Wheezing
Conditions
Keywords
soy isoflavone, PAI-1
Brief summary
In this study, we will assess whether children without established asthma who have a variation in the switch for the PAI-1 gene will have higher PAI-1 levels and remodeling / allergic inflammatory pathways in their airways than children who do not have the gene. We will also determine if soy isoflavones given when presenting for an acute respiratory illness can decrease these changes.
Detailed description
Pediatric asthma affects 8.3% of U.S. children, accounting for 5.92 billion dollars of U.S. health care expenditure annually. Approximately 80% of the children who progress to have asthma will have wheeze in early childhood, suggesting that primary prevention should target infancy. In particular, severe early life viral lower respiratory tract infection (LRTI) shows strong associations with asthma development which are modified by genetic predisposition.1-5 A gain of function plasminogen activator inhibitor-1 (PAI-1) promoter variant is present in up to 60% of the population who develop asthma in either homozygote or heterozygote form. If children with ≥1 copy of the PAI-1 risk allele had a respiratory viral illness requiring a physician visit before 2 years old, these subjects had a 12-fold (any virus) to 18-fold (self-reported Respiratory Syncytial Virus (RSV)) increased risk of developing asthma. PAI-1 production increases in the airway at the time of a viral illness and promotes both fibrosis and an allergic airway milieu. We have found that soy isoflavones decrease the production of PAI-1 and decrease rates of asthma exacerbations by 75% in subjects with the risk gene. This pilot will allow for preliminary data to determine if on-demand treatment with soy isoflavone improves epithelial integrity and decreases Th2 airway responses if dosed with onset of illness. This would establish the viability of on demand treatment for early life viral illness which may modulate acute outcomes. In this study, we will assess whether children without established asthma who have the PAI-1 genotype will have higher PAI-1 levels and remodeling / allergic inflammatory pathways in their airways than children who do not have the genotype. We will also determine if soy isoflavones given when presenting for an acute respiratory illness can decrease these changes in children both with and without the genotype. Finally, we will also study these questions in a lung organoid / Air Liquid Interface (ALI) model with cells from subjects with the risk allele, which will allow us to compare soy isoflavone pre-inoculation treatment with treatment post infection in a controlled experiment. These data would be essential to set up the team to assess the effects of on demand treatment of children with LRTI irrespective of asthma after presentation to the ED. This would be an important step forward compared to chronic treatment in high-risk populations which will have barriers to implementation.
Interventions
Soy isoflavone will be administered orally at a dose of 1.5 mg/ kg divided bid from presentation to day 7 of illness
Sponsors
Ann & Robert H Lurie Children's Hospital of Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will administer soy isoflavone till day 7 of illness in an unblinded manner to milder subjects who present to the ED within 1-3 days of onset of wheezing illness. Those who are more severe will serve as a control arm and have standard of care treatment. Both groups have initial and followup swabs carried out for endotyping at days 4-7.
Eligibility
Sex/Gender
ALL
Age
4 Months to 24 Months
Healthy volunteers
No
Inclusion criteria
1. Parent or guardian must be an adult (≥18 years of age) and able to understand and provide informed consent. 2. Age: Term infants (≥37 weeks) aged 4 months to 24 months at recruitment. 3. Admitted to Lurie Children's Hospital or presenting to ED for an acute viral lower respiratory tract infection within 1-3 days of onset.
Exclusion criteria
1. Inability or unwillingness of a parent or guardian to give written informed consent or comply with study protocol 2. Parents who will not include either a puree or some form of bottle feeding such that the infant would be able to take the investigational product in a puree or a liquid (expressed breast milk, supplemental formula, or a small amount of water) 3. Currently on a soy based formula as determined by the judgement of the study investigators 4. Breastfeeding mothers who are taking soy supplements or soy enriched foods more than 2 times a week and will not stop this level of ingestion while breastfeeding (assessed by soy intake questionnaire). Note there is no coercion to change dietary practices. This is simply an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Eos3 transcriptional module expression | on day 4-7 of illness after 2-3 days of dosing | The mean expression level of the Th2 and ciliated epithelium (eos3) transcriptional module at day 4-7 of viral illness |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Th2 and epithelial module expression | day 4-7 of illness | This will include the mean expression level of other key transcriptional modules representing Th2 and epithelial processes, including expression of m24\<squamous epithelium\>, squa1 \<tight junctions and epithelial integrity\>, and m27 \<TGFB/SMAD3 regulation of PAI-1\> modules at day 4-7 of viral illness of viral illness |
Countries
United States
Contacts
CONTACTCaroline Merck, MPH
CONTACTAliviya Schulze, BS
PRINCIPAL_INVESTIGATORRajesh Kumar, MD, MSCI
Ann & Robert H Lurie Children's Hospital of Chicago
Outcome results
None listed