Dr. Khine is a Clinical Teaching Fellow in the Department of Clinical Medicine at Ross University School of Medicine, Commonwealth of Dominica, West Indies. Dr. Khosrodad is a PGY1 Internal Medicine Resident at St. Joseph Mercy Oakland Hospital, Pontiac, MI. Dr. Selfridge is Professor and Chair of the Department of Clinical Medicine, Ross University School of Medicine, Commonwealth of Dominica, West Indies.
Dr. Khine, Dr. Khosrodad, and Dr. Selfridge report no financial relationships relevant to this field of study.
SYNOPSIS: A 12-week intervention of daily supplementation with probiotics Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus rhamnosus (LGG) 10 billion colony-forming units produced no reduction in the number of days absent from day care in Danish infants 8 to 14 months old.
SOURCE: Laursen RP, Larnkjær A, Ritz C, et al. Probiotics and child care absence due to infections: A randomized controlled trial. Pediatrics 2017;140:e20170735. doi:10.1542/peds.2017-0735. [Epub ahead of print].
SUMMARY POINTS
- Children in day care are at increased risk of community-acquired respiratory and gastrointestinal infections, contributing to absenteeism, medical costs, and lost work productivity by parents.
- A randomized, double-blind, placebo-controlled parallel study of day care infants in Denmark showed no reduction in sick days in infants given daily probiotics consisting of Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus rhamnosus (LGG) 10 billion colony-forming units compared to infants given daily placebo.
- Further studies are needed considering current evidence about the total effective daily dose of probiotic and confounding factors, such as simultaneous or previous history of breastfeeding, to further determine if probiotics may be valuable in reducing the incidence of infection in the pediatric population.
Children in day care centers have a two to three times greater risk of developing community-acquired respiratory and gastrointestinal infections than their home care counterparts.1,2 This increase in exposure is thought to be attributed to factors such as crowding and sharing of toys and, subsequently, sharing of bacteria and viruses. Illnesses in children and days of absenteeism have been strongly correlated with increased rates of parents missing work and, consequently, increases in both indirect costs due to lost productivity and direct costs of healthcare for the infant.3
Laursen et al conducted a double-blind, placebo-controlled, parallel study, with the main intervention being administration of daily doses of probiotics containing Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus rhamnosus (LGG) to infants, aged 8-14 months, who were expected to enter day care within 12 weeks of the start of the intervention. These infants had prohibited probiotic intake (fermented milk or probiotic supplements) for two weeks prior to the start of the study and for an additional six months thereafter as part of the trial protocol. Out of 11,516 parents invited to the study in the Denmark capitol area, 290 respondents gave informed consent and were randomly assigned into one of two groups: those whose infants took approximately 10 billion colony-forming units (CFU) of LGG and BB-12 probiotics in 1 g of maltodextrin powder (n = 144) and those whose infants took 1 g of maltodextrin without probiotics (n = 146). The probiotic and placebo packets were indistinguishable. Parents logged administration and returned unused packets at the end of the intervention to assess compliance. Parents were instructed to dissolve one packet into a small amount of the child’s food or drink each day. A daily parent-reporting journal was given to each participating family to document the number of days absent from day care because of gastrointestinal or respiratory infections, the primary endpoints. Secondary endpoints also were recorded and included days absent because of other illness, number of doctor-diagnosed upper or lower respiratory infections, episodes of diarrhea, episodes of vomiting, number of days with fever, number of days with cold symptoms, number of doctors’ visits, antibiotic treatments, and number of days caregiver was absent from work because of infant illness.
Table 1 displays results for primary and secondary outcomes in this study. There was no difference in the days absent from day care between the intervention and control groups (1.14 days; 95% confidence interval [CI], -0.55 to 2.82; P = 0.19). Additionally, probiotic administration was found to have no effect on secondary endpoints. Initial data suggested that infants taking probiotics experienced significantly more days of fever than their placebo counterparts (1.84 days; 95% CI, 0.060-3.63; P = 0.04). However, adjusting for infants with occurrence of at least one episode of upper respiratory tract infection since birth rendered this effect nonsignificant (1.39; 95% CI, -0.41 to 3.18; P = 0.13; data not shown). Remarkably, only 25 participants were lost to follow-up, 13 from the intervention group and 12 from the placebo group. Missing data sets accounted for only 6% of the total possible. There were no adverse effects reported related to the intervention.
Table 1: Primary and Secondary Outcome Data Comparing Probiotic and Placebo |
|||||
LGG and BB-12
|
Placebo
|
LGG and BB-12 vs. placebo mean difference (95% CI) |
LGG and BB-12 vs. placebo odds ratio (95% CI) |
P value |
|
Primary Outcome |
|||||
|
Days absent from child care because of infection |
11.0 |
11.0 |
1.14 (-0.55 to 2.82) |
- |
0.19 |
Secondary OutcomesRespiratory Infections |
|||||
|
Days with symptoms of common cold |
25 |
24 |
1.94 (-4.70 to 8.59) |
- |
0.59 |
|
Number of children with > 1 episode of upper respiratory tract infection (URTI) |
54 (38) |
47 (33) |
- |
1.22 (0.74-2.00) |
0.43 |
|
Number of URTI episodes per child |
0 (0-1) |
0 (0-1) |
0.15 (-.07 to 0.37) |
- |
0.17 |
|
Number of children with > 1 episode of lower respiratory tract infection |
25(18) |
31(22) |
- |
0.74 (0.41-1.31) |
0.33 |
|
Gastrointestinal Infections |
|||||
|
Number of children with > 1 episode of diarrhea |
91 (64) |
70 (56) |
- |
1.42 (0.88-2.32) |
0.15 |
|
Number of diarrheal episodes per child |
1 (0-2) |
1 (0-2) |
0.22 (-0.06 to 0.51) |
- |
0.12 |
|
Duration of diarrheal episodes (d) |
2.0 (1.0-3.0) |
1.0 (1.0-3.0) |
0.20 (-0.28 to 0.68) |
- |
0.43 |
|
Days of vomiting |
2.0 (1.0-5.8) |
2.0 (1.0-4.0) |
0.68 (-0.16 to 1.52) |
- |
0.11 |
|
Other |
|||||
|
Days with fever |
11.0 |
10.0 |
1.48 (-0.16 to 3.12) |
- |
0.08 |
|
Number of antibiotic treatments |
0 (0-1) |
0 (0-1) |
0.03 (-0.16 to 0.23) |
- |
0.70 |
|
Caregiver absence from work because of child Illness (d) |
|||||
|
Illness (total) |
7.0 (4.0-13.0) |
7.0 (3.0-11.9) |
1.02 (-0.48 to 2.52) |
- |
0.18 |
|
Infections |
6.0 (3.0-0.0) |
5.0 (2.0-9.4) |
0.61 (-0.64 to 1.85) |
- |
0.34 |
|
Other illness |
0.0 (0.0-2.0) |
1.0 (0.0-2.0) |
0.41 (-0.29 to 1.11) |
- |
0.25 |
|
Days absent from child care because of illness |
|||||
|
Illness (total) |
13.0 |
13.0 |
0.94 (-0.89 to 2.77) |
- |
0.31 |
|
Other illnesses (not infections) |
1.0 (0.0-3.9) |
1.0 (0.0-5.0) |
-0.19 (-0.90 to 0.51) |
- |
0.59 |
|
Adapted from: Laursen RP, Larnkjær A, Ritz C, et al. Probiotics and child care absence due to infections: A randomized controlled trial. Pediatrics 2017;140:e20170735. doi:10.1542/peds.2017-0735. [Epub ahead of print]. |
|||||
COMMENTARY
This trial reinforces some previous conclusions regarding the use of probiotics in varying age groups around Europe,4-6 but flies in the face of other studies showing significant reduction in number of days absent.7 These differences may be attributed to a variety of factors including, but not limited to, the specific sub-strain of probiotics administered, the number of CFU per dose, the age of participants, and the duration of the treatment and study. Among the strongest variables that may have played a significant role in this study is that both groups had 44.3% to 50.3% of infants actively breastfeeding in the placebo and intervention groups, respectively. Two previous studies by Smerud et al4 and Weizman et al5 included only participants who were not actively breastfed at baseline, since breast milk is an effective protector against infection and stimulates development of the infant immune system. The theoretical protective effects of probiotics may have no additional benefits when added to that of breastfeeding. Similar studies focusing either on infants who are solely formula-fed or toddlers who are no longer breastfeeding would be helpful. In the latter case, it still would be important to distinguish if the toddlers were previously breastfed, formula-fed, or both.
The authors hypothesized that their dose of 2 × 109 CFU per day was too low when compared to a recent meta-analysis, suggesting that the most effective correlation to decrease acute gastroenteritis is doses of 1010 or more.8
Even though parents were instructed to refrain from feeding their infants yogurt or supplemental products containing probiotics or prebiotics, many common commercial products and infant formulas contain such additives. It is impossible to completely ascertain that these indeed were avoided in the study participants. Half (50.3%) of the probiotic infants were only children and half (49.7%) had at least one sibling, whereas slightly more infants in the placebo group were only children (53.5% vs. 46.5%). Increased potential exposure to bacteria and viruses from siblings attending school or day care was an additional confounding factor in this study. The strength and validity of this trial is primarily in the remarkably low dropout rate of only 8.7%. Additionally, self-reporting compliance was high. On the other hand, because the data collected on the infants were accomplished through parental questionnaires, it is reasonable to assume that not every illness incident was diagnosed by a physician and, thus, the etiology of symptoms, either gastrointestinal or respiratory, could not be confirmed.
The use of probiotics continues to be an area begging further investigation about optimal species, dosing, length of treatment, and target populations for maximum efficacy. Since diet and dietary prebiotics influence probiotic gut colonization, this is another variable that requires consideration in future studies. Geographic, socioeconomic, and even population genetic factors have not been addressed sufficiently in previous studies, preventing generalization of conclusions about the protective effects of probiotic use. At the same time, advertising and sale of probiotics in dairy and supplemental products has an estimated market value of approximately $3.4 billion annually, while the estimated loss of productivity due to parents missing work days to care for sick infants has been estimated to cost $1.8 billion annually.3 These economic figures call for further investigations to determine the possible efficacy of probiotics for decreasing the number of sick days because of community-acquired respiratory and gastrointestinal infections in infants and children in day care settings. In the meantime, dietary recommendations for young children attending day care should be aimed at maximizing general health, growth, and development. Breastfeeding infants has incontrovertible benefits. Fermented dairy products have many health benefits outside of their probiotic content and can be included in a child’s diet safely. However, supplementation with probiotics for normal healthy infants and children, although apparently safe, requires further investigation before it can be a strategy that is strongly recommended to reduce the incidence of day care-acquired respiratory and gastrointestinal infections.
REFERENCES
- Kamper-Jorgensen M, Wohlfahrt J, Simonsen J, et al. Population-based study of the impact of childcare attendance on hospitalizations for acute respiratory infections. Pediatrics 2006;118:1439-1446.
- Zutavern A, Rzehak P, Brockow I, et al. Day care in relation to respiratory-tract and gastrointestinal infections in a German birth cohort study. Acta Paediatr 2007;96:1494-1499.
- Carabin H, Gyorkos TW, Soto JC, et al. Estimation of direct and indirect costs because of common infections in toddlers attending day care centers. Pediatrics 1999;103:556-564.
- Kloster Smerud H, Ramstad Kleiveland C, Roll Mosland A, et al. Effect of a probiotic milk product on gastrointestinal and respiratory infections in children attending day-care. Microb Ecol Health Dis 2008;20:80-85.
- Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: Comparison of two probiotic agents. Pediatrics 2005;115:5-9.
- Hojsak I, Močić Pavić A, Kos T, et al. Bifidobacterium animalis subsp. lactis in prevention of common infections in healthy children attending day care centers - Randomized, double blind, placebo-controlled study. Clin Nutr 2016;35:587-591.
- Hojsak I, Snovak N, Abdović S, et al. Lactobacillus GG in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers: A randomized, double-blind, placebo-
- controlled trial. Clin Nutr 2010;29:312-316.
- Szajewska H, Skórka A, Ruszczynski M, Gieruszczak-Bialek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children — updated analysis of randomised controlled trials. Aliment Pharmacol Ther 2013;38:467-476.
A 12-week intervention of daily supplementation with probiotics Bifidobacterium animalis subsp. lactis (BB-12) and Lactobacillus rhamnosus (LGG) 10 billion colony-forming units produced no reduction in the number of days absent from day care in Danish infants 8 to 14 months old.
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