Factors Influencing Pediatric Asthma into Adulthood (FIPA2)

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 (