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Principal Investigator: LYLE G BEST
Organization: MISSOURI BREAKS RESEARCH, INC.
Fiscal Year: 2024
Award: $120,454
Funding agency: National Institute on Minority Health and Health Disparities
A. Summary of Funded Parent Grant:
Factors Influencing Pediatric Asthma into Adulthood (R01MD019027)
The prevalence of asthma among American Indian (AI) children is 9.3% as compared to 5.5% in non- Hispanic
White children. Asthma disparities become even more pronounced into adulthood, with AI adults having the
highest prevalence of asthma as compared to all other racial/ethnic groups in the US, with 60% uncontrolled.
Asthma is influenced by social and environmental factors (SEF) including adverse childhood events (ACEs),
tobacco smoke, and everyday life stressors that may alter immunological state. ACEs in particular, including
abuse, neglect, and household challenges have been associated with immune dysregulation, may have
implications for clinical outcomes of respiratory viral infections in children that have been linked to asthma and
persistent respiratory symptoms. For example, Infants who develop severe RSV bronchiolitis in the first year of
life are more likely to develop asthma, and children with asthma are at increased risk of experiencing
complications from respiratory viral infections due to SARS-CoV-2, respiratory syncytial virus (RSV), influenza,
and rhinovirus C. In the Factors Influencing Pediatric Asthma (FIPA) study including children from a Northern
Plains American Indian community, we found children with asthma experienced an increased clinical burden
from RSV infection and had lower levels of serum RSV-specific Immunoglobulin G (IgG) than children without
asthma, indicative of immune suppression or dysfunction. However, the complex interplay between social,
environmental and immunological response to viral respiratory infections remains largely unknown, and these
factors have not been investigated among AI children with respect to their influence on immunological
response and asthma development and control of asthma symptoms. In this continued AI community-focused
study, we will test the hypothesis that social and environmental factors contribute to asthma susceptibility
through stress-induced immune dysregulation, including the alteration of immunological response to viral
respiratory infections. We will also investigate the role of viral respiratory infections and SEF on asthma
control, including frequency of symptoms, exacerbations, ER visits/hospitalizations, and use of asthma
medications.
Aim 1: Identify social and environmental factors (SEF) that contribute to asthma susceptibility,
asthma control, and long-term respiratory health in American Indian children. We will follow-up on our
previously NIMHD-funded case/control study of 324 children recruited between the ages of 6-17 from 2013-
2017 as they transition into adulthood (now ages 11-27). We will recontact original study participants,
evaluating their current asthma status to investigate the role of age and gender on long-term respiratory health
including current asthma and asthma control. We will also expand our study to 400 new participants with and
without asthma between the ages of 6-17, including Tribal members living in Rapid City, SD, and offspring of
original study participants (~30% of original study participants have since become parents). We will obtain
detailed measures of SEF, and retrospective information on adverse childhood events (ACE) using an
established screener to evaluate their role in asthma susceptibility and asthma control, including comparisons
between urban vs. rural and multi-generational effects in this community-engaged study. We hypothesize that
domains of biological and behavioral influences acting on the individual and interpersonal levels generate
social stress and have an impact on asthma development and control.
Aim 2: Investigate the role of SEF on immunological response to viral respiratory infections
(VRIs) in AI children with and without asthma. We will investigate the impact of social and environmental
factors measured using validated and Tribally-developed surveys on the immune system of AI children with
and without asthma, including response to viral respiratory infections (viral-specific serum IgG and IgM
concentrations to RSV and other VRI pathogens known to cause long-term respiratory sequelae). We will
quantify serological measurements of participants’ humoral immune responses including serum biomarkers of
inflammation (Th1/Th2/Th17 cytokines), atopy (serum total IgE), and total immunoglobulins. We will test our
hypothesis that interactions with detailed survey measures of SEF with immunological and clinical outcomes of
VRIs, including viral responses in participants with and without asthma are the strongest and most significant
predictors in our AI participants.
Aim 3: Engage with an existing Tribal Community Advisory Board (CAB) using continuous
bidirectional process evaluation to develop an intervention and policy framework of asthma
prevention. We will engage with the CRST’s dedicated community and Tribal cultural experts and active
volunteers in building our local CAB. We will leverage the scientific knowledge gained under this proposal to
work with the CAB to create a sustainable, feasible, and Lakota-driven, intervention and policy framework,
including the creation of structures to allow integration of social stressers including ACEs into existing referral
services and policy initiatives. We will collect detailed information using questionnaires and semi-structured
interviews among CAB members and the community about the study development and processes. We
recognize that Tribal children with mild, moderate to severe asthma who are experiencing humoral immune
response alterations and a combination of SEFs need very targeted and specialized preventive measures that
this study will be able to develop and support with implementation.
B. RESEARCH PLAN: Environmental Toxicants and Asthma in American Indian Children
Background: Viral respiratory infections in early life have been linked to the development of asthma and
persistent respiratory symptoms in children 1–3, including respiratory syncytial virus (RSV) of which the majority
of children are exposed before age 2. Infants who develop RSV bronchiolitis in the first year of life have a high
chance of developing asthma 4, and children with asthma have an increased risk of experiencing complications
and lasting respiratory symptoms from infections such as RSV, SARS-CoV-2, influenza, and rhinovirus-C 5–8.
The prevalence of asthma among American Indian (AI) children is 9.3% as compared to 5.5% in non-Hispanic
White children 9. This is a serious but understudied, pediatric health disparity in the U.S. that becomes even
more pronounced into adulthood, with AI adults having the highest prevalence of asthma as compared to all
other racial/ethnic groups 9. Asthma has been linked to a number of social and environmental factors 10–15
including exposure to social stress, tobacco smoke, air pollution, and environmental toxicants including per-
and perfluoroalkyl substances (PFAS) 16. There is mounting evidence that PFAS, a “forever chemical” in the
environment has a deleterious effect on many aspects of health 17, including thyroid and immune activity 18,
inflammation in pregnancy 19, fetal growth 20, immune response to childhood vaccines 21 and viral respiratory
infections 22,23. Thus, exposure to PFAS and environmental toxins during childhood may have a lasting effect
on Tribal health. In summary, we propose to address newly emerging chemical exposures including PFAS in
an at-risk, low income, Native American community in consultation with the Cheyenne River Sioux Tribe
(CRST), including children living in Rapid City South Dakota and the Cheyenne River Sioux and Oglala Lakota
Reservations. In this area of South Dakota, the proportion of children living below the Federal poverty line is
47% and 57% in Ziebach 24 and Dewey 25 Counties, respectively. The adverse health effects of PFAS and
environmental toxins due to community-level exposure in this area of high childhood poverty has yet to be
investigated, nor their effects on immunological response to viral respiratory infections and immune
dysfunction.
Preliminary Research: In the Factors Influencing Pediatric Asthma (FIPA) study we found that AI children
with asthma living on the Cheyenne River Sioux and Oglala Lakota Reservations were more likely to reside in
multi-unit housing, and in residences with rodent or insect infestation resulting in poor indoor air quality as
compared to asthma controls 26. Children with asthma also had higher BMI, total leukocyte counts, %
eosinophils, total serum IgE, and specific IgE to five common indoor airborne antigens 27. We also found
children with asthma to have lower levels of RSV-specific IgG during the winter (Figure 1) and to report
increased hospitalizations and RSV diagnoses (Figure 2), suggesting immune dysregulation with clinical
implications 28. We hypothesize that exposures to environmental toxins, some of which have been linked to
immune dysregulation may play an important role.
Figure 1: A. Asthma cases recruited during the winter (RSV season) had significantly lower RSV IgG as compared to asthma cases
recruited during the summer (p=2.5x10-6). There was no observed difference in seasonality for asthma controls (p=0.60).
B. More children with asthma have low levels of IgG (<40 IU/mL).
In unpublished results, Dr. Erdei (co-PI of parent
study) detected PFAS in 83% of samples from 50
CRST adults who fish regularly from the Tribe's
main public water sources. She has identified an
association between PFAS and a number of tissue-
specific and antinuclear autoantibodies, and found
serum PFAS and other compounds to be predictors
of autoimmune markers indicative of a
hyperreactive immune response in adults (Figure
3). Consuming locally caught fish as part of AI Figure 2: Children with asthma in the FIPA study report a higher
culture and as a dietary source of protein was also clinical burden from RSV.
associated with overall elevation of serum PFAS.
Similar investigations among children in the CRST
will allow us to learn more about PFAS exposure patterns as it relates to immune dysregulation, viral respiratory
infections, and its effect on children’s health in the community.
Figure 3: Quantile Regression plots in CRST adults showing that A. Perfluorononanoic acid (PFNA) exposures are predictive of anti-
native DNA response. B. PFOS and C. PFOA exposures are predictive of thyroid-specific (anti-thyroglobulin) autoimmune response,
with PFOA having an immunosuppressive effect.
In summary, we hypothesize that exposure to environmental toxins, specifically PFAS, contributes to immune
dysregulation and response to viral respiratory infections in American Indian children with asthma. As
recruitment for FIPA2 is starting, this is an opportune time for Dr. Spear to lead a study investigating the role
of PFAS and environmental toxins on the health of AI children. This opportunity will afford Dr. Spear to narrow
in on the role of PFAS on immune dysregulation and response to viral respiratory infections in children with
and without asthma, while making new connections with scientists in the field of environmental research.
Overall, our study will advance knowledge of the effect of environmental toxins on immune dysregulation of
children to inform future policies and interventions.
Thus, our specific aims for this diversity supplement are:
Specific Aim 1: Measure and identify suspect and PFAS chemicals that are present in American Indian
children from Rapid City and the Cheyenne River Sioux/Oglala Lakota Reservations.
Specific Aim 2: Perform correlative and predictive modeling between PFAS/suspect chemicals and
immunological biomarkers and response to viral respiratory infections in AI children with and without
asthma.
Approach: We will perform suspect screening and test for levels of 12 PFAS in serum samples of 52 children
with and without asthma and living in urban vs. rural (Reservation) locations (Figure 4). We will identify suspect
chemicals present in AI children, and perform preliminary correlations with immune biomarkers, viral-specific
immunoglobulins, PFAS and suspect chemicals identified. Characterizing the presence and effect of
environmental toxins on the immune system is an essential step for understanding environmental health
disparities, which the community has been struggling with for decades.
Figure 4: Location and summary of serum samples for study to measure PFAS/suspect chemicals in children ages 6-17 years old in
FIPA2. Recruitment is beginning 5/2024. We also have stored samples for >300 original FIPA participants at -80C (living on
Reservation, only).
Specific Aim 1: Measure and identify suspect and PFAS chemicals that are present in American Indian
children from Rapid City and the Cheyenne River Sioux/Oglala Lakota Reservations. We will work with
the UCSF Bioassay Facility Core to develop a protocol for PFAS and untargeted suspect screening of serum
samples from 52 AI children, including 26 asthma cases and 26 matched controls living in an urban (Rapid City
SD) vs. rural (Reservation) environment.
Specific Aim 2: Perform correlative and predictive modeling between PFAS/suspect chemicals and
immunological biomarkers and response to viral respiratory infections in AI children with and without
asthma. We will test for a correlation of PFAS/suspect chemicals with levels of immune biomarkers and viral-
specific immunoglobulins. Immune biomarkers will include cytokines, Creactive protein, CBCs (white blood cell
counts), total serum IgE, and viral specific IgG/IgM (SARs-CoV2, RSV, influenza, and rhinovirus C). Results
from this aim will provide insights in to 1) the variability in exposure to environmental toxicants in children living
in urban vs. rural (Reservation) locations and 2) the role of exposure to PFAS/suspect chemicals on immune
dysregulation and asthma.
Statistical analyses: We will examine the distribution of individual PFAS chemicals plus untargeted suspect
chemicals to determine the relevant statistical test. In general, for commonly detected chemicals we will utilize
linear and logistic regression models (or nonparametric tests) to test for associations between PFAS/suspect
chemicals adjusting for multiple covariates selected through an iterative process (e.g. BMI, sex, household
size, asthma medications); we will also contrast models with and without an asthma interaction. For rare
chemicals we will apply a fisher’s exact test for detected/undetected. ROC curves will be generated for
individual chemicals by asthma and location, and cluster analyses will be performed over all chemicals using a
principal component analysis (with UMAP projection) and partial least-squares discriminant analysis (PLS-DA)
for predictive modeling and Cox regression. Lastly, we will attempt a mediation analysis to evaluate if exposure
to PFAS/suspect chemicals contributes to asthma via immune dysregulation.
Relevance to the parent grant: The parent grant is centered on identifying social determinants of the
environment including adverse childhood experiences that contribute to the development of asthma through
altering the immunological response to viral respiratory infections. However, there is substantial evidence to
suggest that exposure to environmental toxicants contribute to immune dysregulation in both the context of
asthma and general immune function as discussed above. In this proposal, Dr. Spear will focus on the physical
environment, specifically the role of exposure and accumulation of environmental toxicants on immune
dysregulation in children with and without asthma.
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