by 1 investigator (JM). The analysis was focused on the development of eczema in the participant infants during their observed periods. The primary data extracted from each article were number of treated and control participants with and without eczema. Additional variables included probiotic(s) used, time of exposure to probiotic(s) in utero, time of exposure to probiotic(s) after birth, participant age at final evaluation, and whether the population was considered high risk. If the article covered more than one type of skin manifestation, how those were differentiated was also recorded; MILITARY MEDICINE, Vol. 179, June 2014

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Comparative Probiotic Strain Efficacy in the Prevention of Eczema

multiple studies employed different definitions for the samenamed diagnosis (Table I). Quality Assessment The Cochrane Risk of Bias tool51 was used to assess sequence generation; allocation concealment; blinding of personnel, participants, and outcome assessors; and attrition bias. Attrition bias was defined as participant loss of greater than 20% and multi-/single-center study design bias was included. Statistical Analysis Trials were combined to calculate the pooled relative risk (RR) and the 95% confidence interval (CI) using the random effects model of DerSimonian and Laird25 Data were analyzed using the metan52 command in STATA v.10 (Stata Corp., College Station, Texas).To explore the robustness of the data, a set of subgroup and sensitivity analyses were calculated. Subgroup analyses were based on probiotic genus (alone or in a mixture), in utero exposure, duration of exposure, and probability of eczema development. Where a single study yielded multiple results and/or multiple articles, the results based on the longest period of follow-up were analyzed so as to not double count individual subjects. Metaregressions were calculated to contrast the ratio of RR among subgroups. To assess heterogeneity, I2 was calculated.53 Publication bias was assessed using the Harbord54 and Peters55 tests and by plotting study results (log RR) versus study size as measured by standard error of the log RR2. RESULTS A total of 295 titles and abstracts were identified during the first tier of search, of which 151 were selected for second tier review. Of the 48 that remained after the second tier review, only 27 articles reporting on 16 RCTs13,15,17–19,21–23,26–28,30–32,35–42,44,46–48,56 met the predefined inclusion criteria (Fig. 1). Qualitative Analysis The summarized characteristics on the methodologies and design of included studies are shown in Table II. All included articles used double-blinded RCTs consisting of initial treatment prior to eczema diagnosis followed by evaluation of participants. The probiotic genera under investigation were Lactobacillus and Bifidobacterium. Lactobacillus rhamnosus19,21–23,26–28,32,35,37,38,44,46,47,56 was investigated in 9 trials reported in 16 articles. Kalliomaki et al19,21,56 and Rautava et al22 reported data from the same RCT. Kalliomaki et al reported on the entire patient population with 2 years,56 5 years,21 and 7 years39 of follow-up, whereas Rautava et al focused on a subgroup of participants that had maternal use of probiotics or placebo until the child was 3 months of age.44 Similarly, Kukkonen et al23,27 reported on the entire patient population with 2-year28 and

FIGURE 1.

Selection of publications for inclusion in meta-analysis.

5-year23 follow-ups, whereas Marschan et al28 and Kuitunen et al26 reported on follow-ups of subgroups of the population at 2 and 5 years, respectively. Bifidobacterium longum42,46,47 and Bifidobacterium lactis32,35,39,41,46 was each investigated in 4 separate trials comprising 4 articles respectfully, whereas all other species of probiotic investigated were used in 3 or fewer studies (Table II). Fifteen publications required prenatal exposure of the infant to the probiotic, whereas 12 publications waited until the infant was between 3 days and 4 months to begin treatment. Over 80% of the publications (n = 22) required the participants to be at high risk of eczema development (Table II); the remaining 5 studies did not discriminate based on high risk and low risk. There was significant heterogeneity in regard to the criteria used to define a positive skin finding. Of the 27 articles selected for this review, 8 separate terms were used. Eczema

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583

584

2000–2007

2005

2005

Australia

Australia

Taylor AL, et al30 Jensen MP, et al31

2000–2007

Finland

Finland

1997–1998

Finland

Rautava S, et al22 Kukkonen K, et al23

Marschan E, et al28

1997–1998

Finland

Kalliomaki M, et al56

2000–2007

1997–1998

Finland

Kalliomaki M, et al21

Finland

1997–1998

Finland

Kukkonen AK, et al27

Unclear

Sweden

Bottcher MF, et al37 Kalliomaki M, et al19

2000–2007

2001–2003

Sweden

Abrahamsson TR, et al36

Finland

2001–2003

Sweden

Abrahamsson TR, et al13

Kuitunen M, et al26

2001–2003

Location

Sweden

References

Abrahamsson TR, et al17

Dates Conducted (A)

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

Study Design

Pregnant, atopic women

Pregnant, atopic women

Mothers with infants at high risk for allergy

Mothers with infants at high risk for allergy

Mothers with infants at high risk for allergy

Pregnant women of families with allergic disease (i.e., one or more family members with eczema, asthma, gastrointestinal allergy, allergic urticaria, or allergic rhinoconjunctivitis) Pregnant women of families with allergic disease (i.e., one or more family members with eczema, asthma, gastrointestinal allergy, allergic urticaria, or allergic rhinoconjunctivitis) Pregnant women of families with allergic disease (i.e., one or more family members with eczema, asthma, gastrointestinal allergy, allergic urticaria, or allergic rhinoconjunctivitis) Pregnant women in families with a history of allergic disease Mothers who had at least 1 first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma Mothers who had at least 1 first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma Mothers who had at least 1 first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma Pregnant women from atopic families Mothers with infants at high risk for allergy

Inclusion Criteria

TABLE II.

6 months given to infant (if fomula fed) or mother (if breastfed)

6 months given to infant

2 months given to mother

6 months given to infant

6 months given to infant

3 months given to mother then 3 months given to infant 12 months given to infant

6 months given to mother

6 months given to mother

6 months given to mother

12 months given to infant

12 months given to infant

6 months given to infant

12 months given to infant

Time Exposed After Birth (Mother and/or Infant)

2 years

5 years

2 years

2 years

2 years

2 years

2 years

7 years

1 year

4 years

2 years

4 years

2 years

7 years

Follow-up Time

No

No

No

No

No

No

Yes

No

No

No

Yes

Yes

Yes

Yes

Prenatal Exposure (B)

Publications Reviewed With Sample Details

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

High-risk Population (C)

232/184 (79.3%)

232/162 (69.8%)

232/109 (47.0%) 159/132 (83.0%)

159/115 (72.3%)

159/107 (67.3%)

159/62 (39.0%) 1223/925 (75.6%)

231/178 (77.1%) 231/123 (53.2%)

Lactobacillus reuteri

Lactobacillus reuteri

Lactobacillus reuteri Lactobacillus rhamnosus

Lactobacillus rhamnosus

Lactobacillus rhamnosus

Lactobacillus rhamnosus Lactobacillus rhamnosus, Bifidobacterium breve, Propionibacterium freudenreichii Lactobacillus rhamnosus, Lactobacilus rhamnosus, Bifidobacterium breve, Propionibacterium freudenreichii L.actobacillus rhamnosus, Bifidobacterium breve, Propionibacterium freudenreichii Lactobacillus rhamnosus, L rhamnosus, Bifidobacterium breve, Propionibacterium freudenreichii Lactobacillus acidophilus Lactobacillus acidophilus

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(continued)

1223/98 (08.1%)

1223/131 (10.7%)

1223/891 (72.9%)

232/188 (81.0%)

Probiotic Treatment Lactobacillus reuteri

Number of Participants Beginning Study/Completing Study (% Completing Study)

Comparative Probiotic Strain Efficacy in the Prevention of Eczema

2006–2008

2003–2005

2005–2006

2002–2006

2004–2005

2005–2009

2007–2008

Unclear

2004–2006

2000–2003

Unclear

Australia

Norway

Korea

Germany

Netherlands

Finland

France

Finland

Singapore

Sweden

Allen SJ, et al36

Boyle RJ, et al37 Dotterud CK, et al38

Niers L, et al41

Rautava S, et al42

Roze JC, et al44

Huurre A, et al46

Soh SE, et al47 West CE, et al48 db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

db RCT

Unclear

db RCT

db RCT

Study Design Inclusion Criteria

A gestational age >37 weeks, a postnatal age less than 3 days, fed from birth with probioticand prebiotic-free infant formula, and without human milk Mothers with no chronic or metabolic disease before or during early pregnancy Infants with a family history of allergic disease Healthy, term infants (gestational age 37–42 week) with birth weight >2,500 g who were vaginally delivered, had no allergic manifestation or medication that could have affected the gut microbiota.

Pregnant women carrying infants at high risk of allergic disease Pregnant women, £36 weeks of pregnancy, planning to breastfeed during the first 3 postnatal months Pregnant women with a family history of allergic diseases Pregnant women from families with 1 member (mother, father, or child) with an atopic disease Mothers of high-risk children (i.e., positive family history of allergic disease) Mothers with allergic disease and atopic sensitization

Mother or father [of unborn child] had a history of treated asthma, eczema, or hay fever. Mother or father [of unborn child] had a history of treated asthma, eczema, or hay fever. Pregnant women less than 36 week of gestation

4–13 months given to infant

6 months given to infant

6 months given to infant

3–12 months given to mother

6 months given to infant

3 months given to mother

6 months given to infant

6 months given to infant

3 months given to mother

None given

2 years given to infant, up to 6 months to mother if breastfeeding 2 years given to infant, up to 6 months to mother if breastfeeding 12 months given to infant

Time Exposed After Birth (Mother and/or Infant)

13 months

1 year

1 year

1 year

6 months

2 years

5 years

5 years

2 years

1 year

2 years

2 years

4 years

Follow-up Time

Continued

No

No

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Prenatal Exposure (B)

No

Yes

No

No

Yes

Yes

Yes

Yes

No

Yes

No

Yes

Yes

High-risk Population (C)

112/68 (60.7%)

Bifidobacterium lactis, Lactobacillus acidophilus Lactobacillus rhamnosus

253/245 (96.8%)

B.ifidobacterium longum and Lactobacillus rhamnosus LPR Lactobaccillus paracasei

179/171 (95.5%)

171/140 (81.9%)

97/84 (86.6%)

241/205 (85.1%)

156/98 (62.8%)

105/98 (93.3%)

Bifidobacterium longum and Lactobacillus rhamnosus

Bifidobacterium bifidum, Bifidobacterium lactis, Lactococcus lactis Lactobacillus rhamnosus LPR + Bifidobacterium longum, Lactobacillus paracasei + Bifidobacterium longum L.actobacillus rhamnosus LCS + Bifidobacterium longus + (scGOS/lcFOS) + bovine a-lactalbumin

415/278 (67.0%)

Lactobacillus rhamnosus

UNK/554 (UNK)

499/425 (85.2%)

499/474 (95.0%)

250/210 (84.0%)

Probiotic Treatment Lactobacillus rhamnosus HN001, B. animalis subsp lactis HN019 Lactobacillus rhamnosus HN001, B. animalis subsp. lactis HN019 Two strains of Lactobacilli and 2 strains of Bifidobacterium (no genus specified) Lactobacillus rhamnosus

Number of Participants Beginning Study/Completing Study (% Completing Study)

db, Double blind; UNK, unknown. Publications highlighted with similar color are from same trial; (A) Dates when trial was conducted; (B) Probiotic treatment given to mother while infant was in utero; (C) Mother or first order relative having history of eczema and/or allergic diseases.

Kim JY, et al39 Kopp MV, et al40

2004–2005

New Zealand

Wickens K, et al35

Unclear

2004–2005

Location

New Zealand

References

Wickens K, et al32

Dates Conducted (A)

TABLE II.

Comparative Probiotic Strain Efficacy in the Prevention of Eczema

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585

Comparative Probiotic Strain Efficacy in the Prevention of Eczema TABLE III.

Risk of Bias Assessmentsa Number (%)b

Sequence Generation Allocation Concealment Blinding Free of Attrition Bias Single/Multicenter a b

Low Risk of Bias

High Risk of Bias

Unclear Risk of Bias

15 (56) 19 (70) 21 (78) 13 (48) 8 (30)

0 0 0 13 (48) 10 (37)

12 (44) 8 (30) 6 (22) 1 (4) 9 (33)

Assessments made using the Cochrane Risk of Bias Tool (version 2009). Number (%) is based on 27 publications that met inclusion criteria.

(21 publications), Atopic eczema (11 publications), IgEassociated eczema (6 publications), AD (5 publications), Non-IgE-associated eczema(1 publication), Eczema with SCORAD ³10(1), Skin prick test (SPT)+ AD (1 publication),

and SPT+ and Eczema (1 publication) were all used as primary or secondary outcome terms. Table I provides a summary of term definitions by article. Heterogeneity of term definitions was also noted. Of the 20 studies that used eczema as a primary or secondary outcome, 6 separate texts were used to define this term, whereas 2 cited no reference of their definition. Atopic eczema (12) was also defined using 6 distinct texts and 3 uncited texts. The definitions ranged from including IgE levels ³0.35 to ³0.7kU/kL, a positive SPT, to simply “pruritus, typical morphology and distribution, and a chronic relapsing course.”42 IgE-associated eczema (7) included 5 distinct texts, whereas AD (4) included 3. Quality Assessment The quality of the reporting was high; all of the articles reported sequence generation, allocation concealment, and

FIGURE 2. Forest plot of 27 articles describing 16 randomized trials of probiotic use and infant eczema. Articles that are from the same study are grouped by color. Noncolored articles are from distinct studies. Dots represent the RR of eczema in the probiotic group compared to the placebo group in each study, and horizontal lines represent the 95% CI for the RR. Size of the square around each RR is proportional to the study weight.

586

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Comparative Probiotic Strain Efficacy in the Prevention of Eczema

blinding. Results of the quality assessment for individual features are shown in Table III. With sequence generation, allocation concealment, and blinding, low risk of bias was defined as when authors clearly expressed their methodological congruence with the Cochran Risk of Bias Tool51; high risk of bias was defined as clearly expressed methodology not in congruence.25 Studies that did not clearly express their methodology were categorized as unclear. Regarding sequence generation, 15 studies had a low risk of bias and 12 studies had an unclear risk of bias. Regarding allocation concealment, 19 studies had a low risk of bias and 8 studies had an unclear risk of bias. Regarding blinding, 21 studies had a low risk of bias and 6 studies had an unclear risk of bias. Thirteen of the studies demonstrated attrition rates exceeding 20% with one having an unclear attrition rate. Ten of the studies were done in multicenter systems and 9 were unclear. Both attrition rate and multicenter systems introduced additional risk of bias.

QUANTITATIVE RESULTS: META-ANALYSIS Synthesis of Results A summary of the results for each individual study is shown in Figure 2. The overall RR for the incidence of eczema in infants administered probiotics (16 trials) was 0.74 (95% CI 0.67, 0.82). An analysis of studies broken out by probiotic strain revealed several strains that demonstrated a significant protective effect and several strains that did not (Fig. 3). Most protective were mixtures including Lactobacillus rhamnosus (10 studies), with a pooled RR of 0.67 (95% CI 0.54, 0.82). The RR for mixtures including Lactobacillus paracasei (2 studies) was 0.42 (95% CI 0.31, 0.55), whereas its exclusive supplementation (1 study) RR was 0.49 (95% CI 0.23, 1.02 ). For all studies that included a strain of Lactobacillus (15 studies) the RR was 0.74 (95% CI 0.60, 0.90). All studies conducted using strains of Bifidobacterium (10 studies) used multiple strains in mixture and the collective

FIGURE 3. Forest plot of articles describing the most recent follow-up date in 16 randomized trials of probiotic use and infant eczema. Dots represent the RR of eczema in the probiotic group compared to the placebo group in each study, and horizontal lines represent the 95% CI (0) for the RR. Size of the square around each RR is proportional to the study weight. I2, the inconsistency index, represent the degree of heterogeneity in the included studies. Pooled RR (diamond) was calculated using a random effects model.

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FIGURE 4. Forest plot of pooled RRs for subgroups defined by probiotic strain. Dots represent the pooled RR of eczema in the probiotic group compared to the placebo group in each group of studies, and horizontal lines represent the 95% CI for the RR.

RR was 0.70 (95% CI 0.56, 0.88). For Bifidobacterium lactis (5 studies), the RR was 0.72 (95% CI 0.62, 0.85) (Fig. 4). Lactobacillus strains that did not achieve statistical significance were mixtures including Lactobacillus acidophilus (3 studies, RR 0.83, 95% CI 0.44, 1.57); exclusive supplementation of Lactobacillus acidophilus (1 study, RR 1.91, 95% CI 0.94, 3.86); Lactobacillus reuteri (1 study, RR 1.13, 95% CI 0.63, 2.01); and Lactococcus lactis (1 study, RR 0.85, 95% CI 0.62, 1.17). Bifidobacterium strains that did not achieve statistical significance were Bifidobacterium longum (3 studies, RR 0.50, 95%CI 0.24, 1.05); Bifidobacterium breve (1 study, RR 0.90, 95% CI 0.63, 1.27); and Bifidobacterium bifidum (1 study, RR 0.85, 95% CI 0.62, 1.17). Finally, Propionibacterium freudenreichii (1 study) had a RR of 0.91 (95% CI 0.78, 1.06). Despite these differences, we did not find sufficient evidence to conclude that some strains are significantly more effective than others in preventing eczema in infants and children. Meta-regression found no significant differences in RRs among strains, or when comparing 588

FIGURE 5. Funnel plot of 16 randomized trials of probiotic use and infant eczema. LogRR: log(relative risk), se(logRR): standard error of log(relative risk). Minimal asymmetry indicates lack of publication bias.

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Comparative Probiotic Strain Efficacy in the Prevention of Eczema

FIGURE 6. Forest plot of randomized trials of exposure to probiotics and infant eczema, stratified by time of exposure (in utero or postnatal) and duration of exposure. Dots represent the RR of eczema in the probiotic group compared to the placebo group in each study, and horizontal lines represent the 95% CI for the RR. Size of the square around each RR is proportional to the study weight. I 2, the inconsistency index, represent the degree of heterogeneity in the included studies. Diamond represents the pooled RR for each stratum, calculated using a random effect model.

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mixtures that included Lactobacillus (or Bifidobacterium) strains to those that did not (all p values > 0.05, results not shown). The studies were also analyzed by whether or not the infant was exposed to a probiotic in utero and by duration of exposure. For infants exposed in utero (12 studies), the RR was 0.72 (95% CI 0.61, 0.86), whereas for infants not exposed in utero (4 studies), the RR was 0.74 (95% CI 0.62, 0.88), and the RRs did not differ (p = 0.55). For infants exposed to the probiotic less than 6 months (4 studies), the RR was 0.63 (95% CI 0.42, 0.94), whereas for infants exposed for 6 months or longer, the RR was 0.83 (95% CI 0.69, 0.99).Duration of exposure was not significantly associated with effectiveness ( p = 0.18). The funnel plot (Fig. 5) indicates that publication bias is likely to be minimal, and no significant small study effects were found using either the Harbord55 ( p = 0.19) or Peters15 ( p = 0.18) tests. DISCUSSION The principal finding of the meta-analysis was that children given probiotics have a reduced risk of developing eczema. This finding is statistically significant and not likely influenced by trial quality or publication bias. Though metaanalysis of in utero administration of probiotics was shown to be statistically significant with a RR of 0.77 (95% CI 0.64, 0.93), the number of studies with postnatal exposure (Fig. 6) was small, limiting the statistical power of the comparison. Further studies of postnatal exposure with a larger population size could give a more statistically powerful result. A wide range of probiotics was used in this meta-analysis, both in mixtures and alone. Strains of Bifidobacterium were the most efficacious in protecting against eczema although no study conducted tested Bifidobacterium unilaterally. Strains of Lactobacillus also showed to have a protective effect. Further studies are needed to clarify potential differences among strains since none of the observed differences were statistically significant. Though nearly half the studies had high attrition rates and multicentered studies, the blinding, allocation concealment, and sequence generation created a low risk of bias in and between the studies. Bias was further reduced because of the multinational studies included; this improved external validity. Of the 16 trials reviewed, there were 11 separate countries represented on 3 continents, which provided a more global population for review. In review of the literature, both the publications reviewed and the works cited within the publications, there is a distinct lack of homogeneity regarding term definitions. One author defined eczema explicitly as “a history of itchy skin, scratching or rubbing plus at least three of the following: family history of atopic disease; history of generally dry skin; history of skin rash affecting the flexures, cheeks or outer surfaces of the limbs; onset of rash under the age of 2 years; visible dermatitis at any study visit affecting the 590

flexures, cheeks, or outer surfaces of the limbs,”37 whereas another defined it nebulously as “typical skin lesions responsive to topical steroids.”30 The definition “pruritus, facial or extensor involvement, or both, and chronic relapsing course” was used to describe AD, eczema, and atopic eczema in 3 separate studies.19,40,47 The variations cited are a limitation of the meta-analysis. The heterogeneity of terms used by the trial directors as well as the authors of the subsequent studies brings a level of discontinuity that must be considered when analyzing the data as a whole. After careful review of these terms and definitions (Table II), the level of discrepancy regarding the primary or secondary outcomes within the studies is not large enough to require separate analysis of study subsets. Though the terminology, when defining the skin abnormality, being assessed may differ, the intent of the term used was similar enough to allow for collaborative review of the articles. In conclusion, our findings demonstrate that the use of probiotic supplementation beginning in gestation through the first 6 months of life has been shown to decrease the incidence of eczema in infants by 26% (18%–33%). This decrease was expanded to 52% (45%–69%) when the probiotic supplement included Lactobacillus paracasei. When future studies are conducted within this field, authors should use more unified terminology and definitions to decrease likelihood of misrepresentation and misunderstanding of findings. The use of more uniform terminology will help future studies be more homogenous and allow for better clinical application of the results. ACKNOWLEDGMENTS The authors would like to thank Rhonda Allard for assistance with literature searching, Dr. Anne Jerse (Department of Microbiology, USUHS), Dr. Kent DeZee (Department of Medicine, USUHS) for input on scientific aspects of the manuscript, Dr. Thomas Darling (Department of Dermatology, USUHS) for critiquing an early draft, and ENS William King-Lewis for technical support (School of Medicine, USUHS).

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