Kecia N. Carroll

Evidence of a Causal Role of Winter Virus Infection during Infancy in Early Childhood Asthma

RATIONALE Bronchiolitis during infancy is associated with an increased risk of childhood asthma. Whether winter viral infections cause asthma or are a manifestation of a predisposition to asthma development is unknown. OBJECTIVES To study the relationship of winter virus infection during infancy and the development of childhood asthma. METHODS We studied over 95,000 infants born between 1995 and 2000 and followed through 2005 who were enrolled in the Tennessee Medicaid program from birth through early childhood to determine whether infant birth in relationship to the winter virus peak alters the risk of developing early childhood asthma. MEASUREMENTS AND MAIN RESULTS Among 95,310 children studied during five winter virus seasons from birth through early childhood, the risk of developing asthma tracked with the timing of infant birth in relationship to the winter virus peak. Infant birth approximately 4 months before the winter virus peak carried the highest risk, with a 29% increase in odds of developing asthma compared with birth 12 months before the peak (adjusted odds ratio, 1.29; 95% confidence interval, 1.19-1.40). Infant age at the winter virus peak was comparable to or greater than other known risk factors for asthma. CONCLUSIONS Timing of birth in relationship to winter virus season confers a differential and definable risk of developing early childhood asthma, establishing winter virus seasonality as a causal factor in asthma development. Delay of exposure or prevention of winter viral infection during early infancy could prevent asthma.

Maternal asthma and maternal smoking are associated with increased risk of bronchiolitis during infancy.

OBJECTIVE. Our goal was to determine whether maternal asthma and maternal smoking during pregnancy are associated with the incidence and severity of clinically significant bronchiolitis in term, otherwise healthy infants without the confounding factors of small lung size or underlying cardiac or pulmonary disease. PATIENTS AND METHODS. We conducted a population-based retrospective cohort study of term, non–low birth weight infants enrolled in the Tennessee Medicaid Program from 1995 to 2003. The cohort of infants was followed through the first year of life to determine the incidence and severity of bronchiolitis as determined by health care visits and prolonged hospitalization. RESULTS. A total of 101245 infants were included. Overall, 20% of infants had ≥1 health care visit for bronchiolitis. Compared with infants with neither factor, the risk of bronchiolitis was increased in infants with maternal smoking only, maternal asthma only, or both. Infants with maternal asthma only or with both maternal smoking and asthma had the highest risks for emergency department visits and hospitalizations. Infants with a mother with asthma had the highest risk of a hospitalization >3 days, followed by infants with both maternal asthma and smoking, and maternal smoking only. CONCLUSIONS. Maternal asthma and maternal smoking during pregnancy are independently associated with the development of bronchiolitis in term, non–low birth weight infants without preexisting cardiac or pulmonary disease. The risk of bronchiolitis among infants with mothers who both have asthma and smoke during pregnancy is ∼50% greater than that of infants with neither risk factor. Efforts to decrease the illness associated with these 2 risk factors will lead to decreased morbidity from bronchiolitis, the leading cause of hospitalization for severe lower respiratory tract infections during infancy.

Increasing burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state health care insurance plan.

OBJECTIVES. The goals were to estimate the year-round burden of health care visits attributable to bronchiolitis and to identify risk factors for bronchiolitis in term healthy infants. METHODS. We conducted a population-based, retrospective cohort study of 103 670 term, non–low birth weight infants enrolled in Tennessee Medicaid in 1995–2003. We monitored infants through the first year of life. Risk factors for bronchiolitis during infancy and rates of inpatient, emergency department, and outpatient visits during the study period were calculated by using claims data. RESULTS. Over the 9 study years, rates of bronchiolitis visits were 238 outpatient visits per 1000 infant-years, 77 emergency department visits per 1000 infant-years, and 71 hospitalizations per 1000 infant-years. Average annual rates of bronchiolitis visits increased 41%, from 188 visits per 1000 infant-years to 265 visits per 1000 infant-years, from 1996–1997 to 2002–2003. Analysis of the linear trend in 500-g increments demonstrated a negative association between increasing birth weight and bronchiolitis diagnosis. There was a significant negative trend between maternal age and infant bronchiolitis diagnosis. Compared with infants of mothers 20 to 29 years of age, infants of mothers 15 to 19 years of age had a small increase in risk of having a bronchiolitis visit, whereas infants of older mothers (30–39 or 40–44 years of age) were less likely to have a visit. CONCLUSIONS. The disease burden of bronchiolitis is substantial, with increasing rates of all types of visits among term, otherwise-healthy infants enrolled in Tennessee Medicaid between 1995 and 2003. Protective factors in this cohort of term infants included higher birth weight and older maternal age.

Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years.

Background: Prospective data on viral etiology and clinical characteristics of bronchiolitis and upper respiratory illness (URI) in infants are limited. Methods: This prospective cohort enrolled previously healthy term infants during inpatient or outpatient visits for acute URI or bronchiolitis during September to May 2004 to 2008. Illness severity was determined using an ordinal bronchiolitis severity score. Common respiratory viruses were identified by real-time reverse-transcriptase polymerase chain reaction. Results: Of 648 infants, 67% were enrolled during inpatient visits and 33% during outpatient visits. Seventy percent had bronchiolitis, 3% croup and 27% URI. Among infants with bronchiolitis, 76% had respiratory syncytial virus (RSV), 18% human rhinovirus (HRV), 10% influenza, 2% coronavirus, 3% human metapneumovirus and 1% parainfluenza virus. Among infants with croup, 39% had HRV, 28% parainfluenza virus, 28% RSV, 11% influenza, 6% coronavirus and none human metapneumovirus. Among infants with URI, 46% had HRV, 14% RSV, 12% influenza, 7% coronavirus, 6% parainfluenza virus and 4% human metapneumovirus. Individual viruses exhibited distinct seasonal, demographic and clinical expression. Conclusions: The most common infections among infants seeking care in unscheduled medical visits for URI or bronchiolitis were RSV and HRV. Demographic differences were observed between patients with different viruses, suggesting that host and viral factors play a role in phenotypic expression of viral illness.

Growth of Respiratory Syncytial Virus in Primary Epithelial Cells from the Human Respiratory Tract

ABSTRACT Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in infants and children. To study RSV replication, we have developed an in vitro model of human nasopharyngeal mucosa, human airway epithelium (HAE). RSV grows to moderate titers in HAE, though they are significantly lower than those in a continuous epithelial cell line, HEp-2. In HAE, RSV spreads over time to form focal collections of infected cells causing minimal cytopathic effect. Unlike HEp-2 cells, in which wild-type and live-attenuated vaccine candidate viruses grow equally well, the vaccine candidates exhibit growth in HAE that parallels their level of attenuation in children.

Birth cohorts in asthma and allergic diseases: Report of a NIAID/NHLBI/MeDALL joint workshop

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma.

There is a population-based increased risk of early childhood asthma following infant bronchiolitis occurring during rhinovirus-predominant months compared to asthma following infant bronchiolitis during RSV-predominant months.

Risk of childhood asthma following infant bronchiolitis during the respiratory syncytial virus season

To the Editor: The etiology of asthma remains unclear but is thought to include nonmodifiable risk factors such as family history and genetic predisposition, as well as potentially modifiable risk factors including viral bronchiolitis in infancy. During the winter months, the predominant virus detected in infants with viral bronchiolitis is respiratory syncytial virus (RSV). By age 1 year, approximately 70% of the children have been infected with RSV, and this increases to almost 100% by age 2 years. Infant RSV bronchiolitis is associated with recurrent wheeze or asthma throughout childhood and even into early adulthood, with a dose-response relationship identified between the severity of the bronchiolitis and the risk of developing asthma, and evidence for a causal relationship. The aim of our study was to determine what proportion of childhood asthma is associated with infant bronchiolitis during the RSV season. We analyzed cohort data of children born from 1996 to 2003 and cared for at Northern California Kaiser Permanente (KPNC), an integrated health care delivery system, and children born from 1995 to 2003 and enrolled in Tennessee Medicaid (TennCare). KPNC and TennCare provide health insurance for approximately one-third of Northern California residents and approximately one-half of infants born in Tennessee, respectively. Eligible infants had a minimum gestation age of 32 weeks, had no chronic lung disease, and were continuously enrolled in either TennCare or KPNC during the first year of life. The main predictor variable was infant bronchiolitis during the RSV season defined by International Classification of Diseases, Ninth Revision codes for bronchiolitis and limited to the RSV season, October through March, during the first year of life. The main outcome variable was early childhood asthma determined using an algorithm of International Classification of Diseases, Ninth Revision codes for asthma and asthma-specific medication utilization between ages 4.5 and 6 years. The Vanderbilt University Institutional Review Board and the KPNC Institutional Board for the Protection of Human Subjects approved the study. The Bureau of TennCare approved the use of Tennessee Medicaid data. To ascertain the proportion of childhood asthma in the TennCare or KPNC population that is associated with bronchiolitis exposure during the RSV season, we calculated both the attributable risk of infants with a bronchiolitis event during infancy and the population-attributable risk. We estimated the attributable fraction of bronchiolitis from adjusted risk ratios that were calculated from multivariable Poisson regression models with a robust error variance for the early childhood asthma outcome. Adjustment covariates included gender, race, gestational age, birth weight, siblings, maternal age, and maternal smoking. Statistical analyses were performed with R version 2.12.1 software. A total of 264,010 infant births (KPNC 81,550, TennCare 182,460) were included in this study and followed until age 6 years. Table I highlights key characteristics of the 2 cohorts. Compared with the TennCare population, the KPNC population had more Hispanic and Asian participants, less African American participants, higher rates of maternal education beyond high school, and lower rates of maternal smoking. Overall, 15% of the infants had bronchiolitis during the RSV season. The proportion of children diagnosed with asthma among the KPNC and TennCare cohorts was 8% and 12%, respectively, for those without a history of infant bronchiolitis during the RSV season and 16% and 23%, respectively, for those with a history of infant bronchiolitis during the RSV season. The populationattributable risk for asthma contributed by infant bronchiolitis during the RSV season was 10% for the KPNC cohort, and among the subset of children with infant bronchiolitis during the RSV season, the attributable risk was 49% (95% CI, 47% to 52%); in TennCare, it was 13% and 47% (95% CI, 45% to 48%), respectively (see Fig 1). The unadjusted risk ratio of childhood asthma following infant bronchiolitis during the RSV season for KPNC was 1.97 (95% CI, 1.87-2.09), and the multivariate adjusted risk ratio of childhood asthma following infant bronchiolitis during the RSV season was 1.94 (95% CI, 1.84-2.05); for TennCare, it was 1.87 (95% CI, 1.82-1.92) and 1.81 (95% CI, 1.77-1.86), respectively. In our analysis restricting to term infants (gestational age >_37 weeks), results remain unchanged (data not shown). In both the KPNC and TennCare cohorts, the proportion of children who developed asthma was almost 2 times higher in childrenwith a history of infant bronchiolitis during theRSVseason than in the childrenwhodidnot have a history of infant bronchiolitis during the RSV season. The almost identical attributable risk and population-attributable risk findings are notable given the significant differences between the 2 populations. Adjustment of risk ratios for potential confounders did not change the results. Despite the strengths of our large population-based study, several limitations deserve mention. This study relied on existing electronic data; however, the use of electronic data has been previously validated as both sensitive and specific. Second, the study was unable to detect infants with asymptomatic or mild bronchiolitis during the RSV season as well as those who did not seek treatment. In addition, we were unable to confirm the diagnosis of RSV as the etiology of bronchiolitis events although prior studies support that the majority of infant bronchiolitis events during the RSV season are attributable to RSV. In a retrospective study by Stemple et al in which bronchiolitis was defined by International Classification of Diseases, Ninth Revision codes for bronchiolitis, RSV was detected in the nasal wash samples of 77% of the children younger than age 2 years collected between October and April. By limiting our study to bronchiolitis episodes during the winter months, RSV is likely to be the associated viral pathogen. Last, while human rhinovirus infection has also been implicated in asthma inception, infant rhinovirus bronchiolitis is far less common than infant RSV bronchiolitis, and occurs in older infants, those born to parents with asthma, or those who have already been allergically sensitized, suggesting that rather than being causal, rhinovirus bronchiolitis is a clinical biomarker of future asthma risk. In summary, in 2 representative US populations with significantly varying baseline characteristics, there were consistent findings that nearly 50% of the asthma cases in children with a history of infant bronchiolitis during the RSV season were associated with bronchiolitis. On a population level, 13% of the

Increase in Incidence of Medically Treated Thyroid Disease in Children With Down Syndrome After Rerelease of American Academy of Pediatrics Health Supervision Guidelines

OBJECTIVE. The purpose of this work was to estimate the incidence of medically treated thyroid disease in children with Down syndrome enrolled in Tennessee Medicaid (TennCare) during 1995–2005 and to determine whether rates increased after rerelease of American Academy of Pediatrics guidelines in 2001. PATIENTS AND METHODS. We conducted a population-based retrospective cohort study in which we identified children with Down syndrome by using TennCare files and birth certificates. We included 1- to 18-year-olds who were continuously enrolled in TennCare and did not fill a prescription for thyroid medication during a 90-day prestudy period. The rate of medically treated thyroid disease (prescription filled for thyroid medication) was the main outcome. We used Poisson regression to estimate rates of medically treated thyroid disease according to study year, age, gender, race, region of residence, and payer type. RESULTS. During the 11-year study period, 1257 children with Down syndrome (28% black, 72% white) met inclusion criteria. Overall, 10.8% filled a new prescription for thyroid medication. Rates of medically treated thyroid disease per 1000 child-years were 13.25 (1995–1997), 13.34 (1998–1999), 13.62 (2000–2001), 22.37 (2002–2003), and 22.51 (2004–2005). After adjusting for child age and race, there was an increased rate of medically treated thyroid disease in 2002–2003 and 2004–2005 compared with 1995–1997. In a comparison cohort of children without Down syndrome, there was a smaller increase in the rate of medically treated thyroid disease when comparing 2002–2003 and 2004–2005 with 1995–1997. CONCLUSIONS. Over the 11-year period, 10.8% of children with Down syndrome filled a new prescription for a thyroid medication. A 73% increase in the incidence of medically treated thyroid disease occurred after rerelease of American Academy of Pediatrics guidelines, which may have influenced screening.

Racial differences in asthma morbidity during pregnancy.

Objective: Little is known about racial differences in asthma outcomes during pregnancy. We performed a cohort study to estimate racial differences in maternal asthma outcomes in a low-income population of pregnant women in which blacks and whites have similar medical care access and benefits. Methods: We conducted a population-based cohort study of asthma-related morbidity in black and white pregnant women enrolled in Tennessee’s Medicaid Program, TennCare. Pregnant women were identified through TennCare enrollment files linked to birth certificates, 1995–2001. Prepregnancy, women with asthma were identified using International Classification of Diseases, 9th Revision, codes for health care visits and pharmacy files for asthma medication. Adjusted relative rates (RR) of rescue corticosteroid prescriptions, emergency department (ED) visits, and hospitalizations during pregnancy were compared by race using Poisson regression. Results: We identified 4,315 women with asthma (4%) from a population of 112,171 pregnant women of black or white race with at least 180 days of continuous enrollment in TennCare before pregnancy. Blacks were more likely to receive a course of rescue corticosteroids than whites (14.6% versus 11.9%, adjusted RR 1.35, 95% confidence interval [CI] 1.14–1.61), have an emergency department visit (16.7% versus 8.7%, adjusted RR 1.89, 95% CI 1.57–2.27), or be hospitalized for asthma (9.0% versus 5.2%, adjusted RR 1.73, 95% CI 1.34–2.24). Conclusion: Pregnant women with asthma had high asthma-related morbidity. Black women had clinically significantly more morbidity than whites. There is a need to improve the medical care of low-income women with asthma, particularly black women. Level of Evidence: II-2