Determinants of Early Childhood Asthma and Atopy Following Infant RSV Infection
Host and Viral Determinants of Infant and Childhood Allergy and Asthma
Pregnancy Folate Status & Early Childhood Respiratory & Atopic Disease Outcomes
The Population-Based Effectiveness in Asthma and Lung Disease (PEAL) Network
Prematurity and Respiratory Outcomes Program (PROP)
Rates of Rhinovirus Species in Adults and Children with Acute Respiratory Illness
Real-World Patient Responsiveness & Safety of Long-Acting Beta Agonists in Asthma
Statistical Methods for Comparative Treatment Effectiveness Using Claims Data
Tools to Reduce Infant RSV Morbidity and Asthma: Use, Adherence and Effectiveness
RSV bronchiolitis and early childhood asthma are the most common, serious, acute, and chronic conditions of infancy and childhood, respectively, and diseases that disproportionately burden vulnerable populations. Opportunity and Impact. This project draws together three important elements in understanding the role of RSV on recurrent wheezing and asthma inception - RSV infection severity, host response and susceptibility. In studying the association of RSV with asthma inception, studies have overwhelmingly focused on the 3-5% of RSV-infected infants requiring hospitalization, while the vast majority of RSV infections are mild. Whether mild infection confers intermediate risk or has a protective effect is an important question. The answer will influence proposals for primary asthma prevention strategies. The proposed series of investigations will aid in our understanding of the role and mechanisms through which RSV may both lead to chronic lung disease, and may protect from chronic lung disease. Approach. Utilizing the ReSPIRA cohort, established for this investigation and described in Core B, we will investigate the relationship between infant RSV infection, host response to infection, and genetic determinants of recurrent wheezing, asthma and allergic disease development following RSV infection. Our specific aims are to: (1) Establish the association between RSV LRTI, RSV URI/exposure, and no RSV infection in the first 6 months of life on the risk of recurrent wheezing and asthma, (2) Define whether host immune response and/or airway injury biomarkers assessed during infant RSV infection are associated with recurrent wheezing, atopic disease or early childhood asthma, and (3) Identify the genetic determinants of the phenotype of recurrent wheezing, early childhood asthma and atopy following infant RSV infection. Utilizing the ReSPIRA cohort which includes 2000 infants followed from early infancy through early childhood, and established through this U19 grant, this project will answer the following questions: (1) how does RSV cause asthma, (2) does mild RSV infection during infancy increase or decrease the risk of asthma, and (3) what host factors are important in the progression from infant RSV infection to early childhood asthma. Answering these questions will allow us to develop preventive interventions for chronic lung disease in children, and ultimately improve the health of infants and children with bronchiolitis and asthma in the U.S. and worldwide. Read more.
Funding Source: NIH/NIAID
PI: Tina Hartert
This application will examine the effects of both host genetic and immune response determinants, as well as the influence of specific RSV strains on severity of RSV bronchiolitis and childhood asthma, and define the role of a novel therapeutic target, PGI2, in RSV pathogenesis. The long-term objective is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. Read more.
Funding Source: NIH/NIAID
Project and Core PI: Tina Hartert
Asthma is the result of host and environment interactions. Lower respiratory tract infections (LRTI), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis not only experience significant morbidity, but are also at significantly increased risk for both recurrent wheezing and childhood asthma. We have established that respiratory syncytial viral infections appear to directly contribute to asthma causation, not just simply identify persons at risk for subsequent wheezing. Viral infections outside the infant period are also important, as they are modifiable environmental factors that have been established to be the most common cause of asthma exacerbations in both children and adults. This proposal uses a combined, parallel clinical and experimental approach to evaluate the contribution of, causality, and mechanisms through which respiratory syncytial virus, and human rhinovirus, contribute to asthma development and disease natural history. These studies all relate to the central hypothesis that viruses, as one significant environmental factor, alter the risk for developing asthma, as well as the natural history of prevalent disease. Specific testable questions related to this hypothesis include: 1) to determine the host factors among those with RSV and HRV infection that contribute to asthma development, 2) to determine the timing of infection during infancy and how that impacts the risk of developing childhood asthma; 3) to determine the mechanisms through which RSV and HRV contribute to asthma development, specifically focusing on lung injury and differential immune response to infection; 4) to determine if there are allelic variations in host genes involved with severity of respiratory viral infection that correlate with a predisposition or resistance to both infant bronchiolitis and childhood asthma; 5) to determine if there are allelic variation in RSV genes that are associated with both infant LRTI severity, and subsequent risk of asthma development. PROJECT NARRATIVE The aims of this mid-career investigator award will be met by allowing the candidate to translate her experimental expertise to both mentor trainees and to direct patient-oriented studies of the progression and functional outcome of childhood viral illness in asthma development, moving from risk factor determination to intervention studies, and ultimately to disease prevention. Read more.
Funding Source: NIH/NIAID
PI: Tina Hartert
This funding created the PEAL Network, a novel infrastructure for population-based research on lung diseases, by synthesizing and linking standardized datasets from a state Medicaid plan and four health plans. The investigators compare real world adherence to and effectiveness of alternative asthma controller medication regimens in these diverse populations; conduct applied methodologic research that delineates the tradeoffs among different design and analysis options for observational comparative effectiveness research; and lay foundation for future comparative effectiveness trials of pharmacogenetic tests. Read more.
Funding Source: AHRQ
PI: Tina Hartert, T. Lieu
The long-term goal of this project is to determine whether maternal folic acid supplementation during pregnancy increases the risk of early childhood asthma and atopy. Supplementation with folic acid, synthetic folate, is recommended during the periconceptional period to prevent neural tube defects (NTD). Studies in different populations have suggested an association between reported folic acid supplementation during pregnancy and increased risk of infant lower respiratory tract infection and early childhood asthma, but data are limited. While adequate intake of folate is essential for prevention of NTDs, it is important to delineate the impact of supplementation on the risk of common respiratory and atopic diseases. Folate plays an important role in DNA methylation, a regulator of gene expression. A causal relationship between folic acid supplementation and respiratory outcomes in children has not been established. However, this relationship does have some biologic plausibility. In a pregnant mouse model, a diet high in methyl donors, including folate, resulted in an augmented allergic phenotype in the offspring, as seen in asthma. Opportunity and Impact. There is no primary prevention strategy for atopic diseases such as asthma. Our objective is to determine whether higher maternal folate intake or the timing of this intake increases the risk of wheezing, asthma, and other atopic diseases in children. This collective work will characterize maternal folate status using objective measures and will assess childhood wheezing, asthma, allergic rhinitis, and atopic dermatitis using validated tools and objective measures. This will be the first investigation in a country with a national fortification program, where individuals may have high intake of folic acid from the diet. Approach. This work will use complementary retrospective and prospective cohorts of mother-child pairs. Specific aim #1 will investigate the population-based incidence of wheezing and asthma during the first 6 years of life, by the timing of folic acid containing prescriptions filled during pregnancy in a retrospective cohort of 80,000 mother-child dyads from the Tennessee Medicaid population. Specific Aim #2 will determine if a) measured maternal plasma folate levels or b) reported folate intake is associated with prospective development of wheezing, asthma, and/or atopy in the first 5 years of life in mother-child dyads enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort. Innovation and Sustainability. This innovative, cost-efficient project will have the advantages of 1) a well-characterized retrospective cohort with a large number of mother-child dyads and determination of folic acid prescriptions filled by month of pregnancy and 2) a prospective cohort that includes the rich, existing infrastructure of the CANDLE cohort with maternal and infant biospecimens, nutritional data, and prospective follow-up using validated tools and objective measures to assess respiratory and atopic outcomes. This study has potential to inform prenatal recommendations and identify modifiable risk factors for asthma and atopy. Read more.
Funding Source: NIH/NHLBI
PI: Kecia Carroll
This proposal will explore developmental, genetic and environmental interactions and identify biochemical markers to predict BPD development and severity, with the ultimate goal of designing new treatments to prevent BPD and improve long-term lung function in premature infants. Read more.
Funding Source: NIH/NHLBI
PI: Judy Aschner, Tina Hartert, Paul Moore
Human rhinoviruses (HRV) are the leading cause of the common cold and more recently have been implicated in lower respiratory illness, in infants and children. While many respiratory viruses have been associated with asthma exacerbations, HRV are the most common trigger of asthma exacerbations and chronic obstructive pulmonary disease (COPD) in children and adults. The rates of HRV-associated acute respiratory illness medical visits in US adults are not known. Recently, a new group of HRV designated HRVC was identified that may associate with asthma and COPD exacerbations. The impact of the novel HRVC on US adults has not been established, and the association of HRVC with obstructive wheezing diseases such as asthma and COPD is unclear. We propose to define the role of HRV and the novel HRVC group in adults and children seen as outpatients or hospitalized with ARI/fever, including those with asthma or COPD exacerbation. The central hypotheses of our proposal are that HRV are commonly associated with ARI/fever in adults and children and that HRVC associate with wheezing and more severe respiratory disease. The results of the proposed research will help guide vaccine development and elucidate mechanisms of virus-induced asthma. The findings of this work may lead to new approaches to treat and prevent asthma. We propose three Specific Aims: 1) to determine the rates of HRV in adults and children who seek medical care for acute respiratory illness (ARI) or fever, 2) to determine the rates of HRV species A, B, and C that are associated with ARI/fever in adults and children seen in different clinical settings, and 3) to determine rates of HRV and HRV species associated with obstructive wheezing illness such as asthma and chronic obstructive pulmonary disease (COPD) among adults and children. This research allows us to understand the burden of HRV and HRVC in US adults and children, as well as which HRV genotypes affect certain age groups, and elucidates the relationship between severity and type of respiratory disease and viral species. This may ultimately allow for a more targeted vaccine to be developed against HRV and may shed light on certain groups, such as those with asthma or COPD, at risk for more severe HRV-associated disease. Read more.
Funding Source: NIH/NIAID
PI: Eva Kathryn Miller
The comparative effectiveness of long-acting beta agonists (LABA) in asthma management with other controller medicines has not been established. Although LABA monotherapy increases the risk of serious adverse events (AEs) and is recommended to be used in combination with inhaled corticosteroids (ICS), the safety of combination therapy is not known. Also not known, and clinically important to understand, is how, why and to whom LABAs and/or combination therapy are associated with increased risk of serious AEs. Specific Aims. To address the comparative effectiveness and safety concerns of the combination therapy (ICS + LABA), as well as to understand the profile of those who experience AE, and the profile of those who benefit most from the combination therapy, we will (1) determine the effectiveness of LABA-containing therapies in comparison with other available controller regimens in persistent asthma disease management; (2) determine if LABA-containing therapies are associated with an increased risk of asthma-related serious AEs and all-cause mortality; and (3) determine the characteristics of patients who clinically respond to, or have AEs attributable to, LABA-containing therapies. Research Design. In Aim 1, we will conduct a population based cohort study of subjects with persistent asthma. The effect of LABA-containing therapies in the real-world setting will be measured and compared with other asthma controller therapies on asthma control and exacerbation prevention from 1998-2010. This period allows for the study of LABAs during use of LABA monotherapy, and during a period prior to AE recognition and the FDA black box warning. The study will be done in diverse populations of nearly 664,000 asthmatics which we have assembled, including a state Medicaid population, four HMO research populations, and a Department of Defense population. In Aim 2, we will conduct a nested case-control study to evaluate the risk of serious asthma-related AEs with the use of LABA-containing therapies. Asthma-related and all-cause death will be studied separately. In Aim 3, patient characteristics associated with both response to, and serious AEs related to, LABA-containing therapies will be assessed, including patient demographics, disease severity, underlying asthma control, medication utilization patterns, adherence, and definable asthma phenotypes using multivariable regression modeling. For each aim, various subgroup analyses, sensitivity analyses and simulation studies will be performed to provide robust results and to evaluate the accuracy of the estimates. Impact. This project is of critical importance as it addresses comparative effectiveness and safety concerns in asthma pharmacotherapy. It will inform and empower physicians, patients, and healthcare policy makers providing timely knowledge in how, when, and to whom to provide or avoid LABA containing therapies. Such knowledge will have widespread public health impact in asthma disease management. Read more.
Funding Source: AHRQ
PI: Pingsheng Wu
Propensity score methods with a dichotomous treatment (exposed v. unexposed) have been extensively evaluated and proven to be an effective tool for reducing bias and balancing the distribution of confounders between comparison groups in observational studies. Propensity score methods to handle multi- level exposure, with and without ordering, and continuous exposures have been developed. However, there is very limited experience in the application of these methods in either simulated or empirical studies. Important information in establishing both the benefits and risks of medications includes the estimation of a dose effect, duration effect, and multiple medication effect in comparative effectiveness and safety investigations. Real- world medication use involves all three of these issues, and researchers need a thoroughly evaluated analytical method to apply in such scenarios. We will determine the generalizability and practical insight of the performance of propensity scores when considering these three important issues: medication dose, multiple medications, and continuous duration of therapy. This project addresses an important gap in the current analytical approach to evaluating the comparative effectiveness of medications, and will enhance and improve the quality of observational comparative effectiveness research. Specific Aims. We will (1) Evaluate the performance of propensity scores when considering a dose-response relationship of medication exposure and the effects of multiple medication exposures; and (2) Evaluate the performance of propensity scores when considering the effects of continuously varying duration of therapy. Research Design. We will conduct both simulation studies and analyses of real data to answer comparative effectiveness research questions for both specific aims. A propensity score is defined as the conditional probability that a patient receives a particular treatment given all her/his other observed covariates. Such treatment can vary with respect to type, dose, and duration of therapy. Appropriate statistical models will be used to estimate this probability for each subject according to the nature of her/his exposure. Dose and duration effects, and difference in effect among medications will be further estimated. Performance of four common applications of propensity scores and four scenarios for which propensity scores are often applied will be evaluated. Results will be further compared with results from conventional multivariable regression models. Impact. The project will address critically important issues encountered in observational comparative effective research. It will have a wide public health impact by providing researchers with a thoroughly evaluated analytical approach to conduct such studies, and will enhance and improve the quality of observational comparative effectiveness research. . PUBLIC HEALTH RELEVANCE: This project will provide a critically needed and thoroughly evaluated statistical technique to conduct comparative effectiveness research studies using observational data. We will evaluate the application of propensity score methods to common situations when medication dose effect, duration effect, and multiple medication exposures need to be considered. This project addresses an important gap in the current analytical approach to medication comparative effectiveness, and will enhance and improve the quality of observational comparative effectiveness research, and thus have a wide public health impact. Read more.
Funding Source: NIH
PI: Pingsheng Wu
One ubiquitous and modifiable environmental factor associated with both significant infant morbidity, as well as asthma development, is infant respiratory syncytial virus (RSV) infection. While most children who experience RSV infection have mild symptoms, a significant minority experience more severe disease, often requiring hospitalization and sometimes intensive care. We, and others, have shown that, among children with RSV infection severe enough to require medical attention, the severity of the infection has a strong association with subsequent development and severity of asthma. In addition, we have shown a causal relationship between RSV-attributable infant illness and childhood asthma inception. Because an RSV vaccine is not currently available, RSV immunoprophylaxis is the only currently available alternative approach, licensed for use in preventing RSV-attributable morbidity in high-risk infant groups. RSV immunoprophylaxis been evaluated in children who experience excessive RSV morbidity. While there have been a number of randomized clinical trials that have enrolled selective populations investing significant resources to ensure adherence that have established "efficacy" (can it work?), the "effectiveness" (does it work?) data are limited and conflicting. No investigations have assessed patterns of use, adherence, and effectiveness in US Medicaid and insured "real world" populations. Neither are there any investigations of the impact of reducing RSV infant morbidity on long-term outcomes such as asthma. These are critically important questions to answer in informing policy for the most costly preventive therapy in pediatrics, and in assessing effectiveness of our only currently available "tool" for decreasing infant RSV morbidity. Lastly, neither are there investigations of the more long-term impact of reducing RSV infant morbidity on the development of asthma, a lifelong chronic disease known to be more common among most groups of children considered high-risk for RSV. In three specific aims utilizing two denominator-based study populations of children enrolled in Tennessee Medicaid and six Kaiser Permanente-Northern California integrated medical care practices, we will study infants born between 1995 and 2008 and followed longitudinally to: (1) Determine RSV immunoprophylaxis utilization patterns and adherence; (2) Determine the effectiveness of RSV immunoprophylaxis on RSV hospitalizations and outpatient visits as well as comparative effectiveness with birth timing; and (3) assess the impact of RSV immunoprophylaxis on asthma inception, estimate the effect size, and compare the impact of RSV immunoprophylaxis on asthma inception with the effect we have shown of timing of birth on reducing childhood asthma. Read more.
Funding Source: AHRQ
PI: Tina Hartert