To determine if probiotic administration during the first 6 months of life decreases childhood asthma and eczema.
We conducted a randomized, double-blind controlled trial of Lactobacillus rhamnosus GG (LGG) supplementation on the cumulative incidence of eczema (primary end point) and asthma and rhinitis (secondary end points) in high-risk infants. For the first 6 months of life, intervention infants (n = 92) received a daily dose of 10 billion colony-forming units of LGG and 225 mg of inulin (Amerifit Brands, Cromwell, CT), and control infants (n = 92) received 325 mg of inulin alone. We used survival analysis methods to estimate disease incidences in the presence or absence of LGG and to estimate the efficacy of LGG in delaying or preventing these diseases.
Infants were accrued over a 6-year period (median follow-up: 4.6 years; 95% retention rate at 2 years). At 2 years of age, the estimated cumulative incidence of eczema was 30.9% (95% confidence interval [CI], 21.4%–40.4%) in the control arm and 28.7% (95% CI, 19.4%–38.0%) in the LGG arm, for a hazard ratio of 0.95 (95% CI, 0.59–1.53) (log-rank P = .83). At 5 years of age, the cumulative incidence of asthma was 17.4% (95% CI, 7.6%–27.1%) in the control arm and 9.7% (95% CI, 2.7%–16.6%) in the LGG arm, for a hazard ratio of 0.88 (95% CI, 0.41–1.87) (log-rank P = .25).
For high-risk infants, early LGG supplementation for the first 6 months of life does not appear to prevent the development of eczema or asthma at 2 years of age.
Comments
RE: inadequate power
We read with interest the paper by Cabana et al(1) but were surprised that they did not find a significant difference between the groups despite nearly halving the 5 year prevalence of asthma in those treated with Lactobacillus rhamnosus GG (LGG)
The conclusion that LGG supplementation does not confer a benefit relies on the assumption that the study is adequately powered and that asthma can be reliably diagnosed at a young age. These assumptions are not necessarily valid.
The authors have previously noted the difficulty in diagnosing asthma in young children(2) and the attrition of participants by the age of 5 years when spirometry is more reliable may have precluded meaningful comparison between groups.
In addition, while the authors have provided details of their power calculations, it is unclear if they censored them appropriately to account for the fact that not all individuals will go on to develop asthma.
Using Stata v14 (Stata Corp, College Station, Tx) we were unable to reproduce the figures they reported but instead calculated that a much larger sample of 578 participants with 139 diagnoses of asthma would have been required to have an 80% power of detecting a reduction in prevalence from 29% to 19% using a log rank test. This is over three times as many individuals as were recruited to this study.
This combination of a small sample size and limited follow up could easily account for the failure to identify a significant benefit from LGG prophylaxis. In contrast to the authors, we would conclude that the question of whether supplementation significantly reduces the risk of asthma remains largely unresolved although the point estimates suggest some benefit from LGG use.
References
1. Cabana, M. D. et al. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics 140, (2017).
2. Cabana, M. D., McKean, M., Wong, A. R., Chao, C. & Caughey, A. B. Examining the hygiene hypothesis: the Trial of Infant Probiotic Supplementation. Paediatr. Perinat. Epidemiol. 21 Suppl 3, 23–28 (2007).