Use of a Probiotic Supplement to Prevent Asthma in Infants

BACKGROUND:

During infancy, environmental factors may affect immune system development and lead to the
development of asthma. The hygiene hypothesis suggests that the absence of endotoxin
exposure leads to an unfavorable Th1/Th2 balance. Thus, a controlled antigen exposure during
infancy may establish a Th1/Th2 balance that blocks the onset of asthma or slows the
progression of the disease.

Lactobacillus is a bacterium commonly found in many foods (e.g., yogurt) in the typical
childhood diet. It is also used as a probiotic supplement to prevent the development of
diarrhea. Due to its safety and availability, Lactobacillus is an ideal bacterium to use as
an antigen exposure to test the hygiene hypothesis.

Consistent with the hygiene hypothesis, observational studies suggest that early
Lactobacillus exposure leads to decreased risk of developing atopic dermatitis, which has
been associated with asthma in later years. The investigators are aware of no study that has
examined the effect of Lactobacillus on the development of early markers of asthma in
children at risk for developing the disease. They hypothesize that Lactobacillus can be used
as an antigen exposure to establish a Th1/Th2 balance that blocks the development of early
markers of asthma.

DESIGN NARRATIVE:

The hygiene hypothesis suggests that the absence of endotoxin exposure leads to an
unfavorable Th1/Th2 balance. A controlled antigen exposure during infancy may help establish
a Th1/ Th2 balance that blocks the onset or progression of asthma. Lactobacillus is a
bacterium found in many foods in the typical pediatric diet, and is used as a supplement to
prevent diarrhea. Due to the safety, feasibility, and early promising results in preventing
atopic dermatitis, Lactobacillus is an ideal bacterium to use as an exposure to test the
hygiene hypothesis. The investigators hypothesize that such an exposure may block or delay
development of early markers of asthma.

The study will use a randomized placebo-controlled trial design to measure the effect of a
6-month daily exposure of Lactobacillus, as an infant supplement, on immune system and
asthma development during the first 3 years of life.

The study will measure the effect of the antigen exposure on the presence and time to
presentation of: (1) early clinical markers for asthma development (frequent wheezing,
wheezing without colds, rhinitis, and atopic dermatitis); (2) early immunologic markers for
asthma development (eosinophilia, immunoglobulin E); and (3) development of a T-helper
phenotype (Th-1 vs Th-2). Investigators will characterize the Th phenotype by measuring the
whole blood lymphocyte response to stimulants, focusing on Th1 (IFN-gamma, interleukin
(IL)-12) and Th2 cytokines (IL-10, IL-4, IL-13), as well as real-time reverse transcriptase
polymerase chain reaction (RT-PCR) with PCR amplification (TaqMan) to quantify RNA
transcripts. Clinical and immunologic markers will be measured up to 3 years of age.

Adherence will be assessed using diaries, pill count, and Lactobacillus stool cultures.

The study will use intention-to-treat analysis and will control for the impact of family,
environmental, diet, and demographic factors on outcomes using multivariate regression and
survival analysis techniques. Investigators expect that when compared to controls, subjects
receiving Lactobacillus will have decreased and delayed development of markers for asthma,
and a greater likelihood of developing a Th1 phenotype.

Inclusion criteria:

- Expectant parents either of whom have a history of asthma

- Parents willing to add a probiotic supplement or placebo to one feeding each day for
6 months

Exclusion criteria:

- A sibling currently or previously enrolled in the study

- Any major congenital birth deformities, acute illness at enrollment, or chronic
conditions affecting food intake or metabolism

- Participation in another clinical study

- Infants from multiple gestation births (since only one child per family will be
included in the study, incorporating a child from a multiple birth would add
unnecessary burden to parents by requiring them to administer different formulas to
different children)